Sankey, Christopher; Setnik, Beatrice; Harsanyi, Zoltan; Michalko, Ken; Yang, Zejiang; Geoffroy, Pierre
2016-01-01
Emerging data are demonstrating that tamper-resistant opioids may play an important role in changing prescription opioid abuse behaviors. This study was a chart review to examine if the reformulation of OxyContin® into a version with tamper-resistant properties (OxyNEO®) had an impact on oxycodone-positive urine drug screens (UDSs) in opioid-dependent patients receiving methadone maintenance therapy (MMT). The historical element of this study examined 250 eligible charts from patients on MMT who had data during the time periods when only OxyContin was available (baseline period), during the transition to OxyNEO, and when only OxyNEO was available. The prospective element included an exploratory questionnaire regarding retrospective opioid use. The study was conducted at three methadone clinics, in Oshawa, Peterborough, and Scarborough in Ontario, Canada. Male and female patients were eligible if they had a diagnosis of opioid dependency, received MMT, and had at least one oxycodone-positive UDS during the baseline period. This was a noninterventional study. The main outcome was the number of oxycodonepositive UDSs. The results demonstrated a marked reduction in oxycodone-positive UDSs that showed stepwise, statistically significant decreases during the transition and post-OxyContin periods relative to baseline. While the oxycodone-positive UDS results were decreasing, morphine-related-positive UDSs remained relatively stable during the same periods. There were no significant gender differences noted. The introduction of OxyNEO was associated with a statistically significant reduction in oxycodone exposure in a population of methadone-maintained patients.
Maddocks, I; Somogyi, A; Abbott, F; Hayball, P; Parker, D
1996-09-01
We have observed among patients of the Southern Community Hospice Programme that up to 25% experience acute delirium when treated with morphine and improve when the opioid is changed to oxycodone or fentanyl. This study aimed to confirm by a prospective trial that oxycodone produces less delirium than morphine in such patients. Oxycodone was administered by a continuous subcutaneous infusion, as this allowed more flexible and reliable dosing, and patients were monitored for any adverse reactions to the drug. Thirteen patients completed the study. Statistically significant improvements in mental state and nausea and vomiting occurred following a change from morphine to oxycodone. Pain scores improved but did not reach a level of statistical significance. The phenotype status of the patients was tested to establish their capacity to metabolize oxycodone. One patient who did not achieve adequate pain control proved to be a poor metabolizer. These results show that oxycodone administered by the subcutaneous route can provide effective analgesia without significant side effects in patients with morphine-induced delirium. This treatment allows patients to remain more comfortable and lucid in their final days. A small proportion of patients who do not metabolize oxycodone effectively may not receive this benefit.
Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment
Posa, Luca; Accarie, Alison; Marie, Nicolas
2016-01-01
Background: Opiates such as morphine are the most powerful analgesics, but their protracted use is restrained by the development of tolerance to analgesic effects. Recent works suggest that tolerance to morphine might be due to its inability to promote mu opioid receptor endocytosis, and the co-injection of morphine with a mu opioid receptor internalizing agonist like [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin reduces tolerance to morphine. So far, no studies have been conducted to evaluate the ability of methadone to reduce morphine tolerance in morphine-pretreated animals, a treatment sequence that could be encountered in opiate rotation protocol. We investigated the ability of methadone (a mu opioid receptor internalizing agonist used in therapy) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a region involved in pain control. Methods: We measured analgesic response following a challenge dose of morphine in the hot plate test and investigated regulation of mu opioid receptor (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate receptor subunits expression and phosphorylation state. Results: A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a lack of mu opioid receptor endocytosis, adenylate cyclase overshoot, NR2A and NR2B downregulation, and phosphorylation of NR1. We reported that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting mu opioid receptor endocytosis and blocking cellular mechanisms of tolerance. Conclusions: Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation. PMID:26390873
Sng, Ban Leong; Kwok, Sarah Carol; Mathur, Deepak; Ithnin, Farida; Newton-Dunn, Clare; Assam, Pryseley Nkouibert; Sultana, Rehena; Sia, Alex Tiong Heng
2016-01-01
Background and Aims: Epidural morphine after caesarean section may cause moderate to severe pruritus in women. Epidural oxycodone has been shown in non-obstetric trials to reduce pruritus when compared to morphine. We hypothesised that epidural oxycodone may reduce pruritus after caesarean section. Methods: A randomised controlled trial was conducted in pregnant women at term who underwent caesarean section with combined spinal-epidural technique initiated with intrathecal fentanyl 15 μg. Women received either epidural morphine 3 mg or epidural oxycodone 3 mg via the epidural catheter after delivery. The primary outcome was the incidence of pruritus at 24 h after caesarean section. The secondary outcomes were the pruritus scores, treatment for post-operative nausea and vomiting (PONV), pain scores and maternal satisfaction. Results: One hundred women were randomised (group oxycodone O = 50, morphine M = 50). There was no difference between Group O and M in the incidence of pruritus (n [%] 28 [56%] vs. 31 [62%], P = 0.68) and the worst pruritus scores (mean [standard deviation] 2.6 (2.8) vs. 3.3 [3.1], P = 0.23), respectively. Both groups had similar pain scores at rest (2.7 [2.3] vs. 2.0 [2.7], P = 0.16) and sitting up (5.0 [2.3] vs. 4.6 [2.4], P = 0.38) at 24 h. Pruritus scores were lower at 4–8, 8–12 and 12–24 h with oxycodone, but pain scores were higher. Both groups had a similar need for treatment of PONV and maternal satisfaction with analgesia. Conclusion: There was no difference in the incidence of pruritus at 24 h between epidural oxycodone and morphine. However, pruritus scores were lower with oxycodone between 4 and 24 h after surgery with higher pain scores in the same period. PMID:27053782
Bhalla, Shaifali; Andurkar, Shridhar V; Gulati, Anil
2013-10-01
Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de
Jokinen, Viljami; Lilius, Tuomas; Laitila, Jouko; Niemi, Mikko; Kambur, Oleg; Kalso, Eija; Rauhala, Pekka
2017-01-01
Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
Stress-opioid interactions: a comparison of morphine and methadone.
Taracha, Ewa; Mierzejewski, Paweł; Lehner, Małgorzata; Chrapusta, Stanisław J; Kała, Maria; Lechowicz, Wojciech; Hamed, Adam; Skórzewska, Anna; Kostowski, Wojciech; Płaźnik, Adam
2009-01-01
The utility of methadone and morphine for analgesia and of methadone for substitution therapy for heroin addiction is a consequence of these drugs acting as opioid receptor agonists.We compared the cataleptogenic and antinociceptive effects of single subcutaneous doses of methadone hydrochloride (1-4 mg/kg) and morphine sulfate (2.5-10 mg/kg) using catalepsy and hot-plate tests, and examined the effects of the highest doses of the drugs on Fos protein expression in selected brain regions in male Sprague-Dawley rats. Methadone had greater cataleptogenic and analgesic potency than morphine. Fos immunohistochemistry revealed substantial effects on the Fos response of both the stress induced by the experimental procedures and of the drug exposure itself. There were three response patterns identified: 1) drug exposure, but not stress, significantly elevated Fos-positive cell counts in the caudate-putamen; 2) stress alone and stress combined with drug exposure similarly elevated Fos-positive cell counts in the nucleus accumbens and cingulate cortex; and 3) methadone and morphine (to a lesser extent) counteracted the stimulatory effect of nonpharmacological stressors on Fos protein expression in the somatosensory cortex barrel field, and Fos-positive cell counts in this region correlated negatively with both the duration of catalepsy and the latency time in the hot-plate test. The overlap between brain regions reacting to nonpharmacological stressors and those responding to exogenous opioids suggests that stress contributes to opioid-induced neuronal activation.
Colombini, Nathalie; Elias, Riad; Busuttil, Muriel; Dubuc, Myriam; Einaudi, Marie-Ange; Bues-Charbit, Martine
2008-06-01
This study was undertaken to evaluate the adequacy of a hospital formulated oral morphine preparation for management of neonatal abstinence syndrome (NAS) and to compare clinical features in infants exposed to methadone or buprenorphine in utero. Between October 1998 and October 2004 all infants born to mothers treated with buprenorphine or methadone during pregnancy were enrolled into this prospective study. Morphine hydrochloride solution (0.2 mg/ml) was prepared without preservatives under a flow laminar air box (class 100). Morphine solution: quantitative and qualitative HPLC analysis and microbiological study at regular intervals during storage at 4 degrees C for 6 months. Maternal characteristics: age, opiate dose during pregnancy. Neonatal characteristics: gestational age at delivery, birth weight, Lipsitz scores. Morphine dose: daily morphine dose, maximum morphine dose, duration of NAS, and duration of treatment required to achieve stable Lipsitz scores below 4. Kruskal-Wallis test for comparison of median values. Microbiological and HPLC analysis showed that the morphine preparation remained stable for 6 months at 4 degrees C. Nine methadone-exposed infants and 13 buprenorphine-exposed infants were included in the study. All infants presented NAS requiring treatment with the morphine solution. Lipsitz scores at birth were significantly different in the methadone and buprenorphine groups (P < 0.05). The methadone group required significantly higher doses of morphine preparation than the buprenorphine group during the first 38 days of treatment (P < 0.05): 0.435 +/- 0.150 mg/kg/day vs. 0.257 +/- 0.083 mg/kg/day. This hospital morphine solution is adequate for management of NAS. Preparations showed good stability and doses could be adjusted with a margin of 0.02 mg. The onset of NAS occurred within 24 h after birth in methadone-exposed infants (range 6-24 h) and within 48 h after birth in buprenorphine-exposed infants (range 24-168 h). Due to the possibility
Ibach, Bethany W.; Johnson, Peter N.; Ernst, Kimberly D.; Harrison, Donald; Miller, Jamie L.
2016-01-01
Background: Methadone and morphine are commonly used to treat neonatal abstinence syndrome (NAS). Limited data exist to describe the most appropriate initial doses and taper regimens of these agents. Objectives: Describe the median initial dose and frequency of methadone and morphine for NAS. Compare dose adjustments, time to symptom relief, and taper complexity between groups. Methods: Retrospective study of neonates receiving enteral methadone or morphine for NAS over a 4-year period. Data collection included medication regimen, abstinence scores based on the Modified Finnegan Neonatal Abstinence Scoring Tool, and adverse events. Planned home taper complexity was assessed using the Medication Taper Complexity Score–Revised (MTCS-R). The primary outcome was initial opioid dose. Secondary outcomes included number of dose adjustments, time to symptom relief, and MTCS-R score. Results: Fifty neonates were initially treated for NAS with methadone (n = 36) or morphine (n = 14). The median initial dose was 0.09 mg/kg (range = 0.03-0.2) for methadone and 0.04 mg/kg (range = 0.03-0.4) for morphine. The most common initial dosing interval was q8h for methadone versus q3h for morphine. Number of dose adjustments and time to symptom relief were similar between groups. Median MTCS-R scores were similar between groups. There was no difference in adverse events between groups. Limitations included small sample size, preference toward methadone use, and variability of initial opioid dosing and titration. Conclusions: There was significant variability in initial doses of both agents. Neonates receiving methadone required less frequent dosing than morphine, which may result in easier administration and may allow for safer outpatient administration.
Chen, Hwei-Hsien; Chiang, Yao-Chang; Yuan, Zung Fan; Kuo, Chung-Chih; Lai, Mei-Dan; Hung, Tsai-Wei; Ho, Ing-Kang; Chen, Shao-Tsu
2015-01-01
Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light-dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders.
Chen, Hwei-Hsien; Chiang, Yao-Chang; Yuan, Zung Fan; Kuo, Chung-Chih; Lai, Mei-Dan; Hung, Tsai-Wei; Ho, Ing-kang; Chen, Shao-Tsu
2015-01-01
Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3–20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light–dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light–dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders. PMID:25834439
Comparison of the cardio-respiratory effects of methadone and morphine in conscious dogs.
Maiante, A A; Teixeira Neto, F J; Beier, S L; Corrente, J E; Pedroso, C E B P
2009-08-01
The effects of methadone and morphine were compared in conscious dogs. Six animals received morphine sulfate (1 mg/kg) or methadone hydrochloride (0.5 mg/kg [MET0.5] or 1.0 mg/kg [MET1.0]) intravenously (i.v.) in a randomized complete block design. Cardiopulmonary variables were recorded before (baseline), and for 120 min after drug administration. One outlier was not included in the statistical analysis for hemodynamic data. Morphine decreased heart rate (HR) compared to baseline from 30 to 120 min (-15% to -26%), while cardiac index (CI) was reduced only at 120 min (-19%). Greater and more prolonged reductions in HR (-32% to -46%) and in CI (-24% to -52%) were observed after MET1.0, while intermediate reductions were recorded after MET0.5 (-19 to -28% for HR and -17% to -27% for CI). The systemic vascular resistance index (SVRI) was increased after methadone; MET1.0 produced higher SVRI values than MET0.5 (maximum increases: 57% and 165% for MET0.5 and MET1.0, respectively). Compared to morphine, oxygen partial pressure (PaO(2)) was lower (-12% to -13%) at 5 min of methadone (0.5 and 1.0 mg/kg), while carbon dioxide partial pressure (PaCO(2)) did not change significantly. It was concluded that methadone induces cardiovascular changes that are dose-related and is a more potent cardiovascular depressant agent than morphine in conscious dogs.
Ono, Hiroko; Nakamura, Atsushi; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Shinohara, Shunji
2016-02-15
Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. β-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+β-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (μ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A. Copyright © 2016 Elsevier B.V. All rights reserved.
Contrasting cardiovascular properties of the µ-opioid agonists morphine and methadone in the rat.
Tung, Kenneth H; Angus, James A; Wright, Christine E
2015-09-05
Morphine and methadone share the property of μ-opioid receptor agonism yet have markedly different cardiovascular actions suggesting additional properties are at play. We investigated the i.v. dose-response relationships of the opioids on cardiovascular metameters in anaesthetised rats in the absence or presence of H1- and H2-receptor antagonism and the μ-opioid antagonist naloxone. In vitro tissue assays were employed to define more clearly cardiac and vascular mechanisms of action. Morphine (9, 30, 90mg/kg i.v.) decreased heart rate (HR) and mean arterial pressure (MAP) - responses that were blocked by naloxone pretreatment (10mg/kg i.v.). In contrast, methadone (3, 10, 30mg/kg i.v.) caused dramatic short-lived (1-3min) bradycardia, hypotension and lengthening of the QT interval before stabilising 5min after i.v. dosing. Only the steady-state responses of HR and MAP were blocked by naloxone. Mepyramine (10mg/kg i.v.) and cimetidine (100mg/kg i.v.) also blocked the naloxone-sensitive components. In isolated small mesenteric arteries precontracted by K(+) 62mM or endothelin-1, methadone (1-30μM) relaxed vessels while morphine (1-100μM) had no effect. Pretreatment with naloxone (10μM), indomethacin (30μM) or nitro-l-arginine (100μM) did not affect the relaxation to methadone. In rat isolated left atria, morphine and methadone inhibited inotropic responses at high concentrations (100μM). In rat papillary muscle and right atria, methadone was more than 30 times more potent at lengthening the refractory period and slowing the atrial rate than morphine. We conclude that methadone is a potent vasodilator agent, possibly through blocking L-type calcium channels. Copyright © 2015 Elsevier B.V. All rights reserved.
Quillinan, Nidia; Lau, Elaine; Virk, Michael; von Zastrow, Mark; Williams, John T
2011-01-01
Chronic treatment with morphine results in a decrease in mu-opioid receptor sensitivity, an increase in acute desensitization and a reduction in the recovery from acute desensitization in locus coeruleus neurons. With acute administration, morphine is unlike many other opioid agonists in that it does not mediate robust acute desensitization or induce receptor trafficking. This study compares mu-opioid receptor desensitization and trafficking in brain slices taken from rats treated for 6–7 days with a range of doses of morphine (60, 30, 15 mg/kg/day) and methadone (60, 30, 5 mg/kg/day) applied by subcutaneous implantation of osmotic mini pumps. Mice were treated with 45 mg/kg/day. In morphine treated animals, recovery from acute [Met]5enkephalin-induced desensitization and receptor recycling was diminished. In contrast, recovery and recycling were unchanged in slices from methadone treated animals. Remarkably the reduced recovery from desensitization and receptor recycling found in slices from morphine treated animals were not observed in animals lacking β-arrestin2. Further, pharmacological inhibition of GRK2, while not affecting the ability of [Met]5enkephalin to induce desensitization, acutely reversed the delay in recovery from desensitization produced by chronic morphine treatment. These results characterize a previously unidentified function of the GRK/arrestin system in mediating opioid regulation in response to chronic morphine administration. They also suggest that the GRK/arrestin system, rather then serving as a primary mediator of acute desensitization, controls recovery from desensitization by regulating receptor reinsertion to the plasma membrane after chronic treatment with morphine. The sustained GRK/arrestin dependent desensitization is another way in which morphine and methadone are distinguished. PMID:21430144
Laur, D F; Sinkovich, J; Betley, K
1995-02-01
Morphine sulfate and methadone hydrochloride exhibit very different half-lives but are described as having an analgesic potency of one. The use of a drug like methadone may provide prolonged and constant analgesia in the perioperative setting. This double-blinded investigation used methadone and morphine intraoperatively and measured pain scores and narcotic requirements in the first 24 hours postoperatively. Thirty American Society of Anesthesiology (ASA) patients, physical status I through III, between the ages of 18 to 65 years were scheduled for orthopedic surgery and randomly assigned to receive morphine or methadone at 0.30 mg/kg. Fifteen patients received morphine and fifteen patients received methadone. There was no significant difference between the two groups in terms of age, height, weight, and ASA status. No statistically significant difference was observed among the two groups between the amount of analgesic requirements postoperatively or in the visual analogue scale pain score.
Oxycodone: a pharmacological and clinical review.
Ordóñez Gallego, A; González Barón, M; Espinosa Arranz, E
2007-05-01
Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma halflife is 3-5 h (half that of morphine) and stable plasma levels are reached within 24 h (2-7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone--which is also a very potent analgesic--and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5-2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3-4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin) is marketed as 10-, 20-, 40- or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm) is also available in capsules and oral solution. Side effects are those common to opioids
Alizadeh, Maryam; Zahedi-Khorasani, Mahdi; Miladi-Gorji, Hossein
2018-05-30
This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT. Copyright © 2018. Published by Elsevier B.V.
Pypendop, B H; Ilkiw, J E; Shilo-Benjamini, Y
2014-06-01
Buccal administration of buprenorphine is commonly used to treat pain in cats. It has been argued that absorption of buprenorphine through the buccal mucosa is high, in part due to its pKa of 8.24. Morphine, methadone, hydromorphone, and oxymorphone have a pKa between 8 and 9. This study characterized the bioavailability of these drugs following buccal administration to cats. Six healthy adult female spayed cats were used. Buccal pH was measured prior to drug administration. Morphine sulfate, 0.2 mg/kg IV or 0.5 mg/kg buccal; methadone hydrochloride, 0.3 mg/kg IV or 0.75 mg/kg buccal; hydromorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal; or oxymorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal were administered. All cats received all treatments. Arterial blood was sampled immediately prior to drug administration and at various times up to 8 h thereafter. Bioavailability was calculated as the ratio of the area under the time-concentration curve following buccal administration to that following IV administration, each indexed to the administered dose. Mean ± SE (range) bioavailability was 36.6 ± 5.2 (12.7-49.5), 44.2 ± 7.9 (18.7-70.5), 22.4 ± 6.9 (6.4-43.4), and 18.8 ± 2.0 (12.9-23.5)% for buccal administration of morphine, methadone, hydromorphone, and oxymorphone, respectively. Bioavailability of methadone was significantly higher than that of oxymorphone. © 2013 John Wiley & Sons Ltd.
Ise, Yuya; Wako, Tetsuya; Miura, Yoshihiko; Katayama, Shirou; Shimizu, Hisanori
2009-12-01
The present study was undertaken to determine the pharmacoeconomics of switching from sustained-release morphine tablet to matrix type (MT) of transdermal fontanel or sustained-release Oxycodone tablet. Cost-effective analysis was performed using a simulation model along with decision analysis. The analysis was done from the payer's perspective. The cost-effective ratio/patient of transdermal MT fontanel (22, 539 yen)was lower than that of sustained -release Oxycodone tablet (23, 630 yen), although a sensitivity analysis could not indicate that this result was reliable. These results suggest the possibility that transdermal MT fontanel was much less expensive than a sustained-release Oxycodone tablet.
Pypendop, Bruno H; Shilo-Benjamini, Yael; Ilkiw, Jan E
2016-11-01
To determine the effects of morphine, methadone, hydromorphone or oxymorphone on the thermal threshold in cats, following buccal and intravenous (IV) administration. Randomized crossover study. Six healthy adult female ovariohysterectomized cats weighing 4.5 ± 0.4 kg. Morphine sulfate (0.2 mg kg -1 IV or 0.5 mg kg -1 buccal), methadone hydrochloride (0.3 mg kg -1 IV or 0.75 mg kg -1 buccal), hydromorphone hydrochloride (0.1 mg kg -1 IV or 0.25 mg kg -1 buccal) or oxymorphone hydrochloride (0.1 mg kg -1 IV or 0.25 mg kg -1 buccal) were administered. All cats were administered all treatments. Skin temperature and thermal threshold were measured in duplicate prior to drug administration, and at various times up to 8 hours after drug administration. The difference between thermal threshold and skin temperature (ΔT) was analyzed. Administration of methadone and hydromorphone IV resulted in significant increases in ΔT at 40 minutes after drug administration. Buccal administration of methadone resulted in significant increases in thermal threshold, although no significant difference from baseline measurement was detected at any time point. IV administration of morphine and oxymorphone, and buccal administration of morphine, hydromorphone and oxymorphone did not cause significant thermal antinociception. At the doses used in this study, IV administration of methadone and hydromorphone, and buccal administration of methadone resulted in transient thermal antinociception. The results of this study do not allow us to predict the usefulness of these drugs for providing analgesia in clinical patients. © 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.
Cuppoletti, John; Chakrabarti, Jayati; Tewari, Kirti; Malinowska, Danuta H
2013-05-01
In clinical trials, methadone, but not morphine, appeared to prevent beneficial effects of lubiprostone, a ClC-2 Cl(-) channel activator, on opioid-induced constipation. Effects of methadone and morphine on lubiprostone-stimulated Cl(-) currents were measured by short circuit current (Isc) across T84 cells. Whole cell patch clamp of human ClC-2 (hClC-2) stably expressed in HEK293 cells and in a high expression cell line (HEK293EBNA) as well as human CFTR (hCFTR) stably expressed in HEK293 cells was used to study methadone and morphine effects on recombinant hClC-2 and hCFTR Cl(-) currents. Methadone but not morphine inhibited lubiprostone-stimulated Isc in T84 cells with half-maximal inhibition at 100 nM. Naloxone did not affect lubiprostone stimulation or methadone inhibition of Isc. Lubiprostone-stimulated Cl(-) currents in hClC-2/HEK293 cells, but not forskolin/IBMX-stimulated Cl(-) currents in hCFTR/HEK293 cells, were inhibited by methadone, but not morphine. HEK293EBNA cells expressing hClC-2 showed time-dependent, voltage-activated, CdCl2-inhibited Cl(-) currents in the absence (control) and the presence of lubiprostone. Methadone, but not morphine, inhibited control and lubiprostone-stimulated hClC-2 Cl(-) currents with half-maximal inhibition at 100 and 200-230 nM, respectively. Forskolin/IBMX-stimulated hClC-2 Cl(-) currents were also inhibited by methadone. Myristoylated protein kinase inhibitor (a specific PKA inhibitor) inhibited forskolin/IBMX- but not lubiprostone-stimulated hClC-2 Cl(-) currents. Methadone caused greater inhibition of lubiprostone-stimulated currents added before patching (66.1 %) compared with after patching (28.7 %). Methadone caused inhibition of lubiprostone-stimulated Cl(-) currents in T84 cells and control; lubiprostone- and forskolin/IBMX-stimulated recombinant hClC-2 Cl(-) currents may be the basis for reduced efficacy of lubiprostone in methadone-treated patients.
Oxycodone for cancer-related pain.
Schmidt-Hansen, Mia; Bennett, Michael I; Arnold, Stephanie; Bromham, Nathan; Hilgart, Jennifer S
2015-02-27
Many patients with cancer experience moderate to severe pain that requires treatment with strong opioids, of which oxycodone and morphine are examples. Strong opioids are, however, not effective for pain in all patients, nor are they well-tolerated by all patients. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for patients with cancer pain. To assess the effectiveness and tolerability of oxycodone for pain in adults with cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In-Process (Ovid), EMBASE (Ovid), Science Citation Index, Conference Proceedings Citation Index - Science (ISI Web of Science), BIOSIS (ISI), PsycINFO (Ovid) and PubMed to March 2014. We also searched Clinicaltrials.gov, metaRegister of Controlled Trials (mRCT), EU Clinical Trials Register and World Health Organization International Clinical Trials Registry Platform (ICTRP). We checked the bibliographic references of relevant identified studies and contacted the authors of the included studies to find additional trials not identified by the electronic searches. No language, date or publication status restrictions were applied to the search. We included randomised controlled trials (parallel-group or cross-over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults. Two authors independently extracted study data (study design, participant details, interventions and outcomes) and independently assessed the quality of the included studies according to standard Cochrane methodology. Where possible, we meta-analysed the pain intensity data using the generic inverse variance method, otherwise these data were summarised narratively along with the adverse event and patient preference data. The overall quality of the evidence for each outcome
Pacifici, R; Patrini, G; Venier, I; Parolaro, D; Zuccaro, P; Gori, E
1994-06-01
This report describes the 24-hr time course of the immunomodulatory effects of an acute s.c. injection of morphine in C57BL6 mice, and correlates these effects with the drug's analgesic properties and serum levels. Acute morphine treatment had a biphasic effect on various immune parameters: there was an increase in in vitro phagocytosis and the killing of Candida Albican cells by peritoneal polymorphonuclear leukocytes 20 and 40 min after the injection of morphine, 20 mg/kg, when analgesia and serum morphine concentrations were at their peak. Interestingly, 24 hr after morphine administration (when antinociception and morphine blood levels were no longer detectable) these parameters underwent a marked reduction. Similarly, macrophage-mediated inhibition of tumor cells proliferation was first stimulated (at 20 and 40 min) and then depressed (at 24 hr). Splenic natural killer cell cytotoxicity, determined by standard 51Cr release from YAC-1 target cells, also was evaluated. No differences in natural killer activity was observed at any of the monitored time points. In addition, we evaluated the immunomodulatory effects of an acute injection of methadone (a synthetic narcotic compound) at a dose inducing the same degree of analgesia as morphine. None of the tested immunoparameters were affected by the administration of methadone, which indicates the different drug-sensitivity of immunological correlates in vivo.
Hudec, R; Tisonova, J; Foltan, V; Kristova, V
2013-01-01
The aim was to analyse the consumption of selected strong opioid analgesics during a seven-year period of 2003-2009 in order to compare Slovak consumption with that in six other European countries and to determine our position. Drug consumption data from the State Institute for Drug Control in Slovak Republic were used. As to the data from other countries, annual health statistics published on websites were used in comparison. Obviously the consumption of one of studied opioid drugs with transdermal aplication route, particularly fentanyl, tended to increase in all countries during the observed period. Oxycodone tends to yield a rapid increase in consumption as well. As opposed to the latter drugs, the consumption of morphine was decreasing throughout the observed period. The consumption of these drugs in Slovakia remains low (except for that of fentanyl). Our analysis confirmed a clear shift from oral to transdermal therapy as well as usage of newer drugs. Drug consumption data are a relatively new source of information for health research. Our analysis showed increasing trends in fentanyl (patch opioid) consumption in all compared countries as well as an increasing consumption of oxycodone and decreasing consumption of morphine (Fig. 3, Ref. 17).
Beck, Thilo; Haasen, Christian; Verthein, Uwe; Walcher, Stephan; Schuler, Christoph; Backmund, Markus; Ruckes, Christian; Reimer, Jens
2014-01-01
Aims To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone. Design Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment. Setting Fourteen out-patient addiction treatment centres in Switzerland and Germany. Participants Adults with opioid dependence in methadone maintenance programmes (dose ≥50 mg/day) for ≥26 weeks. Measurements The efficacy end-point was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analysed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%. Findings One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least-squares mean difference 0.05; 95% CI = 0.02, 0.08; P > 0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: P = 0.50, period 2: P = 0.19). Overall, safety outcomes were similar between the two groups. Conclusions Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder. PMID:24304412
Morrish, Glynn A; Foster, David J R; Somogyi, Andrew A
2006-01-01
Aims To determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. Methods M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70–500 µm) using three microsomal samples. Results Glucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean ± SD) was 4.8-fold greater than M6G Vmax (555 ± 110 vs. 115 ± 19 nmol mg−1 protein h−1; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg−1 protein h−1). Km values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 mm; P = 0.89, 0.02; −0.29, 0.32 mm). M3G and M6G formation was inhibited (P < 0.01) with a significant increase in the M3G/M6G ratio (P < 0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320 ± 42 µm and 192 ± 12 µm for M3G and M6G, respectively, and (S)-methadone Ki of 226 ± 30 µm and 152 ± 20 µm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P = 0.017, 128; 55, 202 µm) and (S)-methadone (P = 0.026, 75; 22, 128 µm). Conclusions Both methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G. PMID:16487227
... takes drugs such as heroin, codeine, oxycodone (Oxycontin), methadone or buprenorphine. These and other substances pass through ... babies with severe symptoms need medicines such as methadone and morphine to treat withdrawal symptoms. These babies ...
... please enable JavaScript. Methadone is a very strong painkiller. It is also used to treat heroin addiction. ... occur if a person takes methadone with certain painkillers. These painkillers include oxycontin, hydrocodone (Vicodin), or morphine. ...
Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.
Jacob, Joanna C; Poklis, Justin L; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L
2017-07-01
This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.
Ruiz, F; Fournié-Zaluski, M C; Roques, B P; Maldonado, R
1996-09-01
1. The dual inhibitor of enkephalin degrading enzymes, RB 101, is able to block endogenous enkephalin metabolism completely, leading to potent antinociceptive responses potentiated by blockade of CCKB receptors. In this study we have investigated the effects induced by RB 101 given alone, or with the CCKB antagonist, PD-134,308, on a model of spontaneous morphine withdrawal and substitutive maintenance in rats. 2. Animals were chronically treated with morphine for 7 days followed, 36 h after the interruption of drug administration, by a maintenance treatment for 5 days with methadone (2 mg kg-1, i.p.), clonidine (0.025 mg kg-1, i.p.), RB 101 (40 mg kg-1, i.p.), PD-134,308 (3 mg kg-1, i.p.) or a combination of RB 101 plus PD-134,308. Several behavioural observations were made during this period in order to evaluate the acute effects as well as the consequence of chronic maintenance induced on spontaneous withdrawal by the different treatments. 3. Methadone was the most effective compound in decreasing the spontaneous withdrawal syndrome after acute administration. Both, methadone and RB 101 had similar effectiveness in reducing opiate abstinence during the period of substitutive treatment. PD-134,308 did not show any effect when administered alone and did not modify the effect of RB 101. 4. Naloxone (1 mg kg-1, s.c.) failed to precipitate any sign of withdrawal when injected at the end of the chronic maintenance treatment suggesting that, under the present conditions, methadone and RB 101 did not induce significant physical opiate-dependence. 5. The mildness of the side effects induced by chronic RB 101, suggests that systemically active inhibitors of enkephalin catabolism could represent a promising treatment in the maintenance of opiate addicts.
Ruiz, F.; Fournié-Zaluski, M. C.; Roques, B. P.; Maldonado, R.
1996-01-01
1. The dual inhibitor of enkephalin degrading enzymes, RB 101, is able to block endogenous enkephalin metabolism completely, leading to potent antinociceptive responses potentiated by blockade of CCKB receptors. In this study we have investigated the effects induced by RB 101 given alone, or with the CCKB antagonist, PD-134,308, on a model of spontaneous morphine withdrawal and substitutive maintenance in rats. 2. Animals were chronically treated with morphine for 7 days followed, 36 h after the interruption of drug administration, by a maintenance treatment for 5 days with methadone (2 mg kg-1, i.p.), clonidine (0.025 mg kg-1, i.p.), RB 101 (40 mg kg-1, i.p.), PD-134,308 (3 mg kg-1, i.p.) or a combination of RB 101 plus PD-134,308. Several behavioural observations were made during this period in order to evaluate the acute effects as well as the consequence of chronic maintenance induced on spontaneous withdrawal by the different treatments. 3. Methadone was the most effective compound in decreasing the spontaneous withdrawal syndrome after acute administration. Both, methadone and RB 101 had similar effectiveness in reducing opiate abstinence during the period of substitutive treatment. PD-134,308 did not show any effect when administered alone and did not modify the effect of RB 101. 4. Naloxone (1 mg kg-1, s.c.) failed to precipitate any sign of withdrawal when injected at the end of the chronic maintenance treatment suggesting that, under the present conditions, methadone and RB 101 did not induce significant physical opiate-dependence. 5. The mildness of the side effects induced by chronic RB 101, suggests that systemically active inhibitors of enkephalin catabolism could represent a promising treatment in the maintenance of opiate addicts. Images Figure 4 PMID:8872371
DeRossi, Rafael; Hermeto, Larissa Correa; Jardim, Paulo Henrique Affonseca; de Andrade Bicudo, Natalia; de Assis, Klebs Tavares
2016-11-01
Objectives The aim of the study was to evaluate the effectiveness of epidural lidocaine in combination with either methadone or morphine for postoperative analgesia in cats undergoing ovariohysterectomy. Methods Under general anesthesia, 24 cats that underwent ovariohysterectomy were randomly allocated into three treatment groups of eight each. Treatment 1 included 2% lidocaine (4.0 mg/kg); treatment 2 included lidocaine and methadone (4.0 mg/kg and 0.3 mg/kg, respectively); and treatment 3 included lidocaine and morphine (4.0 mg/kg and 0.1 mg/kg, respectively). All drugs were injected in a total volume of 0.25 ml/kg via the lumbosacral route in all cats. During the anesthetic and surgical periods, the physiologic variables (respiratory and heart rate, arterial blood pressure and rectal temperature) were measured at intervals of time zero, 10 mins, 20 mins, 30 mins, 60 mins and 120 mins. After cats had recovered from anesthesia, a multidimensional composite pain scale was used to assess postoperative analgesia 2, 4, 8, 12, 18 and 24 h after epidural. Results The time to first rescue analgesic was significantly ( P <0.05) prolonged in cats that received both lidocaine and methadone or lidocaine and morphine treatments compared with those that received lidocaine treatment alone. All cats that received lidocaine treatment alone required rescue analgesic within 2 h of epidural injections. All treatments produced significant cardiovascular and respiratory changes but they were within an acceptable range for healthy animals during the surgical period. Conclusions and relevance The two combinations administered via epidural allowed ovariohysterectomy with sufficient analgesia in cats, and both induced prolonged postoperative analgesia.
False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.
Tenore, Peter L
2012-01-01
In monitoring a patient with chronic pain who was taking high-dose morphine and oxycodone with weekly urine enzymatic immunoassay (EIA) toxicology testing, the authors noted consistent positives for buprenorphine. The patient was not taking buprenorphine, and gas chromatography/mass spectroscopy (GCMS) testing on multiple samples revealed no buprenorphine, indicating a case of false-positive buprenorphine EIAs in a high-dose opiate case. The authors discontinued oxycodone for a period of time and then discontinued morphine. Urine monitoring with EIAs and GCMS revealed false-positive buprenorphine EIAs, which remained only when the patient was taking morphine. When taking only oxycodone and no morphine, urine samples became buprenorphine negative. When morphine was reintroduced, false-positive buprenorphine results resumed. Medical practitioners should be aware that high-dose morphine (with morphine urine levels turning positive within the 15,000 to 28,000 mg/mL range) may produce false-positive buprenorphine EIAs with standard urine EIA toxicology testing.
Hill, Rob; Dewey, William L; Kelly, Eamonn; Henderson, Graeme
2018-06-01
Oxycodone, a prescription opioid, is a major drug of abuse, especially in the USA, and contributes significantly to opioid overdose deaths each year. Overdose deaths result primarily from respiratory depression. We have studied respiratory depression by oxycodone and have characterized how tolerance develops on prolonged exposure to the drug. We have investigated the role of PKC in maintaining tolerance and have examined whether ethanol or pregabalin reverses oxycodone-induced tolerance. Respiration was measured in male CD-1 mice by whole-body plethysmography. Mice were preinjected with oxycodone then implanted with mini-pumps (s.c.) delivering 20, 45 or 120 mg·kg -1 ·day -1 oxycodone for 6 days and subsequently challenged with oxycodone (3 mg·kg -1 , i.p.) or morphine (10 mg·kg -1 , i.p.) to assess the level of tolerance. Oxycodone-treated mice developed tolerance to oxycodone and cross tolerance to morphine-induced respiratory depression. Tolerance was less with 20 mg·kg -1 ·day -1 than with 45 or 120 mg·kg -1 ·day -1 oxycodone treatment. At doses that do not depress respiration, ethanol (0.3 g·kg -1 ), pregabalin (20 mg·kg -1 ) and calphostin C (45 μg·kg -1 ) all reversed oxycodone-induced tolerance resulting in significant respiratory depression. Reversal of tolerance was less in mice treated with oxycodone (120 mg·kg -1 ·day -1 ). In mice receiving ethanol and calphostin C or ethanol and pregabalin, there was no greater reversal of tolerance than seen with either drug alone. These data suggest that oxycodone-induced tolerance is mediated by PKC and that reversal of tolerance by ethanol or pregabalin may be a contributory factor in oxycodone overdose deaths. © 2018 The British Pharmacological Society.
Antidiuretic effect of morphine in the rat: tolerance and physical dependence.
Huidobro, F
1978-01-01
1 Injection of rats with morphine or methadone, before they received a water load equivalent to 5% of their body weight, produced a dose-dependent antidiuretic effect. Following the antidiuresis, urine was eliminated with kinetics similar to control untreated rats. 2 The antidiuretic effect of morphine or methadone was blocked by naloxone administered before the opiate, or reversed when given after the opiate. 3 Rats implanted with morphine pellets developed a marked degree of tolerance to the antidiuretic effect of morphine. Tolerance was also obtained on injection of three daily doses of morphine or methadone over two days. 4 Withdrawal symptoms were precipitated by naloxone in rats implanted with pellets of morphine; under these conditions the animals showed a marked reduction in urine production as compared to naive rats. PMID:568501
Gelston, Eloise A; Coller, Janet K; Lopatko, Olga V; James, Heather M; Schmidt, Helmut; White, Jason M; Somogyi, Andrew A
2012-01-01
AIMS To compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODS Ten methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide. RESULTS The urinary metabolic ratio for O-demethylation was significantly higher (P = 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P < 0.0002), but there was no significant difference (P = 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P = 0.72) and lower morphine-3- and -6- and codeine-6-glucuronide concentrations (P < 0.008). CONCLUSION Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6. PMID:22092298
Morphine tolerance as a function of ratio schedule: response requirement or unit price?
Hughes, Christine E; Sigmon, Stacey C; Pitts, Raymond C; Dykstra, Linda A
2005-05-01
Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.
Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist
Doi, Seira; Mori, Tomohisa; Uzawa, Naoki; Arima, Takamichi; Takahashi, Tomoyuki; Uchida, Masashi; Yawata, Ayaka; Narita, Michiko; Uezono, Yasuhito; Suzuki, Tsutomu
2016-01-01
Background Methadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated β-arrestin recruitment. Results We found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of β-arrestin-2 in µ-opioid receptor-overexpressing cells. Conclusions These results suggest that methadone may, at least partly, produce its pharmacological effect as a β-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone. PMID:27317580
Brase, D A; Ward, C R; Bey, P S; Dewey, W L
1991-01-01
The mouse locomotor activation test of opiate action in a 2+2 dose parallel line assay was used in a repeated testing paradigm to determine the test, opiate and hexose specificities of a previously reported antagonism of morphine-induced antinocociception by hyperglycemia. In opiate specificity studies, fructose (5 g/kg, i.p.) significantly reduced the potency ratio for morphine and methadone, but not for levorphanol, meperidine or phenazocine when intragroup comparisons were made. In intergroup comparisons, fructose significantly reduced the potencies of levorphanol and phenazocine, but not methadone or meperidine. In hexose/polyol specificity studies, tagatose and fructose significantly reduced the potency ratio for morphine, whereas glucose, galactose, mannose and the polyols, sorbitol and xylitol, caused no significant decrease in potency. Fructose, tagatose, glucose and mannose (5 g/kg, i.p.) were tested for effects on brain morphine levels 30 min after morphine (60 min after sugar), and all four sugars significantly increased brain morphine relative to saline-pretreated controls. It is concluded that the antagonism of morphine by acute sugar administration shows specificity for certain sugars and occurs despite sugar-induced increases in the distribution of morphine to the brain. Furthermore, the effects of fructose show an opiate specificity similar to that of glucose on antinociception observed previously in our laboratory, except that methadone was also significantly inhibited in the present study, when a repeated-testing experimental design was used.
Out-of-hospital mortality among patients receiving methadone for noncancer pain.
Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Cooper, William O; Hall, Kathi; Stein, C Michael
2015-03-01
Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate. A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients' median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively. The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P < .001), resulting in 72 (95% CI, 27-130) excess deaths per 10 000 person-years of follow-up. Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (<60 mg/d). The increased risk of death
Methadone enhances human influenza A virus replication.
Chen, Yun-Hsiang; Wu, Kuang-Lun; Tsai, Ming-Ta; Chien, Wei-Hsien; Chen, Mao-Liang; Wang, Yun
2017-01-01
Growing evidence has indicated that opioids enhance replication of human immunodeficiency virus and hepatitis C virus in target cells. However, it is unknown whether opioids can enhance replication of other clinically important viral pathogens. In this study, the interaction of opioid agonists and human influenza A/WSN/33 (H1N1) virus was examined in human lung epithelial A549 cells. Cells were exposed to morphine, methadone or buprenorphine followed by human H1N1 viral infection. Exposure to methadone differentially enhanced viral propagation, consistent with an increase in virus adsorption, susceptibility to virus infection and viral protein synthesis. In contrast, morphine or buprenorphine did not alter H1N1 replication. Because A549 cells do not express opioid receptors, methadone-enhanced H1N1 replication in human lung cells may not be mediated through these receptors. The interaction of methadone and H1N1 virus was also examined in adult mice. Treatment with methadone significantly increased H1N1 viral replication in lungs. Our data suggest that use of methadone facilitates influenza A viral infection in lungs and might raise concerns regarding the possible consequence of an increased risk of serious influenza A virus infection in people who receive treatment in methadone maintenance programs. © 2015 Society for the Study of Addiction.
Pain therapy with oxycodone/naloxone prolonged-release combination: case report
Droń, Aleksandra
2013-01-01
Pain afflicts patients suffering from many chronic diseases and is present in 80% of cases of patients with advanced cancer who suffer from persistent pain. The aim of the pain treatment is to achieve the maximum analgesic effect while minimizing side effects. The main analgesic agent – morphine is unfortunately a therapy associated with gastrointestinal side effects. It appears that the combination of oxycodone and naloxone available as Targin® (Mundipharma) is an alternative. The paper presents a case of a 45-year-old patient who was treated effectively with oxycodone/naloxone prolonged-release tablets. This treatment has proven to be effective in providing pain and constipation control. PMID:24592131
Pain therapy with oxycodone/naloxone prolonged-release combination: case report.
Błaszczyk, Feliks; Droń, Aleksandra
2013-01-01
Pain afflicts patients suffering from many chronic diseases and is present in 80% of cases of patients with advanced cancer who suffer from persistent pain. The aim of the pain treatment is to achieve the maximum analgesic effect while minimizing side effects. The main analgesic agent - morphine is unfortunately a therapy associated with gastrointestinal side effects. It appears that the combination of oxycodone and naloxone available as Targin(®) (Mundipharma) is an alternative. The paper presents a case of a 45-year-old patient who was treated effectively with oxycodone/naloxone prolonged-release tablets. This treatment has proven to be effective in providing pain and constipation control.
Ward, Alexandra; Bozkaya, Duygu; Fleischmann, Jochen; Dubois, Dominique; Sabatowski, Rainer; Caro, J Jaime
2007-10-01
The Osmotic controlled-Release Oral delivery System (OROS) hydromorphone ensures continuous release of hydromorphone over 24 hours. It is anticipated that this will facilitate optimal pain relief, improve quality of sleep and compliance. This simulation compared managing chronic osteoarthritis pain with once-daily OROS hydromorphone with an equianalgesic dose of extended-release (ER) oxycodone administered two or three times a day. This discrete event simulation follows patients for a year after initiating opioid treatment. Pairs of identical patients are created; one receives OROS hydromorphone the other ER oxycodone; undergo dose adjustments and after titration can be dissatisfied or satisfied, suffer adverse events, pain recurrence, or discontinue the opioid. Each is assigned an initial sleep problems score, and an improved score from a treatment dependent distribution at the end of titration; these are translated to a utility value. Utilities are assigned pre-treatment, updated until the patient reaches the optimal dose or is non-compliant or dissatisfied. The OROS hydromorphone and ER oxycodone doses are converted to equianalgesic morphine doses using the following ratios: hydromorphone to morphine ratio; 1:5, oxycodone to morphine ratio; 1:2. Sensitivity analyses explored uncertainty in the conversion ratios and other key parameters. Direct medical costs are in 2005 euros. Over 1 year on a mean daily morphine-equivalent dose of 90 mg, 14% were estimated to be dissatisfied with each opioid. OROS hydromorphone was predicted to yield 0.017 additional quality-adjusted life years (QALYs)/patient for a small additional annual cost (E141/patient), yielding an incremental cost-effectiveness ratio (ICER) of E8343/QALY gained. Changing the assumed conversion ratio for oxycodone:morphine to 1:1.5 led to lower net costs of E68 per patient, E3979/QALY, and for hydromorphone to 1:7.5 to savings. Based on these analyses, OROS hydromorphone is expected to yield health
Synthetic substances with morphine-like effect
Braenden, Olav J.; Eddy, Nathan B.; Halbach, H.
1955-01-01
For morphine-, morphinan-, pethidine-, methadone-, and dithienyl-butenylamine groups of analgesic compounds a systematic survey is given of how analgesic activity is quantitatively affected by alteration of the chemical constitution. Features common to the structural formulae of substances with morphine-like analgesic effect are pointed out. ImagesFIG. 1FIG. 1(Contd.) PMID:13284565
Methadone and Metabolites in Hair of Methadone-Assisted Pregnant Women and Their Infants
Himes, Sarah K; Goodwin, Robert S; Rock, Colleen M; Jones, Hendrée E; Johnson, Rolley E; Wilkins, Diana G; Huestis, Marilyn A
2012-01-01
Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes. Materials and Methods Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3cm), washed (maternal hair only) and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP) by liquid chromatography tandem mass spectrometry. Results There was large inter-subject variability and no dose-concentration relationship for cumulative methadone dose and methadone, EDDP, EMDP or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone’s induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference or amount of neonatal morphine pharmacotherapy. Maternal cumulative 3rd trimester methadone dose was positively correlated with infant birth weight. Conclusion Methadone and EDDP in pregnant women’s hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure. PMID
Destro, Massimo; Ottolini, Luca; Vicentini, Lorenza; Boschetti, Silvia
2012-10-01
The parenteral administration of combinations of drugs is often necessary in palliative medicine, particularly in the terminal stage of life, when patients are no longer able to take medication orally. The use of infusers to administer continuous subcutaneous infusions is a well-established practice in the palliative care setting and enables several drugs to be given simultaneously, avoiding the need for repeated administrations and the effects of peaks and troughs in the doses of medication. The method is also appreciated by patients and caregivers in the home care setting because the devices and infusion sites are easy to manage. Despite their frequent use, however, the mixtures of drugs adopted in clinical practice are sometimes not supported by reliable data concerning their chemical and physical compatibility. The present study investigates the chemical compatibility of binary mixtures (morphine with ketorolac) and the physical compatibility of binary (morphine or methadone with ketorolac) or ternary mixtures (morphine with ketorolac and/or haloperidol, and/or dexamethasone, and/or metoclopramide, and/or hyoscine butylbromide) with a view to reducing the aleatory nature of the empirical use of such combinations, thereby increasing their safety and clinical appropriateness.
Kawabata, Masahiro; Kaneishi, Keisuke
2013-05-01
Pain and dyspnea are the most prevalent and distressing symptoms in patients with terminally ill cancer. Evidences have accumulated for the effects of morphine on dyspnea, whereas little is known about the effects of oxycodone on dyspnea. We investigated the effectiveness of oxycodone for dyspnea in patients with terminally ill cancer. The injectable form of compound oxycodone (iOC) containing hydrocotarnine was administered continuously via subcutaneous route. We administered iOC to 136 patients. The effect on dyspnea was less conspicuous than pain, yet iOC was effective for dyspnea with varying degrees. None of the adverse effects observed were serious. These results suggest that continuous subcutaneous administration of oxycodone could be one of the reasonable alternatives in the management of dyspnea in patients with terminally ill cancer.
Fatal methadone intoxication in an infant listed as a homicide.
Bonsignore, Alessandro; Groppi, Angelo; Ventura, Francesco; De Stefano, Francesco; Palmiere, Cristian
2016-09-01
Voluntary methadone administration for the purpose of sedation eventually resulting in the infant's death is extremely infrequent, though it has been observed. In this report, we describe an autopsy case pertaining to a 32-month-old infant who was repeatedly exposed to methadone by his parents. Autopsy revealed a coarctation of the aorta with a focal stenosis located at the junction of the distal aortic arch and the descending aorta. Left ventricular hypertrophy was also observed. Both these findings were considered to not have played a role in the child's death. Methadone was detected in the femoral blood (0.633 mg/l), urine (5.25 mg/l), bile (2.64 mg/l), and gastric contents (1.08 mg). A segmental hair analysis showed the presence of methadone and morphine in both the proximal and distal portion of the lock. Methadone was also detected in nail samples. A segmental hair analysis performed on the younger brother of the deceased revealed the presence of methadone and morphine in both the proximal and distal segments, as well as the presence of 6-monoacetylmorphine exclusively in the distal portion. Though the parents denied any involvement in methadone administration or exposure for the purpose of sedation, the manner of death was listed as homicide. The case emphasizes the usefulness of hair analysis to identify threatening situations for the children of drug-dependent parents and possibly support measures by the authorities to recognize and intervene in these potentially fatal situations.
Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine
Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme
2016-01-01
Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths. PMID:26171718
Morphine Antidependence of Erythroxylum cuneatum (Miq.) Kurz in Neurotransmission Processes In Vitro
Adenan, Mohd Ilham; Amom, Zulkhairi
2016-01-01
Opiate abuse has been studied to cause adaptive changes observed in the presynaptic release and the mediated-synaptic plasticity proteins. The involvement of neuronal SNARE proteins reveals the role of the neurotransmitter release in expressing the opioid actions. The present study was designed to determine the effect of the alkaloid extract of Erythroxylum cuneatum (E. cuneatum) against chronic morphine and the influences of E. cuneatum on neurotransmission processes observed in vitro. The human neuroblastoma cell line, SK-N-SH, was treated with the morphine, methadone, or E. cuneatum. The cell lysates were collected and tested for α-synuclein, calmodulin, vesicle-associated membrane protein 2 (VAMP 2), and synaptotagmin 1. The extract of E. cuneatum was observed to upregulate the decreased expression of dependence proteins, namely, α-synuclein and calmodulin. The effects were comparable to methadone and control. The expressions of VAMP 2 and synaptotagmin 1 were normalised by the plant and methadone. The extract of E. cuneatum was postulated to treat dependence symptoms after chronic morphine and improve the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) protein involved in synaptic vesicle after. PMID:27974903
Hickman, Matthew; Madden, Peter; Henry, John; Baker, Allan; Wallace, Chris; Wakefield, Jon; Stimson, Gerry; Elliott, Paul
2003-04-01
To test the hypothesis that methadone is responsible for a greater increase in overdose deaths than heroin, and causes proportionally more overdose deaths than heroin at weekends. Multivariate analysis of 3961 death certificates mentioning heroin, morphine and/or methadone held on the Office for National Statistics drug-related poisoning mortality database from 1993 to 1998 in England and Wales. Percentage increase in deaths by year by drug, odds ratio (OR) of dying at the weekend from methadone-related overdose compared to dying from heroin/morphine overdose. From 1993 to 1998, annual opiate overdose deaths increased from 378 to 909. There was a 24.7% (95% confidence interval (CI) 22-28%) yearly increase in heroin deaths compared to 9.4% (95% CI 6-13%) for methadone only. This difference was significant (P < 0.001 by test of interaction) after adjustment for sex, age group, polydrug use, area of residence and underlying cause of death. The largest number of deaths occurred on Saturday (673). The OR of death from methadone overdose on Saturday and Sunday was 1.48 (95% CI 1.29-1.71) for methadone-only deaths compared to dying from heroin/morphine at the weekend after adjustment for other covariates, but the OR was not significant (1.09, 95% CI 0.95-1.25) if the weekend was defined as Friday and Saturday. There was no evidence that the threefold increase in deaths over time was due to methadone. There was equivocal support only for the hypothesis that there was an excess of deaths from methadone at weekends. Increased interventions to prevent overdose among injectors in England and Wales are long overdue.
Oxycodone Ingestion Patterns in Acute Fracture Pain With Digital Pills.
Chai, Peter R; Carreiro, Stephanie; Innes, Brendan J; Chapman, Brittany; Schreiber, Kristin L; Edwards, Robert R; Carrico, Adam W; Boyer, Edward W
2017-12-01
Opioid analgesics are commonly prescribed on an as-needed (PRN) basis for acute painful conditions. Uncertainty of how patients actually take PRN opioids, coupled with a desire to completely cover pain, leads to variable and overly generous opioid prescribing practices, resulting in a surplus of opioids. This opioid surplus becomes a source for diversion and nonmedical opioid use. Understanding patterns of actual opioid ingestion after acute painful conditions can help clinicians counsel patients on safe opioid use, and allow timely recognition and intervention when escalating opioid self-dosing occurs, to prevent tolerance and addiction. We used a novel oxycodone digital pill system (ingestible biosensor within a standard gelatin capsule combined with 5-mg oxycodone) that when ingested, is activated by the chloride ion gradient in the stomach thereby emitting a radiofrequency signal captured by a wearable reader. The reader relays ingestion data to a cloud-based server that displays ingestion events to the study team. We deployed the oxycodone digital pill among opioid-naive individuals discharged from the emergency department with acute fracture pain. Participants were trained on digital pill operation and discharged with twenty-one 5-mg oxycodone digital pills. They were instructed to take digital pills PRN for pain on discharge. We conducted a brief interview 7 days after study enrollment, at which point participants returned the digital pill system. We identified oxycodone ingestion events in real time by data from the digital pill system and performed pill counts at the return visit to validate digital pill reporting of medication ingestion. In this study, 26 individuals were approached; 16 enrolled with 15 completing the study. Participants ingested a median of 6 (3-9.5) oxycodone digital pills over the course of 7 days, with 82% of the oxycodone dose ingested in the first 3 days. In individuals who required operative repair, 86% (N = 6) continued to ingest
Peterson, S. J.; Laudenbach, M.; Baruffaldi, F.; Carroll, F. I.; Comer, S. D.; Navarro, H. A.; Langston, T. L.; Runyon, S. P.; Winston, S.; Pravetoni, M.; Pentel, P. R.
2017-01-01
Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose. PMID:29194445
Relationship between LAAM-methadone preference and treatment outcomes.
White, Jason M; Danz, Cath; Kneebone, Joanne; La Vincente, Sophie F; Newcombe, David A L; Ali, Robert L
2002-05-01
Studies of relative LAAM-methadone preference have indicated that a significant proportion of patients prefer levo-alpha-acetylmethadol (LAAM). The present study was designed to determine whether this preference is associated with better treatment outcomes. Sixty-two stable methadone patients participated in a randomised crossover clinical trial. They received LAAM (alternate days) and methadone (daily) for 3 months each, followed by a further 6-month period during which they were free to choose between the drugs. LAAM maintenance was associated with a lower rate of heroin use than methadone maintenance based on analysis of morphine concentration in hair and equivalent health outcomes. The majority of subjects showed a preference for LAAM (n=27, 69.2%) rather than methadone (n=12, 30.8%). The main reasons given for the LAAM preference were that it produced less withdrawal (39.3%), fewer side effects (28.5%), less craving for heroin (17.9%), and entailed fewer pick-up days (14.3%). Those who chose LAAM had lower levels of heroin use during LAAM maintenance, significantly better outcomes on two sub-scales of the SF-36 (Vitality and Mental Health), and reported that they felt more normal and that they were 'held' better when on LAAM. For those who chose methadone, there were no differences in outcomes between the LAAM and methadone maintenance periods. Preference for LAAM is associated with treatment outcomes as good or better than those with methadone.
Kokubun, Hideya; Nakamura, Kazuyo; Fukawa, Misako; Matoba, Motohiro; Hoka, Sumio; Yago, Kazuo
2007-12-01
The demand for oxycodone increases in the treatment of patients with cancer pain, but there is no injection formulation containing oxycodone as a single ingredient in Japan. Instead, we have an oxycodone/hydrocotarnine compound product. Long ago, hydrocotarnine was added to enhance the analgesic effect of oxycodone. However, the mechanism of hydrocotarnine is unclear, and few studies have mentioned the conversion ratio between intravenous and oral oxycodone. In the present study, in order to define the conversion ratio between them, we investigated 18 patients treated by intravenous or oral oxycodone and changed to another administration route during their treatment. We surveyed the change in pain level and adverse effects before and after changing the administration route. The conversion ratio from oral oxycodone to intravenous oxycodone/hydrocotarnine was 0.71+/-0.12 (mean+/-S. D.), and no obvious change in adverse effect was observed.
Armstrong, Scott C; Cozza, Kelly L
2003-01-01
Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. This understanding is important so that clinicians can choose the proper dosages for analgesia and anticipate potential drug-drug interactions.
Opioid management and dependency among adult patients with sickle cell disease.
Feliu, Miriam H; Wellington, Chante; Crawford, Regina D; Wood, Mary; Edwards, Lekisha; Byrd, Goldie; Edwards, Christopher L
2011-01-01
While pain is one of the most debilitating symptoms of sickle cell disease, narcotics remain an effective although controversial widely practiced intervention. Vaso-occlusive crises are the most common cause for seeking pharmacological treatment. The influence of stigmatization and pseudo addiction in emergency departments and outpatient clinics was reviewed. We analyzed patterns of narcotic utilization in a sample of 63 adult patients with sickle cell disease to determine if their psychological functioning and reports of pain differed as a function of the primary narcotics they were taking for oral pain management. Fifty-one percent of patients reported treatment of Oxycodone, 35% OxyContin, 24% methadone and 11% morphine. Patients who were treated with Oxycodone reported greater sensory reactions to pain (p = 0.001), visual analog scale (VAS) (p = 0.02), and averaged weekly pain intensity ratings than patients who did not use this medication. There were no differences in pain or affective response in patients treated with OxyContin, methadone or morphine. We suggest there are clear differences between the reports of pain in patients with sickle cell disease taking short-acting narcotics for pain management as compared to those who are not, a pattern that does not distinguish patients who are managed with long-acting preparations. We discuss the relevance of addressing narcotic management in the context of the perception of health care providers and patients with sickle cell disease.
Aleksa, Katarina; Walasek, Paula; Fulga, Netta; Kapur, Bhushan; Gareri, Joey; Koren, Gideon
2012-05-10
The analysis of pediatric and adult hair is a useful non-invasive biomarker to effectively detect long term exposure to various xenobiotics, specifically drugs of abuse such as cocaine, opiates and amphetamines. Very often individuals are using, or are exposed to multiple drugs simultaneously and therefore it is important to be able to detect them in the same analysis. We have developed a sensitive and specific solid phase micro extraction (SPME) coupled with gas chromatography mass spectrometry (GC/MS) to detect 17 different analytes in hair using a single extraction method. Five milligrams of hair is extracted overnight, subjected to solid phase extraction (SPE) and then to SPME-GC/MS. The aimed analytes include amphetamine, methamphetamine, MDA, MDMA, cocaine, benzoylecognine, norcocaine, cocaethylene, methadone, codeine, morphine, 6-AM, oxycodone, oxymorphone, hydrocodone, hydromorphone and meperidone. The following are the LOD of the various drugs: 0.2ng/mg hair for amphetamine, methamphetamine, MDA, MDMA, morphine, codeine, 6-AM, oxycodone, oxymorphone, hydromorphone, hydrocodone, meperidine and 0.13ng/mg hair for cocaine, benzoylecognine, cocaethylene, norcocaine and methadone. This GC/MS method is sensitive and specific to detect the presence of these 17 analytes in as little as 5mg of hair and is especially useful for newborn and child hair analysis where the amount of hair is often very limited. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Nilsson, Matias; Brock, Christina; Poulsen, Jakob Lykke; Bindslev, Niels; Hansen, Mark Berner; Louring Christrup, Lona; Drewes, A M
2016-01-01
Opioid therapy is associated with altered secretion and motility of the gut. The relative contribution of decreased secretion to the development of opioid-induced constipation remains unknown. Twenty-five healthy males were treated with oxycodone for 5 d in a placebo-controlled, randomised cross-over design. Gastrointestinal adverse effects were assessed with validated questionnaires (bowel function index and gastrointestinal symptom rating scale). Rectosigmoid mucosal biopsies were taken at baseline and on day 5 during both treatments and mounted in Ussing chambers. Electrogenic ion transport parameters (short circuit current (SCC) and slope conductance) were measured after addition of secretagogues (prostaglandin E2 (PGE2) (6 μm), theophylline (400 μm)), and an inhibitor (ouabain (200 μm)). Additionally, morphine (50 μm) was added to investigate the direct opioid effect on colonic mucosa. Questionnaires showed pronounced bowel symptoms, including constipation during oxycodone treatment (eight-fold increase in bowel function index score from day 1 to day 5 (p < 0.001) while no significant change occurred during placebo treatment (p = 0.47). Basal SCC and slope conductance did not differ between treatments (all p > 0.05) and application with PGE2, theophylline, and ouabain yielded comparable results on all examinations (all p > 0.05). Morphine application consistently did not evoke a change in ion transport. Compared to placebo, epithelial electrogenic ion transport is not altered in mucosal biopsies from the rectosigmoid colon following 5-d oxycodone treatment. The secretory mechanisms in isolated mucosa appear to play a negligible role in the development of opioid-induced constipation.
Wang, Rongrong; Ding, Yingying; Bai, Hongling; Duan, Song; Ye, Runhua; Yang, Yuecheng; Wang, Jibao; Tang, Renhai; Gao, Meiyang; He, Na
2015-01-01
Methadone maintenance treatment (MMT) was introduced to China in 2004 to reduce the harm of injecting drug users (IDUs). However, little is known about continued drug use, especially methamphetamine (MAMP), among MMT patients. A survey was conducted among patients attending five major MMT clinics in Dehong Prefecture in 2014 to investigate the heroin and MAMP use and their associated risk factors. Participants were administered with face-to-face interviews, and urine tests for morphine and MAMP. A total of 2,121 were eligible and participated in the study. Among them, 220 (10.4%) were only positive for morphine, 12.9% were only positive for MAMP, and 196 (9.2%) were positive for both morphine and MAMP. Compared with neither use of heroin nor MAMP during MMT, heroin use (not using MAMP) was associated with ethnicity, shorter duration of MMT, lower dose of methadone, and having had no more than two sex partners in the past year; MAMP use (not using heroin) was associated with ethnicity, longer duration of MMT, higher dose of methadone and being aged <30 years (vs. ≥50 years); use of both heroin and MAMP was associated with being Dai minority (vs. Han), a marital status of divorced or widowed, having used drugs for ≥10 years and shorter duration of MMT. These findings indicate the complexity in the treatment of heroin users and underscore the importance in prescribing appropriate methadone dosages in order to reduce both heroin and MAMP use.
de Castro, Ana; Concheiro, Marta; Shakleya, Diaa M.; Huestis, Marilyn A.
2011-01-01
A liquid chromatography mass spectrometric selected reaction monitoring mode (SRM) method for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine (BE), 6-acetylmorphine, morphine and codeine quantification in human umbilical cord was developed and fully validated. Analytes were extracted from homogenized tissue (1 g) by solid phase extraction. Linearity was 2.5–500 ng/g, except for methadone (10–2000 ng/g). Method imprecision was <12.7%CV with analytical recovery 85.9–112.7%, extraction efficiency >59.2%, matrix effect 4.5–39.5%, process efficiency 48.6–92.6% and stability >84.6%. Analysis of an umbilical cord following controlled methadone administration and illicit drug use contained in ng/g, 40.3 morphine, 3.6 codeine, 442 BE, 186 methadone and 45.9 EDDP. PMID:19656745
Poulsen, Jakob Lykke; Brock, Christina; Grønlund, Debbie; Liao, Donghua; Gregersen, Hans; Krogh, Klaus; Drewes, Asbjørn Mohr
2017-11-01
Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction (OIBD). However, it is unknown whether the inhibition can be reduced by opioid antagonism with prolonged-release (PR) naloxone and how this compares to laxative treatment. To compare the effects of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350 on anal sphincter function and gastrointestinal symptoms. A randomized, double-blind, crossover trial was conducted in 20 healthy men. Participants were treated for 5 days with combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Resting anal pressure, anal canal distensibility, and relaxation of the internal sphincter to rectal distension were evaluated before treatment (baseline) and on day 5. The Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire, stool frequency, and stool consistency were assessed daily. Both PR oxycodone/naloxone and PR oxycodone plus macrogol treatment decreased sphincter relaxation compared to baseline (- 27.5%; P < 0.001 and - 14.7%; P = 0.01). However, sphincter relaxation was increased after PR naloxone/oxycodone treatment compared to macrogol (difference = + 17.6%; P < 0.001). Resting anal pressure and anal canal distensibility did not differ between treatments. PAC-SYM abdominal symptoms score was lower during PR naloxone compared to macrogol (0.2 vs. 3.2; P = 0.002). The number of bowel movements was lower during PR naloxone versus macrogol (4.2 vs. 5.4; P = 0.035). Relaxation of the internal anal sphincter was significantly better after PR oxycodone/naloxone treatment compared to PR oxycodone plus macrogol 3350. These findings highlight that OIBD may require specific therapy against the complex, pan-intestinal effects of opioids.
Schaffer, Andrea L; Buckley, Nicholas A; Degenhardt, Louisa; Larance, Briony; Cairns, Rose; Dobbins, Timothy A; Pearson, Sallie-Anne
2018-03-26
Australia introduced tamper-resistant controlled-release (CR) oxycodone in April 2014. We quantified the impact of the reformulation on dispensing, switching and poisonings. We performed interrupted time-series analyses using population-representative national dispensing data from 2012 to 2016. We measured dispensing of oxycodone CR (≥ 10 mg), discontinuation of use of strong opioids and switching to other strong opioids after the reformulation compared with a historical control period. Similarly, we compared calls about intentional opioid poisoning using data from a regional poisons information centre. After the reformulation, dispensing decreased for 10-30 mg (total level shift -11.1%, 95% confidence interval [CI], -17.2% to -4.6%) and 40-80 mg oxycodone CR (total level shift -31.5%, 95% CI -37.5% to -24.9%) in participants less than 65 years of age but was unchanged in people 65 years of age or older. Compared with the previous year, discontinuation of use of strong opioids did not increase (adjusted hazard ratio [HR] 0.95, 95% CI 0.91 to 1.00), but switching to oxycodone/naloxone did increase (adjusted HR 1.54, 95% CI 1.32 to 1.79). Switching to morphine varied by age ( p < 0.001), and the greatest increase was in participants less than 45 years of age (adjusted HR 4.33, 95% CI 2.13 to 8.80). Participants switching after the reformulation were more likely to be dispensed a tablet strength of 40 mg or more (adjusted odds ratio [OR] 1.40, 95% CI 1.09 to 1.79). Calls for intentional poisoning that involved oxycodone taken orally increased immediately after the reformulation (incidence rate ratio (IRR) 1.31, 95% CI 1.05-1.64), but there was no change for injected oxycodone. The reformulation had a greater impact on opioid access patterns of people less than 65 years of age who were using higher strengths of oxycodone CR. This group has been identified as having an increased risk of problematic opioid use and warrants closer monitoring in clinical practice.
Severe pruritus and myoclonus following intrathecal morphine administration in a dog
Iff, Isabelle; Valeskini, Karin; Mosing, Martina
2012-01-01
During epidural needle placement in a 32-kg dog the subarachnoid space was punctured and half the intended dose of lidocaine, bupivacaine, and morphine was injected. After recovery from anesthesia the dog showed signs of severe pruritus of the tail base and limbs and myoclonus of the tail and hind limbs. Methadone, acepromazine, ketamine, buprenorphine, and butorphanol were administered to control myoclonus and pruritus, but were unsuccessful. Diazepam was used to control myoclonus until the effects of morphine abated. PMID:23450863
Controlled-release oxycodone-induced seizures.
Klein, Moti; Rudich, Zvia; Gurevich, Boris; Lifshitz, Matityahu; Brill, Silviu; Lottan, Michael; Weksler, Natan
2005-11-01
The use of the opioid oxycodone hydrochloride in the management of chronic pain is gaining popularity principally because of its tolerability. However, opioid-related seizure in patients with epilepsy or other conditions that may decrease seizure threshold has been described in the literature; in particular, oxycodone has been associated with seizure in a patient with acute renal failure. The aim of this article was to report a patient with a history of seizures but normal renal and hepatic function who developed seizure on 2 occasions after oxycodone ingestion. A 54-year-old male patient presented with a history of tonic-clonic seizures that developed immediately after intracranial surgery. Long-term treatment with carbamazepine 400 mg QD was started, and the patient was free of convulsions for approximately 7 years. The patient presented to us with severe headache that was nonresponsive to an NSAID and the opiate agonist tramadol. Treatment with controlled-release (CR) oxycodone and tramadol drops (50 mg QID if necessary) was started, and tonic-clonic seizures developed 3 days later. Based on laboratory analysis, the patient had normal renal and hepatic function. On discontinuation of oxycodone treatment, the seizures resolved. However, due to effective pain relief with oxycodone, the patient decided to continue treatment, and seizures recurred. Carbamazepine was then administered 4 hours before oxycodone dosing, which allowed continuation of treatment without seizure. A patient with a history of seizures controlled with long-term carbamazepine therapy developed seizures when he started treatment with oxycodone CR at recommended doses. Oxycodone CR should be used with extreme caution in patients with epilepsy or other conditions that may decrease seizure threshold.
Buckley, Nicholas A.; Degenhardt, Louisa; Larance, Briony; Cairns, Rose; Dobbins, Timothy A.; Pearson, Sallie-Anne
2018-01-01
BACKGROUND: Australia introduced tamper-resistant controlled-release (CR) oxycodone in April 2014. We quantified the impact of the reformulation on dispensing, switching and poisonings. METHODS: We performed interrupted time-series analyses using population-representative national dispensing data from 2012 to 2016. We measured dispensing of oxycodone CR (≥ 10 mg), discontinuation of use of strong opioids and switching to other strong opioids after the reformulation compared with a historical control period. Similarly, we compared calls about intentional opioid poisoning using data from a regional poisons information centre. RESULTS: After the reformulation, dispensing decreased for 10–30 mg (total level shift −11.1%, 95% confidence interval [CI], −17.2% to −4.6%) and 40–80 mg oxycodone CR (total level shift −31.5%, 95% CI −37.5% to −24.9%) in participants less than 65 years of age but was unchanged in people 65 years of age or older. Compared with the previous year, discontinuation of use of strong opioids did not increase (adjusted hazard ratio [HR] 0.95, 95% CI 0.91 to 1.00), but switching to oxycodone/naloxone did increase (adjusted HR 1.54, 95% CI 1.32 to 1.79). Switching to morphine varied by age (p < 0.001), and the greatest increase was in participants less than 45 years of age (adjusted HR 4.33, 95% CI 2.13 to 8.80). Participants switching after the reformulation were more likely to be dispensed a tablet strength of 40 mg or more (adjusted odds ratio [OR] 1.40, 95% CI 1.09 to 1.79). Calls for intentional poisoning that involved oxycodone taken orally increased immediately after the reformulation (incidence rate ratio (IRR) 1.31, 95% CI 1.05–1.64), but there was no change for injected oxycodone. INTERPRETATION: The reformulation had a greater impact on opioid access patterns of people less than 65 years of age who were using higher strengths of oxycodone CR. This group has been identified as having an increased risk of problematic opioid
Beneficial effects of co-treatment with dextromethorphan on prenatally methadone-exposed offspring.
Chiang, Yao-Chang; Ye, Li-Ci; Hsu, Kuei-Ying; Liao, Chien-Wei; Hung, Tsai-Wei; Lo, Wan-Jou; Ho, Ing-Kang; Tao, Pao-Luh
2015-03-20
Heroin use among young women of reproductive age has drawn much attention around the world. Although methadone is widely used in maintenance therapy for heroin/morphine addiction, the long-term effects of prenatal exposure to methadone and preventative therapy remain unclear. For revealing this question, female pregnant Sprague-Dawley rats were sub-grouped to receive (1) vehicle, (2) methadone 5 mg/kg at embryonic day 3 (E3) and then 7 mg/kg from E4 to E20, (3) dextromethorphan (DM) 3 mg/kg, and (4) methadone + DM (the rats received methadone followed by DM treatment), subcutaneously, twice a day from E3 to E20. The body weight, natural withdrawal, pain sensitivity, ED50, conditioned place preference and water maze were conducted at different postnatal stages (P1 to P79) of offspring. The quantitative real-time RT-PCR and electrophysiology were also used to measure the gene expression of opioid receptors in the spinal cord and changes of LTP/LTD in the hippocampus, separately. Prenatal exposure to methadone or DM did not affect survival rate, body weight, water maze and LTP or LTD of offspring. However, prenatal methadone significantly increased the withdrawal symptoms, pain sensitivity, addiction liability and decreased the mRNA expression of pain related opioid receptors. Co-administration of DM with methadone in the maternal rats effectively prevented these abnormalities of offspring induced by methadone. Our study clearly showed that co-administration of dextromethorphan with methadone in the maternal rats prevented the adverse effects induced by prenatal methadone exposure. It implies that dextromethorphan may have a potential to be used in combination with methadone for maintenance treatment in pregnant heroin-addicted women to prevent the adverse effects induced by methadone on offspring.
Komen, Helga; Brunt, L Michael; Deych, Elena; Blood, Jane; Kharasch, Evan D
2018-05-25
Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery. A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects. Median (interquartile range) methadone doses were 6 (5-6) and 9 (8-9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3-11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1-3.3; P < .001) but not 0.1 mg/kg methadone (5.0 mg, 3.3-8.1; P = .60). Dose-escalation ended at 0.15 mg/kg methadone. Total in-hospital nonmethadone opioid use after short-duration opioid, 0.1 mg/kg methadone, and 0.15 mg/kg methadone was 35.3 (25.0-44.0), 7.1 (3.7-10.0), and 3.3 (0.1-5.8) mg morphine equivalents, respectively (P < .001 for both versus
Methadone detoxification of tramadol dependence.
Leo, R J; Narendran, R; DeGuiseppe, B
2000-10-01
Tramadol hydrochloride is a centrally acting analgesic with a partial affinity for the opiate receptor (mu), having an analgesic potency estimated to be one tenth that of morphine. While preclinical investigations suggested that abuse liability associated with tramadol use is low, there are increasing numbers of cases reported to the U.S. Food and Drug Administration of abuse, dependence, and withdrawal associated with tramadol use. A case of a patient with tramadol dependence requiring detoxification with methadone is presented. Acute management of significant tramadol dependence has not yet been reported in the literature. Long-term treatment issues are also discussed.
Gomes, Tara; Mastorakos, Andrea; Paterson, J Michael; Sketris, Ingrid; Caetano, Patricia; Greaves, Simon; Henry, David
2017-11-22
In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population ( p < 0.01). This effect varied across Canada and was largest in Ontario (reduction of 22.8%) ( p = 0.01) and British Columbia (reduction of 30.0%) ( p = 0.01). The national rate of oxycodone dispensing fell by 46.4% after the introduction of OxyNeo ( p < 0.001); this was partially offset by an increase of 47.8% in hydromorphone dispensing ( p < 0.001). Although dispensing of immediate-release opioids was a substantial contributor to overall population opioid exposure across Canada, it was unaffected by the introduction of OxyNeo ( p > 0.05 in all provinces). The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available. Copyright 2017, Joule Inc. or its licensors.
... this type of medication for at least one week. Oxycodone is in a class of medications called ... have stopped taking them within the past two weeks: isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), ...
Methadone, Morphine, or Oxycodone in Treating Pain in Patients With Cancer
2012-11-09
Brain and Central Nervous System Tumors; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Pain; Precancerous Condition; Unspecified Adult Solid Tumor, Protocol Specific
Nosyk, Bohdan; Fischer, Benedikt; Sun, Huiying; Marsh, David C.; Kerr, Thomas; Rehm, Juergen T.; Anis, Aslam H.
2014-01-01
Background and Objectives The nonmedical use of prescription opioids (PO) has increased dramatically in North America. Special consideration for PO prescription is required for individuals in methadone maintenance treatment (MMT). Our objective is to describe the prevalence and correlates of PO use among British Columbia (BC) MMT clients from 1996-2007. Methods This study was based on a linked, population-level medication dispensation database. All individuals receiving 30 days of continuous MMT for opioid dependence were included in the study. Key measurements included the proportion of clients receiving >7 days of a PO other than methadone during MMT from 1996 to 2007. Factors independently associated with PO co-prescription during MMT were assessed using generalized linear mixed effects regression. Results 16,248 individuals with 27,919 MMT episodes at least 30 days in duration were identified for the study period. Among them, 5,552 individuals (34.2%) received a total of 290,543 PO co-prescriptions during MMT. The majority (74.3%) of all PO dispensations >7 days originated from non-MMT physicians. The number of PO prescriptions per person-year nearly doubled between 1996 and 2006, driven by increases in morphine, hydromorphone and oxycodone dispensations. PO co-prescription was positively associated with female gender, older age, higher levels of medical co-morbidity as well as higher MMT dosage, adherence, and retention. Conclusion and Scientific Significance A large proportion of MMT clients in BC received co-occurring PO prescriptions, often from physicians and pharmacies not delivering MMT. Experimental evidence for the treatment of pain in MMT clients is required to guide clinical practice. PMID:24724883
Lloyd, Renae A; Hotham, Elizabeth; Hall, Catherine; Williams, Marie; Suppiah, Vijayaprakash
2017-12-01
Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011.
Atluri, Sairam; Sudarshan, Gururau; Manchikanti, Laxmaiah
2014-01-01
The epidemic of medical use and abuse of opioid analgesics is linked to the economic burden of opioid-related abuse and fatalities in the United States. Multiple studies have estimated the extent to which prescription opioid analgesics contribute to the national drug abuse problem; studies also assessing the trends in medical use and abuse of opioid analgesics have confirmed the relationship between increasing medical use of opioids and increasing fatalities.The available data is limited until 2002. Retrospective analysis of data from 2004 to 2011 from 2 databases: Automation of Reports and Consolidated Orders System (ARCOS) for opioid use data and Drug Abuse Warning Network (DAWN) for drug misuse data. To determine the proportion of drug abuse related to opioid analgesics and the various trends in the medical use and abuse of 8 opioid analgesics commonly used to treat pain: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone. The data obtained from DAWN is a nationally representative sample of hospital emergency department admissions resulting from drug abuse. Main outcome measure was the identification of trends in the medical use and misuse of opioid analgesics from 2004 to 2011. From 2004 to 2011, there was an increase in the medical use of all opioids except for a 20% decrease in codeine. The abuse of all opioids including codeine increased during this period. Increases in medical use ranged from 2,318% for buprenorphine to 35% for fentanyl, including 140% for hydromorphone, 117% for oxycodone, 73% for hydrocodone, 64% for morphine, and 37% for methadone. The misuse increased 384% for buprenorphine with available data from 2006 to 2011, whereas from 2004 to 2011, it increased 438% for hydromorphone, 263% for oxycodone, 146% for morphine, 107% for hydrocodone, 104% for fentanyl, 82% for methadone, and 39% for codeine. Comparison of opioid use showed an overall increase of 1,448% from 1996 to 2011, with increases of
Evaluation of poly-drug use in methadone-related fatalities using segmental hair analysis.
Nielsen, Marie Katrine Klose; Johansen, Sys Stybe; Linnet, Kristian
2015-03-01
In Denmark, fatal poisoning among drug addicts is often related to methadone. The primary mechanism contributing to fatal methadone overdose is respiratory depression. Concurrent use of other central nervous system (CNS) depressants is suggested to heighten the potential for fatal methadone toxicity. Reduced tolerance due to a short-time abstinence period is also proposed to determine a risk for fatal overdose. The primary aims of this study were to investigate if concurrent use of CNS depressants or reduced tolerance were significant risk factors in methadone-related fatalities using segmental hair analysis. The study included 99 methadone-related fatalities collected in Denmark from 2008 to 2011, where both blood and hair were available. The cases were divided into three subgroups based on the cause of death; methadone poisoning (N=64), poly-drug poisoning (N=28) or methadone poisoning combined with fatal diseases (N=7). No significant differences between methadone concentrations in the subgroups were obtained in both blood and hair. The methadone blood concentrations were highly variable (0.015-5.3, median: 0.52mg/kg) and mainly within the concentration range detected in living methadone users. In hair, methadone was detected in 97 fatalities with concentrations ranging from 0.061 to 211ng/mg (median: 11ng/mg). In the remaining two cases, methadone was detected in blood but absent in hair specimens, suggesting that these two subjects were methadone-naive users. Extensive poly-drug use was observed in all three subgroups, both recently and within the last months prior to death. Especially, concurrent use of multiple benzodiazepines was prevalent among the deceased followed by the abuse of morphine, codeine, amphetamine, cannabis, cocaine and ethanol. By including quantitative segmental hair analysis, additional information on poly-drug use was obtained. Especially, 6-acetylmorphine was detected more frequently in hair specimens, indicating that regular abuse of
Treatment of severe cancer pain by low-dose continuous subcutaneous morphine.
Drexel, H; Dzien, A; Spiegel, R W; Lang, A H; Breier, C; Abbrederis, K; Patsch, J R; Braunsteiner, H
1989-02-01
In a prospective and intraindividually controlled trial, we have compared the efficacy and safety of a continuous subcutaneous morphine infusion with conventional intermittent oral or subcutaneous morphine application. Twenty-eight in-patients with cancer pain received a short-term infusion lasting 2-42 days, and 8 out-patients underwent long-term infusion from 49 to 197 days during the terminal stage of their disease. Continuous subcutaneous morphine infusion significantly (P less than 0.001) improved both pain and quality of life when compared to conventional morphine application. With continuous infusion, 5-48 mg (median 19 mg) of morphine was required daily, significantly (P less than 0.001) less than the 10-90 mg (median 50 mg) necessary with conventional use. As a result of lower dosage, side effects under continuous infusion were infrequent and mild. Constipation occurred in 3 of the 36 patients and was always controlled by the addition of laxatives; no nausea, sedation or respiratory depression were observed. Signs of tolerance developed in 2 patients on long-term infusion, but the use of continuous subcutaneous methadone for 2 weeks reversed the tolerance. The study presented indicates that low-dose continuous subcutaneous morphine provides a valuable treatment modality for severe terminal cancer pain exhibiting a high degree of both efficacy and safety.
Morphine Tolerance as a Function of Ratio Schedule: Response Requirement or Unit Price?
ERIC Educational Resources Information Center
Hughes, Christine; Sigmon, Stacey C.; Pitts, Raymond C.; Dykstra, Linda A.
2005-01-01
Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, "l"-methadone, and cocaine dose-dependently decreased…
An evaluation of the histological effects of intra-articular methadone in the canine model.
Jones, Timothy A; Hand, Walter R; Ports, Michael D; Unger, Daniel V; Herbert, Daniel; Pellegrini, Joseph E
2003-02-01
Methadone hydrochloride is an opiate that has pharmacodynamic and pharmacokinetic properties that suggest it may provide longer analgesia than morphine when administered via the intra-articular route. However, no studies to date have been conducted examining the effects of intra-articular methadone hydrochloride on local tissues. Therefore, the purpose of this study was to determine the histopathologic effects of intra-articular methadone hydrochloride on local tissues in the canine knee. Nine canines, 1 to 4 years old, weighing between 20 kg and 23 kg were used. All canines had their knees randomized to receive either bupivacaine, 0.5% with epinephrine 1:200,000 (4.5 mL), and 5 mg methadone hydrochloride (0.5 mL) for the study knee, or bupivacaine, 0.5% with epinephrine 1:200,000 (4.5 mL), and 0.5 mL normal saline for the control knee. Serum methadone hydrochloride levels were obtained on all canines at 6 and 24 hours. Canines were randomly assigned to 1 of 3 groups to be euthanized at either 24 hours, 14 days, or 28 days. Following euthanization and necropsy, synovial fluid levels and tissue samples were obtained and examined for histopathologic changes. Synovial fluid samples noted a few white blood cells at 24 hours and none at 14 and 28 days. Tissue samples showed no histopathologic changes, and serum concentration levels of methadone hydrochloride were negligible.
Use of Oxycodone in Pain Management
Moradi, Mohammad; Esmaeili, Sara; Shoar, Saeed; Safari, Saeid
2012-01-01
Oxycodone is widely used to alleviate moderate-to severe acute pain, It is an effective analgesic for many types of pain, and is especially useful for paroxysmal spontaneous pain, steady pain, allodynia associated with postherpetic neuralgia, and it is also increasingly used in the management of cancer-related and chronic pain, oxycodone has been found to improve the quality of life of patients with many types of pain. In 2011, following chemical and physical manipulation, an extended-release form of oxycodone was developed in order to maintain its rate-controlling mechanism. This new formulation significantly improved analgesia among patients with moderate-to-severe chronic osteoarthritis pain with an adverse event profile similar to that of other opioids. The long-term safety and efficacy of extended-release form of oxycodone in relieving moderate-to-severe chronic pain has been demonstrated. In this study we discussed about different aspects of this drug in managing of various types of pain. PMID:24904812
Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band
2015-02-25
Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong
2015-01-01
Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT. PMID:25716777
Gaalema, Diann E.; Scott, Teresa Linares; Heil, Sarah H.; Coyle, Mara G.; Kaltenbach, Karol; Badger, Gary J.; Arria, Amelia M.; Stine, Susan M.; Martin, Peter R.; Jones, Hendrée E.
2014-01-01
Aims To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine-exposed infants. Design, setting and participants Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined. Measurements For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (methadone = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition. Findings Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine-exposed infants (36 versus 59 hours postnatal, respectively). Conclusions The profile of neonatal abstinence syndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal
Ethanol Reversal of Oxycodone Tolerance in Dorsal Root Ganglia Neurons.
Jacob, Joanna C; Sakakibara, Kensuke; Mischel, Ryan A; Henderson, Graeme; Dewey, William L; Akbarali, Hamid I
2018-05-01
Oxycodone is a semisynthetic opioid compound that is widely prescribed, used, and abused today, and has a well-established role in shaping the current opioid epidemic. Previously, we have shown that tolerance develops to the antinociceptive and respiratory depressive effects of oxycodone in mice, and that a moderate dose of acute ethanol or a protein kinase C (PKC) inhibitor reversed that tolerance. To investigate further if tolerance was occurring through neuronal mechanisms, our aims for this study were to assess the effects of acute and prolonged oxycodone in isolated dorsal root ganglia (DRG) neurons and to determine if this tolerance was reversed by either ethanol or a PKC inhibitor. We found that an acute exposure to 3 μ M oxycodone reduced neuronal excitability, as measured by increased threshold potentials and reduced action potential amplitude, without eliciting measurable changes in resting membrane potential. Exposure to 10 μ M oxycodone for 18-24 hours prevented oxycodone's effect on neuronal excitability, indicative of tolerance development. The development of opioid tolerance was mitigated in DRG neurons from β -arrestin 2 knockout mice. Oxycodone tolerance was reversed in isolated DRG neurons by the acute application of either ethanol (20 mM) or the PKC inhibitor, bisindolylmaleimide XI hydrochloride (Bis XI), when a challenge of 3 µ M oxycodone significantly reduced neuronal excitability following prolonged exposure. Through these studies, we concluded that oxycodone acutely reduced neuronal excitability, tolerance developed to this effect, and reversal of that tolerance occurred at the level of a single neuron, suggesting that reversal of oxycodone tolerance by either ethanol or Bis XI involves cellular mechanisms. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
Increasing deaths involving oxycodone, Victoria, Australia, 2000-09.
Rintoul, Angela C; Dobbin, Malcolm D H; Drummer, Olaf H; Ozanne-Smith, Joan
2011-08-01
In light of an emerging epidemic identified in the United States and Canada, to identify trends in fatal drug toxicity involving oxycodone and the demographic characteristics and indicators of socioeconomic disadvantage of the deceased. Population-based observational study in Victoria, Australia. Decedents whose death was reported to the Victorian Coroner between 2000 and 2009 and where oxycodone was detected. Association between supply of oxycodone and deaths. Demographic characteristics of decedents. Rate ratios of the rural or metropolitan location and socioeconomic indicators of disadvantage of the deceased. Supply to Victoria has increased nine-fold from 7.5 mg per capita in 2000 to 67.5 mg per capita in 2009. Detection of oxycodone in deaths reported to the Victorian Coroner has increased from 4 (0.08/100,000 population) in 2000 to 97 (1.78/100,000 population) in 2009-a 21-fold increase in deaths. Of the 320 cases described, 53.8% (172) were the result of drug toxicity. Of these, 52.3% were unintentional and 19.8% intentional self-harm; the remaining 27.9% are either still under investigation by the coroner or intent is unknown. Drug toxicity deaths were overrepresented in both rural areas and areas indexed with high levels of disadvantage. The substantial increase in the number of deaths involving oxycodone is strongly and significantly associated with the increase in supply. Most drug toxicity deaths involving oxycodone were unintentional. This newly identified trend in fatalities in Victoria supports concerns that a pattern of increasing deaths involving oxycodone is emerging globally.
de Castro, Ana; Concheiro, Marta; Shakleya, Diaa M.; Huestis, Marilyn A.
2011-01-01
A validated method for quantifying methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, cocaine, benzoylecgonine, 6-acetylmorphine, morphine, and codeine in human placenta by liquid chromatography–ion trap mass spectrometry is described. Specimens (1 g) were homogenized and subjected to solid-phase extraction. Chromatographic separation was performed on a Synergi Polar RP column with a gradient of 0.1% formic acid and acetonitrile. The method was linear from 10 to 2000 ng/g for methadone and 2.5 to 500 ng/g for other analytes. Limits of detection were 0.25–2.5 ng/g, imprecisions < 9.1%CV, analytical recoveries 84.4–113.3%, extraction efficiencies > 46%, matrix effects −8.0–129.9%, and process efficiencies 24.2–201.0%. Method applicability was demonstrated by analysis of five placenta specimens from opioid-dependent women receiving methadone pharmacotherapy, with methadone doses ranging from 65 to 95 mg on the day of delivery. These are the first data on placenta concentrations of methadone and metabolites after controlled drug administration. Detection of other common drugs of abuse in placenta will also improve our knowledge of the usefulness of this matrix for detecting in utero drug exposure and studying disposition of drugs in the maternal-fetal dyad. PMID:19671243
A fatal drug interaction between oxycodone and clonazepam.
Burrows, David L; Hagardorn, Andrea N; Harlan, Gretel C; Wallen, Ellen D B; Ferslew, Kenneth E
2003-05-01
A case is presented of a fatal drug interaction caused by ingestion of oxycodone (Oxycontin) and clonazepam (Klonapin). Oxycodone is an opium alkaloid used in long-term pain management therapy. Clonazepam is a benzodiazepine used for the treatment of seizures and panic disorders. The Drug Abuse Warning Network (DAWN) has reported an increase of 108% in the last two years of emergency department episodes related to Oxycontin. Six billion prescriptions were written for Oxycontin in the year 2000, an 18-fold increase from four years previous (1). Oxycontin has recently gained enormous notoriety at the local and national levels; however, there are very few previously documented cases of lethal drug interactions between oxycodone and clonazepam. Synergistic effects between these two drugs are postulated to arise from different agonistic mechanisms producing similar physiological changes. It is also theorized that clonazepam may inhibit the metabolism of oxycodone. A 38-year-old white female was found dead in Jefferson County, Tennessee in March of 2001. The deceased had physical evidence of previous drug abuse and positive serological findings of hepatitis B and C. Prescription pill bottles filled under the name of the deceased, as well as another name, were found with the body. Serum, urine and gastric contents from the deceased were screened for numerous drugs and metabolites using a combination of thin layer chromatography and immunoassay techniques (EMIT and FPIA). Analysis of biological specimens from the deceased revealed the presence of: benzodiazepines, opiates (oxycodone), and trazodone metabolites in the serum; cannabinoids, benzodiazepines, opiates (oxycodone), trazodone, trazodone metabolites, nicotine, and nicotine metabolite in the urine; and benzodiazepines, opiates (oxycodone), nicotine, and nicotine metabolite in the gastric contents. Quantitative analyses for clonazepam was performed by high performance liquid chromatography (HPLC) and revealed a
Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A; Yoburn, Byron C
2007-06-01
It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal mu-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine>morphine>oxycodone. Other mice were infused for 7 days with oxycodone (10-150 mg/kg/day, s.c.) or etorphine (50-250 microg/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with
Favretto, Donata; Tucci, Marianna; Monaldi, Alice; Ferrara, Santo Davide; Miolo, Giorgia
2014-06-01
The drug content of hair may be affected by washing, chemical or thermal treatments, the use of cosmetics, or exposure to the environment. Knowledge concerning the effect of natural or artificial light on drug content in hair can be helpful to the forensic toxicologist, in particular when investigating drug concentrations above or below pre-determined cut-offs. The photodegradation of methadone and its metabolite, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was studied in authentic positive hair samples by comparing drug concentrations determined by liquid chromatrography-high resolution mass spectrometry before and after exposure to UVB light (in vivo study). The same approach was applied in order to investigate the light sensitivity of opiates (6-monoacetylmorphine and morphine) and cocainics (cocaine and benzoylecgonine) in true positive hair. The yields of photodegradation were calculated for each drug class in eight different positive hair samples irradiated by UVB at 300 J/cm(2) obtaining averages, ranges and standard deviations. In parallel, the photostability of all the compounds as 10(-5) -10(-4) M standard solutions in methanol were examined by means of UVB light irradiation in the range 0-100 J/cm(2) followed by UV/Vis spectroscopic analysis and direct infusion electrospray ionization-high resolution mass spectrometry (in vitro study). In hair, methadone was shown to be significantly affected by light (photodegradation of 55% on average), while its metabolite EDDP proved to be more photostable (17%). 6-monoacetylmorphine, morphine, benzoylecgonine, and cocaine were more photostable than methadone in vivo (on average, 21%, 17%, 20%, and 11% of degradation, respectively). When irradiated in standard solutions, the target molecules exhibited a larger photodegradation than in vivo with the exception of cocaine (photodegradation for methadone up to 70%, 6-monoacetylmorphine and morphine up to 90%, benzoylecgonine up to 67%, cocaine up to 15
Zosel, Amy; Bartelson, Becki Bucher; Bailey, Elise; Lowenstein, Steven; Dart, Rick
2013-01-01
Objective To describe the characteristics and health effects of adolescent (age 13–19 years) prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS®) System. Method Secondary analysis of data collected from RADARS System participating poison centers was performed. Data for all intentional exposures from 2007 through 2009 were used to describe adolescent prescription opioid (oxycodone, fentanyl, hydrocodone, hydromorphone, morphine, methadone, buprenorphine, and tramadol) and stimulant (methylphenidate and amphetamines) exposures. Results A total of 16,209 intentional adolescent exposures to prescription drugs were identified, 68% to opioids and 32% to stimulants. The mean age was 16.6 years (SD ± 1.7 years). Slightly more than half (52.4%) of drug mentions involved females. The five most frequently misused or abused drugs were hydrocodone (32%), amphetamines (18%), oxycodone (15%), methylphenidate (14%), and tramadol (11%). Of all exposures, 38%were classified as suspected suicidal. Of adolescents who intentionally exposed themselves to prescription drugs, 30% were treated in a health care facility, 2,792 of whom were admitted to the hospital, including 1,293 to the intensive care unit. A total of 17.2% of intentional exposures were associated with no effect, 38.9% minor effects, 23.3% moderate effects, 3.6% major effects, and 0.1% were associated with death. Oxycodone and methadone were associated with the most deaths. No deaths were associated with exposures to stimulants. Conclusions Prescription drug misuse and abuse poses an important health problem and results in thousands of hospitalizations of adolescents per year. Further work is needed to develop focused interventions and educational programs to prevent prescription drug abuse and misuse by adolescents. PMID:23357446
Fields, Marcia D.; Abate, Marie A.; Hu, Lan; Long, D. Leann; Blommel, Matthew L.; Haikal, Nabila A.; Kraner, James C.
2016-01-01
Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl-, hydrocodone-, methadone-, or oxycodone-related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co-intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored. PMID:26223761
Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval.
Ansermot, Nicolas; Albayrak, Ozgür; Schläpfer, Jürg; Crettol, Séverine; Croquette-Krokar, Marina; Bourquin, Michel; Déglon, Jean-Jacques; Faouzi, Mohamed; Scherbaum, Norbert; Eap, Chin B
2010-03-22
Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias. To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken. The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of -3.9 ms (95% confidence interval [CI], -7.7 to -0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006). Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.
Population pharmacokinetics of oxycodone in patients with cancer-related pain.
Komatsu, Toshiaki; Kokubun, Hideya; Suzuki, Ai; Takayanagi, Risa; Yamada, Yasuhiko; Matoba, Motohiro; Yago, Kazuo
2012-09-01
Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.
Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice.
Yang, Pao-Pao; Yeh, Geng-Chang; Huang, Eagle Yi-Kung; Law, Ping-Yee; Loh, Horace H; Tao, Pao-Luh
2015-09-22
Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model. Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone. The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.
Peacock, Amy; Degenhardt, Louisa; Hordern, Antonia; Larance, Briony; Cama, Elena; White, Nancy; Kihas, Ivana; Bruno, Raimondo
2015-12-01
In April 2014, a tamper-resistant controlled-release oxycodone formulation was introduced into the Australian market. This study aimed to identify the level and methods of tampering with reformulated oxycodone, demographic and clinical characteristics of those who reported tampering with reformulated oxycodone, and perceived attractiveness of original and reformulated oxycodone for misuse (via tampering). A prospective cohort of 522 people who regularly tampered with pharmaceutical opioids and had tampered with the original oxycodone product in their lifetime completed two interviews before (January-March 2014: Wave 1) and after (May-August 2014: Wave 2) introduction of reformulated oxycodone. Four-fifths (81%) had tampered with the original oxycodone formulation in the month prior to Wave 1; use and attempted tampering with reformulated oxycodone amongst the sample was comparatively low at Wave 2 (29% and 19%, respectively). Reformulated oxycodone was primarily swallowed (15%), with low levels of recent successful injection (6%), chewing (2%), drinking/dissolving (1%), and smoking (<1%). Participants who tampered with original and reformulated oxycodone were socio-demographically and clinically similar to those who had only tampered with the original formulation, except the former were more likely to report prescribed oxycodone use and stealing pharmaceutical opioid, and less likely to report moderate/severe anxiety. There was significant diversity in the methods for tampering, with attempts predominantly prompted by self-experimentation (rather than informed by word-of-mouth or the internet). Participants rated reformulated oxycodone as more difficult to prepare and inject and less pleasant to use compared to the original formulation. Current findings suggest that the introduction of the tamper-resistant product has been successful at reducing, although not necessarily eliminating, tampering with the controlled-release oxycodone formulation, with lower
Hashimoto, Keisuke; Amano, Taku; Kasakura, Akiko; Uhl, George R; Sora, Ichiro; Sakai, Norio; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru
2009-03-27
Most reports in the literature have shown that the effects of opioid analgesics are primarily mediated by mu-opioid receptor (MOR), whereas other potential targets of opioid analgesics have not been thoroughly characterized. In this study, we found that extracellular application of morphine, fentanyl or oxycodone, which are all considered to be MOR agonists, at relatively high concentrations, but not endogenous mu-opioid peptides, produced a concentration-dependent suppression of sodium currents in cultured thalamic neurons. These effects of opioids were not affected by either a MOR antagonist naloxone or a deletion of MOR gene. Among these opioids, fentanyl strongly suppressed sodium currents to the same degree as lidocaine, and both morphine and oxycodone slightly but significantly reduced sodium currents when they were present extracellularly. In contrast, the intracellular application of morphine, but not oxycodone, fentanyl or lidocaine, reduced sodium currents. These results suggest that morphine, fentanyl and oxycodone each produce the MOR-independent suppression of sodium currents by distinct mechanisms in thalamic neurons.
Monteiro, Eduardo Raposo; Junior, Adolfo Rodrigues; Assis, Hemir Martins Quirilos; Campagnol, Daniela; Quitzan, Juliany Gomes
2009-01-01
To compare the effects of morphine (MOR), methadone (MET), butorphanol (BUT) and tramadol (TRA), in combination with acepromazine, on sedation, cardiorespiratory variables, body temperature and incidence of emesis in dogs. Prospective randomized, blinded, experimental trial. Six adult mixed-breed male dogs weighing 12.0 +/- 4.3 kg. Dogs received intravenous administration (IV) of acepromazine (0.05 mg kg(-1)) and 15 minutes later, one of four opioids was randomly administered IV in a cross-over design, with at least 1-week intervals. Dogs then received MOR 0.5 mg kg(-1); MET 0.5 mg kg(-1); BUT 0.15 mg kg(-1); or TRA 2.0 mg kg(-1). Indirect systolic arterial pressure (SAP), heart rate (HR), respiratory rate (f(R)), rectal temperature, pedal withdrawal reflex and sedation were evaluated at regular intervals for 90 minutes. Acepromazine administration decreased SAP, HR and temperature and produced mild sedation. All opioids further decreased temperature and MOR, BUT and TRA were associated with further decreases in HR. Tramadol decreased SAP whereas BUT decreased f(R) compared with values before opioid administration. Retching was observed in five of six dogs and vomiting occurred in one dog in MOR, but not in any dog in the remaining treatments. Sedation scores were greater in MET followed by MOR and BUT. Tramadol was associated with minor changes in sedation produced by acepromazine alone. When used with acepromazine, MET appears to provide better sedation than MOR, BUT and TRA. If vomiting is to be avoided, MET, BUT and TRA may be better options than MOR.
Setnik, Beatrice; Schoedel, Kerri; Bartlett, Cindy; Dick, Chris; Hakim, Nasrat; Geoffroy, Pierre
To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose. Single site in Canada (INC Research Toronto). Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30mg/3mg). Peak effect (E max ) for bipolar Drug Liking (0-100 point visual analog scale). Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking E max relative to placebo. Significant reductions (p<0.001) in median Drug Liking [E max ] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower E max for IN ELI-200 (p<0.001) compared to IN oxycodone IR. IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.
Maternal Methadone Dose, Placental Methadone Concentrations, and Neonatal Outcomes
de Castro, Ana; Jones, Hendreé E.; Johnson, Rolley E.; Gray, Teresa R.; Shakleya, Diaa M.; Huestis, Marilyn A.
2015-01-01
BACKGROUND Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs. METHODS We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation. RESULTS Positive correlations were found between placental methadone and EDDP concentrations (r = 0.685), and between methadone concentration and methadone dose at delivery (r = 0.542), mean daily dose (r = 0.554), mean third-trimester dose (r = 0.591), and cumulative daily dose (r = 0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r = 0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r = 0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r = 0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta. CONCLUSIONS Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed. PMID:21245372
Chhabra, Shalini; Bull, Janet
2008-01-01
Methadone hydrochloride is an old drug that has been in vogue off and on. It has complex pharmacodynamics and can be potentially fatal in inexperienced settings. Drug switching from an opioid to methadone or vice versa requires knowledge of equianalgesic dosing. It is critical when using the drug to monitor for signs and symptoms of toxicity so that overdosing or toxicity can be identified in a timely manner. This review discusses these important topics so that methadone can be used safely and effectively.
Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients
Foster, David J R; Somogyi, Andrew A; Dyer, Kyle R; White, Jason M; Bochner, Felix
2000-01-01
Aims To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma α1-acid glycoprotein concentrations were quantified by radial immunoassay. Results (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCτSS, (167%) was significantly (P < 0.001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCτSS, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to
Cholestatic hepatitis as a possible new side-effect of oxycodone: a case report
Ho, Vincent; Stewart, Maxwell; Boyd, Peter
2008-01-01
Introduction Oxycodone is a widely-used semisynthetic opioid analgesic that has been used for over eighty years. Oxycodone is known to cause side effects such as nausea, pruritus, dizziness, constipation and somnolence. As far as we are aware cholestatic hepatitis as a result of oxycodone use has not been reported so far in the world literature. Case presentation A 34-year-old male presented with cholestatic jaundice and severe pruritus after receiving oxycodone for analgesia post-T11 vertebrectomy. Extensive laboratory investigations and imaging studies did not reveal any other obvious cause for his jaundice and a liver biopsy confirmed canalicular cholestatis suggestive of drug-induced hepatotoxicity. The patient's symptoms and transaminases normalised on withdrawal of oxycodone confirming that oxycodone was the probable cause of the patient's hepatotoxicity. Conclusion We conclude that cholestatic hepatitis is possibly a rare side effect of oxycodone use. Physicians should be aware of the possibility of this potentially serious picture of drug-induced hepatotoxicity. PMID:18452597
Choice between delayed food and immediate oxycodone in rats.
Secci, Maria E; Factor, Julie A; Schindler, Charles W; Panlilio, Leigh V
2016-12-01
The choice to seek immediate drug effects instead of more meaningful but delayed rewards is a defining feature of addiction. To develop a rodent model of this behavior, we allowed rats to choose between immediate intravenous delivery of the prescription opioid oxycodone (50 μg/kg) and delayed delivery of palatable food pellets. Rats preferred food at delays up to 30 s, but they chose oxycodone and food equally at 60-s delay and preferred oxycodone over food at 120-s delay. Comparison of food-drug choice, food-only, and drug-only conditions indicated that food availability decreased drug intake, but drug availability increased food intake. In the food-only condition, food was effective as a reinforcer even when delayed by 120 s. Pre-session feeding with chow slowed acquisition of food and drug self-administration, but did not affect choice. To establish procedures for testing potential anti-addiction medications, noncontingent pre-treatment with oxycodone or naltrexone (analogous to substitution and antagonist therapies, respectively) were tested on a baseline in which oxycodone was preferred over delayed food. Naltrexone pre-treatment decreased drug intake and increased food intake. Oxycodone pre-treatment decreased drug intake, but also produced extended periods with no food or drug responding. These findings show that the contingencies that induce preference for drugs over more meaningful but less immediate rewards in humans can be modeled in rodents, and they suggest that the model could be useful for assessing the therapeutic potential of treatments and exploring the underlying behavioral and neural mechanisms involved in addiction.
Choice between delayed food and immediate oxycodone in rats
Secci, Maria E.; Factor, Julie A.; Schindler, Charles W.; Panlilio, Leigh V.
2016-01-01
Rationale The choice to seek immediate drug effects instead of more meaningful but delayed rewards is a defining feature of addiction. Objectives To develop a rodent model of this behavior, we allowed rats to choose between immediate intravenous delivery of the prescription opioid oxycodone (50 μg/kg) and delayed delivery of palatable food pellets. Results Rats preferred food at delays up to 30 s, but they chose oxycodone and food equally at 60-s delay and preferred oxycodone over food at 120-s delay. Comparison of food-drug choice, food-only, and drug-only conditions indicated that food availability decreased drug intake, but drug availability increased food intake. In the food-only condition, food was effective as a reinforcer even when delayed by 120 s. Pre-session feeding with chow slowed acquisition of food and drug self-administration, but did not affect choice. To establish procedures for testing potential anti-addiction medications, noncontingent pretreatment with oxycodone or naltrexone (analogous to substitution and antagonist therapies, respectively) were tested on a baseline in which oxycodone was preferred over delayed food. Naltrexone pretreatment decreased drug intake and increased food intake. Oxycodone pretreatment decreased drug intake, but also produced extended periods with no food or drug responding. Conclusions These findings show that the contingencies that induce preference for drugs over more meaningful but less immediate rewards in humans can be modeled in rodents, and they suggest that the model could be useful for assessing the therapeutic potential of treatments and exploring the underlying behavioral and neural mechanisms involved in addiction. PMID:27678551
Goeree, Ron; Goeree, Jeff
2016-01-01
Approximately 20-30% of Canadians suffer from chronic pain. Guidelines for the management of chronic pain support the use of controlled-release (CR) opioids to treat chronic pain. Although effective in managing chronic pain, oxycodone is associated with high rates of opioid-induced constipation (OIC). The cost-effectiveness of a combination of oxycodone for the management of pain and naloxone for the relief of OIC has not previously been evaluated for Canada. A decision analytic model was developed to estimate the cost-utility of combination oxycodone/naloxone compared to oxycodone alone in four populations. Drug costs for managing pain and healthcare costs related to managing OIC were included in the analysis and the primary measure of effectiveness was quality adjusted life years (QALYs) derived from OIC rates observed in clinical trials. The analysis was conducted from a healthcare system perspective, used a 1-year time horizon, and results were expressed in 2015 Canadian dollars. In all four patient populations, there was a trade-off between slightly higher total expected costs for Targin treated patients compared to oxycodone treated patients, but also improved clinical benefits in terms of reduced OIC, which resulted in higher QALYs for patients. Although analgesic costs were found to be slightly higher for Targin treated patients, Targin also resulted in cost offsets to the healthcare system in terms of less rescue laxative drug use and other resources required for the management of OIC. The resulting 1-year cost-utility of Targin compared to oxycodone ranged from $2178-$7732 per QALY gained in the base case analysis, and it was found that these cost-utility results remained robust and at low values throughout a series of one-way deterministic analyses of uncertainty. The clinical effectiveness of oxycodone/naloxone in managing pain and OIC compared to CR oxycodone alone resulted in low cost-utility estimates.
Zosel, Amy; Bartelson, Becki Bucher; Bailey, Elise; Lowenstein, Steven; Dart, Rick
2013-02-01
To describe the characteristics and health effects of adolescent (age 13-19 years) prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS(®)) System. Secondary analysis of data collected from RADARS System participating poison centers was performed. Data for all intentional exposures from 2007 through 2009 were used to describe adolescent prescription opioid (oxycodone, fentanyl, hydrocodone, hydromorphone, morphine, methadone, buprenorphine, and tramadol) and stimulant (methylphenidate and amphetamines) exposures. A total of 16,209 intentional adolescent exposures to prescription drugs were identified, 68% to opioids and 32% to stimulants. The mean age was 16.6 years (SD ± 1.7 years). Slightly more than half (52.4%) of drug mentions involved females. The five most frequently misused or abused drugs were hydrocodone (32%), amphetamines (18%), oxycodone (15%), methylphenidate (14%), and tramadol (11%). Of all exposures, 38% were classified as suspected suicidal. Of adolescents who intentionally exposed themselves to prescription drugs, 30% were treated in a health care facility, 2,792 of whom were admitted to the hospital, including 1,293 to the intensive care unit. A total of 17.2% of intentional exposures were associated with no effect, 38.9% minor effects, 23.3% moderate effects, 3.6% major effects, and 0.1% were associated with death. Oxycodone and methadone were associated with the most deaths. No deaths were associated with exposures to stimulants. Prescription drug misuse and abuse poses an important health problem and results in thousands of hospitalizations of adolescents per year. Further work is needed to develop focused interventions and educational programs to prevent prescription drug abuse and misuse by adolescents. Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
Setnik, Beatrice; Roland, Carl L; Sommerville, Kenneth W; Pixton, Glenn C; Berke, Robert; Calkins, Anne; Goli, Veeraindar
2015-01-01
To evaluate the conversion of opioid-experienced patients with chronic moderate-to-severe pain to extended-release morphine sulfate with sequestered naltrexone hydrochloride (MSN) using a standardized conversion guide. This open-label, single-arm study was conducted in 157 primary care centers in the United States. A total of 684 opioid-experienced adults with chronic moderate-to-severe pain were converted to oral administration of MSN from transdermal fentanyl and oral formulations of hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and other morphine products using a standardized conversion guide. The primary endpoint was the percentage of patients achieving a stable MSN dose within a 6-week titration phase. Secondary endpoints included duration of time to stable dose, number of titration steps, safety and efficacy measures, and investigator assessment of conversion guide utility. Of the 684 patients, 51.3% were converted to a stable dose of MSN (95% confidence interval: 47.5%, 55.1%). The mean (standard deviation) number of days to stable dose was 20 (8.94), and number of titration steps to stable dose was 2.4 (1.37). The majority of adverse events were mild/moderate and consistent with opioid therapy. Mean pain scores at stable dose decreased from baseline. Investigators were generally satisfied with the conversion guide and, in 94% of cases, reported they would use it again. Conversion to MSN treatment using the standardized MSN conversion guide was an attainable goal in approximately half of the population of opioid-experienced patients with chronic moderate-to-severe pain. Investigators found the guide to be a useful tool to assist conversion of opioid-experienced patients to MSN.
Lejeune, Claude; Simmat-Durand, Laurence; Gourarier, Laurent; Aubisson, Sandrine
2006-05-20
Specialized prenatal care and substitution programs improve the perinatal prognoses of pregnant drug-abusers and their infants. Although methadone is well documented, little is known about high-dose buprenorphine (HDB). This prospective, multicenter (n = 35) observational study included 259 women on maintenance during pregnancy: 39% on methadone and 61% on HDB. Major findings were: 46% of them received good prenatal care; 62% had peridural analgesia; 12.3% delivered prematurely (<37 weeks); mean gestational age, 38.6 weeks; mean birth weight, 2822g. Three-quarters of the newborns developed neonatal abstinence syndrome (NAS) beginning at a mean age of 40h, with the mean maximum Lipsitz score of 9.1 at 72 h; half of them were treated, mainly with morphine hydrochloride. No baby died. Newborns were discharged with their mothers (96%) or placed in foster care (4%). Comparing methadone with HDB, respectively, mean age at the maximum Lipsitz score was 81 h versus 66 h (P = 0.066). The perinatal medical and social prognoses for these 259 drug addicts and their infants appeared to be improved by specialized prenatal care and was similar for methadone or BHD substitution during pregnancy.
Lorcaserin suppresses oxycodone self-administration and relapse vulnerability in rats
Neelakantan, Harshini; Holliday, Erica D.; Fox, Robert G.; Stutz, Sonja J.; Comer, Sandra D.; Haney, Margaret; Anastasio, Noelle C.; Moeller, F. Gerard; Cunningham, Kathryn A.
2017-01-01
Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses (“cue reactivity”) that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT2C receptor (5-HT2CR), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT2CR agonist lorcaserin, which is FDA-approved for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT2CR antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex (“cue reactivity”) previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25–1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD. PMID:28107783
Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats.
Neelakantan, Harshini; Holliday, Erica D; Fox, Robert G; Stutz, Sonja J; Comer, Sandra D; Haney, Margaret; Anastasio, Noelle C; Moeller, F Gerard; Cunningham, Kathryn A
2017-05-17
Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses ("cue reactivity") that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT 2C receptor (5-HT 2C R), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT 2C R agonist lorcaserin, which is approved by the United States Food and Drug Administration (FDA) for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT 2C R antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex ("cue reactivity") previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25-1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD.
Comparison of opioid doctor shopping for tapentadol and oxycodone: a cohort study.
Cepeda, M Soledad; Fife, Daniel; Vo, Lien; Mastrogiovanni, Gregory; Yuan, Yingli
2013-02-01
Obtaining opioids from multiple prescribers, known as doctor shopping, is 1 example of opioid abuse and diversion. The dual mechanism of action of tapentadol could make tapentadol less likely to be abused than other opioids. The aim of this retrospective cohort study was to compare the risk of shopping behavior between tapentadol immediate release (IR) and oxycodone IR. Subjects exposed to tapentadol or oxycodone with no recent opioid use were included and followed for 1 year. The primary outcome was the proportion of subjects who developed shopping behavior defined as subjects who had opioid prescriptions written by >1 prescriber with ≥1 day of overlap filled at ≥3 pharmacies. The opioids involved in the shopping episodes were assessed. A total of 112,821 subjects were exposed to oxycodone and 42,940 to tapentadol. Shopping behavior was seen in .8% of the subjects in the oxycodone group and in .2% of the subjects in the tapentadol group, for an adjusted odds ratio of 3.5 (95% confidence interval, 2.8 to 4.4). In the oxycodone group, 28.0% of the shopping events involved exclusively oxycodone, whereas in the tapentadol group, .6% of the shopping events involved exclusively tapentadol. Results suggest that the risk of shopping behavior is substantially lower with tapentadol than with oxycodone. The risk of opioid doctor shopping, ie, obtaining opioid prescriptions from multiple prescribers, is lower with tapentadol than with oxycodone. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.
Russell-Taylor, W J
1975-07-01
Management of heroin addiction with oral methadone continues to create controversy. Since the first Dole-Nyswander experiments were reported almost a decade ago, methadone maintenance programs have been started in every major city in North America at an estimated public cost in the hundreds of millions of tax dollars. By the end of 1972, the United States alone spending at an annual rate in excess of $250 million, and an expenditure rate in excess of one billion dollars was occurring by the end of 1973. Despite the FDA investigational New Drug status of methadone when used for this purpose, objective data have still not been generated to substantiate the worth of Narcotic Substitution Therapy. Iatrogenic consequences are on the increase, and scepticism is growing among most pharmacologists. A critical evaluation of the entire methadone maintenance approach is being advocated by many and being attempted by some. Data currently being generated at the Philadelphia General Hospital suggest that many patients may have been better managed without methadone.
Layson-Wolf, Cherokee; Goode, Jean-Venable; Small, Ralph E
2002-01-01
Methadone hydrochloride is a mu-opioid agonist that has been used for the treatment of pain and for the management and maintenance of opioid withdrawal for over 50 years. Several characteristics make methadone a useful drug. However, these same characteristics and wide interpatient variability can make methadone difficult to use safely. A MEDLINE search was conducted on publications between January 1996 and May 2001 to identify literature relevant to this subject. Those publications were reviewed, and from them, other literature was identified and reviewed. Published studies demonstrate methadone's efficacy in pain management and in opioid withdrawal. However, interpatient variability in pharmacokinetic variables of methadone produces difficulties in developing guidelines for methadone use. Clinicians should not be deterred from use of this drug which has been shown to benefit patients in both pain management and methadone maintenance, but an individualized patient approach must be taken to use methadone safely.
Barratt, Daniel T; Coller, Janet K; Hallinan, Richard; Byrne, Andrew; White, Jason M; Foster, David JR; Somogyi, Andrew A
2012-01-01
Background: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. Methods: Opioid-dependent subjects (n = 119) maintained on methadone (15–300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (Ctrough) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and Ctrough (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher Ctrough than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or Ctrough without taking into account confounding genetic variability at the other locus. Therefore, two
A morphine/heroin vaccine with new hapten design attenuates behavioral effects in rats.
Li, Qian-Qian; Luo, Yi-Xiao; Sun, Cheng-Yu; Xue, Yan-Xue; Zhu, Wei-Li; Shi, Hai-Shui; Zhai, Hai-Feng; Shi, Jie; Lu, Lin
2011-12-01
Heroin use has seriously threatened public heath in many countries, but the existing therapies continue to have many limitations. Recently, immunotherapy has shown efficacy in some clinical studies, including vaccines against nicotine and cocaine, but no opioid vaccines have been introduced in clinical studies. The development of a novel opioid antigen designed specifically for the prevention of heroin addiction is necessary. A morphine-keyhole limpet hemocyanin conjugate was prepared and administered subcutaneously in rats. Antibody titers in plasma were measured using an enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess the selectivity of the antibodies. Dopamine concentrations in the nucleus accumbens in rats after vaccine administration were determined by high-performance liquid chromatography with electrochemical detection. The effects of the vaccine on the heroin-primed restatement of self-administration and locomotor sensitization were evaluated. A novel hapten, 6-glutarylmorphine, was produced, and the vaccine generated a high antibody titer response. This vaccine displayed specificity for both morphine and heroin, but the anti-morphine antibodies could not recognize dissimilar therapeutic opioid compounds, such as buprenorphine, methadone, naloxone, naltrexone, codeine, and nalorphine. The morphine antibody significantly decreased morphine-induced locomotor activity in rats after immunization. Importantly, rats immunized with this vaccine did not exhibit heroin-primed reinstatement of heroin seeking when antibody levels were sufficiently high. The vaccine reduced dopamine levels in the nucleus accumbens after morphine administration, which is consistent with its behavioral effects. These results suggest that immunization with a novel vaccine is an effective means of inducing a morphine-specific antibody response that is able to attenuate the behavioral and psychoactive effects of heroin. © 2011 The Authors. Journal of
Krizman-Matasic, Ivona; Kostanjevecki, Petra; Ahel, Marijan; Terzic, Senka
2018-01-19
Although published literature provides a clear demonstration of widespread occurrence of opioid analgesics (OAs) in the aquatic environment, analytical methods suitable for a systematic study of this pharmaceutical class, which would include a broad spectrum of opioid analgesics and their metabolites, are still missing. In this work, a comprehensive multiresidue method for quantitative analysis of 27 opioid analgesics and their metabolites, including 2 morphine glucuronide conjugates, was developed and validated for three matrices: raw wastewater (RW), secondary effluent (SE) and river water. The method comprised different classes of opioid analgesics, including natural opiates (morphine and codeine), their semi-synthetic derivatives (hydrocodone, hydromorphone, oxycodone, oxymorphone and buprenorphine) as well as fully synthetic opioids such as methadone, fentanyl, sufentanil, propoxyphene and tramadol. The optimized enrichment procedure involved mixed-mode, strong cation-exchange sorbent in combination with a sequential elution procedure. The extracts were analyzed by reversed-phase liquid chromatography using a Synergy Polar column coupled to electrospray ionization tandem mass spectrometry (LC-MS/MS). Accurate quantification of target OAs was achieved using 19 deuterated analogues as surrogate standards. Method accuracies for RW, SE and river water varied in the range from 91 to 126%, 74 to 120% and 75 to 116%, respectively. Careful optimization of the procedure allowed reliable determination of OAs with method quantification limits in the low ng/L range (RW: 0.3-3.5 ng/L; SE: 0.2-1.9 ng/L, river water: 0.1-0.8 ng/L. The developed method was applied for analysis of RW, SE and river water samples from Croatia. The concentrations of individual OAs in municipal wastewater varied in a wide range (from < QL to 859 ng/L) and the most prevalent representatives were tramadol, codeine, morphine and methadone and their derivatives. Elevated concentrations of
Opioid Concentrations in Oral Fluid and Plasma in Cancer Patients With Pain.
Heiskanen, Tarja; Langel, Kaarina; Gunnar, Teemu; Lillsunde, Pirjo; Kalso, Eija A
2015-10-01
Measuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach. To assess the usefulness of oral fluid (OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy. We collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone, or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days. A total of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R(2) = 0.628 and 0.700, respectively), but not morphine (R(2) = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL vs. plasma concentrations of oxycodone compared with morphine and fentanyl. OFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series
2011-01-01
Introduction The use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone. Case presentation We describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman (aged 59) experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other (aged 49) did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations. Conclusions The marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic
Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.
Cooper, Ziva D; Bedi, Gillinder; Ramesh, Divya; Balter, Rebecca; Comer, Sandra D; Haney, Margaret
2018-02-05
Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals. Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability. This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability. Healthy cannabis smokers (N = 18) were administered oxycodone (0, 2.5, and 5.0 mg, PO) with smoked cannabis (0.0, 5.6% Δ 9 tetrahydrocannabinol [THC]) and analgesia was assessed using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4 °C); times to report pain (pain threshold) and withdraw the hand from the water (pain tolerance) were recorded. Abuse-related effects were measured and effects of oxycodone on cannabis self-administration were determined. Alone, 5.0 mg oxycodone increased pain threshold and tolerance (p ≤ 0.05). Although active cannabis and 2.5 mg oxycodone alone failed to elicit analgesia, combined they increased pain threshold and tolerance (p ≤ 0.05). Oxycodone did not increase subjective ratings associated with cannabis abuse, nor did it increase cannabis self-administration. However, the combination of 2.5 mg oxycodone and active cannabis produced small, yet significant, increases in oxycodone abuse liability (p ≤ 0.05). Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis's abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.
Stability indicating HPLC method for the estimation of oxycodone and lidocaine in rectal gel.
Gebauer, M G; McClure, A F; Vlahakis, T L
2001-07-31
An HPLC method for the quantification of oxycodone and lidocaine in a gel matrix is described. The mobile phase consisted of methanol--water--acetic acid (35:15:1 v/v/v) and was delivered at 1.5 ml/min through a 4.6 x 250 mm Zorbax SB-C8 column. Oxycodone was detected at 285 nm and lidocaine at 264 nm. Linear calibration curves were obtained for oxycodone in the range of 0.05--1.5% (w/w) and for lidocaine in the range of 0.1--5.0% (w/w). Oxycodone and lidocaine were treated with hydrogen peroxide and the oxidation products were readily separated on the column. The method was applied to assess the stability of a gel containing oxycodone hydrochloride (0.3% w/w) and lidocaine (1.5% w/w). The gel was stored under refrigeration in ready-to-use syringes and under these conditions oxycodone and lidocaine were stable for at least 1 year. The gel is useful in the management of tenesmus in rectal cancer.
Kokubun, Hideya; Fukawa, Misako; Matoba, Motohiro; Hoka, Sumio; Yamada, Yasuhiko; Yago, Kazuo
2007-11-01
Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLC-electrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V(d)=226.7+/-105.5 l (mean+/-S.D.), CL=37.9+/-25.1 l/h, t(1/2)=4.1+/-1.9 h. Hydrocotarnine; V(d)=276.8+/-237.2 l, CL=95.1+/-64.3 l/h, t(1/2)=2.0+/-0.7 h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.
Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.
Enga, Rachel M; Jackson, Asti; Damaj, M Imad; Beardsley, Patrick M
2016-10-15
Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid. Copyright © 2016 Elsevier B.V. All rights reserved.
Reversal of oxycodone and hydrocodone tolerance by diazepam.
Gonek, Maciej; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L
2017-11-01
The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. Copyright © 2017 Elsevier B.V. All rights reserved.
Khashan, M; Dolkart, O; Amar, E; Chechik, O; Sharfman, Z; Mozes, G; Maman, E; Weinbroum, A A
2016-02-01
Rotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24-48 h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline. In this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20 mg/10 ml), ketamine (50 mg + morphine 10 mg/10 ml), or saline (0.9 % 10 ml) (n = 15/group), were administered to all patients. First 24 h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000 mg or oxycodone 5 mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented. Patients' demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (p < 0.05) lower in both treatment groups compared to placebo, but were not significantly different between the two intervention groups. PCA-morphine and oral analgesics were consumed similarly among the groups throughout the study phases. Pre-incisional intra-articular morphine reduced pain in the first 2 weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects.
Inoue, Satoshi; Saito, Yoji; Tsuneto, Satoru; Aruga, Etsuko; Ide, Azusa; Kakurai, Yasuyuki
2017-01-01
In Japan, there are limited options for switching opioid analgesics. Hydromorphone is an opioid analgesic that is routinely used instead of morphine for cancer pain; however, it is not yet available in Japan. The aim of this study was to assess the efficacy and safety of hydromorphone (DS-7113b) extended-release tablets in opioid-naïve patients with cancer pain not relieved by non-opioid analgesics. This was a multicenter, randomized, double-blind, parallel-group trial. A double-dummy method was used for blinding. Each randomized subject received either hydromorphone extended-release tablets plus placebo oxycodone hydrochloride extended-release tablets 4 mg/day (n=88) or placebo hydromorphone extended-release tablets plus oxycodone hydrochloride extended-release tablets 10 mg/day (n=93) orally for 7 days (once-daily dosing for hydromorphone and twice-daily dosing for oxycodone). The doses were adjusted as necessary. Efficacy was evaluated by change in visual analog scale (VAS) score from baseline to completion of treatment. The between-group difference in least squares mean changes in VAS score from baseline to completion or discontinuation of treatment was -0.4 mm (95% CI -5.9 to 5 mm) by analysis of covariance where the baseline VAS score was used as a covariate. The upper limit of the 95% CI was below 10 mm, which was predefined as the noninferiority limit. This verified the noninferiority of hydromorphone tablets relative to oxycodone tablets. The incidence of adverse events was 80.7% (71 of 88) in the hydromorphone group and 83.7% (77 of 93) in the oxycodone group. The most common adverse events were nausea, vomiting, somnolence, diarrhea, and constipation, most of which are commonly observed with opioid analgesics. The efficacy and safety of hydromorphone extended-release tablets were equivalent to those of the oxycodone extended-release formulation.
The safety of methadone hydrochloride.
Swegle, John M; Wensel, David D
2008-01-01
Methadone is an interesting analgesic for multiple reasons. The unique properties of the agent, low cost and widespread availability have led to increases in methadone prescribing. Despite advantages, methadone is challenging to work with, particularly in patients with high opioid requirements. Recent concerns regarding cardiac arrhythmias and respiratory depression have led to changes in the labeling of methadone. This editorial highlights some of these concerns and provides some recommendations for the appropriate use of methadone in the setting of pain.
[Pharmacokinetics of controlled-release oxycodone in patients with cancer pain].
Nakamura, Kazuyo; Kokubun, Hideya; Komatsu, Toshiaki; Matoba, Motohiro; Hoka, Sumio; Yago, Kazuo
2007-09-01
Oxycodone is a useful analgesic for cancer patients in pain. However, its pharmacokinetics have not been sufficiently examined and there is a lack of information, with very few reports on pharmacokinetics concerning the absorption process in particular. With this in mind, we studied the pharmacokinetics of controlled-release oxycodone (Oxy contin). We measured its serum concentration in patients with cancer pain, and calculated parameters derived using the nonlinear least-squared method program (MULTI). In the result, pharmacokinetic parameters calculated at CL/F were: 45.6+/-22.0 L/hr (Mean+/-SD), Vd/F: 473.0+/-19 6.7 L, t(1/2): 7.2+/- 6.2 hr, kel: 0.103+/-0.034, kal: 1.082+/-0.604, Lag time: 0.9 9+/-0.40 hr. In addition, the serum oxycodone concentration hardly rose until 1 hour after and just before medication, whereupon a rapid increase was evident after 1 hour. The pharmacokinetics of controlled-release oxycodone in patients with cancer pain were clarified in this study. Especially during the absorption process, the lag time was calculated specifically at about 1 hour, making it approximately equal to MS contin.
Cerasoli, Ilaria; Tutunaru, Alexandru; Cenani, Alessia; Ramirez, Juan; Detilleux, Johann; Balligand, Marc; Sandersen, Charlotte
2017-03-01
To evaluate the efficacy, in terms of the amount of rescue analgesia required, and the clinical usefulness of epidural injection of morphine with bupivacaine or levobupivacaine for elective pelvic limb surgery in dogs during a 24-hour perioperative period. Prospective, blinded, randomized clinical study. A group of 26 dogs weighing 31.7 ± 14.2 (mean ± standard deviation) kg and aged 54 ± 36 months. All dogs were premedicated with methadone intravenously (0.2 mg kg -1 ) and anaesthesia induced with diazepam (0.2 mg kg -1 ) and propofol intravenously to effect. After induction of anaesthesia, dogs randomly received a lumbosacral epidural injection of morphine 0.1 mg kg -1 with either levobupivacaine 0.5% (1 mg kg -1 ; group LevoBM) or bupivacaine 0.5% (1 mg kg -1 ; group BM). Cardiovascular, respiratory and temperature values were recorded during the intra- and postoperative period. A visual analogue scale, subjective pain scale, sedation scale and the short form of the Glasgow pain scale were assessed every 6 hours after epidural injection during 24 hours. The ability to stand and walk, neurological deficits and other side effects were assessed at the same time points. The amount of rescue analgesia (sufentanil intraoperatively and methadone postoperatively) was recorded. No statistically significant differences were found between groups for any of the recorded data, with the exception of the incidence of spontaneous urination and postoperative rescue analgesia requirement. In group LevoBM four dogs spontaneously urinated at recovery while none of the dogs in group BM did (p = 0.03) and seven dogs of group LevoBM required postoperative rescue analgesia versus none of the dogs in the BM group (p = 0.005). and clinical relevance Epidural LevoBM is a suitable alternative to BM in healthy dogs during elective pelvic limb surgery. Epidural BM produced more urinary retention but better pain control compared to the same concentration and dose of LevoBM in dogs
Opioid Rotation in Cancer Pain Treatment.
Schuster, Michael; Bayer, Oliver; Heid, Florian; Laufenberg-Feldmann, Rita
2018-03-02
Rotating several different WHO level III opioid drugs is a therapeutic option for patients with chronic cancer-related pain who suffer from inadequate analgesia and/or intolerable side effects. The evidence favoring opioid rotation is controversial, and the current guidelines in Germany and other countries contain only weak recommendations for it. This review is based on pertinent publications retrieved by a systematic review of the literature on opioid rotation for adult patients with chronic cancerrelated pain who are regularly taking WHO level III opioids by the oral or trans - dermal route. 9 individual studies involving a total of 725 patients were included in the analysis, and 3 previous systematic reviews of studies involving a total of 2296 patients were also analyzed. Morphine, oxycodone, fentanyl, hydromorphone, and buprenorphine were used as first-line opioid drugs, and hydromorphone, bupre - norphine, tapentadol, fentanyl, morphine, oxymorphone, and methadone were used as second-line opioid drugs. In all of the studies, pain control was achieved for 14 days after each rotation. In most of them, the dose of the new drug introduced in each rotation needed to be increased above the dose initially calculated from a rotation ratio, with the exception of rotations to methadone. The frequency of side effects was only rarely lessened, but patients largely considered the result of opioid rotation to be positive. No particular opioid drug was found to be best. Opioid rotation can improve analgesia and patient satisfaction. The success of opioid rotation appears to depend on the magnitude of the initial dose, among other factors. Tables of equianalgesic doses should be considered no more than a rough guide for determining the dose of the new drug. Rotations to methadone should be carried out under clinical supervision in experienced hands.
Resolution of an apparent hook effect in Roche partner DRI oxycodone immunoassay.
Colón-Franco, Jessica M; Cox, Elbert T; Crosby, David B; Dawling, Sheila
2013-01-01
A presumed hook effect in the semiquantitative DRI Oxycodone immunoassay, OXY3S (Cobas Integra, Roche Diagnostics), was investigated in 14 urine samples with gas chromatography/mass spectrometry (GC-MS) >10,000 ng/mL but OXY3S <1,000 ng/mL. These samples included the index case, a false-negative OXY3S result with >75,000 ng/mL oxycodone + oxymorphone by GC-MS confirmation. Patient samples needed 2- to 16-fold dilution to obtain the correct OXY3S response. The OXY3S test did not hook at high-spiked concentrations of oxycodone, oxymorphone or oxymorphone-3β-d-glucuronide in drug-free urine. The OXY3S test parameters were replicated in a development channel on the Cobas using DRI Reagents (Microgenics, CA, USA) and were subsequently modified. Delayed sample addition or doubling of Reagent 1 (R1: antibody/substrate/co-factor) yielded maximal immunoassay response (>10,000 ng/mL) in 12 of 14 and 14 of 14 undiluted patient samples, respectively. Supplementation of R1 with substrate alone did not correctly recover oxycodone from any of the samples, while co-factor supplementation resulted a maximal OXY3S response in 13 of 14 samples. The remaining (index) sample could only be corrected by supplemental R1. The semiquantitative utility of the DRI Oxycodone assay is questionable. Although the precise cause of the under-recovery could not be determined, the modification presented permits reliable oxycodone determination at the high concentrations frequently seen in clinical urine samples.
Mayer-Blackwell, B.; Schlussman, S. D.; Butelman, E. R.; Ho, A.; Ott, J.; Kreek, M. J.; Zhang, Y.
2014-01-01
Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n= 12) and of adult mice (11 weeks old, n= 11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1 h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice. PMID:24220688
Jones, Hendrée E; Jansson, Lauren M; O'Grady, Kevin E; Kaltenbach, Karol
2013-01-01
Compared to untreated opioid dependence, methadone maintenance treatment of opioid-dependent pregnant women has been found to be associated with better maternal and neonatal outcomes. Secondary analysis of data from 73 maternal and neonatal participants in the MOTHER study (H. E. Jones et al., New England Journal of Medicine, 2010) found no relationship between maternal methadone dose at delivery and any of 9 neonatal outcomes--peak neonatal abstinence syndrome (NAS) score, total amount of morphine needed to treat NAS, duration of neonatal hospital stay, duration of treatment for NAS, estimated gestational age at delivery, Apgar score at 5 min, and neonatal head circumference, length, and weight at birth. These results are consistent with a recent systematic review and meta-analysis (B. J. Cleary et al., Addiction, 2010) and extend findings to outcomes other than NAS. Methodological and design issues that might have adversely impacted the ability of researchers to establish the existence or non-existence of these relationships are considered. Copyright © 2013 Elsevier Inc. All rights reserved.
Hutchinson, Mark R.; Northcutt, Alexis L.; Chao, Lindsey W.; Kearney, Jeffrey J.; Zhang, Yingning; Berkelhammer, Debra L.; Loram, Lisa C.; Rozeske, Robert R.; Bland, Sondra T.; Maier, Steven F.; Gleeson, Todd T.; Watkins, Linda R.
2008-01-01
Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression, reward, and pain modulation. PMID:18706994
Preston, K L; Umbricht, A; Epstein, D H
2000-04-01
Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.
Perioperative pharmacokinetics of methadone in adolescents.
Sharma, Anshuman; Tallchief, Danielle; Blood, Jane; Kim, Thomas; London, Amy; Kharasch, Evan D
2011-12-01
Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed. Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone. The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients. Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.
Zacny, James P; Paice, Judith A; Coalson, Dennis W
2012-08-01
There are epidemiological data indicating that medical and/or nonmedical use of prescription opioids oftentimes involves concurrent use of other substances. One of those substances is benzodiazepines. It would be of relevance to characterize the effects of an opioid and a benzodiazepine when taken together to determine if measures related to abuse liability-related effects and psychomotor performance impairment are increased compared to when the drugs are taken alone. Twenty volunteers participated in a crossover, randomized, double-blind study in which they received placebo, 0.5mg alprazolam, 10mg oxycodone, and 0.5mg alprazolam combined with 10 mg oxycodone, all p.o. Subjective, psychomotor, and physiological measures were assessed during each of the four sessions. Oxycodone by itself increased drug liking and "take again" ratings relative to placebo, but these ratings were not increased when oxycodone was taken with alprazolam, which by itself did not increase either of these ratings. The two drugs in combination produced stronger effects (larger in magnitude or longer lasting) than when either was taken alone on a number of measures, including psychomotor performance impairment. In healthy volunteers, abuse liability-related subjective effects of oxycodone were not enhanced by alprazolam. There was enhanced behavioral toxicity when the drugs were taken together, and thus, this is of significant concern from a public safety standpoint. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Zacny, James P.; Paice, Judith A.; Coalson, Dennis W.
2013-01-01
Background There are epidemiological data indicating that medical and/or nonmedical use of prescription opioids oftentimes involves concurrent use of other substances. One of those substances is benzodiazepines. It would be of relevance to characterize the effects of an opioid and a benzodiazepine when taken together to determine if measures related to abuse liability-related effects and psychomotor performance impairment are increased compared to when the drugs are taken alone. Methods Twenty volunteers participated in a crossover, randomized, double-blind study in which they received placebo, 0.5 mg alprazolam, 10mg oxycodone, and 0.5 mg alprazolam combined with 10mg oxycodone, all p.o. Subjective, psychomotor, and physiological measures were assessed during each of the four sessions. Results Oxycodone by itself increased drug liking and “take again” ratings relative to placebo, but these ratings were not increased when oxycodone was taken with alprazolam, which by itself did not increase either of these ratings. The two drugs in combination produced stronger effects (larger in magnitude or longer lasting) than when either was taken alone on a number of measures, including psychomotor performance impairment. Conclusions In healthy volunteers, abuse liability-related subjective effects of oxycodone were not enhanced by alprazolam. There was enhanced behavioral toxicity when the drugs were taken together, and thus, this is of significant concern from a public safety standpoint. PMID:22365897
Bossert, Jennifer M; Hoots, Jennifer K; Fredriksson, Ida; Adhikary, Sweta; Zhang, Michelle; Venniro, Marco; Shaham, Yavin
2018-05-19
Relapse to nonmedical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction-induced abstinence. We also determined the role of mu, delta, and kappa opioid receptors (MOR, DOR, KOR) in this reinstatement. We trained rats to self-administer oxycodone for 6 h/d in Context A; lever pressing was paired with a discrete cue. Next, we extinguished the lever pressing in the presence of the discrete cue in Context B and then tested the rats for reinstatement of oxycodone seeking in both contexts. We retrained rats to self-administer oxycodone in Context A, re-extinguished their lever pressing in Context B, and retested them for reinstatement in both contexts. Prior to testing, we injected the rats with vehicle or antagonists of MOR (naltrexone; 0.5 or 1.0 mg/kg), DOR (naltrindole; 7.5 or 15 mg/kg), or KOR (LY2456302; 5 or 10 mg/kg). We also tested the effect of naltrexone, naltrindole, and LY2456302 on oxycodone self-administration under fixed-ratio-1 (FR1) and progressive-ratio (PR) reinforcement schedules. We observed context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction. Naltrexone, but not naltrindole or LY2456302, injections decreased this reinstatement. Additionally, naltrexone increased oxycodone self-administration under the FR1 schedule and decreased oxycodone self-administration under the PR schedule; naltrindole and LY2456302 were ineffective. Results demonstrate a critical role of MOR, but not DOR or KOR, in context-induced reinstatement of oxycodone seeking and oxycodone self-administration. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Methadone Treatment: Overview and Bibliography.
ERIC Educational Resources Information Center
Greenfield, Lawrence; Tang, Beth Archibald
This overview focuses on methadone treatment. Briefly, it describes the clinical uses of methadone for substance abuse treatment, explores dosage guidelines, and discusses counseling components. This overview also reviews research data on the application of methadone treatment to special populations, such as pregnant women, polydrug users, and…
Wu, Hsiang-en; Hong, Jau-Shyong; Tseng, Leon F
2007-10-01
We have previously demonstrated that (+)-morphine and (-)-morphine given spinally stereoselectively attenuate the spinally-administered (-)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia. Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (-)-morphine also stereoselectively attenuates the systemic (-)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (-)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01-10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneously-administered (-)-morphine (5 mg/kg). Pretreatment with (-)-morphine (0.01-1.0 mg/kg) given subcutaneously also attenuates the (-)-morphine-produced tail-flick inhibition. The ED50 values for (+)-morphine and (-)-morphine for inhibiting the (-)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 microg/kg, respectively. The attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine or (-)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/kg) given subcutaneously also attenuates (-)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (-)-morphine given systemically in attenuating the systemic (-)-morphine-produced antinociception and the antianalgesic effect of (+)-morphine and (-)-morphine is mediated by activation of the naloxone-sensitive sigma receptor.
Frauger, Elisabeth; Pochard, Liselotte; Boucherie, Quentin; Giocanti, Adeline; Chevallier, Cécile; Daveluy, Amélie; Gibaja, Valérie; Caous, Anne-Sylvie; Eiden, Céline; Authier, Nicolas; Le Boisselier, Reynald; Guerlais, Marylène; Jouanjus, Émilie; Lepelley, Marion; Pizzoglio, Véronique; Pain, Stéphanie; Richard, Nathalie; Micallef, Joëlle
2017-09-01
It is important to assess drug abuse liability in 'real life' using different surveillance systems. OPPIDUM ('Observation of illegal drugs and misuse of psychotropic medications') surveillance system anonymously collects information on drug abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. The aim of this article is to demonstrate the utility of OPPIDUM system using 2015 data. OPPIDUM is a cross-sectional survey repeated each year since 1995. In 2015, 5003 patients described the modality of use of 10,159 psychoactive drugs. Among them, 77% received an opiate maintenance treatment: 68% methadone (half of them consumed capsule form) and 27% buprenorphine (39% consumed generic form). Brand-name buprenorphine is more often injected than generic buprenorphine (10% vs. 2%) and among methadone consumers 7% of methadone capsule consumers have illegally obtained methadone (vs. 9% for syrup form). The proportion of medications among psychoactive drugs injected is important (42%), with morphine representing 21% of the total psychoactive drugs injected and buprenorphine, 16%. OPPIDUM highlighted emergent behaviors of abuse with some analgesic opioids (like tramadol, oxycodone or fentanyl), pregabalin, or quetiapine. OPPIDUM highlighted variations of drugs use regarding geographic approaches or by drug dependence care centers (like in harm reduction centers). OPPIDUM clearly demonstrated that collection of valid and useful data on drug abuse is possible, these data have an interest at regional, national and international levels. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
Brunet, Bertrand R.; Barnes, Allan J.; Scheidweiler, Karl B.; Mura, Patrick
2009-01-01
A sensitive and specific method is presented to simultaneously quantify methadone, heroin, cocaine and metabolites in sweat. Drugs were eluted from sweat patches with sodium acetate buffer, followed by SPE and quantification by GC/MS with electron impact ionization and selected ion monitoring. Daily calibration for anhydroecgonine methyl ester, ecgonine methyl ester, cocaine, benzoylecgonine (BE), codeine, morphine, 6-acetylcodeine, 6-acetylmorphine (6AM), heroin (5–1000 ng/patch) and methadone (10–1000 ng/patch) achieved determination coefficients of >0.995, and calibrators quantified to within ±20% of the target concentrations. Extended calibration curves (1000–10,000 ng/patch) were constructed for methadone, cocaine, BE and 6AM by modifying injection techniques. Within (N=5) and between-run (N=20) imprecisions were calculated at six control levels across the dynamic ranges with coefficients of variation of <6.5%. Accuracies at these concentrations were ±11.9% of target. Heroin hydrolysis during specimen processing was <11%. This novel assay offers effective monitoring of drug exposure during drug treatment, workplace and criminal justice monitoring programs. PMID:18607576
Savić Vujović, Katarina R; Vučković, Sonja; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Vučetić, Čedomir; Džoljić, Eleonora; Prostran, Milica
2013-04-01
In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of μ-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (±)-cis-3-methyl fentanyl (CM), (±)-cis-3-carbomethoxy fentanyl (C), (±)trans-3-carbomethoxy fentanyl (T) and (±)-cis-3 butyl fentanyl (B) produced dose-dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27)>F(1)>C(0.35)≥T(0.11)≥B(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43)>F(1)>C(0.46)≥T(0.11)≥B(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-α,α,17-trimethyl-, (5α,7α) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56)>O(5)≥T(2.6)>M(1), and similar to this, the relative order of hyperthermic potency was: E(37)>O(3)≥T(2.3)>M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings.
Slow-release oral morphine for opioid maintenance treatment: a systematic review
Jegu, Jeremie; Gallini, Adeline; Soler, Pauline; Montastruc, Jean-Louis; Lapeyre-Mestre, Maryse
2011-01-01
This review article summarizes the results of all available clinical trials considering the use of slow-release oral morphine (SROM) for opioid maintenance treatment (OMT). All studies published up to October 2010 and assessing SROM for OMT in adult patients are included. Three independent reviewers assessed the selected articles using a standardized checklist. Study design, study length and number of subjects included were recorded. Data about retention rate (proportion of participants remaining under maintenance treatment at the end of the study), quality of life, withdrawal symptoms, craving, additional drug consumption, driving capacity and adverse events were collected. We identified 13 articles corresponding to nine clinical trials considering the use of SROM for OMT. Among them, only one was a randomized trial and one was a controlled not randomized trial. All other studies were uncontrolled. Retention rates were good (from 80.6 to 95%) with SROM maintenance, but similar retention rates were obtained with methadone. Most of the studies showed that quality of life, withdrawal symptoms, craving and additional drug consumption improved with SROM. However, there was no comparison with other maintenance drugs. As most of the studies assessing SROM efficacy were uncontrolled, there is no definite evidence that SROM is an effective alternative to methadone for OMT. PMID:21265874
Willson, N J; Schneider, J F; Roizin, L; Fleiss, J F; Rivers, W; Demartini, J E
1976-11-01
Male and female Sprague-Dawley rats were given dl-methadone (5 mg/kg) for at least 3 months and then mated. The drug was continued throughout pregnancy and after delivery. The newly born pups were divided into two groups. One group was tested for in vivo methadone tolerance, while the animals in the othergroup were used to prepare organotypic cerebellar cultures. Various amounts of dl-methadone were added to the media of half of these cerebellum cultures. The effect of the drug in the medium was assessed by measuring explant outgrowth. Similar experiments were carried out with control animals. Statistical analysis of the data obtained in the in vivo portion of the experiment indicates that the pups of methadone-treated mothers tolerate methadone better than those of untreated mothers. The culture experiments revealed that the addition of methadone to the medium reduced explant outgrowth size and this was a dose-related effect. Also, there was significantly less outgrowth from explants prepared using pups of methadone-treated mothers as compared to the controls. There was no significant difference in the effect of methadone on the growth of cultures prepared from the methadone-tolerant and control animals.
Larochelle, Marc R; Zhang, Fang; Ross-Degnan, Dennis; Wharam, J Frank
2015-06-01
In the second half of 2010, abuse-deterrent extended-release oxycodone hydrochloride (OxyContin; Purdue Pharma) was introduced and propoxyphene was withdrawn from the US market. The effect of these pharmaceutical market changes on opioid dispensing and overdose rates is unknown. To evaluate the association between 2 temporally proximate changes in the opioid market and opioid dispensing and overdose rates. Claims from a large national US health insurer were analyzed, using an interrupted time series study design. Participants included an open cohort of 31.3 million commercially insured members aged 18 to 64 years between January 1, 2003, and December 31, 2012, with median follow-up of 20 months (last follow-up, December 31, 2012). Introduction of abuse-deterrent OxyContin (resistant to crushing or dissolving) on August 9, 2010, and market withdrawal of propoxyphene on November 19, 2010. Standardized opioid dispensing rates and prescription opioid and heroin overdose rates were the primary outcomes. We used segmented regression to analyze changes in outcomes from 30 quarters before to 8 quarters after the 2 interventions. Two years after the opioid market changes, total opioid dispensing decreased by 19% from the expected rate (absolute change, -32.2 mg morphine-equivalent dose per member per quarter [95% CI, -38.1 to -26.3]). By opioid subtype, the absolute change in dispensing by milligrams of morphine-equivalent dose per member per quarter at 2 years was -11.3 (95% CI, -12.4 to -10.1) for extended-release oxycodone, 3.26 (95% CI, 1.40 to 5.12) for other long-acting opioids, -8.19 (95% CI, -9.30 to -7.08) for propoxyphene, and -16.2 (95% CI, -18.8 to -13.5) for other immediate-release opioids. Two years after the market changes, the estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, -1.10 per 100,000 members per quarter [95% CI, -1.47 to -0.74]), but heroin overdose increased by 23% (absolute change, 0.26 per 100
Bhalla, Shaifali; Ali, Izna; Lee, Hyaera; Andurkar, Shridhar V; Gulati, Anil
2013-01-01
The potentiation of oxycodone antinociception by BMS182874 (endothelin-A (ET(A)) receptor antagonist) and agmatine (imidazoline receptor/α(2)-adrenoceptor agonist) is well-documented. It is also known that imidazoline receptors but not α(2)-adrenoceptors are involved in potentiation of oxycodone antinociception by agmatine and BMS182874 in mice. However, the involvement of specific imidazoline receptor subtypes (I(1), I(2), or both) in this interaction is not clearly understood. The present study was conducted to determine the involvement of imidazoline I(1) and I(2) receptors in agmatine- and BMS182874-induced potentiation of oxycodone antinociception in mice. Antinociceptive (tail flick and hot-plate) latencies were determined in male Swiss Webster mice treated with oxycodone, agmatine, BMS182874, and combined administration of oxycodone with agmatine or BMS182874. Efaroxan (imidazoline I(1) receptor antagonist) and BU224 (imidazoline I(2) receptor antagonist) were used to determine the involvement of I(1) and I(2) imidazoline receptors, respectively. Oxycodone produced significant antinociceptive response in mice which was not affected by efaroxan but was blocked by BU224. Agmatine-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. Similarly, BMS182874-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. This is the first report demonstrating that BMS182874- or agmatine-induced enhancement of oxycodone antinociception is blocked by BU224 but not by efaroxan. We conclude that imidazoline I(2) receptors but not imidazoline I(1) receptors are involved in BMS182874- and agmatine-induced potentiation of oxycodone antinociception in mice. Copyright © 2012 Elsevier Inc. All rights reserved.
Tran, T; Taylor, S E; Hardidge, A; Findakly, D; Aminian, P; Elliott, R A
2017-10-01
Overprescribing of oxycodone is a contributor to the epidemic of prescription opioid misuse and deaths. Practice models to optimize oxycodone prescribing and supply need to be evaluated. We explored the impact of pharmacist-assisted discharge prescribing and medication review on oxycodone prescribing and supply for patients discharged from surgical wards. A retrospective audit was conducted on two surgical inpatient wards following a 16-week prospective pre- and post-intervention study. During the pre-intervention period, discharge prescriptions were prepared by hospital doctors and then reviewed by a ward pharmacist (WP) before being dispensed. Post-intervention, prescriptions were prepared by a project pharmacist in consultation with hospital doctors and then reviewed by a WP and dispensed. Proportion of patients who were prescribed, and proportion supplied, oxycodone on discharge; Median amount (milligrams) of oxycodone prescribed and supplied, for patients who were prescribed and supplied at least one oxycodone-containing preparation, respectively. A total of 320 and 341 patients were evaluated pre- and post-intervention, respectively. Pre-intervention, 75.6% of patients were prescribed oxycodone; after WP review, 60.3% were supplied oxycodone (P<.01); the median amount both prescribed and supplied was 100 milligrams/patient. Post-intervention, 68.6% of patients were prescribed oxycodone; after WP review, 57.8% were supplied oxycodone (P<.01); median amount prescribed and supplied was 50 milligrams/patient (difference in amount prescribed and supplied: 50 milligrams, P<.01). WP review of doctor-prepared prescriptions reduced the proportion of patients who were supplied oxycodone but not the amount supplied/patient. Having a pharmacist assist with prescribing reduced the amount of oxycodone supplied. © 2017 John Wiley & Sons Ltd.
Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr
2017-07-01
To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.
Clinical pharmacology of methadone in dogs.
Ingvast-Larsson, Carina; Holgersson, Anja; Bondesson, Ulf; Lagerstedt, Anne-Sofie; Olsson, Kerstin
2010-01-01
To investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs. Randomized, cross-over, experimental trial. Nine adult dogs (beagle and beagle cross breeds), four males and five females. Methadone hydrochloride, 0.4 mg kg(-1), was administered intravenously (IV) and subcutaneously (SC) with a crossover design. Drug and hormone analyses in plasma were performed using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and radioimmunoassay respectively. Behavioural data were collected using a standardized protocol. After IV administration, the plasma concentration of methadone at 10 minutes was 82.1 +/- 9.2 ng mL(-1) (mean +/- SD), the terminal half-life was 3.9 +/- 1.0 hours, the volume of distribution 9.2 +/- 3.3 L kg(-1) and plasma clearance 27.9 +/- 7.6 mL minute(-1) kg(-1). After SC administration, time to maximal plasma concentration was 1.26 +/- 1.04 hours and maximal plasma concentration of methadone was 23.9 +/- 14.4 ng mL(-1), the terminal half-life was 10.7 +/- 4.3 hours and bioavailability was 79 +/- 22%. Concentrations of both cortisol and vasopressin were increased for an hour following IV methadone. The observed behavioural effects of methadone were decreased licking and swallowing and an increase in whining after SC administration. The latter finding is notable as it can be misinterpreted as pain when methadone is used as an analgesic. When methadone was administered by the SC route, the half-life was longer, but the individual variation in plasma concentrations was greater compared with IV administration. Increased frequency of whining occurred after administration of methadone and may be a drug effect and not a sign of pain. Cortisol and vasopressin concentrations in plasma may not be suitable for evaluating analgesia after methadone treatment.
Comparison of fatal poisonings by prescription opioids.
Häkkinen, Margareeta; Launiainen, Terhi; Vuori, Erkki; Ojanperä, Ilkka
2012-10-10
There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14-44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5 mg/l, respectively) than in other causes of death (0.09 and 5.9 mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8 mg/l, respectively) than in other causes of death (0.6 and 0.2 mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35 mg/l) was not different from that in other causes of death (0.30 mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Winkle, P.; Custodio, J. M.; Wei, X.; Rhee, M. S.; Kearney, B. P.; Ramanathan, S.; Friedland, Gerald H.
2013-01-01
Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered. PMID:24080665
Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah
2016-04-01
This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats.
Cancer Pain Management and Bone Metastases: An Update for the Clinician
Schneider, Guido; Voltz, Raymond; Gaertner, Jan
2012-01-01
Breast cancer patients with bone metastases often suffer from cancer pain. In general, cancer pain treatment is far from being optimal for many patients. To date, morphine remains the gold standard as first-line therapy, but other pure μ agonists such as hydromorphone, fentanyl, or oxycodone can be considered. Transdermal opioids are an important option if the oral route is impossible. Due to its complex pharmacology, methadone should be restricted to patients with difficult pain syndromes. The availability of a fixed combination of oxycodone and naloxone is a promising development for the reduction of opioid induced constipation. Especially bone metastases often result in breakthrough pain episodes. Thus, the provision of an on-demand opioid (e.g., immediate-release morphine or rapid-onset fentanyl) in addition to the baseline (regular) opioid therapy (e.g., sustained-release morphine tablets) is mandatory. Recently, rapid onset fentanyls (buccal or nasal) have been strongly recommended for breakthrough cancer pain due to their fast onset and their shorter duration of action. If available, metamizole is an alternative non-steroid-anti-inflammatory-drug. The indication for bisphosphonates should always be checked early in the disease. In advanced cancer stages, glucocorticoids are an important treatment option. If bone metastases lead to neuropathic pain, coanalgetics (e.g., pregabalin) should be initiated. In localized bone pain, radiotherapy is the gold standard for pain reduction in addition to pharmacologic pain management. In diffuse bone pain radionuclids (such as samarium) can be beneficial. Invasive measures (e.g., neuroaxial blockage) are rarely necessary but are an important option if patients with cancer pain syndromes are refractory to pharmacologic management and radiotherapy as described above. Clinical guidelines agree that cancer pain management in incurable cancer is best provided as part of a multiprofessional palliative care approach and all
Gandelman, Kuan; Lamson, Michael; Salageanu, Joanne; Bramson, Candace; Matschke, Kyle; Malhotra, Bimal
2015-09-01
ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of
Opioid overdose mortality in Kansas, 2001-2011: toxicologic evaluation of intent.
Okic, Merisa; Cnossen, Leslie; Crifasi, Joseph A; Long, Christopher; Mitchell, Erik K
2013-01-01
Drug concentration is a factor in the determination of the manner of death, but considerable overlap exists between therapeutic and toxic concentrations. This study aims to quantify opioid mortality in Kansas from use of fentanyl, methadone and oxycodone and to evaluate utility of drug concentrations for the determination of the manner of death. Cases referred to a forensic pathology practice in Kansas for autopsy from 1 January 2001 to 31 December 2011 were considered. The criterion for inclusion was detection of fentanyl, methadone and/or oxycodone in postmortem toxicology. Of 9,789 cases, 3,315 had positive toxicology: 180 of fentanyl, 299 of methadone and 310 of oxycodone. There were 207 single opioid fatalities, 264 polydrug overdoses and 318 deaths where an opioid was present but not contributory to the mechanism of death. In line with published studies, incidence of opioid overdose deaths increased over the time of the study. Drug concentrations within each cause and manner of death covered broad ranges. Non-natural and natural manners had less overlap than existed within non-natural manners in limited comparisons. This study shows that drug concentration is independent of manner for non-natural deaths and although insufficient to identify intent, can provide a guideline in differentiating non-natural from natural deaths.
Enantiomeric metabolic interactions and stereoselective human methadone metabolism.
Totah, Rheem A; Allen, Kyle E; Sheffels, Pamela; Whittington, Dale; Kharasch, Evan D
2007-04-01
Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation evaluated stereoselectivity, models, and kinetic parameters for methadone N-demethylation by recombinant CYP2B6, CYP3A4, and CYP2C19, and the potential for interactions between enantiomers during racemate metabolism. CYP2B6 metabolism was stereoselective. CYP2C19 was less active, and stereoselectivity was opposite that for CYP2B6. CYP3A4 was not stereoselective. With all three isoforms, enantiomer N-dealkylation rates in the racemate were lower than those of (R)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (R-methadone) or (S)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (S-methadone) alone, suggesting an enantiomeric interaction and mutual metabolic inhibition. For CYP2B6, the interaction between enantiomers was stereoselective, with S-methadone as a more potent inhibitor of R-methadone N-demethylation than R-of S-methadone. In contrast, enantiomer interactions were not stereoselective with CYP2C19 or CYP3A4. For all three cytochromes P450, methadone N-demethylation was best described by two-site enzyme models with competitive inhibition. There were minor model differences between cytochromes P450 to account for stereoselectivity of metabolism and enantiomeric interactions. Changes in plasma R/S methadone ratios observed after rifampin or troleandomycin pretreatment in humans in vivo were successfully predicted by CYP2B6- but not CYP3A4-catalyzed methadone N-demethylation. CYP2B6 is a predominant catalyst of stereoselective methadone metabolism in vitro. In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic
A randomized controlled trial of interim methadone maintenance.
Schwartz, Robert P; Highfield, David A; Jaffe, Jerome H; Brady, Joseph V; Butler, Carol B; Rouse, Charles O; Callaman, Jason M; O'Grady, Kevin E; Battjes, Robert J
2006-01-01
Effective alternatives to long waiting lists for entry into methadone hydrochloride maintenance treatment are needed to reduce the complications of continuing heroin dependence and to increase methadone treatment entry. To compare the effectiveness of interim methadone maintenance with that of the usual waiting list condition in facilitating methadone treatment entry and reducing heroin and cocaine use and criminal behavior. Randomized, controlled, clinical trial using 2 conditions, with treatment assignment on a 3:2 basis to interim maintenance-waiting list control. A methadone treatment program in Baltimore. A total of 319 individuals meeting the criteria for current heroin dependence and methadone maintenance treatment. Participants were randomly assigned to either interim methadone maintenance, consisting of an individually determined methadone dose and emergency counseling only for up to 120 days, or referral to community-based methadone treatment programs. Entry into comprehensive methadone maintenance therapy at 4 months from baseline; self-reported days of heroin use, cocaine use, and criminal behavior; and number of urine drug test results positive for heroin and cocaine at the follow-up interview conducted at time of entry into comprehensive methadone treatment (or at 4 months from baseline for participants who did not enter regular treatment). Significantly more participants assigned to the interim methadone maintenance condition entered comprehensive methadone maintenance treatment by the 120th day from baseline (75.9%) than those assigned to the waiting list control condition (20.8%) (P<.001). Overall, in the past 30 days at follow-up, interim participants reported significantly fewer days of heroin use (P<.001), had a significant reduction in heroin-positive drug test results (P<.001), reported spending less money on drugs (P<.001), and received less illegal income (P<.02) than the waiting list participants. Interim methadone maintenance results in a
Fairbanks, C A; Wilcox, G L
1997-09-01
The mechanistic similarity between acutely and chronically induced morphine tolerance has been previously proposed but remains largely unexplored. Our experiments examined the modulation of acutely induced tolerance to spinally administered morphine by agonists that affect the N-methyl-D-aspartate receptor and nitric oxide synthase systems. Antinociception was detected via the hot water (52.5 degrees C) tail flick test in mice. Intrathecal pretreatment with morphine (40 nmol) produced a 9.6-fold rightward shift in the morphine dose-response curve. This shift confirmed the induction of acute spinal morphine tolerance. Intrathecal copretreatment with the receptor antagonists (competitive and noncompetitive, respectively) dizolcipine (MK801, 3 nmol) or LY235959 (4 pmol) and morphine [40 nmol, intrathecally (i.t.)] attenuated acute tolerance to morphine measured 8 hr later. A 60-min pretreatment of 7-nitroindazole (6 nmol, i.t.), a selective neuronal NOS inhibitor, followed by administration of morphine (40 nmol, i.t.) blocked the induction of morphine tolerance. Intrathecal copretreatment with morphine (40 nmol, i.t.) and agmatine (4 nmol, i.t.), an imidazoline, receptor agonist and putative nitric oxide synthase inhibitor, almost completely abolished acute spinal morphine tolerance. The results of these experiments agree with previous reports using models of chronically induced morphine tolerance. This evidence supports the proposal that the mechanisms responsible for acute morphine tolerance parallel those underlying chronic morphine tolerance. This study attests to the powerful predictive value of acute induction as a model for morphine tolerance.
Comparison of epidural morphine versus intramuscular morphine for postoperative analgesia.
Baftiu, Nehat; Hadri, Burhan; Mustafa, Aziz
2010-01-01
To compare effects and side effects or complications of epidural versus intramuscularly administered morphine for relieve of postoperative pain. In the first group (epidural) analgesia is achieved by application of morphine through epidural catheter. To the amount of morphine is added physiological solution until 10 ml of total volume of the mixture is achieved. This mixture is given to 150 patients, by epidural route before the exit from the operation room. Epidural catheter is removed after 48 hours. Second group (intramuscular) analgesia is realized by application of 10 mg of morphine by intramuscular route. Morphine is injected at the end of surgery. Pain is assessed with combination of verbal categorical scale and visual analog scale. Verbal categorical scale used is 8 points scale and contains words of Tursky: 0 no pain, 1 very low pain, 2 week pain, 3 mild pain, 4 moderate pain, 5 strong pain, 6 severe pain, 7 untolerated pain. Awareness is assed during first 24 hours. For this Reynolds 4 points scale is used: awaked 1, somnolent 2, sleepy 3, deep sleep 4. Pain assessed by visual analog scale (VAS) is 15.17-29.62 in the epidural group patients versus 26.39-70.83 in intramuscular group. Variation of respiration rate in both groups is not significant 22.21 +/- 4.23 and 23.98 +/- 2.72 in minute, in epidural and intramuscular morphine groups, respectively. PaCO2 and PaO2 values are similar without significant variation 35.34 +/- 4.72 mmHg in the epidural morphine group and 31.3 +/- 3.21 mmHg in intramuscular morphine group. Epidural administration of morphine provides better analgesia in quality, since it is deeper, longer in duration and with less inhibitory supra-spinal actions when compared to intramuscular administered morphine.
Lebin, Jacob A; Murphy, David L; Severtson, Stevan Geoffrey; Bau, Gabrielle E; Dasgupta, Nabarun; Dart, Richard C
2018-05-15
Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription opioid black market. This study examined variables that may influence the street price of diverted oxycodone and oxymorphone. A cross-sectional study was conducted utilizing data from the previously validated, crowdsourcing website StreetRx. Street price reports of selected oxycodone and oxymorphone products, between August 22, 2014 and June 30, 2016, were considered for analysis. Geometric means and 95% confidence intervals were calculated comparing prices per milligram of drug in US dollars. Univariate and multivariable regressions were used to examine the influence of dosage strength, drug formulation, and bulk purchasing on street price. A total of 5611 oxycodone and 1420 oxymorphone reports were analyzed. Across various dosages and formulations, geometric mean prices per milligram ranged between $0.12 and $1.07 for oxycodone and $0.73 and $2.90 for oxymorphone. For a 2-fold increase in dosage strength, there is a 24.0% (95% CI: -28.1%, -19.6%, P < 0.001) and a 22.5% (95% CI: -24.2%, -20.8%, P < 0.001) decrease on average in price per milligram for oxycodone and oxymorphone, respectively. Lower potency, high dosage strength, crush-resistant opioids, and those purchased in bulk were significantly cheaper. Street prices for diverted oxycodone and oxymorphone are influenced by multiple factors including potency, dosage, formulation, and bulk purchasing. Buyers who purchase large quantities of low potency, large dosage, crush-resistant formulation prescription opioids can expect to achieve the lowest price. Copyright © 2018 John Wiley & Sons, Ltd.
Athanasos, Peter; Ling, Walter; Bochner, Felix; White, Jason M; Somogyi, Andrew A
2018-03-05
Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Ambulatory. Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1
Design and in vivo evaluation of oxycodone once-a-day controlled-release tablets
Kim, Ju-Young; Lee, Sung-Hoon; Park, Chun-Woong; Rhee, Yun-Seok; Kim, Dong-Wook; Park, Junsang; Lee, Moonseok; Seo, Jeong-Woong; Park, Eun-Seok
2015-01-01
The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone. PMID:25678774
Bates, M L Shawn; Emery, Michael A; Wellman, Paul J; Eitan, Shoshana
2014-09-01
Adolescent opioid abuse is on the rise, and current treatments are not effective in reducing rates of relapse. Our previous studies demonstrated that social housing conditions alter the acquisition rate of morphine conditioned place preference (CPP) in adolescent mice. Specifically, the acquisition rate of morphine CPP is slower in morphine-treated animals housed with drug-naïve animals. Thus, here we tested the effect of social housing conditions on the development of morphine dependence and the extinction rate of an acquired morphine CPP. Adolescent male mice were group-housed in one of two housing conditions. They were injected for 6 days (PND 28-33) with 20 mg/kg morphine. Morphine only mice are animals where all four mice in the cage received morphine. Morphine cage-mate mice are morphine-injected animals housed with drug-naïve animals. Mice were individually tested for spontaneous withdrawal signs by quantifying jumping behavior 4, 8, 24, and 48 h after the final morphine injection. Then, mice were conditioned to acquire morphine CPP and were tested for the rate of extinction. Morphine cage-mates express less jumping behavior during morphine withdrawal as compared to morphine only mice. As expected, morphine cage-mate animals acquired morphine CPP more slowly than the morphine only animals. Additionally, morphine cage-mates extinguished morphine CPP more readily than morphine only mice. Social housing conditions modulate morphine dependence and the extinction rate of morphine CPP. Extinction testing is relevant to human addiction because rehabilitations like extinction therapy may be used to aid human addicts in maintaining abstinence from drug use. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Trends in the Distribution of Opioids in Puerto Rico, 1999-2013.
El Burai Félix, Sausan; Mack, Karin A; Jones, Christopher M
2016-09-01
Limited information has been published about opioid prescribing practices in Puerto Rico. The objective of this study was to create baseline trends of opioids distributed over a period of fourteen years in Puerto Rico. We examined data from the U.S. Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) for the period 1999-2013. ARCOS data reflects the amount of controlled substances legally dispensed. Analyses include the distribution of opioids (in morphine milligram equivalent kg per 10,000 persons) by year and entity (pharmacy, hospital, practitioner). The distribution of four drugs (fentanyl, hydromorphone, methadone, oxycodone) increased over 100% between 1999 and 2013. The distribution of two drugs (hydrocodone and meperidine) declined between 1999 and 2013. Oxycodone distribution grew from 0.13 MME kg grams per 10,000 persons in 1999 to 0.29 MME kg in 2013. ARCOS data showed that the overall amount of opioid pain relievers distributed in Puerto Rico increased by 68% between 1999 and 2013. Currently, prescription opioid pain reliever overdose deaths in Puerto Rico do not appear to be skyrocketing as they are in the mainland U.S. However, the ongoing problem with prescription opioid pain reliever overdoses in certain areas should serve as a warning to monitor consumption of opioid pain relievers, as well as changes in prescription drug abuse, overdoses, and deaths.
Adamson, S J; Sellman, J D
1998-06-01
Sixty-four patients on the Christchurch Methadone Treatment Programme waiting list were questioned on their drug-use behaviour, criminal activity and sources of income, both legal and illegal, for the preceding 7 days. Opioids used included morphine sulphate tablets, methadone and opium poppies, while other drugs used included tranquillizers, cannabis and alcohol. A significant minority were prescribed opioids. The mean cost of drugs used in 7 days across all subjects was 882 dollars. The mean financial gain from criminal sources for the same period was 1079 dollars and was derived from drug-related crime, property crime and prostitution. Few gender differences were found relating to criminal activity or drug use. The majority of the sample were on unemployment benefits of varying types while a minority were in paid employment. Those in paid employment did not earn significantly less from criminal activity, nor did they spend significantly less on drug use than did those not in paid employment. An important implication of these findings is that untreated opioid users are a substantial financial burden to the community, strongly supporting the argument for greater treatment provision.
Garzón-Rodríguez, Cristina; Villavicencio-Chávez, Christian; Llorens-Torromé, Silvia; González-Barboteo, Jesús
2016-01-01
Introduction. Most clinical reports on methadone rotation describe outcomes in hospitalized patients. The few studies that have included outpatients are retrospective. The aim of this study was to assess the efficacy and safety of methadone as a second-line opioid in adult patients with advanced cancer after rotation in routine clinical practice at a palliative care outpatient clinic. Patients and Methods. This was a prospective, open-label study of 145 patients whose treatment was rotated from other opioids to methadone. Informed consent was obtained in all cases. The main outcome measure was change in the variable “worst pain” at day 28. Pain and pain interference were assessed with the Brief Pain Inventory, with side effects evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. Pain levels were evaluated at study entry and at days 3, 7, 9, 14, 21, and 28. Results. Rotation to methadone was performed for the following reasons: poor pain control (77.9%), opioid side effects (2.1%), or both (20%). The mean daily oral morphine equivalent dose before rotation was 193.7 mg. The median worst and average pain scores decreased significantly (p < .0001) from baseline to day 28: The median worst pain score decreased from 9 (interquartile range [IQR]: 8–10) to 6 (IQR: 3–8), and the median average pain score decreased from 6 (IQR: 5–7) to 4 (IQR: 2–5). The proportions of patients with moderate to severe worst and average pain decreased by 30.3% and 47.5%, respectively, by day 28. No increase in opioid toxicity was observed during the study. Conclusion. In outpatients with advanced cancer, rotation to methadone as a second-line opioid was efficacious and safe when using a tiered scheme with close follow-up by experienced health professionals. Implications for Practice: The results of this study, conducted prospectively under real clinical conditions, support the efficacy and safety of oral methadone as a second-line opioid in
Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats.
Farahmandfar, Maryam; Naghdi, Nasser; Karimian, Seyed Morteza; Kadivar, Mehdi; Zarrindast, Mohammad-Reza
2012-05-15
The present study investigated the effect of morphine sensitization on the impairment of spatial memory retrieval induced by acute morphine in adult male rats. Spatial memory was assessed by 2-day Morris water maze task which included training and test day. On the training day, rats were trained by a single training session of 8 trials. On the test day, a probe trial consisting of 60s free swim period without a platform and the visible test were administered. Morphine sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days without drug treatment before training. The results indicated that acute administration of morphine (7.5mg/kg, s.c.) before testing impaired spatial memory on the test day. Pre-test morphine-induced amnesia decreased in morphine-sensitized (15 and 20mg/kg, s.c.) rats. Improvement in spatial memory retrieval in morphine-sensitized rats was inhibited by once daily administration of naloxone (1 and 2mg/kg, s.c.) 30 min prior to the injection of morphine for three days. The results suggest that morphine sensitization reverses the impairment of spatial memory retrieval induced by acute morphine and it is implied that mu-opioid receptors may play an important role in this effect. Copyright © 2012 Elsevier B.V. All rights reserved.
2012-01-01
Background Although methadone has been used for the maintenance treatment of opioid dependence for decades, it was not introduced in China or Taiwan until 2000s. Methadone-drug interactions (MDIs) have been shown to cause many adverse effects. However, such effects have not been scrutinized in the ethnic Chinese community. Methods The study was performed in two major hospitals in southern Taiwan. A total of 178 non-HIV patients aged ≥ 20 years who had participated in the Methadone Maintenance Treatment Program (MMTP) ≥ 1 month were recruited. An MDI is defined as concurrent use of drug(s) with methadone that may result in an increase or decrease of effectiveness and/or adverse effect of methadone. To determine the prevalence and clinical characteristics of MDIs, credible data sources, including the National Health Insurance (NHI) database, face-to-face interviews, medical records, and methadone computer databases, were linked for analysis. Socio-demographic and clinical factors associated with MDIs and co-medications were also examined. Results 128 (72%) MMTP patients took at least one medication. Clinically significant MDIs included withdrawal symptoms, which were found among MMTP patients co-administered with buprenorphine or tramadol; severe QTc prolongation effect, which might be associated with use of haloperidol or droperidol; and additive CNS and respiratory depression, which could result from use of methadone in combination with chlorpromazine or thioridazine. Past amphetamine use, co-infection with hepatitis C, and a longer retention in the MMTP were associated with increased odds of co-medication. Among patients with co-medication use, significant correlates of MDIs included the male gender and length of co-medication in the MMTP. Conclusions The results demonstrate clinical evidence of significant MDIs among MMTP patients. Clinicians should check the past medical history of MMTP clients carefully before prescribing medicines. Because combinations of
Hughes, Alice A; Bogdan, Gregory M; Dart, Richard C
2007-01-01
Prescription opioids are abused throughout the United States. Several monitoring programs are in existence, however, none of these systems provide up-to-date information on prescription opioid abuse. This article describes the use of poison centers as a real-time, geographically specific, surveillance system for prescription opioid abuse and compares our system with an existing prescription drug abuse monitoring program, the Drug Abuse Warning Network (DAWN). Data were collected from eight geographically dispersed poison centers for a period of twelve months. Any call involving buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone was considered a case. Any case coded as intentional exposure (abuse, intentional misuse, suicide, or intentional unknown) was regarded as misuse and abuse. Comparative data were obtained from DAWN. Poison center rates of abuse and misuse were highest for hydrocodone at 3.75 per 100,000 population, followed by oxycodone at 1.81 per 100,000 population. DAWN emergency department (ED) data illustrate a similar pattern of abuse with most mentions involving hydrocodone and oxycodone. Poison center data indicate that people aged 18 to 25 had the highest rates of abuse. DAWN reported the majority of ED mentions among 35 to 44-year-olds. Geographically, Kentucky had the uppermost rates of abuse and misuse for all opioids combined at 20.69 per 100,000 population. CONCLUSIONS. Comparing poison center data to DAWN yielded mostly comparable results, including hydrocodone as the most commonly mentioned drug. Our results suggest poison center data can be used as an indicator for prescription opioid abuse and misuse and can provide timely, geographically specific information on prescription drug abuse.
Luong, Susan; Fu, Shanlin
2014-03-01
In vitro urine adulteration is a well-documented practice adopted by individuals aiming to evade detection of drug use, when required to undergo mandatory sports and workplace drug testing. Potassium nitrite is an effective urine adulterant due to its oxidizing potential, and has been shown to mask the presence of many drugs of abuse. However, limited research has been conducted to understand its mechanism of action, and to explore the possibility of the drugs undergoing direct oxidation to form stable reaction products. In this study, opiates including morphine, codeine, morphine-3-glucuronide and morphine-6-glucuronide were exposed to potassium nitrite in water and urine to mimic the process of nitrite adulteration. It was found that two stable reaction products were detected by liquid chromatography-mass spectrometry (LC-MS) when morphine and morphine-6-glucuronide were exposed to nitrite. Isolation and elucidation using spectrometric and spectroscopic techniques revealed that they were 2-nitro-morphine and 2-nitro-morphine-6-glucuronide, respectively. These reaction products were also formed when an authentic morphine-positive urine specimen was fortified with nitrite. 2-Nitro-morphine was found to be stable enough to undergo the enzymatic hydrolysis procedure and also detectable by gas chromatography-mass spectrometry (GC-MS) after forming a trimethylsilyl derivative. On the contrary, morphine-3-glucuronide did not appear to be chemically manipulated when exposed to potassium nitrite in urine. These reaction products are not endogenously produced, are relatively stable and can be monitored with both LC-MS and GC-MS confirmatory techniques. As a result, these findings have revealed the possibility for the use of 2-nitro-morphine and 2-nitro-morphine-6-glucuronide as markers for the indirect monitoring of morphine and morphine-6-glucuronide in urine specimens adulterated with nitrite. Copyright © 2013 John Wiley & Sons, Ltd.
Pravetoni, Marco; Vervacke, Jeffrey S.; Distefano, Mark D.; Tucker, Ashli M.; Laudenbach, Megan; Pentel, Paul R.
2014-01-01
Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund’s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID:24797666
Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.
Koek, Wouter; Gerak, Lisa R; France, Charles P
2015-08-01
In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9)-tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks.
Chiavaccini, Ludovica; Claude, Andrew K; Meyer, Robert E
We aimed to compare antinociceptive effects of IV infusions of morphine (M), morphine-lidocaine (ML), or morphine-lidocaine-ketamine (MLK) combined, in a mild-to-moderate pain model in dogs. Eighteen adult hounds were heavily sedated with IV morphine (0.2 mg/kg) and dexmedetomidine to undergo thoracic skin incisions. After reversal, dogs were randomly assigned to receive loading doses of lidocaine and ketamine (MLK), lidocaine and saline (ML), or equivalent volume of saline (M), followed by 18 hr constant infusions of morphine (0.12 mg/kg/hr), lidocaine (3 mg/kg/hr) and ketamine (0.6 mg/kg/hr); morphine (0.12 mg/kg/hr) and lidocaine (3 mg/kg/hr); or morphine (0.12 mg/kg/hr), respectively. Pain was assessed with Short Form Glasgow Composite Measure Pain Scale and mechanical nociception with von Frey filaments (VFFS). Data were analyzed with linear mixed model on ranks. Independently of treatment, Short Form Glasgow Composite Measure Pain Scale was significantly higher than baseline for 24 hr (p < .0001), while VFFS was significantly lower than baseline for 48 hr post-recovery (p < .0001), with no difference between MLK and M groups. The ML group recorded significantly lower VFFS (p = .02) than the M group for the entire study. In conclusion, there was no significant analgesic difference between MLK and M alone.
Dosing and Monitoring of Methadone in Pregnancy: Literature Review
Shiu, Jennifer R; Ensom, Mary H H
2012-01-01
Background: The pharmacokinetics of methadone is altered during pregnancy, but the most appropriate dosing and monitoring regimen has yet to be identified. Objective: To review dosing and monitoring of methadone therapy in pregnancy. Methods: A literature search was performed in several databases (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews) from inception to May 2012. The search terms were “methadone”, “pregnancy”, “pharmacokinetic”, “clearance”, “metabolism”, “therapeutic drug monitoring”, and “methadone dosing”. Additional papers were identified by searching the bibliographies of primary and review articles. All English-language primary articles related to methadone pharmacokinetics in pregnancy were included. Articles not related to maternal outcomes were excluded. Results: The literature search yielded 1 case report and 10 studies discussing use of methadone by pregnant women. Methadone pharmacokinetics in pregnancy has been studied in 3 pharmacokinetic trials, and split dosing of methadone in pregnant women has been described in 1 case report and 3 dosing trials. Only 4 trials evaluated monitoring of methadone concentration in pregnancy. The studies included in this review confirm that methadone pharmacokinetics is altered in pregnancy and is potentially correlated with increases in maternal withdrawal symptoms. Insufficient evidence is available to warrant routine monitoring of serum methadone concentrations in pregnant women with opioid dependence. Conclusions: Few studies of methadone pharmacokinetics and therapeutic drug monitoring are available for pregnant women with opioid dependence. Although it is known that methadone pharmacokinetics is altered in pregnancy, there is insufficient evidence to guide dosage adjustments and serum concentration monitoring. Until further studies are available, regular follow-up of maternal withdrawal symptoms and empiric
The nature of methadone diversion in England: a Merseyside case study
2012-01-01
Background Methadone maintenance treatment (MMT) is a key element in treatment for opiate addiction; however concerns about the diversion of methadone remain. More current empirical data on methadone diversion are required. This research investigated the market for diverted methadone in Merseyside, UK, in order to provide a case study which can be transferred to other areas undertaking methadone maintenance treatment on a large scale. Methods Questionnaires were completed (in interview format) with 886 past year users of methadone recruited both in and out of prescribing agencies. Topic areas covered included current prescribing, obtaining and providing methadone, reasons for using illicit methadone and other drug use. Results Large proportions of participants had obtained illicit methadone for use in the past year with smaller proportions doing so in the past month. Proportions of participants buying and being given methadone were similar. Exchange of methadone primarily took place between friends and associates, with 'dealers' rarely involved. Gender, age, whether participant's methadone consumption was supervised and whether the aims of their treatment had been explained to them fully, influenced the extent to which participants were involved in diverting or using diverted methadone. Conclusion Methadone diversion is widespread although drug users generally do not make use of illicit methadone regularly (every month). The degree of altruism involved in the exchange of methadone does not negate the potential role of this action in overdose or the possibility of criminal justice action against individuals. Treatment agencies need to emphasise these risks whilst ensuring that treatment aims are effectively shared with clients to ensure adherence to treatment. PMID:22243982
Eckart, K; Röhrich, J; Breitmeier, D; Ferner, M; Laufenberg-Feldmann, R; Urban, R
2015-09-15
A liquid chromatography-tandem mass spectrometry method using electrospray ionization in positive ionization mode was developed for the simultaneous detection of multiple opioid-type drugs in plasma. The presented assay allows the quantitative determination of alfentanil, buprenorphine, codeine, desomorphine, dextromethorphan, dextrorphan, dihydrocodeine, dihydromorphine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, pholcodine, piritramide, remifentanil, sufentanil, and tramadol as well as the metabolites 6-monoacetylmorphine, bisnortilidine, morphine-3-glucuronide, morphine-6-glucuronide, naltrexol, norbuprenorphine, norfentanyl, norpethidine, nortilidine, and O-desmethyltramadol. Serum and blood samples were purified by solid-phase extraction. The analytes were separated on a phenyl-hexyl (100mm) column by formic acid/acetonitrile gradient elution using an UPLC 1290 Infinity coupled with a 6490 Triple Quadrupole mass spectrometer. The limits of detection ranged from 0.02 to 0.6ng/mL and the lower limits of quantification ranged from 0.1 to 2.0ng/mL. The calibration curves were linear between Calibration Levels 1-6 for all 35 substances. Recovery rates ranged between 51 and 88% for all compounds except alfentanil, bisnortilidine, pethidine, and morphine-3-glucuronide. The matrix effect ranged from 86% for ethylmorphine to 105% for desomorphine. Using the validation procedure proposed by the German Society of Toxicological and Forensic Chemistry, acceptable precision and accuracy data for almost all analytes were obtained. The method was successfully applied to 206 authentic serum samples provided by the palliative and intensive care units of the University Medical Center and the police authorities. Furthermore, a suspected fatal intoxication is demonstrated by an analysis of the sufentanil in post mortem body fluids and tissues. Copyright © 2015 Elsevier B.V. All
Fathi, Marzieh; Zare, Mohammad Amin; Bahmani, Hamid Reza; Zehtabchi, Shahriar
2015-09-01
This randomized clinical trial compares the efficacy and safety of oral oxycodone (an oral opioid) with naproxen (a nonsteroidal anti-inflammatory drug) in acute pain control in patients with soft tissue injury. It also evaluates the need for additional doses of analgesics in the first 24 hours of discharge from emergency department (ED). Adult (>18 years old) patients with soft tissue injuries were enrolled in a teaching urban ED. Subjects were randomly allocated to receive a single dose of oral oxycodone (5 mg) or oral naproxen (250 mg). Pain scores and drugs' adverse effects were assessed before, 30 minutes, and 60 minutes after medication. efficacy in pain control (reduction in pain scale >2 points) and safety (rate of side effects). The need for additional pain medication after discharge was assessed by follow-up phone call 24 hours after discharge. A total of 150 patients were enrolled. Pain scores were similar in oxycodone vs naproxen groups before (6.21 ± 0.9 in vs 6.0 ± 1.0), 30 minutes (4.5 ± 1.4 vs 4.4 ± 1.2), and 60 minutes (2.5 ± 1.3 in vs 2.6 ± 1.3) after medication, respectively. Twelve (16.0%) patients in oral oxycodone group and 5 (6.6%) patients in naproxen group needed more analgesics in first 24 hours after ED discharge. Adverse effects were more common in oxycodone group (statistically significant difference). The most common adverse effects in oxycodone group were nausea, (13.3%); vomiting, (8.0%); dizziness, (5.3%); drowsiness, 3 (4.0%); and pruritis, (2.7%). Oral oxycodone is as effective as naproxen in soft tissue injury pain control but has a less favorable safety profile. Copyright © 2015 Elsevier Inc. All rights reserved.
2010-01-01
Background Methadone is a synthetic opiate mu receptor agonist that is widely used to substitute for illicit opiates in the management of opiate dependence. It helps prevent opiate users from injecting and sharing needles which are vehicles for the spread of HIV and other blood borne viruses. This study has the objective of determining the utility of daily methadone dose to predict retention rates and re-injecting behaviour among opiate dependents. Methods Subjects comprised opiate dependent individuals who met study criteria. They took methadone based on the Malaysian guidelines and were monitored according to the study protocols. At six months, data was collected for analyses. The sensitivity and specificity daily methadone doses to predict retention rates and re-injecting behaviour were evaluated. Results Sixty-four patients volunteered to participate but only 35 (54.69%) remained active and 29 (45.31%) were inactive at 6 months of treatment. Higher doses were significantly correlated with retention rate (p < 0.0001) and re-injecting behaviour (p < 0.001). Of those retained, 80.0% were on 80 mg or more methadone per day doses with 20.0% on receiving 40 mg -79 mg. Conclusions We concluded that a daily dose of at least 40 mg was required to retain patients in treatment and to prevent re-injecting behaviour. A dose of at least 80 mg per day was associated with best results. PMID:21167035
Exploring the Etiologic Factors and Dynamics of Prescription Drug Abuse in Southwest Virginia
Redican, Kerry J; Marek, Lydia I; Brock, Donna JP; McCance-Katz, Elinore F
2012-01-01
Background: Prescription drug abuse in Southwest Virginia is a serious problem affecting indi-viduals, families, and communities. The aim of this study was to characterize and understand the extent of the prescription drug abuse problem in Southwest, Virginia as well as the dynamics that surround that abuse. More specifically, the study focused on learning the extent of the problem along with which prescription drugs are typically used prior to entering treatment, reasons for prescription drug and methadone abuse, and the sources for prescription drug use, misuse and abuse. Methods: Mixed methodology was employed which included surveying methadone clinic con-sumers at two treatment clinics in Southwest, Virginia and seven focus field interviews of key community stakeholders. Results: The extent of prescription drug abuse is high and that the demographics of prescription drug users are getting younger and now involve more males than females. Oxycodone, hydroco¬done, methadone, and morphine were the most commonly used drugs prior to enrollment in the clinics with over one-half of methadone-maintained consumers reporting that they had abused benzodiazepines along with opioids. Focus groups and clinic consumer data highlighted the key etiological factors in prescription drug abuse: use (due to workforce related injuries) turning to abuse, wanting to get high, overprescribing and physician issues, lack of information, and cultural acceptance of drug taking as problem solving behavior. The two most common sources for the abused prescription drugs were physicians and street dealers. Conclusions: A constellation of conditions have led to the epidemic of prescription drug abuse in Southwest Virginia, including poverty, unemployment and work-related injuries, besides, public health education programs on the dangers of prescription opiate misuse and abuse are urgently needed. PMID:24688929
Meissner, Konrad; Blood, Jane; Francis, Amber M.; Yermolenka, Viktar; Kharasch, Evan D.
2015-01-01
Background Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans. Methods Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 hr). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures). Results Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis, or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4 ± 0.4 and 1.3 ± 0.5 mm/mg, respectively) and IV methadone (3.1 ± 1.0 and 3.2 ± 0.8 mm respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain. Conclusions Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution. PMID:25072223
Wu, Li-Tzy; Blazer, Dan G.; Stitzer, Maxine L.; Patkar, Ashwin A.; Blaine, Jack D.
2009-01-01
We sought to determine the prevalence, patterns, and correlates of past-month illicit methadone use and history of regular illicit use among stimulant-using methadone maintenance treatment patients. We obtained self-reported information on illicit methadone use from 383 participants recruited from six community-based methadone maintenance programs. Overall, 1.6% of participants reported illicit use in the past month, and 4.7% reported a history of regular use. Younger age and history of outpatient psychological treatment were associated with increased odds of past-month illicit use. Illicit methadone use among patients in maintenance programs is infrequent; however, a number of factors may increase risk of illicit use. PMID:18612886
Bioavailabilities of rectal and oral methadone in healthy subjects
Dale, Ola; Sheffels, Pamela; Kharasch, Evan D
2004-01-01
Aims Rectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. Methods Seven healthy subjects (six males, one female, aged 20–39 years) received 10 mg d5-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d0-methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was peformed at the same time as blood sampling. Results The mean absolute rectal bioavalability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. Conclusions Rectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care. PMID:15255797
PASHAEI, Tahereh; SHOJAEIZADEH, Davoud; RAHIMI FOROUSHANI, Abbas; GHAZITABATABAE, Mahmoud; MOEENI, Maryam; RAJATI, Fatemeh; M RAZZAGHI, Emran
2013-01-01
Background: To evaluate the effectiveness of a relapse prevention cognitive-behavioral model, based on Marlatt treatment approach, in Opioid-dependent patients participating in the Methadone Maintenance Treatment (MMT) in Iran. Methods: The study consisted of 92 individuals treated with methadone in Iranian National Center of Addiction Studies (INCAS). Participants were randomized into two groups: educational intervention group (N=46) and control group (N=46). The intervention was comprised of 10 weekly 90 minute sessions, done during a period of 2.5 months based on the most high risk situations determined using Inventory Drug Taking Situation instrument. Relapse was defined as not showing up for MMT, drug use for at least 5 continuous days, and a positive urinary morphine test. Results: While, only 36.4% of the intervention group relapsed into drug use, 63.6% of the control group relapsed. The result of the logistic regressions showed that the odd ratio of the variable of intervention program for the entire follow up period was 0.43 (P<0.01). Further, the odd ratio of this variable in one month, three months, and 195 days after the therapy were 0.48 (P<.03), 0.31 (P<.02), and 0.13 (P<.02) respectively that revealed that on average, the probability of relapse among individuals in the intervention group was lower than patients in control group Conclusion: Relapse prevention model based on Marlatt treatment approach has an effective role in decreasing relapse rate. This model can be introduced as a complementary therapy in patients treated with methadone maintenance. PMID:26056645
Pashaei, Tahereh; Shojaeizadeh, Davoud; Rahimi Foroushani, Abbas; Ghazitabatabae, Mahmoud; Moeeni, Maryam; Rajati, Fatemeh; M Razzaghi, Emran
2013-08-01
To evaluate the effectiveness of a relapse prevention cognitive-behavioral model, based on Marlatt treatment approach, in Opioid-dependent patients participating in the Methadone Maintenance Treatment (MMT) in Iran. The study consisted of 92 individuals treated with methadone in Iranian National Center of Addiction Studies (INCAS). Participants were randomized into two groups: educational intervention group (N=46) and control group (N=46). The intervention was comprised of 10 weekly 90 minute sessions, done during a period of 2.5 months based on the most high risk situations determined using Inventory Drug Taking Situation instrument. Relapse was defined as not showing up for MMT, drug use for at least 5 continuous days, and a positive urinary morphine test. While, only 36.4% of the intervention group relapsed into drug use, 63.6% of the control group relapsed. The result of the logistic regressions showed that the odd ratio of the variable of intervention program for the entire follow up period was 0.43 (P<0.01). Further, the odd ratio of this variable in one month, three months, and 195 days after the therapy were 0.48 (P<.03), 0.31 (P<.02), and 0.13 (P<.02) respectively that revealed that on average, the probability of relapse among individuals in the intervention group was lower than patients in control group. Relapse prevention model based on Marlatt treatment approach has an effective role in decreasing relapse rate. This model can be introduced as a complementary therapy in patients treated with methadone maintenance.
Winhusen, Theresa; Wilder, Christine; Wexelblatt, Scott L; Theobald, Jeffrey; Hall, Eric S; Lewis, Daniel; Van Hook, James; Marcotte, Michael
2014-09-01
In recent years, the U.S. has experienced a significant increase in the prevalence of pregnant opioid-dependent women and of neonatal abstinence syndrome (NAS), which is caused by withdrawal from in-utero drug exposure. While methadone-maintenance currently is the standard of care for opioid dependence during pregnancy, research suggests that buprenorphine-maintenance may be associated with shorter infant hospital lengths of stay (LOS) relative to methadone-maintenance. There is no "gold standard" treatment for NAS but there is evidence that buprenorphine, relative to morphine or methadone, treatment may reduce LOS and length of treatment. Point-of-care clinical trial (POCCT) designs, maximizing external validity while reducing cost and complexity associated with classic randomized clinical trials, were selected for two planned trials to compare methadone to buprenorphine treatment for opioid dependence during pregnancy and for NAS. This paper describes design considerations for the Medication-assisted treatment for Opioid-dependent expecting Mothers (MOMs; estimated N = 370) and Investigation of Narcotics for Ameliorating Neonatal abstinence syndrome on Time in hospital (INFANTs; estimated N = 284) POCCTs, both of which are randomized, intent-to-treat, two-group trials. Outcomes would be obtained from participants' electronic health record at three participating hospitals. Additionally, a subset of infants in the INFANTs POCCT would be from mothers in the MOMs POCCT and, thus, potential interaction between medication treatment of mother and infant could be evaluated. This pair of planned POCCTs would evaluate the comparative effectiveness of treatments for opioid dependence during pregnancy and for NAS. The results could have a significant impact on practice. Copyright © 2014 Elsevier Inc. All rights reserved.
Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A.; Mao, Jianren
2014-01-01
Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether 1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and 2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3 to 4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10 mg/kg, subcutaneous, s.c.), followed 30 min later by either saline or midazolam (2 mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10 mg/kg, s.c.), midazolam (2 mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor 10 nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism. PMID:24713351
Kokubun, Hideya; Ouki, Makiko; Matoba, Motohiro; Kubo, Hiroaki; Hoka, Sumio; Yago, Kazuo
2005-03-01
We developed an HPLC procedure using electrochemical detection for the quantitation of oxycodone and hydrocotarnine in cancer patients serum. An eluent of methanol:acetonitrile:5 mM pH 8 phosphate buffer (2:1:7) was used for the mobile phase. The calibration curve was linear in the range from 10 ng/mL to 100 ng/mL. The recovery of oxycodone and hydrocotarnine was 97.2% and 90.5%, respectively. The relative standard deviations within-runs and between-runs for the assay of oxycodone or hydrocotarnine were less than 4.8%. The method developed here was better than the method reported previously.
Ramírez Fernández, María del Mar; Van Durme, Filip; Wille, Sarah M R; di Fazio, Vincent; Kummer, Natalie; Samyn, Nele
2014-06-01
The aim of this work was to automate a sample preparation procedure extracting morphine, hydromorphone, oxymorphone, norcodeine, codeine, dihydrocodeine, oxycodone, 6-monoacetyl-morphine, hydrocodone, ethylmorphine, benzoylecgonine, cocaine, cocaethylene, tramadol, meperidine, pentazocine, fentanyl, norfentanyl, buprenorphine, norbuprenorphine, propoxyphene, methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine from urine samples. Samples were extracted by solid-phase extraction (SPE) with cation exchange cartridges using a TECAN Freedom Evo 100 base robotic system, including a hydrolysis step previous extraction when required. Block modules were carefully selected in order to use the same consumable material as in manual procedures to reduce cost and/or manual sample transfers. Moreover, the present configuration included pressure monitoring pipetting increasing pipetting accuracy and detecting sampling errors. The compounds were then separated in a chromatographic run of 9 min using a BEH Phenyl analytical column on a ultra-performance liquid chromatography-tandem mass spectrometry system. Optimization of the SPE was performed with different wash conditions and elution solvents. Intra- and inter-day relative standard deviations (RSDs) were within ±15% and bias was within ±15% for most of the compounds. Recovery was >69% (RSD < 11%) and matrix effects ranged from 1 to 26% when compensated with the internal standard. The limits of quantification ranged from 3 to 25 ng/mL depending on the compound. No cross-contamination in the automated SPE system was observed. The extracted samples were stable for 72 h in the autosampler (4°C). This method was applied to authentic samples (from forensic and toxicology cases) and to proficiency testing schemes containing cocaine, heroin, buprenorphine and methadone, offering fast and reliable results. Automation resulted in improved precision and accuracy, and a minimum operator intervention, leading to safer sample
Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo
2015-09-14
Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Dosing adjustments in postpartum patients maintained on buprenorphine or methadone.
Jones, Hendrée E; Johnson, Rolley E; O'Grady, Kevin E; Jasinski, Donald R; Tuten, Michelle; Milio, Lorraine
2008-06-01
Scant scientific attention has been given to examining the need for agonist medication dose changes in the postpartum period. Study objectives were: 1) to determine the need for medication dose adjustments in participants stabilized on buprenorphine or methadone 3 weeks before and 4 weeks after delivery, and 2) to evaluate the need for methadone dose adjustments during the first 7 days in participants transferred from buprenorphine to methadone at 5 weeks postpartum. Participants were opioid-dependent pregnant women who had completed a randomized, double-blind, double-dummy, flexible dosing comparison of buprenorphine to methadone. Participants received a stable dose of methadone (N = 10) or buprenorphine (N = 8) before and 4 weeks after delivery. Buprenorphine-maintained participants were transferred to methadone at 5 weeks postpartum. There were no significant differences predelivery and/or postdelivery between the buprenorphine and methadone conditions in the mean ratings of dose adequacy, "liking," "hooked," and "craving" of heroin or cocaine. Patient response to the conversion from buprenorphine to methadone seems variable. Buprenorphine-maintained participants required dose changes postpartum only after they transferred to methadone. Regardless of type of medication, postpartum patients should be monitored for signs of overmedication.
The disposition and behavioral effects of methadone in Greyhounds.
KuKanich, Butch; Borum, Stacy L
2008-05-01
To determine the behavioral effects and pharmacokinetics of methadone in healthy Greyhounds. Prospective experimental study. Three male and three female healthy Greyhounds. Methadone hydrochloride, 0.5 mg kg(-1) IV (equivalent to 0.45 mg kg(-1) methadone base), was administered as an IV bolus. Trained observers subjectively assessed the behavioral effects of methadone. Blood samples were obtained at predetermined time points and plasma methadone concentrations were measured by liquid chromatography with tandem mass spectrometry. Pharmacokinetic variables were estimated with computer software. Methadone was well tolerated by the dogs with panting and defecation observed as adverse effects. Mild sedation was present, but no vomiting, excitement, or dysphoria was observed. The elimination half-life, volume of distribution, and plasma clearance were 1.53 +/- 0.18 hours, 7.79 +/- 1.87 L kg(-1), and 56.04 +/- 9.36 mL minute(-1) kg(-1), respectively. Methadone was well tolerated by Greyhounds. The volume of distribution was larger than expected, with resultant lower plasma concentrations than expected. Higher doses may need to be administered to Greyhounds in comparison with non-Greyhound dogs in order to achieve similar plasma drug concentrations. A dosage of 1-1.5 mg kg(-1) every 3-4 hours is suggested for future studies of analgesic efficacy of methadone in Greyhounds.
Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.
Webster, Lynn R
2007-08-01
Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.
Experience-Seeking Characteristics of Methadone Clients.
ERIC Educational Resources Information Center
Kohn, Paul M.; And Others
1979-01-01
Methadone clients scored higher than controls on measures reflecting boredom, desire for change and attraction to physically thrilling activities. Correlations of these measures with length of most recent dependency before treatment, time on program, and time since initial dependency suggest peculiarities of methadone clients antedated involvement…
Fadaei, Atefeh; Gorji, Hossein Miladi; Hosseini, Shahrokh Makvand
2015-01-15
Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10 mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45 min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (P<0.05). Also, the swimmer morphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (P<0.05), higher levels of sucrose preference (P<0.001) than sedentary rats. Voluntary consumption of oral morphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (P<0.01). We conclude that regular swimming exercise reduces the severity of morphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence. Copyright © 2014 Elsevier B.V. All rights reserved.
The Source of Methadone in Overdose Deaths in Western Virginia in 2004
Weimer, Melissa B.; Korthuis, P. Todd; Behonick, George S.; Wunsch, Martha J.
2011-01-01
Objectives Methadone-related overdose deaths increased in the United States by 468% from 1999 to 2005. Current studies associate the nonmedical use of methadone with methadone-related deaths. This study describes medical examiner cases in rural Virginia in 2004 with methadone identified by toxicology and compares cases according to source of methadone. Methods In 2004, all intentional and unintentional poisoning deaths from the Office of The Chief Medical Examiner, Western District of Virginia, were reviewed to identify cases in which methadone was a direct or contributing cause of death. The Virginia Prescription Monitoring Program was reviewed for prescription opioids in the name of these identified decedents. Decedent participation in local opioid treatment programs (OTP) was also assessed. Results The source of methadone in the 61 methadone-related overdose deaths was mostly nonprescribed (67%), although 28% of decedents were prescribed methadone for analgesia. Only 5% of decedents were actively enrolled in an OTP. The majority of deaths were attributed to polysubstance overdose. Conclusions The majority of methadone overdose deaths in this study were related to illicit methadone use, rather than prescribed or OTP uses. Interventions to decrease methadone-related deaths should focus on reduction of nonprescription use of methadone. PMID:21844834
Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W.
2017-01-01
Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. PMID:18468954
Dhalla, Irfan A.; Mamdani, Muhammad M.; Sivilotti, Marco L.A.; Kopp, Alex; Qureshi, Omar; Juurlink, David N.
2009-01-01
Introduction Opioid-related mortality appears to be increasing in Canada. We examined the true extent of the problem and the impact of the introduction of long-acting oxycodone. Methods We examined trends in the prescribing of opioid analgesics in the province of Ontario from 1991 to 2007. We reviewed all deaths related to opioid use between 1991 and 2004. We linked 3271 of these deaths to administrative data to examine the patients’ use of health care services before death. Using time-series analysis, we determined whether the addition of long-acting oxycodone to the provincial drug formulary in January 2000 was associated with an increase in opioid-related mortality. Results From 1991 to 2007, annual prescriptions for opioids increased from 458 to 591 per 1000 individuals. Opioid-related deaths doubled, from 13.7 per million in 1991 to 27.2 per million in 2004. Prescriptions of oxycodone increased by 850% between 1991 and 2007. The addition of long-acting oxycodone to the drug formulary was associated with a 5-fold increase in oxycodone-related mortality (p < 0.01) and a 41% increase in overall opioid-related mortality (p = 0.02). The manner of death was deemed unintentional by the coroner in 54.2% and undetermined in 21.9% of cases. Use of health care services in the month before death was common: for example, of the 3066 patients for whom data on physician visits were available, 66.4% had visited a physician in the month before death; of the 1095 patients for whom individual-level prescribing data were available, 56.1% had filled a prescription for an opioid in the month before death. Interpretation Opioid-related deaths in Ontario have increased markedly since 1991. A significant portion of the increase was associated with the addition of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional. The frequency of visits to a physician and prescriptions for opioids in the month before death suggests a missed
Largent-Milnes, Tally M; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H; Vanderah, Todd W
2008-08-01
Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting
The Mechanism of Autoinduction of Methadone N-demethylation in Human Hepatocytes
Campbell, Scott D.; Crafford, Amanda; Williamson, Brian L.; Kharasch, Evan D.
2013-01-01
Background There is considerable inter-and intraindividual variability in methadone metabolism and clearance. Methadone dosing is particularly challenging during initiation of therapy, due to time-dependent increases in hepatic clearance (autoinduction). Although methadone N-demethylation is catalyzed in vitro by cytochrome P4502B6 (CYP2B6) and CYP3A4, and clearance in vivo depends on CYP2B6, mechanism(s) of autoinduction are incompletely understood. In this investigation we determined mechanism(s) of methadone autoinduction using human hepatocytes. Methods Fresh human hepatocytes were exposed to 0.1-10 μM methadone for 72 hr. Cells were washed and methadone N-demethylation assessed. CYP2B6, CYP3A4, and CYP3A5 mRNA, protein expression (by gel-free high performance liquid chromatography-mass spectrometry) and catalytic activity (bupropion hydroxylation and alfentanil dealkylation for CYP2B6 and CYP3A4/5, respectively) were measured. Mechanisms of CYP induction were characterized using pregnane X receptor and constitutive androstane receptor reporter gene assays. Results Methadone (10 μM) increased methadone N-demethylation 2-fold, CYP2B6 and CYP3A4 mRNA 3-fold, and protein expression 2-fold. CYP3A5 mRNA was unchanged. CYP2B6 and CYP3A4/5 activities increased 2-fold. Induction by methadone enantiomers (R- vs S-methadone) did not differ. Induction was relatively weak compared with maximum induction by phenobarbital and rifampin. Lower methadone concentrations had smaller effects. Methadone was an agonist for the pregnane X receptor but not the constitutive androstane receptor. Conclusions Methadone caused concentration-dependent autoinduction of methadone N-demethylation in human hepatocytes, related to induction of CYP2B6 and CYP3A4 mRNA expression, protein expression, and catalytic activity. Induction was related to pregnane X receptor but not constitutive androstane receptor activation. These in vitro findings provide mechanistic insights into clinical
Attitudes toward buprenorphine and methadone among opioid-dependent individuals
Schwartz, Robert P.; Kelly, Sharon M.; O'Grady, Kevin E.; Mitchell, Shannon Gwin; Peterson, James A.; Reisinger, Heather Schacht; Agar, Michael H.; Brown, Barry S.
2009-01-01
Attitudes and beliefs about drug abuse treatment have long been known to shape response to that treatment. Two major pharmacological alternatives are available for opioid dependence: methadone, which has been available for the past 40 years, and buprenorphine, a recently-introduced medication. This mixed methods study examined the attitudes of opioid-dependent individuals toward methadone and buprenorphine. A total of 195 participants (n = 140 who were enrolling in one of 6 Baltimore area methadone programs and n = 55 who were out-of-treatment) were administered the Attitudes toward Methadone and toward Buprenorphine Scales and a subset (n = 46) received an ethnographic interview. In-treatment group had significantly more positive attitudes toward methadone than did the out-of-treatment group (p < .001), while they did not differ in their attitudes toward buprenorphine. Both groups had significantly more positive attitudes toward buprenorphine than methadone. Addressing these attitudes may increase treatment entry and retention. PMID:18770082
Rhodes, Tim
2018-03-01
This analysis treats the recent introduction of methadone treatment in Kenya as a case of 'evidence-making intervention'. Using 30 qualitative interviews with people in receipt of methadone treatment in Nairobi, Kenya, methadone's becoming is treated as an effect of its narrative and material implementations. The interviews are shown to enact a narrative of methadone recovery potential towards normalcy beyond addiction. Such recovery potential is materialised in practice through social interactions wherein methadone's embodied effects are seen to be believed. Here, the recovering body affects others' recovery potential. In a context of competing claims about methadone's effects, including the circulation of doubt about experimenting with methadone treatment, embodied methadone effect helps moderate the multiverse of methadone knowledge. The material dynamics of methadone treatment delivery also affect its recovery potential, with the methadone queue enacting a rationing of recovery hope. Here, the experience of methadone's implementation loops back to a life with drugs. I conclude that there is a coexistence of potentiality and actuality, a 'methadone multiple', produced through its narrative and material implementations. Copyright © 2018 Elsevier Ltd. All rights reserved.
Hanna, Julia; Foster, David JR; Salter, Amy; Somogyi, Andrew A; White, Jason M; Bochner, Felix
2005-01-01
Aims To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state. Methods Six non-holder subjects were studied on three occasions at 7–16 day intervals; doses (20–170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10–12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value. Results Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2–12.8 for pharmacodynamic measures, and 1.3–7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged ≤2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging ≤2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance. Conclusions Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1–2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population. PMID:16187972
Jacobs, W J; Zellner, D A; LoLordo, V M; Riley, A L
1981-06-01
In the following experiment, multiple injections of morphine sulfate following the acquisition of a morphine-induced taste aversion had no effect on the retention of the previously acquired aversion. Post-conditioning injections of morphine resulted in the development of physical dependence to morphine and led to a decrement in the ability of morphine to induce a subsequent aversion to a second novel taste. This failure of post-conditioning exposures to morphine to affect a previously acquired morphine-induced taste aversion even though tolerance to morphine had occurred was discussed in the context of Rescorla's event-memory model of conditioning.
Kunko, P M; Smith, J A; Wallace, M J; Maher, J R; Saady, J J; Robinson, S E
1996-06-01
Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that the following prenatal/postnatal exposure groups were obtained: water/water, methadone/water, water/methadone and methadone/methadone. Methadone slightly reduced litter size, particularly the number of male offspring, and reduced litter birth weight. The induction or maintenance of physical dependence in the postnatal methadone exposure groups was confirmed by an experiment in which PD19 pups were challenged with naloxone (1 mg/kg, s.c.). Methadone concentrations were assayed in pup brain on postnatal days 4, 10 and 22. Postnatal exposure to methadone via maternal milk produced measurable levels of methadone which decreased with age. Neuromuscular and physical development were assessed. Exposure to methadone accelerated acquisition of the righting reflex, but tended to delay the acquisition of the negative geotaxic response. Postnatal exposure to methadone was associated with decreased somatic growth as measured through postnatal day 21. The older pups (postnatal day 21) exposed to methadone exhibited variations in activity levels: pups exposed to methadone both prenatally and postnatally exhibited the least amount of spontaneous locomotor activity and pups exposed only postnatally exhibited the most activity. Therefore, it is possible to induce and/or maintain physical dependence via lactation in rat pups fostered to methadone-treated dams. Perinatal exposure to methadone by this route produces several subtle disruptions of pup development in the absence of gross maternal or fetal toxicity.
Webster, Lynn R.; Smith, Michael D.; Lawler, John; Lindhardt, Karsten; Dayno, Jeffrey M.
2017-01-01
Abstract Objective. To compare the relative human abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets. Methods. A randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover study was performed with adult volunteers who were experienced, nondependent, recreational opioid users. After intranasal (IN) administration of manipulated high-volume (HV) morphine-ADER-IMT (60 mg), participants were randomized (1:1:1:1) to receive IN manipulated low-volume (LV) morphine ER (60 mg), IN manipulated LV morphine-ADER-IMT, intact oral morphine-ADER-IMT (60 mg), and placebo in crossover fashion. Pharmacodynamic and pharmacokinetic assessments included peak effect of drug liking (Emax; primary endpoint) using drug liking visual analog scale (VAS) score, Emax using overall drug liking, and take drug again (TDA) VASs scores, and mean abuse quotient (AQ), a pharmacokinetic parameter associated with drug liking. Results. Forty-six participants completed the study. After insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT, drug liking Emax was significantly lower (P < 0.0001) compared with IN morphine ER. Overall drug liking and TDA Emax values were significantly lower (P < 0.0001) after insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT compared with IN morphine ER. Mean AQ was lower after insufflation of HV (9.2) and LV (2.3) morphine-ADER-IMT or ingestion of oral morphine-ADER-IMT (5.5) compared with insufflation of LV morphine ER (37.2). Conclusions. All drug liking, take drug again, and abuse quotient endpoints support a significantly lower abuse potential with insufflation of manipulated morphine-ADER-IMT compared with manipulated and insufflated non-AD ER morphine. PMID:27651510
Disposition of nasal, intravenous, and oral methadone in healthy volunteers.
Dale, Ola; Hoffer, Christine; Sheffels, Pamela; Kharasch, Evan D
2002-11-01
Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers. The study was approved by the Institutional Review Board of the University of Washington, Seattle. Eight healthy volunteers (6 men and 2 women) aged 19 to 33 years were enrolled after informed written consent was obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or intravenously on 3 separate occasions in a crossover design. Nasal methadone (50 mg/mL in aqueous solution) was given as a 100-microL spray in each nostril (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography-mass spectrometry analyses of methadone and the metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was measured by noninvasive infrared pupilometry coincident with blood sampling. Nasal uptake of methadone was rapid, with maximum plasma concentrations occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral methadone, on the basis of dark-adapted pupil diameter, were reached in about 15 minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24, 10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects reported that nasal methadone caused a burning sensation. Nasal administration of methadone results in rapid absorption and onset of effect and high bioavailability, which was greater than that reported for other nasal opioids, with a similar duration of effect. Nasal administration may be an alternative route of methadone administration; however, improved formulations are desirable to reduce nasal irritation.
Webster, Lynn R.; Lawler, John; Lindhardt, Karsten; Dayno, Jeffrey M.
2017-01-01
Objective. To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods. This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results. Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact (P < 0.0001) or manipulated (P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions. Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products. PMID:27633773
Natoli, Silvia; Lazzari, Marzia; Carpenedo, Roberta; Palombo, Elisa; Silvi, Maria Beatrice; Mammucari, Massimo; Dauri, Mario
2016-06-01
Oxycodone is one of the most commonly used opioid analgesics in the clinical management of pain. The present retrospective analysis aimed to determine the dose of oxycodone that could achieve effective control of moderate pain when combined with a fixed dose of acetaminophen, and the time required to reach a clinically relevant reduction in intensity of pain. Data of patients treated with a combination of oxycodone (5, 10, and 20 mg) and acetaminophen (325 mg) were evaluated for gender, current disease condition, basal pain intensity, total daily dose, days of controlled pain at the initial low dose, and pain intensity after treatment using a numeric pain rating scale. Data from a total of 491 patients were assessed; of these 93.5% of patients experienced persistent non-cancer pain and had an average baseline pain score of 5.68 ± 1.35. For the overall population, the pain score was reduced to 2.49 ± 1.71 with a mean dose of 8.68 ± 4.96 mg oxycodone after 21.60 ± 6.12 days of treatment with the combination. Almost 97% of the patients who reported relief of pain received 1.61 ± 0.67 doses of oxycodone 5 mg combined with 325 mg of acetaminophen. A low-dose combination of oxycodone with acetaminophen can be effective in the management of moderate pain and may help in reducing the treatment-associated adverse reactions and drug dependence. Sponsorship for article processing charges was provided by Molteni Farmaceutici, Florence, Italy.
Chilcoat, Howard D; Coplan, Paul M; Harikrishnan, Venkatesh; Alexander, Louis
2016-08-01
Doctor-shopping (obtaining prescriptions from multiple prescribers/pharmacies) for opioid analgesics produces a supply for diversion and abuse, and represents a major public health issue. An open cohort study assessed changes in doctor-shopping in the U.S. for a brand extended release (ER) oxycodone product (OxyContin) and comparator opioids before (July, 2009 to June, 2010) versus after (January, 2011 to June, 2013) introduction of reformulated brand ER oxycodone with abuse-deterrent properties, using IMS LRx longitudinal data covering >150 million patients and 65% of retail U.S. prescriptions. After its reformulation, the rate of doctor-shopping decreased 50% (for 2+ prescribers/3+ pharmacies) for brand ER oxycodone, but not for comparators. The largest decreases in rates occurred among young adults (73%), those paying with cash (61%) and those receiving the highest available dose (62%), with a 90% decrease when stratifying by all three characteristics. The magnitude of doctor-shopping reductions increased with increasing number of prescribers/pharmacies (e.g., 75% reduction for ≥2 prescribers/≥4 pharmacies). The rate of doctor-shopping for brand ER oxycodone decreased substantially after its reformulation, which did not occur for other prescription opioids. The largest reductions in doctor-shopping occurred with characteristics associated with higher abuse risk such as youth, cash payment and high dose, and with more specific thresholds of doctor-shopping. A higher prescriber and/or pharmacy threshold also increased the magnitude of the decrease, suggesting that it better captured the effect of the reformulation on actual doctor-shoppers. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Mercer, Susan L; Coop, Andrew
2011-01-01
Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.
Value for money in drug treatment: economic evaluation of prison methadone.
Warren, Emma; Viney, Rosalie; Shearer, James; Shanahan, Marian; Wodak, Alex; Dolan, Kate
2006-09-15
Although methadone maintenance treatment in community settings is known to reduce heroin use, HIV infection and mortality among injecting drug users (IDU), little is known about prison methadone programs. One reason for this is the complexity of undertaking evaluations in the prison setting. This paper estimates the cost-effectiveness of the New South Wales (NSW) prison methadone program. Information from the NSW prison methadone program was used to construct a model of the costs of the program. The information was combined with data from a randomised controlled trial of provision of prison methadone in NSW. The total program cost was estimated from the perspective of the treatment provider/funder. The cost per heroin free day, compared with no prison methadone, was estimated. Assumptions regarding resource use were tested through sensitivity analysis. The annual cost of providing prison methadone in NSW was estimated to be 2.9 million Australian dollars (or 3,234 Australian dollars per inmate per year). The incremental cost effectiveness ratio is 38 Australian dollars per additional heroin free day. From a treatment perspective, prison methadone is no more costly than community methadone, and provides benefits in terms of reduced heroin use in prisons, with associated reduction in morbidity and mortality.
Rohrmeister, K; Bernert, G; Langer, M; Fischer, G; Weninger, M; Pollak, A
2001-01-01
To evaluate the outcome of infants of drug dependent mothers (IDM) after establishing an interdisciplinary attention concept at the University Hospital in Vienna. To compare the influence of different maintenance agents on neonatal morbidity. All newborns of opiate dependent mothers were prospectively included from III 1995 to IX 1999. The following data were collected: maintenance agent (methadone, slow release morphine, buprenorphine), infectious status, demographic data, congenital malformations, perinatal complications, as well as incidence and duration of the neonatal abstinence syndrome (NAS). Medical treatment with phenobarbital (1995 - 96) or morphine hydrochloride (MoHCl) (1997 - 99), respectively, was indicated when Finnegan score exceeded 10. 88 neonates (38 females/50 males) with a median gestational age of 39 weeks were included, 18 (20.5 %) were born prematurely. The median birthweight was 2905 g, 24 (27.3 %) infants were small for date (< 10th percentile), 15 (17 %) microcephalic. The malformation incidence was 7.4 %. 63 (72 %) of all newborns had to be treated due to abstinence syndrome: in the methadone group 76 %, in the morphine group 93 %, but in the buprenorphine group 19 % only (p < 0.01). Median duration of withdrawal was 15.1 days (d) with significant difference after antenatal buprenorphine exposure compared to methadone and morphine exposure (8.3 d versus 15 d and 16.5 d respectively). In neonates treated with phenobarbital duration of NAS was 17.6 d, whereas NAS in infants with MoHCl therapy lasted 12.8 d (p < 0.05). Incidence and duration of NAS after buprenorphine exposure was significantly lower than after methadone and morphine exposure. Withdrawal time under morphin-hydrochloride therapy was reduced by one third compared to treatment with phenobarbital.
Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs.
KuKanich, Butch; KuKanich, Kate
2015-11-01
To assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. Non-randomized, sequential design. Six healthy Greyhound dogs (three male, three female). Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL(-1)) and CMAX (6 ng mL(-1)) of methadone significantly increased to 541 hours ng mL(-1) and 47.8 ng mL(-1), respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.
Management of neonatal abstinence syndrome in neonates born to opioid maintained women.
Ebner, Nina; Rohrmeister, Klaudia; Winklbaur, Bernadette; Baewert, Andjela; Jagsch, Reinhold; Peternell, Alexandra; Thau, Kenneth; Fischer, Gabriele
2007-03-16
Neonates born to opioid-maintained mothers are at risk of developing neonatal abstinence syndrome (NAS), which often requires pharmacological treatment. This study examined the effect of opioid maintenance treatment on the incidence and timing of NAS, and compared two different NAS treatments (phenobarbital versus morphine hydrochloride). Fifty-three neonates born to opioid-maintained mothers were included in this study. The mothers received methadone (n=22), slow-release oral morphine (n=17) or buprenorphine (n=14) throughout pregnancy. Irrespective of maintenance treatment, all neonates showed APGAR scores comparable to infants of non-opioid dependent mothers. No difference was found between the three maintenance groups regarding neonatal weight, length or head circumference. Sixty percent (n=32) of neonates required treatment for NAS [68% in the methadone-maintained group (n=15), 82% in the morphine-maintained group (n=14), and 21% in the buprenorphine-maintained group (n=3)]. The mean duration from birth to requirement of NAS treatment was 33 h for the morphine-maintained group, 34 h for the buprenorphine-maintained group and 58 h for the methadone-maintained group. In neonates requiring NAS treatment, those receiving morphine required a significantly shorter mean duration of treatment (9.9 days) versus those treated with phenobarbital (17.7 days). Results suggest that morphine hydrochloride is preferable for neonates suffering NAS due to opioid withdrawal.
Perinatal exposure to methadone affects central cholinergic activity in the weanling rat.
Robinson, S E; Mo, Q; Maher, J R; Wallace, M J; Kunko, P M
1996-06-01
Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. Perinatal methadone exposure disrupted cholinergic activity on postnatal day 21 as measured by the turnover rate of acetylcholine (TRACh) in both female and male rats, although there were some sexually-dimorphic responses. The most profoundly affected brain region was the striatum, where prenatal exposure to methadone increased ACh turnover, whether or not the rats continued to be exposed to methadone postnatally. It appears unlikely that neonatal withdrawal contributes to brain regional changes in ACh turnover, as continued postnatal exposure to methadone did not prevent the prenatal methadone induced changes.
Sason, Anat; Adelson, Miriam; Schreiber, Shaul; Peles, Einat
2018-05-29
Drug users reportedly abuse pregabalin, and its combination with opiates was related to fatalities. We aimed to estimate the prevalence of pregabalin misuse and risk factors among patients in methadone maintenance treatment (MMT). A cross-sectional study included all current MMT patients (n = 300) after excluding 9 with prescriptions, from a large tertiary medical center university-affiliated MMT clinic in Israel. Pregabalin was tested in one of the routine urine tests for other substances in December 2017. Data on urine results and patients' characteristics were retrieved from the patients' records. Pregabalin was detected among 53 (17.7%) patients. The group had higher depressive symptoms severity score (21-HAM-D) (11.1 ± 8.4 vs. 8.3 ± 7.8, p = 0.03), a higher prevalence of sero-positive HIV (13.7% vs. 4.2%, p = 0.02), sero-positive hepatitis C (66.7% vs. 50.4%, p = 0.04), DSM-IV-TR Axis I psychiatric diagnosis (54.0% vs. 41.7%, p = 0.03), and positive urine for opiates (22.6% vs. 8.9%, p = 0.008), cannabis (39.6% vs. 4.0 p < 0.0005) benzodiazepine (BDZ) (77.4% vs. 18.2%, p < 0.0005) and oxycodone (11.3% vs. 0.4%, p < 0.0005). Logistic regression found pregabalin group as more likely to be urine positive to BDZ (OR = 12.8 95%CI 5.0-32.5) cannabis (OR = 22.7, 95%CI 6.3-81.6) and oxycodone (OR = 43.9, 95%CI 3.6-541.4), with higher 21-HAM-D scores (OR = 1.1, 95%CI 1.04-1.2) and hepatitis C sera-positive (OR = 4.1, 95% CI 1.5-11.4). Unexpectedly, 13.2% of the pregabalin group had take-home dose privileges, which are rewards to non-drug abusers. High prevalence of pregabalin misuse among both BDZ abusers and non-abusers and patients with depressive symptoms supports both the inclusion of routine monitoring for pregabalin and intervention in MMT population. Copyright © 2018. Published by Elsevier B.V.
Monkey motor stimulation and altered social behavior during chronic methadone administration.
Crowley, T J; Hydinger, M; Stynes, A J; Feiger, A
1975-08-21
To assess the effects of chronic methadone administration on locomotor, social, and eating behavior od drug-native individuals under circumstances approximating those of methadone "maintenance" clinics, we gave single, daily oral doses of methadone to 5 Macaca radiata monkeys living in a social group. We obtained motor activity counts automatically during 6 weeks of baseline, 10 weeks of drug administration, and 3 weeks of post-drug abstinence. Social behaviors of association, dominance, submission, and sexuality were counted 5 days per week, and animal weights, food eaten and food-reinforced work were recorded. Plasma methadone levels were near those achieved in mechadone clincs. Methadone produced mixed stimulation and sedation in the daytime, with stimulation predominating for 4 hrs following administration. At night the subjects moved less while taking the drug. Associative behaviors were reduced by methadone, but dominance, submission, and sexual behaviors were not altered. The monkeys ate less while taking the drug, losing weight and working less for food. In these primates methadone had significant stimulant properties, impaired important social behaviors, and reduced the potency of food as a reinforcer of work. The results are compared with methadone's effects upon humans.
García-Pérez, Daniel; Laorden, M Luisa; Milanés, M Victoria
2017-01-01
Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPβ/ζ. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPβ/ζ expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines.
Kharasch, Evan D.; Regina, Karen J.; Blood, Jane; Friedel, Christina
2015-01-01
Background Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Methods Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), and CYP2B6*6/*6 (n=17), and also CYP2B6*1/*4 (n=1), CYP2B6*4/*6 (n=3), CYP2B6*5/*5 (n=2) subjects received single doses of intravenous and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Results Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1, and R-methadone apparent oral clearance was 25 and 30% lower. R- and S-methadone apparent oral clearance was 3- and 4-fold greater in CYP2B6*4 carriers. Intravenous and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with CYP2B6*1 homozygotes, and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African-Americans due to the CYP2B6*6 genetic polymorphism. Conclusions CYP2B6 polymorphisms influence methadone plasma concentrations, due to altered methadone metabolism and thus clearance. Genetic influence is greater for oral than intravenous, and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions. PMID:26389554
Chang, Andrew K; Bijur, Polly E; Holden, Lynne; Gallagher, E John
2015-11-01
The objective was to test the hypothesis that oxycodone/acetaminophen provides superior analgesia to hydrocodone/acetaminophen for the treatment of acute extremity pain following emergency department (ED) discharge. This was a prospective, randomized, double-blind clinical trial of nonelderly adult ED patients with acute musculoskeletal extremity pain, randomly allocated at discharge to receive oxycodone/acetaminophen (5 mg/325 mg) or hydrocodone/acetaminophen (5 mg/325 mg). The primary outcome was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug, obtained during telephone contact 24 hours after ED discharge. Secondary outcomes included proportionate decrease in pain, comparative side-effect profiles, and patient satisfaction. A total of 240 patients were enrolled. The final sample consisted of 220 patients, 107 randomly allocated to oxycodone/acetaminophen and 113 to hydrocodone/acetaminophen. At 24 hours after ED discharge, the mean NRS pain scores prior to the most recent dose of outpatient pain medication were 7.8 and 7.9 in the oxycodone/acetaminophen and hydrocodone/acetaminophen groups, respectively. The mean decreases in pain scores over 2 hours were 4.4 NRS units in the oxycodone/acetaminophen group versus 4.0 NRS units in the hydrocodone/acetaminophen group, for a difference of 0.4 NRS units (95% confidence interval = -0.2 to 1.1 NRS units). Satisfaction with the analgesics was similar. This study design could not detect a clinically or statistically significant difference in analgesic efficacy between oxycodone/acetaminophen (5 mg/325 mg) and hydrocodone/acetaminophen (5 mg/325 mg) for treatment of acute musculoskeletal extremity pain in adults following ED discharge. Both opioids reduced pain scores by approximately 50%. © 2015 by the Society for Academic Emergency Medicine.
Methadone: A Substrate and Mechanism-Based Inhibitor of CYP19 (Aromatase)
Bies, Robert; Kamden, Landry K.; Desta, Zeruesenay; Flockhart, David A.
2010-01-01
The peripheral conversion of testosterone to estradiol by aromatase is the primary source of endogenous estrogen in postmenopausal women. Studies indicating that placental aromatase is able to metabolize methadone to its primary metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidin (EDDP), led us to test the hypothesis that methadone is able to act as an inhibitor of aromatase. Using recombinant human CYP19, we examined the ability of methadone to bring about either reversible or mechanism-based inhibition of the conversion of testosterone to estradiol. To test for reversible inhibition, racemic methadone or its metabolite EDDP or 2-ethyl-5-methyl-3, 3-diphenylpyrroline (EMDP) was incubated for 30 min with testosterone at the Km (4 μM). To test for mechanism-based inhibition, microsomal preincubations were performed for up to 30 min using racemic methadone (1–1000 μM), R- or S-methadone (0.5–500 μM), or EDDP or EMDP (10 and 100 μM) followed by incubation with testosterone at a Vmax concentration (50 μM). Racemic methadone, EDDP, and EMDP did not act as competitive inhibitors of CYP19. Preincubation of methadone, EDDP, or EMDP with CYP19 resulted in time- and concentration-dependent inhibition, indicating a mechanism-based reaction that destroys CYP19 activity. The KI and kinact values for racemic methadone were calculated to be 40.6 ± 2.8 μM and 0.061 ± 0.001 min−1, respectively. No stereoselectivity was observed. Methadone is metabolized by CYP19 and may act as a potent inhibitor of CYP19 in vivo. These findings may contribute to variability in methadone clearance, to drug-drug interactions, and to side effects observed in individual patients. PMID:20410453
Methadone prolongs cardiac conduction in young patients with cancer-related pain
Anghelescu, Doralina L.; Patel, Rakesh M.; Mahoney, Daniel P.; Trujillo, Luis; Faughnan, Lane G.; Steen, Brenda D.; Baker, Justin N.; Pei, Deqing
2016-01-01
Objective Methadone prolongs cardiac conduction, from mild corrected QT (QTc) prolongation to torsades de pointes and ventricular fibrillation, in adults. However, methadone use for pain and its effects on cardiac conduction have not been investigated in pediatric populations. Methods A retrospective review of QTc intervals in patients receiving methadone analgesia was conducted. Medical records from a 4-year period (September 2006 to October 2010) at a pediatric oncology institution were reviewed, and correlations were tested between cardiac conduction and methadone dosage and duration of therapy, electrolyte levels, renal and hepatic dysfunction, and concurrent medications. Results Of the 61 patients who received methadone, 37 met our inclusion criteria and underwent 137 electrocardiograms (ECGs). During methadone treatment, the mean QTc was longer than that at baseline (446.5 vs 437.55 ms). The mean methadone dose was 27.0 ± 24.3 mg/d (range, 5–125 mg/d; median, 20 mg/d) or 0.47 ± 0.45 mg/kg per day (range, 0.05–2.25 mg/kg per day; median, 0.37 mg/kg per day), and the mean duration of therapy was 49 days. The authors identified a correlation between automated and manual ECG readings by two cardiologists (Pearson r = 0.649; p < 0.0001), but the authors found no correlations between methadone dose or duration and concurrent QTc-prolonging medications, sex, age, electrolyte abnormalities, or renal or hepatic dysfunction. Conclusion At a clinically effective analgesic dose, methadone dosage and duration were not correlated with QTc prolongation, even in the presence of other risk factors, suggesting that methadone use may be safe in pediatric populations. The correlation between automated and manual ECG readings suggests that automated ECG readings are reliable for monitoring cardiac conductivity during the reported methadone-dosage regimens. PMID:27194198
Chang, Andrew K; Bijur, Polly E; Lupow, Jason B; Gallagher, E John
2015-12-01
To test the hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen following emergency department (ED) discharge. Prospective, randomized, double-blind, trial. Adult inner city ED. ED patients with acute extremity pain who were discharged home. Patients randomized to oxycodone/acetaminophen (5 mg/325 mg) or codeine/acetaminophen (30 mg/300 mg). The primary outcome, obtained via telephone one day after ED discharge, was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug. Secondary outcomes included proportion of patients with >50% pain reduction, side-effect profile, and patient satisfaction. Two hundred and forty patients were enrolled. Mean baseline NRS scores were 7.9 in both groups. Mean decrease over 2 hours was 4.5 NRS units in the oxycodone/acetaminophen group vs 4.2 NRS units in the codeine/acetaminophen group, for a clinically and statistically nonsignificant difference of 0.2 NRS units (95% CI -0.4-0.9 NRS units). Similarly, 66% vs 61% achieved >50% pain relief for a nonsignificant difference of 5% (95% CI -8% to 17%). Side-effect profile and patient satisfaction were similar. Our hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen was rejected. Although pain within each group was reduced by more than half, the between-group difference was not significant. Pending independent validation, these unexpected findings suggest that codeine/acetaminophen, a Schedule III agent, may be a clinically reasonable outpatient opioid alternative to oxycodone/acetaminophen, a more tightly restricted Schedule II agent thought to be more prone to misuse. Wiley Periodicals, Inc.
Mégarbane, Bruno; Declèves, Xavier; Bloch, Vanessa; Bardin, Christophe; Chast, François; Baud, Frédéric J
2007-01-01
Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations. We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay. Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects. After the ingestion of a toxic dose of a racemic mixture, plasma R- and S
Hwang, Boo-Young; Kwon, Jae-Young; Lee, Do-Won; Kim, Eunsoo; Kim, Tae-Kyun; Kim, Hae-Kyu
2015-01-01
Nefopam is a centrally-acting non-opioid analgesic, which has no effect on bleeding time and platelet aggregation. There has been no study about nefopam and oxycodone combination for postoperative analgesia. In this study, we present efficacy and side effects of nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled analgesia (PCA) after gynecologic surgery. 120 patients undergoing gynecologic surgery were divided randomly into two groups: Nefopam group treated with oxycodone 1 mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the pain with a numeric rating scale (NRS), infused PCA dose and sedation score at 1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation. Nefopam group showed less nausea than Ketorolac group within 6 h after the operation. There were no significant differences in demographic data and other complications between both groups. At 48 h after operation, satisfaction and the infused PCA volumes of Nefopam group (34.0± 19.7 ml) showed no significant differences compared to Ketorolac group (30.7± 18.4 ml, P-value= 0.46). Nefopam showed a similar efficacy and lower incidence of nausea within 6 h after the operation to that of ketorolac in PCA. Nefopam may be a useful analgesic drug for the opioid-based PCA after gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam as well as pharmacokinetics of bolus administration is required.
Horns, W H; Rado, M; Goldstein, A
1975-06-01
Plasma methadone levels, symptom complaints, and urine tests for illicit opiate use were followed weekly in 17 patients on a methadone maintenance program. There were very large differences between patients in the plasma level established at a given dosage, implying large differences in the rate of methadone metabolism. Despite virtually constant daily dosage, the plasma methadone levels fluctuated greatly from week to week and from day to day in individual patients. With rate exceptions there was no relationship between plasma methadone level and symptom complaints or between weekly chamges in plasma methadone level and changes in symptom complaints. Except possible to identify the ocassional patient with unusually low plasam methadone levels, the determination of methadone levels is not likely to be or practical value in methadone programs.
Pharmacological evaluation of narcotic antagonist delivery systems in rhesus monkeys.
Harrigan, S E; Downs, D A
1981-01-01
Rhesus monkeys were chronically restrained, intravenously catheterized, and allowed to self-administer morphine, methamphetamine, and saline. Various sustained-release systems containing naltrexone were then implanted in the animals and examined for selective morphine blockade. Similarly, continuous intravenous infusions of naltrexone, buprenorphine, and methadone were tested against morphine or heroin self-administration.
... direct care, they can be effective in reducing pain. Examples of narcotics include: Codeine Fentanyl -- available as a patch Hydrocodone Hydromorphone Morphine Oxycodone Tramadol Possible side effects of these drugs include: Drowsiness ...
Crosignani, N; Luna, S P; Dalla Costa, T; Pimenta, E L; Detoni, C B; Guterres, S S; Puoli Filho, J N; Pantoja, J C; Pigatto, M C
2017-08-01
We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd ss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone. © 2017 John Wiley & Sons Ltd.
Rothwell, M P; Pearson, D; Hunter, J D; Mitchell, P A; Graham-Woollard, T; Goodwin, L; Dunn, G
2011-06-01
To determine if oral oxycodone (OOXY) could provide equivalent postoperative analgesia and a similar side-effect profile to i.v. patient-controlled morphine in patients undergoing elective primary total hip replacement (THR) under spinal anaesthesia. We studied 110 consecutive patients aged 60-85 yr. After operation, patients were randomly allocated to receive either oral controlled- and immediate-release OOXY or i.v. patient-controlled analgesia (IVPCA) with morphine. Both groups received regular co-analgesia and antiemetics. The primary outcome measures were: (i) postoperative pain at rest and movement and (ii) nausea score recorded 12 hourly. The secondary outcome measures were: (i) time to first mobilization, (ii) total amount of opioid consumed, (iii) number of additional antiemetic doses, and (iv) time to analgesic discontinuation. There were no statistically significant differences in the primary outcome measures of pain at rest and movement (P>0.05, 95% confidence intervals -0.41, +0.96) or nausea score (P>0.5). The secondary outcome measures showed no significant difference in the total amount of opioid consumed (102 vs 63 mg; P>0.05) or time to mobilization (24.45 vs 26.6 h, P=0.2). The number of antiemetic doses required in the first 24 h was significantly lower in the OOXY group (1.1 vs 1.4, P<0.05). The time to analgesic discontinuation was significantly shorter in the OOXY group (50.5 vs 56.6 h, P<0.05). Oral analgesia with OOXY was approximately GBP 10 less expensive per patient than IVPCA. Oral analgesia with OOXY after THR offers non-inferior analgesia to IVPCA and may offer some logistical and cost advantages.
Foster, David J R; Morton, Erin B; Heinkele, Georg; Mürdter, Thomas E; Somogyi, Andrew A
2006-08-01
There is evidence that the apparent oral clearance of rac-methadone is induced during the early phase of methadone maintenance treatment. However, it is not known if this is due to changes in bioavailability or if this phenomenon is stereoselective. This knowledge can be obtained by administering a dose of stable-labeled methadone at selected times during ongoing treatment. Therefore, the authors developed a stereoselective high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry assay for the quantification of the enantiomers of methadone and a d(6)-labeled isotopomer. The compounds were quantified in a single assay after liquid-liquid extraction and stereoselective high performance liquid chromatograph with atmospheric pressure chemical ionization-mass spectrometry detection. The following ions were monitored: m/z 310.15 for unlabeled methadone; m/z 316.15 for methadone-d(6); and m/z 313.15 for the methadone-d(3) (internal standard). Calibration curves ranged from 0.5 to 75 ng/mL for each compound. Extraction recovery was approximately 80% for all analytes, without evidence of differences between the unlabeled and stable-labeled compounds or concentration dependency. Minor ion promotion was observed (<15%) but this was identical for all analytes including the d(3)-labeled internal standard, with peak area ratios in extracted samples identical to control injections. The isotopomers did not alter each others' ionisation, even at 10:1 concentration ratios, and 10-fold diluted samples were within 10% of the nominal concentration. Assay performance was acceptable, with interassay and intra-assay bias and precision <10% for all compounds, including the upper and lower limits of quantitation. In conclusion, the assay was successfully applied to quantify the concentration of the methadone enantiomers of both orally administered unlabeled methadone and an intravenous 5 mg dose of methadone-d(6) in a patient receiving chronic oral
Perinatal methadone exposure affects dopamine, norepinephrine, and serotonin in the weanling rat.
Robinson, S E; Maher, J R; Wallace, M J; Kunko, P M
1997-01-01
On gestational day 7 pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. On postnatal day 21, dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites were analyzed. Perinatal methadone exposure disrupted dopaminergic, noradrenergic, and serotonergic activity in a brain region- and gender-specific fashion. The ratio of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) to DA was reduced in the frontal cortex of males exposed to methadone postnatally. No effects of perinatal methadone exposure were observed on DA and DOPAC in the striatum. The ratio of 3-methoxy-4-hydroxyphenylglycol (MOPEG) to NE in the hippocampus was increased significantly in males exposed to methadone prenatally. Striatal and parietal cortical 5-hydroxyindoleacetic acid (5-HIAA), but not its ratio to 5-HT, was increased slightly in rats exposed to methadone postnatally. Although parietal cortical 5-HT, 5-HIAA, and 5-hydroxytryptophan were all affected by perinatal methadone exposure, the ratios of metabolite and precursor to 5-HT were not affected. Effects of methadone exposure appeared to depend upon the developmental stage at which exposure occurred and did not appear to result from the phenomenon of neonatal withdrawal. Changes in activity of these three neurotransmitter systems may contribute to the effect of perinatal methadone on the activity of other neurons, such as cholinergic neurons.
Morphine induces albuminuria by compromising podocyte integrity.
Lan, Xiqian; Rai, Partab; Chandel, Nirupama; Cheng, Kang; Lederman, Rivka; Saleem, Moin A; Mathieson, Peter W; Husain, Mohammad; Crosson, John T; Gupta, Kalpna; Malhotra, Ashwani; Singhal, Pravin C
2013-01-01
Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes.
Pharmacokinetics and Analgesic Effects of Methadone in Children and Adults with Sickle Cell Disease
Horst, Jennifer; Frei-Jones, Melissa; Deych, Elena; Shannon, William; Kharasch, Evan D.
2017-01-01
Background Vaso-occlusive episodes (VOE) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption. Procedure Participants included children (<18 yr) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient controlled analgesia; control group) or one dose of intravenous methadone (0.1–0.125 mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded. Results Twenty-four children (12 methadone, 12 controls) and twenty-three adults (11 methadone, 12 controls) were studied. In children, the half-life of R-and S-methadone enantiomers was 34±16 and 24±9 hr, respectively. In adults, R- and S-methadone half-lives were 52±17 and 38±12 hr. Pain scores were lower (p=0.002) and pain relief scores were higher (p=0.0396) in children receiving methadone vs controls. There was no difference in pain scores and pain relief in adults receiving methadone vs controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children. Conclusions Intravenous methadone disposition in children and adults with SCD was comparable to subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD. PMID:27572136
QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment.
Hassamal, Sameer; Fernandez, Antony; Moradi Rekabdarkolaee, Hossein; Pandurangi, Ananda
2015-06-01
QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance. In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 ± 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared. ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records. The mean QTc at baseline (pre-methadone) was 426 ± 34 msec and after being on methadone for an average of 8.72 ± 4.50 years was significantly higher at 450 ± 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of ≥ 24 msec (88.48 ± 27.20 mg v.s 68.96 ± 19.84 mg). None of the veterans experienced cardiac arrhythmias. The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination.
There is no age limit for methadone: a retrospective cohort study
2011-01-01
Background Data from the US indicates that methadone-maintained populations are aging, with an increase of patients aged 50 or older. Data from European methadone populations is sparse. This retrospective cohort study sought to evaluate the age trends and related developments in the methadone population of Basel-City, Switzerland. Methods The study included methadone patients between April 1, 1995 and March 31, 2003. Anonymized data was taken from the methadone register of Basel-City. For analysis of age distributions, patient samples were split into four age categories from '20-29 years' to '50 years and over'. Cross-sectional comparisons were performed using patient samples of 1996 and 2003. Results Analysis showed a significant increase in older patients between 1996 and 2003 (p < 0.001). During that period, the percentage of patients aged 50 and over rose almost tenfold, while the proportion of patients aged under 30 dropped significantly from 52.8% to 12.3%. The average methadone dose (p < 0.001) and the 1-year retention rate (p < 0.001) also increased significantly. Conclusions Findings point to clear trends in aging of methadone patients in Basel-City which are comparable, although less pronounced, to developments among US methadone populations. Many unanswered questions on medical, psychosocial and health economic consequences remain as the needs of older patients have not yet been evaluated extensively. However, older methadone patients, just as any other patients, should be accorded treatment appropriate to their medical condition and needs. Particular attention should be paid to adequate solutions for persons in need of care. PMID:21592331
Akbarabadi, Ardeshir; Niknamfar, Saba; Vousooghi, Nasim; Sadat-Shirazi, Mitra-Sadat; Toolee, Heidar; Zarrindast, Mohammad-Reza
2018-02-01
Drug addiction is a chronic disorder resulted from complex interaction of genetic, environmental, and developmental factors. Epigenetic mechanisms play an important role in the development and maintenance of addiction and also memory formation in the brain. We have examined passive avoidance memory and morphine conditioned place preference (CPP) in the offspring of male and/or female rats with a history of adulthood morphine consumption. Adult male and female animals received chronic oral morphine for 21days and then were maintained drug free for 10days. After that, they were let to mate with either an abstinent or control rat. Male offspring's memory was evaluated by step through test. Besides, rewarding effects of morphine were checked with CCP paradigm. Offspring of abstinent animals showed significant memory impairment compared to the control group which was more prominent in the offspring of abstinent females. Conditioning results showed that administration of a high dose of morphine (10mg/kg) that could significantly induce CPP in control rats, was not able to induce similar results in the offspring of morphine abstinent parents; and CPP was much more prominent when it was induced in the offspring of morphine exposed females compared to the progeny of morphine exposed males. It is concluded that parental morphine consumption in adulthood even before mating has destructive effects on memory state of the male offspring and also leads to tolerance to the rewarding effects of morphine. These effects are greater when the morphine consumer parent is the female one. Copyright © 2017 Elsevier Inc. All rights reserved.
Hwang, Boo-Young; Kwon, Jae-Young; Lee, Do-Won; Kim, Eunsoo; Kim, Tae-Kyun; Kim, Hae-Kyu
2015-01-01
Objectives: Nefopam is a centrally-acting non-opioid analgesic, which has no effect on bleeding time and platelet aggregation. There has been no study about nefopam and oxycodone combination for postoperative analgesia. In this study, we present efficacy and side effects of nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled analgesia (PCA) after gynecologic surgery. Methods: 120 patients undergoing gynecologic surgery were divided randomly into two groups: Nefopam group treated with oxycodone 1 mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the pain with a numeric rating scale (NRS), infused PCA dose and sedation score at 1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation. Results: Nefopam group showed less nausea than Ketorolac group within 6 h after the operation. There were no significant differences in demographic data and other complications between both groups. At 48 h after operation, satisfaction and the infused PCA volumes of Nefopam group (34.0± 19.7 ml) showed no significant differences compared to Ketorolac group (30.7± 18.4 ml, P-value= 0.46). Conclusion: Nefopam showed a similar efficacy and lower incidence of nausea within 6 h after the operation to that of ketorolac in PCA. Nefopam may be a useful analgesic drug for the opioid-based PCA after gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam as well as pharmacokinetics of bolus administration is required. PMID:26283884
Xie, Kangjie; Zhang, Wen; Fang, Wumei; Lian, Yanhong; Lin, Sufeng; Fang, Jun
2017-06-01
Problems like body movement, respiratory depression, and complained of pain are still common phenomenon in outpatient artificial abortion general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid and has a good therapeutic effect on visceral pain. We hypothesize that oxycodone hydrochloride would be superior to fentanyl in outpatient artificial abortion surgery. In this clinical trial 149 American Society of Anesthesiologists (ASA) I or II female outpatients scheduled for elective artificial abortion surgeries under general anesthesia were randomly divided into 3 groups: oxycodone hydrochloride 0.06 mg/kg group (group A), oxycodone hydrochloride 0.08 mg/kg group (group B), and control group fentanyl 2 ug/kg (group C). The primary outcome was level body movement and respiratory depression during the surgery, the second outcome included the visual analogue scale (VAS) score 30 minutes after waking. A total of 120 participants completed the study, n = 40 in each group. There was no significant difference in patients' age, body mass index (BMI), preoperative heart rate, mean arterial blood pressure, consumption dose of propofol, intraoperative body movement type and times, and duration of surgery among the 3 groups (P > .05). Comparing the incidence of intraoperative respiratory depression and SPO2 < 90% among the 3 groups, group C's was significantly higher than those of groups A and B, and the difference was statistically significant (P < .05). Group A had no difference compared with group B. In VAS score 30minutes after waking, group C was the highest, followed by group A, with group B as the lowest. The difference among the 3 groups was statistically significant (P < .05), but a difference delta less than 1 on the VAS scale is not clinically significant. The analgesic effect of oxycodone hydrochloride at 0.06 mg/kg applied to painless artificial abortion surgery is not superior than that of fentanyl, but the incidence of
Dealing with aggressive methadone patients in community pharmacy: a critical incident study.
Irwin, Amy; Laing, Christianne; Mearns, Kathryn
2012-01-01
Community pharmacists are an important link between methadone patients and the health service in the United Kingdom. However, many pharmacists feel ill prepared to deal with methadone patients, with aggressive behavior a particular concern. To assess the perceived impact of methadone patient aggression on pharmacy practice. Sixteen registered pharmacists with a minimum of 3 years' work experience were recruited from within 3 Scottish health boards. Critical incident interviews were conducted to assess pharmacist behavior during an interaction with an aggressive methadone patient. Factors considered by pharmacists to have a negative impact on an interaction with an aggressive methadone patient included intoxication of the patient, the presence of a new or an inexperienced pharmacist, and a restricted time frame for dispensing methadone. Positive factors when dealing with aggressive patients were authoritative behavior by the pharmacist, a separate dispensing area for methadone patients, or a solid counter and a positive relationship between pharmacist and patient. Aggression from methadone patients is a risk when dispensing methadone. However, action can be taken by the pharmacist to minimize the impact of that aggression on pharmacy practice. The provision of further training and support, particularly to inexperienced pharmacists, could further reduce the negative impact of patient aggression. The present study indicates that such training could be based on nontechnical skills to strengthen current leadership and teamwork behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.
Attitudes and beliefs towards methadone maintenance treatment among Australian prison health staff.
Gjersing, Linn R; Butler, Tony; Caplehorn, John R M; Belcher, Josephine M; Matthews, Richard
2007-09-01
Justice Health NSW has one of the most extensive prison-based methadone programmes in the world. We examine prison health staff attitudes towards methadone treatment and compare these with community methadone staff. A cross-sectional survey of 202 staff employed by Justice Health New South Wales was undertaken in 2003. Results. The mean scores on the various sub-scales were: abstinence-orientation (AO) 2.9 (95% CI 2.8 - 3.0); disapproval of drug use (DDU) 3.3 (95% CI 3.2 - 3.4); knowledge (Know) 2.7 (95% CI 2.4 - 2.9); and toxicity 4.6 (95% CI 4.2 - 5.0). Both the AO and DDU score were correlated negatively with the Know score (r = -0.37 and r = -0.13, respectively). Prison health staff had higher AO (2.9 vs. 2.6, p < 0.001) and DDU (3.3 vs. 2.6, p < 0.001) scores, and lower Know (2.7 vs. 7.0, p < 0.001) scores than methadone staff working in the Australian community. They were more knowledgeable than US community methadone staff about the toxicity of methadone (4.6 vs. 0.0, p < 0.001). This is the first survey to examine prison health staff attitudes to methadone treatment. Correctional health staff tend to be more abstinence-orientated, more likely to disapprove of drug use, and less knowledgeable about the risks and benefits of methadone than Australian community methadone staff. The findings have important implications for training health staff working in the prison environment with regard to client retention on methadone treatment.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kaufmann, C.A.; Kreek, M.J.; Raghunath, J.
1983-09-01
Narcotic withdrawal is often accompanied by an atypical depression which responds to resumption of narcotics. It was hypothesized that methadone might exert its antidepressant effects through monoamine oxidase (MAO) inhibition. The current study examined /sub 3/H-methadone distribution in rat brain and effects on regional MAO activity with acute doses (2.5 mg/kg) which approximate those found during chronic methadone maintenance in man. Limbic areas (amygdala, basomedial hypothalamus, caudate-putamen, hippocampus, preoptic nucleus), as well as pituitary and liver were assayed for MAO activity and methadone concentration. MAO activities did not differ significantly in acute methadone or saline-treated cage-mates at 1 or 24more » hr. The concentrations of methadone at 1 hr ranged between 17 and 223 ng/100 mg wet wt tissue in the preoptic nucleus and pituitary, respectively. No significant correlation was found between change in MAO activity (MAO methadone/MAO saline) and methadone concentration in any region at 1 or 24 hr. This study does not support the hypothesis that methadone acts as an antidepressant through MAO inhibition, at least not following acute administration of this exogenous opioid.« less
Intermittent subcutaneous methadone administration in the management of cancer pain.
Centeno, Carlos; Vara, Francisco
2005-01-01
Methadone is a strong opioid analgesic that has been used successfully in cancer pain management. The oral route of administration is generally preferred for opioid analgesics. However that route sometimes cannot be used. Experience with continuous subcutaneous methadone infusions has produced local intolerance. The aim of this study was to analyze the use of intermittent subcutaneous methadone injections. Ten patients whose pain was well-controlled with oral methadone (average dose 30 mg, range 10 to 120 mg) participated in the study. A subcutaneous small vein needle (butterfly) was used exclusively for administration of methadone. Over a period of seven days the local discomfort of each injection was evaluated by means of a Verbal Numerical Rating Scale (NRS) and the site of infusion was observed. When any degree of erythema or inflammation was seen, the infusion site was changed. The initial subcutaneous dose was the same as the previously administered oral dose. A daily record was kept of the dose used, level of pain, and toxicity symptoms. This close vigilance was aimed at avoiding dosage errors due to variations among individuals in acceptance to previous oral medication. Changes in dosage were allowed according to standard medical criteria. Two patients were withdrawn from the study due to non-painful irritation at the infusion point. Another eight patients tolerated repeated administration of subcutaneous methadone over seven days. Any local irritation from subcutaneous methadone that occurred was managed satisfactorily by changing the infusion site and limiting doses to 30 mg. In seven of 182 repeat administration, injection site changes were necessitated by local irritation. The NRS for local discomfort was 2/10. The two patients who were intolerant of the subcutaneous injections were receiving injected doses which were significantly higher than the others (42 mg as compared to 25 mg). Dose adjustments needed when changing from the oral to the
Yuferov, Vadim; Zhang, Yong; Liang, Yupu; Zhao, Connie; Randesi, Matthew; Kreek, Mary J
2018-01-01
Oxycodone is one a commonly used medication for pain, and is also a widely abused prescription opioid, like other short-acting MOPr agonists. Neurochemical and structural adaptations in brain following chronic MOPr-agonist administration are thought to underlie pathogenesis and persistence of opiate addiction. Many axon guidance molecules, such as integrins, semaphorins, and ephrins may contribute to oxycodone-induced neuroadaptations through alterations in axon-target connections and synaptogenesis, that may be implicated in the behaviors associated with opiate addiction. However, little is known about this important area. The aim of this study is to investigate alterations in expression of selected integrin, semaphorin, ephrins, netrin, and slit genes in the nucleus accumbens (NAc) and caudate putamen (CPu) of mice following extended 14-day oxycodone self-administration (SA), using RNAseq. Methods: Total RNA from the NAc and CPu were isolated from adult male C57BL/6J mice within 1 h after the last session of oxycodone in a 14-day self-administration paradigm (4h/day, 0.25 mg/kg/infusion, FR1) or from yoked saline controls. Gene expressions were examined using RNA sequencing (RNA-Seq) technology. RNA-Seq libraries were prepared using Illumina's TruSeq® Stranded Total RNA LT kit. The reads were aligned to the mouse reference genome (version mm10) using STAR. DESeq2 was applied to the counts of protein coding genes to estimate the fold change between the treatment groups. False Discovery Rate (FDR) q < 0.1 were used to select genes that have a significant expression change. For selection of a subset of genes related to axon guidance pathway, REACTOME was used. Results: Among 38 known genes of the integrin, semaphorin, and ephrin gene families, RNA-seq data revealed up-regulation of six genes in the NAc: heterodimer receptor, integrins Itgal, Itgb2 , and Itgam , and its ligand semaphorin Sema7a , two semaphorin receptors, plexins Plxnd1 and Plxdc1 . There was down
Prescription opioid abuse based on representative postmortem toxicology.
Häkkinen, Margareeta; Vuori, Erkki; Ojanperä, Ilkka
2014-12-01
Opioids are important medications for pain and opioid maintenance treatment. Increasing use and abuse of prescription opioids has, however, caused worldwide concern. Our aim was to estimate the ratio between prescription opioid abuse and total use, based on representative postmortem toxicology. Our material included all the medico-legally examined deaths in Finland during 2010-2011 involving positive findings involving buprenorphine, codeine, fentanyl, methadone, oxycodone, or tramadol. We studied drug abuse by age group, with "abuse" meaning licit opioids used illicitly as narcotics. Drug-abuse history, drug injecting, or laboratory findings of illicit drugs defined an abuser case. We then compared abuser cases and other opioid-related cases between the opioids with the number of fatal poisonings, accidents, suicides, alcohol findings, concomitant opioid use, and median postmortem blood opioid concentrations. Opioid findings numbered 2499 in 2088 cases. Drug abuse involved 545 opioid-positive cases, which in Finland represented 0.5% of those deceased. The proportion of abuser cases among all opioid-related cases for buprenorphine was 85.5%, for methadone 82.4%, for tramadol 29.4%, for codeine 16.3%, for fentanyl 14.5%, and for oxycodone 6.9%. Abuse in age-groups >60 was rare. Concomitant other opioid findings were more frequent in abuser- than in other cases for codeine, oxycodone, and tramadol, whereas alcohol findings were more frequent in buprenorphine, codeine, and fentanyl abuse. Buprenorphine and methadone were most often related to drug abuse. Every other opioid studied involved some abuse, and especially tramadol. Abuse and fatal poisonings were concentrated in men aged 20-49. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Trends in Reporting Methadone-Associated Cardiac Arrhythmia, 1997–2011
Kao, David; Bartelson, Becki Bucher; Khatri, Vaishali; Dart, Richard; Mehler, Philip S.; Katz, David; Krantz, Mori J.
2013-01-01
Background: Long-acting opioids are a leading cause of accidental death in the United States, and methadone is associated with greater mortality rates. Whether this increase is related to the proarrhythmic properties of methadone is unclear. Objective: To describe methadone-associated arrhythmia events reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Design: Description of national adverse event registry data before and after publication of a 2002 report describing an association between methadone and arrhythmia. Setting: FAERS, November 1997 and June 2011. Patients: Adults with QTc prolongation or torsade de pointes and ventricular arrhythmia or cardiac arrest. Measurements: FAERS reports before and after the 2002 report. Results: 1646 cases of ventricular arrhythmia or cardiac arrest and 379 cases of QTc prolongation or torsade de pointes were associated with methadone. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1 to 0.5) before the 2002 publication to a mean of 3.5 (CI, 2.5 to 4.8) after it. After 2000, methadone was the second-most common primary suspect in cases of QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associated with disproportionate reporting similar to that of antiarrhythmic agents known to promote torsade de pointes. Antiretroviral drugs for HIV were the most common coadministered drugs. Limitation: Reports to FAERs are voluntary and selective, and incidence rates cannot be determined from spontaneously reported data. Conclusion: Since 2002, reports to FAERS of methadone-associated arrhythmia have increased substantially and are disproportionately represented relative to other events with the drug. Coadministration of methadone with antiretrovirals in patients with HIV may pose particular risk. Primary Funding Source: Colorado Clinical and Translational Sciences Institute, National Institutes of Health, and
Harris, Stephen C; Perrino, Peter J; Smith, Ira; Shram, Megan J; Colucci, Salvatore V; Bartlett, Cynthia; Sellers, Edward M
2014-01-01
The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1–2 hours) versus OC and Oxy API (0.5–1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug-liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post-marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real-world patterns of ORF misuse, abuse, and diversion. PMID:24243216
Post-marketing surveillance of methadone and buprenorphine in the United States.
Dasgupta, Nabarun; Bailey, Elise J; Cicero, Theodore; Inciardi, James; Parrino, Mark; Rosenblum, Andrew; Dart, Richard C
2010-07-01
There have been recent increases in the use of methadone and buprenorphine in the United States. Methadone is increasingly being used for pain management, and buprenorphine use has expanded to include treatment for opioid addiction, leading to exposures of these drugs in new populations. There is a debate about the relative safety of these two drugs in routine outpatient medical use. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Programs were used to analyze rates of abuse, misuse, and diversion using the Drug Diversion, Key Informant, Poison Center and Opioid Treatment Programs, 2003-2007. National rate and rate ratios were calculated using population and person-time exposed denominators. Detailed data are presented on severity of medical outcome and drug formulations. Between 2003 and 2007, there were steady increases in the rates of abuse, misuse, and diversion of both methadone and buprenorphine. Rate ratios (per 100,000 population per quarter) of abuse, misuse, and diversion were consistently higher for methadone than buprenorphine. RADARS System poison centers received 7,476 calls for methadone and 1,117 calls for buprenorphine. After accounting for availability, there were higher rates of calls for methadone misuse, abuse, and diversion than buprenorphine in three of the four programs. The numbers of exposures requiring medical attention correspond to 46.8% and 25.8% of all calls, for methadone and buprenorphine, respectively. The most commonly diverted form of methadone was solid oral tablets (which are typically dispensed at pharmacies, not at opioid treatment programs), comprising 73% of cases. Buprenorphine appears to have a better safety profile than methadone during routine outpatient medical use. However, both medications have roles in the treatment of pain and opioid addiction, and further research into their respective benefits and risks should be conducted.
Brain Reward Circuits in Morphine Addiction
Kim, Juhwan; Ham, Suji; Hong, Heeok; Moon, Changjong; Im, Heh-In
2016-01-01
Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID:27506251
Ageing opioid users' increased risk of methadone-specific death in the UK.
Pierce, Matthias; Millar, Tim; Robertson, J Roy; Bird, Sheila M
2018-05-01
The first evidence that the hazard ratio (HR) for methadone-specific death rises more steeply with age-group than for all drug-related deaths (DRDs) came from Scotland's cohort of 33,000 methadone-prescription clients. We aim to examine, for England, whether illicit opioid users' risk of methadone-specific death increases with age; and to pool age-related HRs for methadone-specific deaths with those for Scotland's methadone-prescription clients. The setting is all services in England that provide publicly-funded, structured treatment for illicit opioid users, the methodology linkage of the English National Drug Treatment Monitoring System and mortality database, and key measurements are DRDs, methadone-specific DRDs, or heroin-specific DRDs, by age-group and gender, with proportional hazards adjustment for substances used, injecting status and periods in/out of treatment. Linkage was achieved for 129,979 adults receiving prescribing treatment modalities for opioid dependence during April 2005 to March 2009 and followed-up for 378,009 person-years (pys). There were 1,266 DRDs: 271 methadone-specific (7 per 10,000 pys: irrespective of gender) and 473 heroin-specific (15 per 10,000 pys for males, 7 for females). Methadone-specific DRD-rate per 10,000 person-years was 3.5 (95% CI: 2.7-4.4) at 18-34 years, 8.9 (CI: 7.3-10.5) at 35-44 years and 18 (CI: 13.8-21.2) at 45+ years; heroin-specific DRD-rate was unchanged with age. Relative to 25-34 years, pooled HRs for UK clients' methadone-specific deaths were: 0.87 at <25 years (95% CI: 0.56-1.35); 2.14 at 35-44 years (95% CI: 1.76-2.60); 3.75 at 45+ years (95% CI: 2.99-4.70). International testing and explanation are needed of UK's sharp age-related increase in the risk of methadone-specific death. Clients should be alerted that their risk of methadone-specific death increases as they age. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Selective attention and drug related attention bias in methadone maintenance patients.
Nejati, Majid; Nejati, Vahid; Mohammadi, Mohammad Reza
2011-01-01
One of the main problems of the drug abusers is drug related attention bias, which causes craving, and as a result drive the drug abusers to take narcotics. Methadone is used as a maintenance treatment for drug abusers. The purpose of this study is evaluation of the effect of Methadone maintenance therapy (MMT) on selective attention and drug related attention bias. This study investigated drug cue-related attention bias and selective attention in 16 methadone-maintained patients before and 45 days after methadone therapy period. Stroop color-word test and addiction Stroop test were used as measurement methods. Results show less reaction time and higher accuracy in Color-Word Stroop Test after MMT and less delay for addict related word in addiction Stroop test. It is concluded that methadone can improve selective attention capability and reduce drug related attention bias.
Fatal Methadone Toxicity: Potential Role of CYP3A4 Genetic Polymorphism
Richards-Waugh, Lauren L.; Primerano, Donald A.; Dementieva, Yulia; Kraner, James C.; Rankin, Gary O.
2014-01-01
Methadone is difficult to administer as a therapeutic agent because of a wide range of interindividual pharmacokinetics, likely due to genetic variability of the CYP450 enzymes responsible for metabolism to its principal metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). CYP3A4 is one of the primary CYP450 isoforms responsible for the metabolism of methadone to EDDP in humans. The purpose of this study was to evaluate the role of CYP3A4 genetic polymorphisms in accidental methadone fatalities. A study cohort consisting of 136 methadone-only and 92 combined methadone/benzodiazepine fatalities was selected from cases investigated at the West Virginia and Kentucky Offices of the Chief Medical Examiner. Seven single nucleotide polymorphisms (SNPs) were genotyped within the CYP3A4 gene. Observed allelic and genotypic frequencies were compared with expected frequencies obtained from The National Center for Biotechnology Information dbSNP database. SNPs rs2242480 and rs2740574 demonstrated an apparent enrichment within the methadone-only overdose fatalities compared with the control group and the general population. This enrichment was not apparent in the methadone/benzodiazepine cases for these two SNPs. Our findings indicate that there may be two or more SNPs on the CYP3A4 gene that cause or contribute to the methadone poor metabolizer phenotype. PMID:25217544
Lintzeris, Nicholas; Strang, John; Metrebian, Nicola; Byford, Sarah; Hallam, Christopher; Lee, Sally; Zador, Deborah
2006-01-01
Whilst unsupervised injectable methadone and diamorphine treatment has been part of the British treatment system for decades, the numbers receiving injectable opioid treatment (IOT) has been steadily diminishing in recent years. In contrast, there has been a recent expansion of supervised injectable diamorphine programs under trial conditions in a number of European and North American cities, although the evidence regarding the safety, efficacy and cost effectiveness of this treatment approach remains equivocal. Recent British clinical guidance indicates that IOT should be a second-line treatment for those patients in high-quality oral methadone treatment who continue to regularly inject heroin, and that treatment be initiated in newly-developed supervised injecting clinics. The Randomised Injectable Opioid Treatment Trial (RIOTT) is a multisite, prospective open-label randomised controlled trial (RCT) examining the role of treatment with injected opioids (methadone and heroin) for the management of heroin dependence in patients not responding to conventional substitution treatment. Specifically, the study examines whether efforts should be made to optimise methadone treatment for such patients (e.g. regular attendance, supervised dosing, high oral doses, access to psychosocial services), or whether such patients should be treated with injected methadone or heroin. Eligible patients (in oral substitution treatment and injecting illicit heroin on a regular basis) are randomised to one of three conditions: (1) optimized oral methadone treatment (Control group); (2) injected methadone treatment; or (3) injected heroin treatment (with access to oral methadone doses). Subjects are followed up for 6-months, with between-group comparisons on an intention-to-treat basis across a range of outcome measures. The primary outcome is the proportion of patients who discontinue regular illicit heroin use (operationalised as providing >50% urine drug screens negative for markers of
Cheville, A; Chen, A; Oster, G; McGarry, L; Narcessian, E
2001-04-01
Reliance on "as-needed" analgesia following total knee arthroplasty may lead to inadequate control of pain and delayed recovery of function. Preemptive use of controlled-release opioids may improve pain control, accelerate recovery, and reduce the need for inpatient rehabilitative services. This study was designed to determine whether controlled-release opioids enhance post-arthroplasty pain control and facilitate functional recovery during rehabilitation. Fifty-nine patients admitted for inpatient rehabilitation following unilateral total knee arthroplasty were randomized to receive OxyContin (controlled-release oxycodone) (twenty-nine patients) or a placebo (thirty patients) every twelve hours. Both groups could receive on-request, immediate-release oxycodone (5 mg every four hours). The dose of study medication was increased on the basis of the frequency of requests for immediate-release oxycodone. Measures of interest included pain ratings as determined with a visual-analog scale, changes in the range of motion of the knee and quadriceps strength, and improvements in selected Functional Independence Measure scores during the first eight physical therapy sessions. The duration of the hospital stay for rehabilitation also was compared between the two groups. Baseline demographic, clinical, and functional characteristics were similar between the OxyContin and placebo groups. Compared with the placebo group, the patients who received OxyContin reported significantly less pain as well as significantly greater range of motion of the knee (passive motion, p = 0.036; active motion, p< 0.001) and quadriceps strength (p = 0.001) by the eighth physical therapy session. The patients who received OxyContin also were discharged from the rehabilitation hospital at an average of 2.3 days earlier than the patients in the placebo group (p = 0.013). Preemptive use of controlled-release oxycodone during rehabilitation following total knee arthroplasty leads to improved pain
Concheiro, Marta; Gray, Teresa R.; Shakleya, Diaa M.
2011-01-01
A method for simultaneous determination of buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine (BE), ecgonine methyl ester (EME), anhydroecgonine methyl ester (AEME), morphine, codeine, 6-acetylmorphine (6AM), heroin, 6-acetylcodeine (6AC), nicotine, cotinine, and trans-3′-hydroxycotinine (OH-cotinine) by liquid chromatography tandem mass spectrometry in oral fluid (OF) was developed and extensively validated. Acetonitrile (800 μL) and OF (250 μL) were added to a 96-well Isolute-PPT+protein precipitation plate. Reverse-phase separation was achieved in 16 min and quantification was performed by multiple reaction monitoring. The assay was linear from 0.5 or 1 to 500 μg/L. Intraday, interday, and total imprecision were less than 13% (n=20), analytical recovery was 92–114% (n= 20), extraction efficiencies were more than 77% (n=5), and process efficiencies were more than 45% (n=5). Although ion suppression was detected for EME, cocaine, morphine, 6AC, and heroin (less than 56%) and enhancement was detected for BE and nicotine (less than 316%), deuterated internal standards compensated for these effects. The method was sensitive (limit of detection 0.2–0.8 μg/L) and specific (no interferences) except that 3-hydroxy-4-methoxyamphetamine interfered with AEME. No carryover was detected, and all analytes were stable for 24 h at 22 °C, for 72 h at 4 °C, and after three freeze–thaw cycles, except cocaine, 6AC, and heroin (22–97% loss). The method was applied to 41 OF specimens collected throughout pregnancy with a Salivette® OF collection device from an opioid-dependent BUP-maintained pregnant woman. BUP ranged from 0 to 7,400 μg/L, NBUP from 0 to 71 μg/L, methadone from 0 to 3 μg/L, nicotine from 32 to 5,020 μg/L, cotinine from 125 to 508 μg/L, OH-cotinine from 11 to 51 μg/L, cocaine from 0 to 419 μg/L, BE from 0 to 351 μg/L, EME from 0 to 286 μg/L, AEME from 0 to
Behavioral Flexibility and Response Selection Are Impaired after Limited Exposure to Oxycodone
ERIC Educational Resources Information Center
Seip-Cammack, Katharine M.; Shapiro, Matthew L.
2014-01-01
Behavioral flexibility allows individuals to adapt to situations in which rewards and goals change. Potentially addictive drugs may impair flexible decision-making by altering brain mechanisms that compute reward expectancies, thereby facilitating maladaptive drug use. To investigate this hypothesis, we tested the effects of oxycodone exposure on…
Impact of Cannabis Use During Stabilization on Methadone Maintenance Treatment
Scavone, Jillian L.; Sterling, Robert C.; Weinstein, Stephen P.; Van Bockstaele, Elisabeth J.
2016-01-01
Background and Objectives Illicit drug use, particularly of cannabis, is common among opiate-dependent individuals, and has the potential to impact treatment in a negative manner. Methods To examine this, patterns of cannabis use prior to and during methadone maintenance treatment (MMT) were examined to assess possible cannabis-related effects on MMT, particularly during methadone stabilization. Retrospective chart analysis was used to examine outpatient records of patients undergoing MMT (n=91), focusing specifically on past and present cannabis use and its association with opiate abstinence, methadone dose stabilization, and treatment compliance. Results Objective rates of cannabis use were high during methadone induction, dropping significantly following dose stabilization. History of cannabis use correlated with cannabis use during MMT, but did not negatively impact the methadone induction process. Pilot data also suggested that objective ratings of opiate withdrawal decrease in MMT patients using cannabis during stabilization. Conclusions and Scientific Significance The present findings may point to novel interventions to be employed during treatment for opiate dependence that specifically target cannabinoid-opioid system interactions. PMID:23795873
Pooriamehr, Alireza; Sabahi, Parviz; Miladi-Gorji, Hossein
2017-08-24
Chronic morphine exposure during puberty increased morphine-induced rewarding effects and sensitization in the next generation. Given the well-known beneficial effects of environmental enrichment on the severity of physical and psychological dependence on morphine, we examined effects of enriched environment during morphine abstinence in morphine dependent parental rats before mating on the anxiety and depressive-like behaviors, and voluntary morphine consumption in their offspring. Paternal and/or maternal rats were injected with bi-daily doses (10mg/kg, 12h intervals) of morphine for 14days followed by rearing in a standard environment (SE) or enriched environment (EE) during 30days of morphine abstinence before mating. The pubertal male and female rat offspring were tested for anxiety (the elevated plus maze- EPM) and depression (sucrose preference test-SPT), and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that EE experience in morphine-dependent both parents result in an increase in the percentage of time spent into open arms/time spent on both arms using EPM in male offspring, higher levels of sucrose preference in female offspring and lower levels of voluntary morphine consumption in male and female offspring. Thus, EE experience in morphine-dependent both parents reduced anxiety, depressive-like behavior and also the voluntary morphine consumption in their offspring during puberty which may prevent the vulnerability of the next generation to drug abuse. Copyright © 2017 Elsevier B.V. All rights reserved.
Methadone maintenance treatment (MMT): a review of historical and clinical issues.
Joseph, H; Stancliff, S; Langrod, J
2000-01-01
Methadone maintenance has been evaluated since its development in 1964 as a medical response to the post-World War II heroin epidemic in New York City. The findings of major early studies have been consistent. Methadone maintenance reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity. In addition, enrollment in methadone maintenance has the potential toreduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. A majority of patients require 80-120 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for heroin addiction. Lower doses may not be as effective or provide the blockade effect. Methadone maintenance has been found to be medically safe and nonsedating. It is also indicated for pregnant women addicted to heroin. Reviews issued by the Institute of Medicine and the National Institutes of Health have defined narcotic addiction as a chronic medical disorder and have claimed that methadone maintenance coupled with social services is the most effective treatment for this condition. These agencies recommend reducing governmental regulation to facilitate patients access to treatment. In addition, they recommend that the number of programs be expanded, and that new models of treatment be implemented,if the nationwide problem of addiction is to be brought under control. The National Institutes of Health also recommend that methadone maintenance be available to persons under legal supervision, such as probationers, parolees and the incarcerated. However, stigma and bias directed at the programs and the
Cheek, F E; Holstein, C N; Fullam, F A; Arana, G; Tomarchio, T P; Mandell, S
1976-01-01
This study examines the relevance of reinforcements available to the addict in five critical stages of his career to his success on methadone maintenance. In-depth focused interviews were held with 30 addicts who had completed a program of methadone induction and who were characterized by social worker's evaluations as Successful, Marginally Adjusted, or Failures. The Successful group showed a higher initial negative reinforcement followed by higher positive reinforcement on methadone. The Moderately Successful group showed more negative reinforcement before treatment but continued to show negative reinforcements afterwards. The Failures were low on negative reinforcements earlier but negative reinforcements were high after treatment.
Berner, Todd; Thomson, Heather; Hartry, Ann; Puenpatom, R Amy; Ben-Joseph, Rami; Szeinbach, Sheryl L
2011-03-01
Our goal was to examine the daily average consumption (DACON) of oxycodone controlled-release tablets (OxyContin CR)and oxymorphone extended-release tablets (Opana ER) in patients with low back pain. An observational, retrospective cohort study enrolled patients with multiple prescriptions for oxycodone CR or oxymorphone ER tablets. These patients also had International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for low back pain. Pharmacy prescription medication claims data were obtained from a large commercially insured health plan in the U.S. Mean daily consumption was calculated for a 90-day period. We used descriptive statistics to evaluate patient demographics and health plan characteristics. Univariate analyses were used to examine the data as observed. A generalized linear model with a gamma distribution and log-link function provided a sensitivity measure, adjusting for heterogeneity among patients and the skewed nature of the DACON variable. A total of 4,023 patients received oxycodone CR, and 374 patients received oxymorphone ER. The mean age of patients (standard deviation, SD) was 49.0 (11.6) years for oxycodone CR and 47.3 (10.6) years for oxymorphone ER. DACON of oxycodone CR was 3.2 tablets per day, and DACON of oxymorphone ER was 2.7 tablets per day (P < 0.01). Utilization of maximum-strength tablets of oxycodone CR 80 mg was 3.9 tablets per day, which was significantly higher, by one tablet per day, than the utilization of equipotent oxymorphone ER maximum-strength tablets of 40 mg at 2.9 tablets per day (P < 0.01). The use of oxycodone CR, measured as mean daily consumption over a 90-day period, was significantly higher than that for oxymorphone ER in these patients, a finding that could have financial implications for health care systems.
QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.
Wedam, Erich F; Bigelow, George E; Johnson, Rolley E; Nuzzo, Paul A; Haigney, Mark C P
2007-12-10
Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group
Human Methadone Self-Administration and the Generalized Matching Law
ERIC Educational Resources Information Center
Spiga, Ralph; Maxwell, R. Stockton; Meisch, Richard A.; Grabowski, John
2005-01-01
The present study examined whether in humans the generalized matching law described the relation between relative responding and relative drug intake by humans under concurrent variable interval variable interval (conc VI VI) schedules of drug reinforcement. Methadone-maintained patients, stabilized on 80 mg per day of methadone, were recruited…
Suppression of transmission of nociceptive impulses by morphine
Duggan, A.W.; Hall, J.G.; Headley, P.M.
1977-01-01
1 In spinal cats anaesthetized with α-chloralose, a study was made of the effects of morphine and naloxone, administered electrophoretically from micropipettes, on the responses of dorsal horn neurones to noxious (raising of skin temperature above 45°C) and innocuous (deflection of hairs) peripheral stimuli. 2 Administered near cell bodies, morphine reduced the nociceptive responses of only 2 of 37 cells. Excitation occurred more commonly than depression and abnormalities in action potentials were commonly observed following ejection of morphine. None of these effects of morphine was antagonized by electrophoretically applied naloxone. 3 Administered in the substantia gelatinosa from one micropipette while recording responses of deeper neurones with a second micropipette, morphine reduced the nociceptive responses of 15 of 19 neurones. Firing in response to deflection of hairs was not reduced by morphine. Depression of nociceptive responses by morphine was long lasting (>20 minutes). Naloxone ejected into the substantia gelatinosa or given intravenously in doses as low as 0.1 mg/kg antagonized the effects of morphine. The effectiveness of this dose of intravenous naloxone suggests that the concentrations of morphine in the substantia gelatinosa which reduced nociceptive responses were not unlike those present after analgesic doses of systemic morphine. Naloxone alone, and excitant and depressant amino acids ejected into the substantia gelatinosa had little effect on cell firing. 4 Both the selective action of morphine on nociceptive responses and the reversal of this action by intravenous naloxone suggest that the opiate receptor present in the substantia gelatinosa is relevant to analgesia produced by opiates given systemically. PMID:199311
Schreiber, Shaul; Barak, Yonatan; Hostovsky, Avner; Baratz-Goldstein, Renana; Volis, Ina; Rubovitch, Vardit; Pick, Chaim G
2014-04-01
We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.
Hou, Yuan-Yuan; Cai, You-Qing
2015-01-01
As long-term opioids are increasingly used for control of chronic pain, how pain affects the rewarding effect of opioids and hence risk of prescription opioid misuse and abuse remains a healthcare concern and a challenging issue in current pain management. In this study, using a rat model of morphine self-administration, we investigated the molecular mechanisms underlying the impact of pain on operant behavior of morphine intake and morphine seeking before and after morphine withdrawal. We found that rats with persistent pain consumed a similar amount of daily morphine to that in control rats without pain, but maintained their level-pressing behavior of morphine seeking after abstinence of morphine at 0.2 mg/kg, whereas this behavior was gradually diminished in control rats. In the central nucleus of amygdala (CeA), a limbic structure critically involved in the affective dimension of pain, proteins of GluA1 subunits of glutamate AMPA receptors were upregulated during morphine withdrawal, and viral knockdown of CeA GluA1 eliminated the morphine-seeking behavior in withdrawn rats of the pain group. Chromatin immunoprecipitation analysis revealed that the methyl CpG-binding protein 2 (MeCP2) was enriched in the promoter region of Gria1 encoding GluA1 and this enrichment was significantly attenuated in withdrawn rats of the pain group. Furthermore, viral overexpression of CeA MeCP2 repressed the GluA1 level and eliminated the maintenance of morphine-seeking behavior after morphine withdrawal. These results suggest direct MeCp2 repression of GluA1 function as a likely mechanism for morphine-seeking behavior maintained by long-lasting affective pain after morphine withdrawal. PMID:25716866
Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles
2017-01-01
Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significantly lower (p < .0001) than for all other ER/LA opioid analgesics examined. No fatalities associated with BTDS exposure were reported. This post-marketing evaluation of BTDS indicates infrequent poison center calls for intentional abuse and suspected suicidal intent events, suggesting lower rates of these risks with BTDS compared to other ER/LA opioids.
Mercer, Susan L.; Coop, Andrew
2012-01-01
Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationship development to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation. PMID:21050174
Opioids in people with cancer-related pain
2008-01-01
Introduction Up to 80% of people with cancer experience pain at some time during their illness, and most will need opioid analgesics. This review assesses how different opioid analgesics compare, in terms of both pain control and adverse effects, in people with cancer. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: what are the effects of opioids in treating cancer-related pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: codeine, dihydrocodeine, transdermal fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. PMID:19445735
Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy.
Graziani, Manuela; Nisticò, Robert
2015-01-01
Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic pain. We performed a search in the Medline database from 1990 to 2014 in order to find published literature related to gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) of methadone. None of the studies were carried out with the primary or secondary aim to identify any gender differences in the pharmacokinetic profile of methadone. Importantly; high inter-subjects variability in PK parameters was found also intra female population. The reported differences in volume of distribution could be ascribed to the physiological differences between men and women in body weight and composition, taking into account that the dose of methadone was established irrespective of body weight of patients (Peles and Adelson, 2006). On the other hand, the few studies present in literature found no gender difference in some direct pharmacodynamic parameters. Some reports have suggested that female gender is associated with an increased risk for long-QT-related cardiac arrhythmias in methadone maintenance subjects. Even though it may be too simplistic to expect variability only in one parameter to explain inter-individual variation in methadone response, we believe that a better knowledge of gender-related differences might have significant implications for better outcomes in opioid dependence substitution therapy in women.
An in vitro approach to potential methadone metabolic-inhibition interactions.
Bomsien, Stephanie; Skopp, Gisela
2007-09-01
The aim of this study was to assess the drug interaction potential of psychotropic medication on methadone N-demethylation using cDNA-expressed cytochrome P450 CYP enzymes. Methadone was incubated with various drugs (n = 10) and cDNA-expressed CYP3A4, CYP2D6, CYP2B6, CYP2C19 and CYP1A2 enzymes to screen for their inhibition potency. The nature of enzyme selective activity for inhibition was further investigated for potent inhibitors. To test for a mechanism-based component in inhibition, all substances were tested with preincubation and without. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentration was determined by liquid chromatography/tandem mass spectrometry following liquid/liquid extraction. Formation of EDDP was catalysed by CYP3A4, CYP2D6 and CYP2C19. The N-demethylation of methadone was preferentially inhibited by amitriptyline, buprenorphine, methylenedioxymethamphetamine (MDMA) and zolpidem. Both amitriptyline and buprenorphine were strong, reversible inhibitors of CYP3A4. Similarly, amitriptyline and MDMA were identified as inhibitors of CYP2D6. Zolpidem revealed a mechanism-based inhibition of CYP3A4. Amitriptyline, MDMA and zolpidem are likely to slow down conversion of methadone and to increase its area under the curve (AUC). A consideration of the in vitro evidence of drug-methadone interactions should help to improve patient care during methadone maintenance treatment.
Implementing methadone maintenance treatment in prisons in Malaysia.
Wickersham, Jeffrey A; Marcus, Ruthanne; Kamarulzaman, Adeeba; Zahari, Muhammad Muhsin; Altice, Frederick L
2013-02-01
In Malaysia, human immunodeficiency virus (HIV) infection is highly concentrated among people who inject opioids. For this reason, the country undertook a three-phase roll-out of a methadone maintenance treatment (MMT) programme. In Phase 3, described in this paper, MMT was implemented within prisons and retention in care was assessed. After developing standard operating procedures and agreement between its Prisons Department and Ministry of Health, Malaysia established pilot MMT programmes in two prisons in the states of Kelantan (2008) and Selangor (2009) - those with the highest proportions of HIV-infected prisoners. Community-based MMT programmes were also established in Malaysia to integrate treatment activities after prisoners' release. Having failed to reduce the incidence of HIV infection, in 2005 Malaysia embarked on a harm reduction strategy. STANDARD OPERATING PROCEDURES WERE MODIFIED TO: (i) escalate the dose of methadone more slowly; (ii) provide ongoing education and training for medical and correctional staff and inmates; (iii) increase the duration of methadone treatment before releasing prisoners; (iv) reinforce linkages with community MMT programmes after prisoners' release; (v) screen for and treat tuberculosis; (vi) escalate the dose of methadone during treatment for HIV infection and tuberculosis; and (vii) optimize the daily oral dose of methadone (> 80 mg) before releasing prisoners. Prison-based MMT programmes can be effectively implemented but require adequate dosing and measures are needed to improve communication between prison and police authorities, prevent police harassment of MMT clients after their release, and improve systems for tracking release dates.
The impact of benzodiazepine use on methadone maintenance treatment outcomes.
Brands, Bruna; Blake, Joan; Marsh, David C; Sproule, Beth; Jeyapalan, Renuka; Li, Selina
2008-01-01
The purposes of this study were to examine predictors of benzodiazepine use among methadone maintenance treatment patients, to determine whether baseline benzodiazepine use influenced ongoing use during methadone maintenance treatment, and to assess the effect of ongoing benzodiazepine use on treatment outcomes (i.e., opioid and cocaine use and treatment retention). A retrospective chart review of 172 methadone maintenance treatment patients (mean age = 34.6 years; standard deviation = 8.5 years; 64% male) from January 1997 to December 1999 was conducted. At baseline, 29% were "non-users" (past year) of benzodiazepine, 36% were "occasional users," and 35% were "regular/problem users." Regular/problem users were more likely to have started opioid use with prescription opioids, experienced more overdoses, and reported psychiatric comorbidity. Being female, more years of opioid use, and a history of psychiatric treatment were significant predictors of baseline benzodiazepine use. Ongoing benzodiazepine users were more likely to have opioid-positive and cocaine-positive urine screens during methadone maintenance treatment. Only ongoing cocaine use was negatively related to retention. Benzodiazepine use by methadone maintenance treatment patients is associated with a more complex clinical picture and may negatively influence treatment outcomes.
Linares, Oscar A; Schiesser, William E; Fudin, Jeffrey; Pham, Thien C; Bettinger, Jeffrey J; Mathew, Roy O; Daly, Annemarie L
2015-01-01
There is a need to have a model to study methadone's losses during hemodialysis to provide informed methadone dose recommendations for the practitioner. To build a one-dimensional (1-D), hollow-fiber geometry, ordinary differential equation (ODE) and partial differential equation (PDE) countercurrent hemodialyzer model (ODE/PDE model). We conducted a cross-sectional study in silico that evaluated eleven hemodialysis patients. Patients received a ceiling dose of methadone hydrochloride 30 mg/day. Outcome measures included: the total amount of methadone removed during dialysis; methadone's overall intradialytic mass transfer rate coefficient, km ; and, methadone's removal rate, j ME. Each metric was measured at dialysate flow rates of 250 mL/min and 800 mL/min. The ODE/PDE model revealed a significant increase in the change of methadone's mass transfer with increased dialysate flow rate, %Δkm =18.56, P=0.02, N=11. The total amount of methadone mass transferred across the dialyzer membrane with high dialysate flow rate significantly increased (0.042±0.016 versus 0.052±0.019 mg/kg, P=0.02, N=11). This was accompanied by a small significant increase in methadone's mass transfer rate (0.113±0.002 versus 0.014±0.002 mg/kg/h, P=0.02, N=11). The ODE/PDE model accurately predicted methadone's removal during dialysis. The absolute value of the prediction errors for methadone's extraction and throughput were less than 2%. ODE/PDE modeling of methadone's hemodialysis is a new approach to study methadone's removal, in particular, and opioid removal, in general, in patients with end-stage renal disease on hemodialysis. ODE/PDE modeling accurately quantified the fundamental phenomena of methadone's mass transfer during hemodialysis. This methodology may lead to development of optimally designed intradialytic opioid treatment protocols, and allow dynamic monitoring of outflow plasma opioid concentrations for model predictive control during dialysis in humans.
Kinlock, Timothy W; Gordon, Michael S; Schwartz, Robert P; Fitzgerald, Terrence T; O'Grady, Kevin E
2009-10-01
This study examined the impact of prison-initiated methadone maintenance at 12 months postrelease. Males with pre-incarceration heroin dependence (N = 204) were randomly assigned to (a) Counseling Only: counseling in prison, with passive referral to treatment upon release; (b) Counseling + Transfer: counseling in prison with transfer to methadone maintenance treatment upon release; and (c) Counseling + Methadone: counseling and methadone maintenance in prison, continued in the community upon release. The mean number of days in community-based drug abuse treatment were, respectively, Counseling Only, 23.1; Counseling + Transfer, 91.3; and Counseling + Methadone, 166.0 (p < .01); all pairwise comparisons were statistically significant (all ps < .01). Counseling + Methadone participants were also significantly less likely than participants in each of the other two groups to be opioid-positive or cocaine-positive according to urine drug testing. These results support the effectiveness of prison-initiated methadone for males in the United States. Further study is required to confirm the findings for women.
Immunomodulatory effect of morphine: therapeutic implications.
Dinda, Amit; Gitman, Michael; Singhal, Pravin C
2005-07-01
The immunosuppressive as well as modulatory effects of morphine have been known in clinical medicine for > 100 years. Recent developments in molecular immunology, including experiments in mu (mu) opioid receptor knockout mice has led to a better understanding of central and peripheral mechanisms involved in this process. Though there is a large volume of literature documenting adverse effects of immunosupression following the use of morphine, several reports confirm its potential usefulness as an immunomodulator. In vitro and in vivo animal experiments have demonstrated wide-spectrum effects of morphine, including anti-inflammatory, antifibrotic, antitumour, cardioprotective and renoprotective. Immunomodulation is an important field in modern medicine with rapid advancement in recent years. Though a final statement regarding the clinical relevance of morphine-induced immunomodulation cannot be made at this juncture, nevertheless, it is worthwhile to review current developments. It may encourage further clinical studies to elucidate the influence of morphine treatment on immune regulation in different specialties of medicine.
Baker, David R; Barron, Leon; Kasprzyk-Hordern, Barbara
2014-07-15
This paper presents, for the first time, community-wide estimation of drug and pharmaceuticals consumption in England using wastewater analysis and a large number of compounds. Among groups of compounds studied were: stimulants, hallucinogens and their metabolites, opioids, morphine derivatives, benzodiazepines, antidepressants and others. Obtained results showed the usefulness of wastewater analysis in order to provide estimates of local community drug consumption. It is noticeable that where target compounds could be compared to NHS prescription statistics, good comparisons were apparent between the two sets of data. These compounds include oxycodone, dihydrocodeine, methadone, tramadol, temazepam and diazepam. Whereas, discrepancies were observed for propoxyphene, codeine, dosulepin and venlafaxine (over-estimations in each case except codeine). Potential reasons for discrepancies include: sales of drugs sold without prescription and not included within NHS data, abuse of a drug with the compound trafficked through illegal sources, different consumption patterns in different areas, direct disposal leading to over estimations when using parent compound as the drug target residue and excretion factors not being representative of the local community. It is noticeable that using a metabolite (and not a parent drug) as a biomarker leads to higher certainty of obtained estimates. With regard to illicit drugs, consistent and logical results were reported. Monitoring of these compounds over a one week period highlighted the expected recreational use of many of these drugs (e.g. cocaine and MDMA) and the more consistent use of others (e.g. methadone). Copyright © 2014 Elsevier B.V. All rights reserved.
Methadone induces CAD degradation and AIF-mediated necrotic-like cell death in neuroblastoma cells.
Perez-Alvarez, Sergio; Iglesias-Guimarais, Victoria; Solesio, María E; Melero-Fernandez de Mera, Raquel María; Yuste, Víctor J; Galindo, María F; Jordán, Joaquín
2011-04-01
Methadone (d,l-methadone hydrochloride) is a full-opioid agonist, originally developed as a substitution for heroin or other opiates abusers. Nowadays methadone is also being applied as long-lasting analgesics in cancer, and it is proposed as a promising agent for leukemia therapy. Previously, we have demonstrated that high concentrations of methadone (0.5mM) induced necrotic-like cell death in SH-SY5Y cells. The pathway involved is caspase-independent but involves impairment of mitochondrial ATP synthesis and mitochondrial cytochrome c release. However, the downstream mitochondrial pathways remained unclear. Here, we studied the participation of apoptosis inducing factor (AIF) in methadone-induced cell death. Methadone resulted in a translocation of AIF from mitochondria to the nucleus. Translocation was inhibited by cyclosporine A, but not by lack of Bax protein. Therefore the effect seems mediated by the formation of the mitochondrial transition pore, but is apparently independent of Bax. Furthermore, methadone-treated SH-SY5Y nuclei show characteristics that are typical for stage I nuclear condensation. Methadone did not induce degradation of DNA into oligonucleosomal fragments or into high molecular weight DNA fragments. Absence of DNA fragmentation coincided with a considerable decrease in the levels of the caspase-actived endonuclase DNase and its chaperone-inhibitor ICAD. In conclusion, our results provide mechanistic insights into the molecular mechanisms that underlie methadone-induced cell death. This knowledge may prove useful to develop novel strategies to prevent toxic side-effects of methadone thereby sustaining its use as therapeutical agent against tumors. Copyright © 2010 Elsevier Ltd. All rights reserved.
Children of Methadone-Maintained Mothers: Three-Year Follow-Up.
ERIC Educational Resources Information Center
Johnson, Helen L.; And Others
The physical and neurobehavioral findings at 3 years of age for 39 children born to mothers on methadone- maintenance and 23 children born to drug-free comparison mothers are reported. The methadone children had a higher incidence of head circumferences less than the third percentile, nystagmus/strabismus, and otitis media. No differences were…
Pavlovian conditioning analysis of morphine tolerance.
Siegel, S
1978-01-01
It has been demonstrated that many conditional responses to a variety of drugs are opposite in direction to the unconditional effects of the drug, and the conditioning analysis of morphine tolerance emphasizes the fact that subjects with a history of morphine administration display morphine-compensatory conditional responses when confronted with the usual administration procedure but without the drug. Thus, when the drug is presented in the context of the usual administration cues, these conditional morphine-compensatory responses would be expected to attenuate the drug-induced unconditional responses, thereby decreasing the observed response to the drug. Research has been summarized which supports this compensatory conditioning model of tolerance by demonstrating that the display of tolerance is specific to the environment in which the drug has been previously administered. Further evidence supporting this theory of tolerance has been provided by studies establishing that extinction, partial reinforcement, and latent inhibition--non-pharmacological manipulations known to be effective in generally affecting the display of conditional responses--similarly affect the display of morphine tolerance. Additional research has suggested many parallels between learning and morphine tolerance: Both processes exhibit great retention, both are disrupted by electroconvulsive shock and frontal cortical stimulation, both are retarded by inhibitors of protein synthesis, and both are facilitated by antagonists of these metabolic inhibitors.
Baño Rodrigo, M D; Agujetas Rodríguez, M; López García, M L; Guillén Llera, J L
2000-01-01
The objective of this study was to investigate the potential inductive effect of nevirapine (NVP) with methadone. Eight patients on the methadone maintenance programme with anti-retroviral therapy because of their infection with HIV, well maintained with methadone and without symptoms of abstinence were studied. All were included in a study of measurement of plasma levels of methadone. Anti-retroviral medication was changed, including NVP, and patients began with symptoms of abstinence 5 to 10 days later. Our results indicate an inductive effect of NVP on the methadone metabolism which caused symptoms of abstinence in all patients, which prompted an increase in the dose and plasma concentration of methadone was lost; patients continued with significantly low plasma levels (p < 0.01) after a therapy mean duration of 6.5 months, with no full recovery.
Do abuse deterrent opioid formulations work?
Dart, Richard C; Iwanicki, Janetta L; Dasgupta, Nabarun; Cicero, Theodore J; Schnoll, Sidney H
We performed a systematic review to answer the question, "Does the introduction of an opioid analgesic with abuse deterrent properties result in reduced overall abuse of the drug in the community?" We included opioid analgesics with abuse deterrent properties (hydrocodone, morphine, oxycodone) with results restricted to the metasearch term "delayed onset," English language, use in humans, and publication years 2009-2016. All articles that contained data evaluating misuse, abuse, overdose, addiction, and death were included. The results were categorized using the Bradford-Hill criteria. We included 44 reports: hydrocodone (n = 7), morphine (n = 5), or oxycodone (n = 32) with Food and Drug Administration-approved Categories 1, 2, or 3 abuse deterrent labeling. The data currently available support the Hill criteria of strength (effect size), consistency (reproducibility), temporality, plausibility, and coherence. There was insufficient or no information available for the criteria of biological gradient, experiment, and analogy. We also assessed confounding factors and bias, which indicated that both were present and substantial in magnitude. Our analysis found that only oxycodone extended release (ER) had information available to evaluate abuse deterrence in the community. In Australia, Canada, and the United States, reformulation of oxycodone ER was followed by marked reduction in measures of abuse. The precise extent of reduced abuse cannot be calculated because of heterogeneous data sets, but the reported reductions ranged from 10 to 90 percent depending on the measure and the duration of follow-up.
Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats.
Shahraki, Mohammad Reza; Mirshekari, Hamideh; Sabri, Azame
2014-09-01
Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent. The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats. The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P < 0.05). The results of the present study showed that agitation, disparity, and floppy eyelids in group E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups. The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats .
Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats
Shahraki, Mohammad Reza; Mirshekari, Hamideh; Sabri, Azame
2014-01-01
Background: Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent. Objectives: The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats. Patients and Methods: The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P < 0.05). Results: The results of the present study showed that agitation, disparity, and floppy eyelids in group E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups. Conclusions: The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats . PMID:25593890
Determination of methadone hydrochloride in a maintenance dosage formulation.
Hoffmann, T J; Thompson, R D
1975-07-01
A colorimetric method for direct quantitative assay of methadone hydrochloride in liquid oral dosage forms is presented. The procedure involves the formation of a dye complex with bromothymol blue buffer solution. The resultant complex is extracted with benzene and measured spectrophotometrically. Duplicate tests on the formulation showed 99.2% of the labeled amount of methadone.
Cost-Effectiveness of Tramadol and Oxycodone in the Treatment of Knee Osteoarthritis.
Smith, Savannah R; Katz, Jeffrey N; Collins, Jamie E; Solomon, Daniel H; Jordan, Joanne M; Suter, Lisa G; Yelin, Edward H; David Paltiel, A; Losina, Elena
2017-02-01
To evaluate the cost-effectiveness of incorporating tramadol or oxycodone into knee osteoarthritis (OA) treatment. We used the Osteoarthritis Policy Model to evaluate long-term clinical and economic outcomes of knee OA patients with a mean age of 60 years with persistent pain despite conservative treatment. We evaluated 3 strategies: opioid-sparing (OS), tramadol (T), and tramadol followed by oxycodone (T+O). We obtained estimates of pain reduction and toxicity from published literature and annual costs for tramadol ($600) and oxycodone ($2,300) from Red Book Online. Based on published data, in the base case, we assumed a 10% reduction in total knee arthroplasty (TKA) effectiveness in opioid-based strategies. Outcomes included quality-adjusted life years (QALYs), lifetime cost, and incremental cost-effectiveness ratios (ICERs) and were discounted at 3% per year. In the base case, T and T+O strategies delayed TKA by 7 and 9 years, respectively, and led to reduction in TKA utilization by 4% and 10%, respectively. Both opioid-based strategies increased cost and decreased QALYs compared to the OS strategy. Tramadol's ICER was highly sensitive to its effect on TKA outcomes. Reduction in TKA effectiveness by 5% (compared to base case 10%) resulted in an ICER for the T strategy of $110,600 per QALY; with no reduction in TKA effectiveness, the ICER was $26,900 per QALY. When TKA was not considered a treatment option, the ICER for T was $39,600 per QALY. Opioids do not appear to be cost-effective in OA patients without comorbidities, principally because of their negative impact on pain relief after TKA. The influence of opioids on TKA outcomes should be a research priority. © 2016, American College of Rheumatology.
[Evaluation of the Methadone Maintenance Program of the Risaralda Mental Hospital].
Isaza, Carlos; Henao, Julieta; Velez, Juan; Rodríguez, Miguel A; Sierra, Juan; Beltrán, Leonardo; Sepúlveda, Ana
2014-01-01
Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsatisfactory, justifying the search and intervention of the factors influencing the response to treatment. In order to determine the contribution of demographic, clinical and genetic variables on serum concentrations and response to methadone, we investigated patients on MMT, who were receiving methadone in supervised and unchanged doses at least during the previous two weeks. The age, gender, body mass index (BMI), duration of heroin abuse, addiction to other drugs, criminal background, current daily methadone doses, time spent in the TMM, comorbidity and concomitant medication were recorded. Blood samples were taken for the determination of serum levels of racemic methadone and its R and S-enantiomers, and for typing of candidate alleles of POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH and ARRB2 genes, all associated with the metabolism, tissue distribution and mechanism of action of methadone. Methadone quantification was by HPLC-DAD, and the detection of genetic markers by Real Time PCR and VNTR methods. A total of 80 subject volunteers were enrolled, with a mean age of 23.5 (5) years (86% male), all of them were addicts of multiple drugs, 60% with a criminal background, 5.1 (2.9) years taking heroin, and 5.3 (4) months on MMT, and taking a supervised dose of 41 (12) mg/day methadone. The (R), (S) and (R, S) methadone enantiomer trough plasma levels were, 84 (40), 84 (42), and 168 (77) ng/mL, respectively. All genotypes were in Hardy-Weinberg equilibrium. The two urine tests were negative for heroin in 61.3% (49/80) of the volunteers, the decline in cocaine/crack use was 83%, 30% of marijuana, and other psychoactives (inhalants, benzodiazepines, amphetamines) decreased to zero, while the consumption of snuff remained at 93.5% (75/80). Blood concentrations of racemic methadone and its enantiomers were
Comparison of perioperative analgesic efficacy between methadone and butorphanol in cats.
Warne, Leon N; Beths, Thierry; Holm, Merete; Bauquier, Sébastien H
2013-09-15
To compare the perioperative analgesic effect between methadone and butorphanol in cats. Randomized controlled clinical trial. 22 healthy female domestic cats. Cats admitted for ovariohysterectomy were allocated to a butorphanol group (n = 10) or methadone group (12) and premedicated with butorphanol (0.4 mg/kg [0.18 mg/lb], SC) or methadone (0.6 mg/kg [0.27 mg/lb], SC), respectively, in combination with acepromazine (0.02 mg/kg [0.01 mg/lb], SC). Anesthesia was induced with propofol (IV) and maintained with isoflurane in oxygen. A multidimensional composite scale was used to conduct pain assessments prior to premedication and 5, 20, 60, 120, 180, 240, 300, and 360 minutes after extubation or until rescue analgesia was given. Groups were compared to evaluate isoflurane requirement, propofol requirement, pain scores, and requirement for rescue analgesia. Propofol and isoflurane requirements and preoperative pain scores were not different between groups. During recovery, dysphoria prevented pain evaluation at 5 minutes. Pain scores at 20 minutes were significantly lower in the methadone group, and 6 of 10 cats in the butorphanol group received rescue analgesia, making subsequent pain score comparisons inapplicable. After 6 hours, only 3 of 12 cats in the methadone group had received rescue analgesia. In the present study, methadone appeared to be a better postoperative analgesic than butorphanol and provided effective analgesia for 6 hours following ovariohysterectomy in most cats.
Implementing methadone maintenance treatment in prisons in Malaysia
Wickersham, Jeffrey A; Marcus, Ruthanne; Kamarulzaman, Adeeba; Zahari, Muhammad Muhsin
2013-01-01
Abstract Problem In Malaysia, human immunodeficiency virus (HIV) infection is highly concentrated among people who inject opioids. For this reason, the country undertook a three-phase roll-out of a methadone maintenance treatment (MMT) programme. In Phase 3, described in this paper, MMT was implemented within prisons and retention in care was assessed. Approach After developing standard operating procedures and agreement between its Prisons Department and Ministry of Health, Malaysia established pilot MMT programmes in two prisons in the states of Kelantan (2008) and Selangor (2009) – those with the highest proportions of HIV-infected prisoners. Community-based MMT programmes were also established in Malaysia to integrate treatment activities after prisoners’ release. Local setting Having failed to reduce the incidence of HIV infection, in 2005 Malaysia embarked on a harm reduction strategy. Relevant changes Standard operating procedures were modified to: (i) escalate the dose of methadone more slowly; (ii) provide ongoing education and training for medical and correctional staff and inmates; (iii) increase the duration of methadone treatment before releasing prisoners; (iv) reinforce linkages with community MMT programmes after prisoners’ release; (v) screen for and treat tuberculosis; (vi) escalate the dose of methadone during treatment for HIV infection and tuberculosis; and (vii) optimize the daily oral dose of methadone (> 80 mg) before releasing prisoners. Lessons learnt Prison-based MMT programmes can be effectively implemented but require adequate dosing and measures are needed to improve communication between prison and police authorities, prevent police harassment of MMT clients after their release, and improve systems for tracking release dates. PMID:23554524
Attitudes and practices regarding the use of methadone in US state and federal prisons.
Rich, Josiah D; Boutwell, Amy E; Shield, David C; Key, R Garrett; McKenzie, Michelle; Clarke, Jennifer G; Friedmann, Peter D
2005-09-01
In the United States, vigorous enforcement of drug laws and stricter sentencing guidelines over the past 20 years have contributed to an expanded incarcerated population with a high rate of drug use. One in five state prisoners reports a history of injection drug use, and many are opiate dependent. For over 35 years, methadone maintenance therapy has been an effective treatment for opiate dependence; however, its use among opiate-dependent inmates in the United States is limited. In June 2003, we conducted a survey of the medical directors of all 50 US states and the federal prison system to describe their attitudes and practices regarding methadone. Of the 40 respondents, having jurisdiction over 88% (n =1,266,759) of US prisoners, 48% use methadone, predominately for pregnant inmates or for short-term detoxification. Only 8% of respondents refer opiate-dependent inmates to methadone programs upon release. The results highlight the need to destigmatize the use of methadone in the incarcerated setting, expand access to methadone during incarceration, and to improve linkage to methadone treatment for opiate-dependent offenders who return to the community.
Margolin, Arthur; Kantak, Kathleen; Copenhaver, Michael; Avants, S Kelly
2003-01-01
Based on pre-clinical studies suggesting that magnesium (Mg) reduces cocaine self-administration and potentiates the antinociceptive effects of morphine, we conducted a preliminary randomized clinical trial investigating Mg for the treatment of illicit cocaine and opiate use. Eighteen methadone-maintained patients who used illicit opiates and cocaine received either Mg (732 mg/day) or placebo for 12 weeks. Overall, findings showed that the percentage of urine screens testing positive for opiates in the Mg group (22.6%) was half that of the placebo group (46.4%), p = .04; the difference was even greater in the "medication compliant" sample (Mg: 16.3%, placebo: 47.9%), p = .02. Cocaine craving was lower in the Mg compared to the placebo group, but there was no difference between groups in cocaine use. These preliminary findings suggest that Mg may have a beneficial effect for reducing illicit opiate use. It is possible that a higher dose of Mg than was used in this study may be needed to decrease cocaine use.
The effect of P-glycoprotein on methadone hydrochloride flux in equine intestinal mucosa.
Linardi, R L; Stokes, A M; Andrews, F M
2013-02-01
Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P-glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P-glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapamil. Electrical measurements demonstrated tissue viability for 120 min, and the flux of methadone across the jejunal membrane (mucosal to submucosal direction) was calculated based on the relative drug concentration measured by ELISA. The flux of methadone was significantly higher only in the presence of verapamil. P-glycoprotein was immunolocalized in the apical membrane of the jejunal epithelial cells (enterocytes), mainly located in the tip of the villi compared to cells of the crypts. P-glycoprotein is present in the equine jejunum and may possibly mediate the intestinal transport of methadone. This study suggests that P-glycoprotein may play a role in the poor intestinal absorption of methadone in vivo. © 2012 Blackwell Publishing Ltd.
Morphine clearance in children: does race or genetics matter?
Sadhasivam, Senthilkumar; Krekels, Elke H J; Chidambaran, Vidya; Esslinger, Hope R; Ngamprasertwong, Pornswan; Zhang, Kejian; Fukuda, Tsuyoshi; Vinks, Alexander A
2012-01-01
Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al-though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented. Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care. Tertiary care pediatric institution. Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races. Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated. The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (2161C>T and 802C>T) were not associated with observed racial differences in morphine's clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans. Race of the child is an important factor in perioperative intravenous morphine's clearance and its potential role in personalizing analgesia with morphine needs further investigation.
Social influences on morphine conditioned place preference in adolescent mice.
Cole, Shannon L; Hofford, Rebecca S; Evert, Daniel J; Wellman, Paul J; Eitan, Shoshana
2013-03-01
Social/peer influences are among the strongest predictors of adolescent drug use. However, this important subject does not get much attention in pre-clinical studies. We recently observed that exposure to different social partners modulates morphine locomotor sensitization. Sensitivity to the hyper-locomotor response of drugs of abuse is a predictor of sensitivity to other drug-induced behaviors. Thus, this study examined how exposure to different social partners affected the rewarding properties of morphine. All animals were group-housed four per cage in one of two conditions referred to as 'only' and 'cage-mates'. In the mixed treatment condition, morphine- and saline-treated mice were housed together. These groups are referred to as 'morphine cage-mates' and 'saline cage-mates', respectively. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'), and cages were visually separated from each other. All animals were subsequently individually tested for the acquisition of morphine conditioned place preference (CPP) following one conditioning session with 10, 20 or 40 mg/kg morphine or saline. As expected, one conditioning session established morphine CPP in the morphine only animals, but not in the saline only animals. Notably, morphine CPP was not acquired by the morphine cage-mate animals. Additionally, 40 mg/kg morphine was sufficient to establish morphine CPP in the saline cage-mate animals. These results indicate that social environment has an effect on the rewarding properties of morphine. It suggests that exposure to different peers can alter the abuse potential of opioids and potentially other illicit drugs. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.
1997-01-16
Administration Following Physical and Environmental Stressors in Fischer-344 and Lewis Female Rats" Name of Candidate: Kelly Brown Doctor...Title ofDissertation: Examination ofAcute Sensitivity to Morphine and Morphine Self- Administration Following Physical and Environmental Stressors in...to tolerance, toxicity, or addiction liability. IV Examination ofAcute Sensitivity to Morphine and Morphine Self-Administration Following Physical and
Karanges, Emily A.; Blanch, Bianca; Buckley, Nicholas A.
2016-01-01
Aim The aim of this paper is to investigate 25‐year trends in community use of prescribed opioid analgesics in Australia, and to map these trends against major changes to opioid registration and subsidy. Methods We obtained dispensing data from 1990 to 2014 from two sources: dispensing claims processed under Australia's national drug subsidy programme, the Pharmaceutical Benefits Scheme, including under co‐payment records from 2012; and estimates of non‐subsidized medicine use from a survey of Australian pharmacies (until 2011). Utilization was expressed in defined daily doses (DDD)/1000 population/day. Results Opioid dispensing increased almost four‐fold between 1990 and 2014, from 4.6 to 17.4 DDD/1000 pop/day. In 1990, weak, short‐acting or orally administered opioids accounted for over 90% of utilization. Use of long‐acting opioids increased over 17‐fold between 1990 and 2000, due primarily to the subsidy of long‐acting morphine and increased use of methadone for pain management. Between 2000 and 2011, oxycodone, fentanyl, buprenorphine, tramadol and hydromorphone use increased markedly. Use of strong opioids, long‐acting and transdermal preparations also increased, largely following the subsidy of various opioids for noncancer pain. In 2011, the most dispensed opioids were codeine (41.1% of total opioid use), oxycodone (19.7%) and tramadol (16.1%); long‐acting formulations comprised approximately half, and strong opioids 40%, of opioid dispensing. Conclusions Opioid utilization in Australia is increasing, although these figures remain below levels reported in the US and Canada. The increased use of opioids was largely driven by the subsidy of long‐acting formulations and opioids for the treatment of noncancer pain. PMID:26991673
A 5-year evaluation of a methadone medical maintenance program.
Harris, Kenneth A; Arnsten, Julia H; Joseph, Herman; Hecht, Joe; Marion, Ira; Juliana, Patti; Gourevitch, Marc N
2006-12-01
Methadone medical maintenance (MMM) is a model for the treatment of opioid dependence in which a monthly supply of methadone is distributed in an office setting, in contrast to more highly regulated settings where daily observed dosing is the norm. We assessed patient characteristics and treatment outcomes of an MMM program initiated in the Bronx, New York, in 1999 by conducting a retrospective chart review. Participant characteristics were compared with those of patients enrolled in affiliated conventional methadone maintenance treatment programs. Patients had diverse ethnicities, occupations, educational backgrounds, and income levels. Urine toxicology testing detected illicit opiate and cocaine use in 0.8% and 0.4% of aggregate samples, respectively. The retention rate was 98%, which compares favorably with the four other MMM programs that have been reported in the medical literature. This study demonstrates that selected patients from a socioeconomically disadvantaged population remained clinically stable and engaged in treatment in a far less intensive setting than traditional methadone maintenance.
A 5-year evaluation of a methadone medical maintenance program
Harris, Kenneth A.; Arnsten, Julia H.; Joseph, Herman; Hecht, Joe; Marion, Ira; Juliana, Patti; Gourevitch, Marc N.
2009-01-01
Methadone medical maintenance (MMM) is a model for the treatment of opioid dependence in which a monthly supply of methadone is distributed in an office setting, in contrast to more highly regulated settings where daily observed dosing is the norm. We assessed patient characteristics and treatment outcomes of an MMM program initiated in the Bronx, New York, in 1999 by conducting a retrospective chart review. Participant characteristics were compared with those of patients enrolled in affiliated conventional methadone maintenance treatment programs. Patients had diverse ethnicities, occupations, educational backgrounds, and income levels. Urine toxicology testing detected illicit opiate and cocaine use in 0.8% and 0.4% of aggregate samples, respectively. The retention rate was 98%, which compares favorably with the four other MMM programs that have been reported in the medical literature. This study demonstrates that selected patients from a socioeconomically disadvantaged population remained clinically stable and engaged in treatment in a far less intensive setting than traditional methadone maintenance. PMID:17084798
[Use of methadone in the elderly with cancer pain: a systematic review].
Taberna, Miren; Villavicencio-Chávez, Christian; González-Barboteo, Jesús
2014-01-01
To identify the clinical use of methadone as an analgesic in the management of cancer pain in elderly patients. We performed a systemic review of the literature on the specific use of methadone in elderly with cancer pain in MEDLINE, COCHRANE DATABASE and SCOPUS. A second search was conducted in MEDLINE to look for clinical trials and systematic review of the use of methadone in cancer pain, selecting only those in which the mean age of patients was ≥ 65 years old. Four articles were obtained in the first search, and from the second 7 clinical trials, none of them specific to methadone use in elderly patients with cancer. There are insufficient data on the use of methadone as an analgesic in the elderly with cancer. Given its pharmacological characteristics it must be used by trained personnel. Several recommendations are proposed for its use as an analgesic in the treatment of cancer pain in the elderly. Copyright © 2013 SEGG. Published by Elsevier Espana. All rights reserved.
Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-13
... INFORMATION CONTACT: Astrid Lopez-Goldberg, Center for Drug Evaluation and Research, Food and Drug... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0563] Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration and...
Kinlock, Timothy W.; Gordon, Michael S.; Schwartz, Robert P.; Fitzgerald, Terrence T.; O’Grady, Kevin E.
2009-01-01
This study examined the impact of prison-initiated methadone maintenance at 12-months post-release. Males with pre-incarceration heroin dependence (n=204) were randomly assigned to: 1) Counseling Only: counseling in prison, with passive referral to treatment upon release; 2) Counseling+Transfer: counseling in prison with transfer to methadone maintenance treatment upon release; and 3) Counseling+Methadone: counseling and methadone maintenance in prison, continued in the community upon release. The mean number of days in community-based drug abuse treatment were, respectively, Counseling Only 23.1, Counseling+Transfer 91.3, and Counseling+Methadone 166.0, p <.01; all pairwise comparisons were statistically significant (all ps < .01). Counseling+Methadone participants were also significantly less likely than participants in each of the other two groups to be opioid-positive or cocaine-positive according to urine drug testing. These results support the effectiveness of prison-initiated methadone for males in the United States. Further study is required to confirm the findings for women. PMID:19339140
Cancer inpatients morphine usage: a new England area survey.
Trollor, John
2003-08-01
This is a one year study of the use of morphine in cancer patients in 10 inpatient facilities in the New England Area Health Service in the north-west of New South Wales. The study explored 170 admissions relating to 122 patients, most of whom were cared for by their general practitioners. The use of morphine in these cancer patients was compared with the recommendations made by the expert working group of the European Association of Palliative Care.1 Those items which matched the recommendations included the initial doses for new users of morphine and the subcutaneous route being the preferred parenteral route. The data in this study differed from the recommendations in that only half of the patients received the immediate release morphine when first given oral morphine, only 43% had orders for immediate release oral morphine for breakthrough pain (with a variable frequency) and a significant number of orders for parenteral and immediate release oral morphine for breakthrough pain were outside the recommended doses (100% and 86.2%, respectively). Written orders for immediate release oral and parenteral morphine involved a dose range in significant numbers while only 30% of patients had orders for parenteral morphine for breakthrough pain. There was a low use of fixed interval variable dose (FIVD) morphine charts despite these being available in most facilities.
Using Poison Center Exposure Calls to Predict Methadone Poisoning Deaths
Dasgupta, Nabarun; Davis, Jonathan; Jonsson Funk, Michele; Dart, Richard
2012-01-01
Purpose There are more drug overdose deaths in the Untied States than motor vehicle fatalities. Yet the US vital statistics reporting system is of limited value because the data are delayed by four years. Poison centers report data within an hour of the event, but previous studies suggested a small proportion of poisoning deaths are reported to poison centers (PC). In an era of improved electronic surveillance capabilities, exposure calls to PCs may be an alternate indicator of trends in overdose mortality. Methods We used PC call counts for methadone that were reported to the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System in 2006 and 2007. US death certificate data were used to identify deaths due to methadone. Linear regression was used to quantify the relationship of deaths and poison center calls. Results Compared to decedents, poison center callers tended to be younger, more often female, at home and less likely to require medical attention. A strong association was found with PC calls and methadone mortality (b = 0.88, se = 0.42, t = 9.5, df = 1, p<0.0001, R2 = 0.77). These findings were robust to large changes in a sensitivity analysis assessing the impact of underreporting of methadone overdose deaths. Conclusions Our results suggest that calls to poison centers for methadone are correlated with poisoning mortality as identified on death certificates. Calls received by poison centers may be used for timely surveillance of mortality due to methadone. In the midst of the prescription opioid overdose epidemic, electronic surveillance tools that report in real-time are powerful public health tools. PMID:22829925
Opioids in oral fluid of Spanish drivers.
Herrera-Gómez, Francisco; García-Mingo, Mercedes; Colás, Mónica; González-Luque, Juan Carlos; Álvarez, F Javier
2018-06-01
Driving under the influence of certain drugs is not allowed, and roadside drug testing is being considered an important tool for deterring driving under the influence of them. This study aimed to assess the presence and concentration of opioids, as well as their combined use with other drugs (laboratory confirmation after the on-road screening) in Spanish drivers between 2011 and 2016. In Spain, mandatory roadside breath alcohol and oral fluid drug testing (screening) are carried out by the Traffic Police using Dräger Alcotest ® 6810 device, and Dräger DrugTest ® 5000, DrugWipe ® , or Alere™ DDS ® 2 Mobile Test System. For positive cases in the period covered, 65,244, confirmation analysis and quantification using chromatographic techniques were performed. Opioids were confirmed in 8.6% of positive cases, being 7.2% positives to 6-acetylmorphine (6-AM), 6.5% to morphine, 5.4% to codeine, and 4.1% to methadone. The majority of the confirmed tests for morphine (96.5%), codeine (88.4%) and methadone (81.9) were also positive for 6-AM. The presence of other drugs, particularly cocaine and cannabis, was very common. Concentration values reached important levels. Positive results for morphine (0.1%), codeine (0.6%) or methadone (0.4%) alone were very infrequent. Drivers with a confirmed positive roadside test for morphine, codeine, and methadone had also consumed heroin and/or other illicit drugs, such as cocaine and/or THC, and at relevant concentrations. Improving interventions to combat the problem of driving under the influence of driving-impairing substances is a priority. Copyright © 2018 Elsevier B.V. All rights reserved.
Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine.
Stine, S M; Grillon, C G; Morgan, C A; Kosten, T R; Charney, D S; Krystal, J H
2001-03-01
Brain noradrenergic systems have been shown to be altered in opioid dependence and to mediate aspects of opioid withdrawal. Pre-clinical and clinical studies by others have shown that yohimbine, which increases noradrenergic activity, also increases both baseline and fear enhancement of the magnitude of the acoustic startle response (ASR). In a separate report from this experiment, it was shown that yohimbine produced opioid withdrawal-like symptoms, including anxiety, in clinically stable methadone-maintained patients and also produced elevations in the norepinepherine (NE) metabolite, 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol serum levels. The current study reports the effects of intravenous yohimbine hydrochloride, 0.4 mg/kg versus saline (double-blind), on ASR magnitude, plasma MHPG, and cortisol levels in eight methadone-maintained patients and 13 healthy subjects in a double-blind fashion. Yohimbine increased startle magnitude in both groups. There was no basal (placebo day) difference between the startle response of the two groups, but methadone patients had a larger startle magnitude increase in response to yohimbine than healthy controls. Methadone-maintained patients had lower baseline plasma levels of MHPG and similar baseline plasma cortisol levels compared with normal subjects. Yohimbine caused significant elevation in cortisol and MHPG in both groups. Methadone-maintained subjects had higher elevations in cortisol levels and MHPG (methadone main effect) levels in response to yohimbine. However, when MHPG levels were corrected for baseline differences by analysis of covariance (ANCOVA), the yohimbine effect, but not the methadone effect remained statistically significant. These results are consistent with the previous report and support the hypothesis that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and of noradrenergic mechanisms of stress response persist in opioid-agonist maintenance. The ASR effect extends the
Emergence of methadone as a street drug in St. Petersburg, Russia.
Heimer, Robert; Lyubimova, Aleksandra; Barbour, Russell; Levina, Olga S
2016-01-01
The syndemic of opioid addiction, HIV, hepatitis, tuberculosis, imprisonment, and overdose in Russia has been worsened by the illegality of opioid substitution therapy. As part of on-going serial studies, we sought to explore the influence of opioid availability on aspects of the syndemic as it has affected the city of St. Petersburg. We employed a sequential approach in which quantitative data collection and statistical analysis were followed by a qualitative phase. Quantitative data were obtained in 2013-2014 from a respondent-driven sample (RDS) of people who inject drugs (PWID). Individuals recruited by RDS were tested for antibodies to HIV and interviewed about drug use and injection practices, sociodemographics, health status, and access to medical care. Subsequently, we collected in-depth qualitative data on methadone use, knowledge, and market availability from PWID recruited at nine different locations within St. Petersburg. Analysis of interview data from the sample revealed the percentage of PWID injecting methadone in the 30 days prior to interview increased from 3.6% in 2010 to 53.3% in 2012-2013. Injection of only methadone, as compared to injecting only heroin or both drugs, was associated with less frequent injection and reduced HIV-related injected risk, especially a lower rate of injecting with a previously used syringe. In-depth questioning of methadone injectors corroborated the finding from serial quantitative surveys of PWID that methadone's black market availability is a recent phenomenon. Spatial analysis revealed widespread methadone availability but no concentration in any specific districts of the city. Despite the prohibition of substitution therapy and demonization of methadone, the drug has emerged to rival heroin as the most commonly available opioid in St. Petersburg. Ironically, its use is associated with reduced injection-related HIV risk even when its use is illegal. Copyright © 2015 Elsevier B.V. All rights reserved.
The cost-effectiveness of methadone maintenance as a health care intervention.
Barnett, P G
1999-04-01
Cost-effectiveness analysis using life-years of survival as the measure of treatment benefit is widely used in the economic evaluation of health care interventions but has not been applied to substance abuse treatment. The cost-effectiveness of methadone maintenance was evaluated to demonstrate the feasibility of applying this method to substance abuse treatment. A literature review was undertaken to determine the effect of methadone treatment on the rate of mortality associated with opiate addiction. Information was also obtained on the average cost and duration of treatment. A two-state Markov model was used to estimate the incremental effect of methadone on the life span and treatment cost of a cohort of 25-year-old heroin users. Providing opiate addicts with access to methadone maintenance has an incremental cost-effectiveness ratio of $5915 per life-year gained (that is, for every year of life that is saved by providing methadone to opiate addicts, an additional $5915 in treatment costs are incurred). One-way sensitivity analysis determined that the ratio was less than $10,000 per-life year over a wide range of modeling assumptions. The ratio determined for methadone is lower than that of many common medical therapies, and well within the $50,000 threshold for judging cost-effectiveness. Even if decision makers do not wish use the same ratio that is applied to the general population, this method allows substance abuse treatment enhancements to be compared to improvements in health services offered to individuals with substance abuse disorders. Future work will require information on the impact of methadone treatment on the cost of health care and public programs, the indirect costs incurred by patients, and adjustments to reflect quality of life.
Laccase catalyzed elimination of morphine from aqueous systems.
Huber, Daniela; Bleymaier, Klaus; Pellis, Alessandro; Vielnascher, Robert; Daxbacher, Andreas; Greimel, Katrin J; Guebitz, Georg M
2018-05-25
Pharmaceuticals contaminate the environment for several reasons, including metabolic excretion after intake, industrial waste and improper disposal. The narcotic drug morphine is commonly utilized for chronic pain management, and the distribution of morphine in aqueous systems and in waste waters is of high concern. Here, the removal of morphine by a laccase from Myceliophthora thermophila both in its free form as well as immobilized on Accurel MP1000 beads was investigated. Complete morphine elimination was achieved within 30 min for the free and the immobilized enzyme (70% bound protein) for concentrations between 1 and 1,000 mg L -1 according to LC-TOF mass spectrometry analysis. Higher morphine concentrations up to 60 g L -1 were also tested and total elimination was achieved within 6 h. Therefore, laccases are ideal candidates for removing morphine from aqueous systems. Copyright © 2018 Elsevier B.V. All rights reserved.
Prescribing methadone for pain management in end-of-life care.
Manfredonia, John F
2005-03-01
Methadone hydrochloride is an effective, inexpensive, and relatively safe opioid to use in the treatment of patients with chronic pain. It is especially effective in management of pain during the final stages of life, as it is the only long-acting analgesic available in liquid form. However, because methadone has a long half-life, individual wide variations, and potential for accumulation and overdosage, physicians must judiciously and conscientiously prescribe it. Also, they should closely monitor patients during the titration phase and educate them with regard to basic pharmacologic properties and potential side effects. A plan to start at low doses and proceed slowly is applicable to methadone.
Miranda, Hugo F; Noriega, Viviana; Zanetta, Pilar; Prieto, Juan Carlos; Prieto-Rayo, Juan Carlos; Aranda, Nicolás; Sierralta, Fernando
2014-07-15
Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.
[Morphine in the treatment of acute pulmonary oedema].
Ellingsrud, Christoffer; Agewall, Stefan
2014-12-09
Morphine is still used in Norway and the rest of Europe as part of the treatment for pulmonary oedema, but the scientific basis for this is tenuous. In this article we assess the literature that supports and challenges the use of morphine in cases of pulmonary oedema. The article is based on a literature search in Medline and EMBASE and on the articles which form the basis of Norwegian and international guidelines. Morphine has been used for several decades in cases of pulmonary oedema due to the anxiolytic and vasodilatory properties of the drug. Vasodilation caused by morphine has been described in other patient groups, but there is little evidence in the literature to suggest that morphine causes vasodilation in patients with pulmonary oedema. Non-specific depression of the central nervous system is probably the most significant factor for the changes in haemodynamics in pulmonary oedema. Retrospective studies have shown both negative and neutral effects in acute decompensated heart failure. There are no reliable clinical studies that document better prognosis from the use of morphine. Based on the available studies, the possibility cannot be excluded that the use of morphine results in increased mortality among patients with acute pulmonary oedema. In addition, there is little evidence that the vasodilatory properties of morphine are of any significance for this condition. The benefits and risks of using morphine in cases of acute pulmonary oedema are still unclear, but so far there is little evidence to support the beneficial use of the drug.
NASA Astrophysics Data System (ADS)
Wu, Hsin-Yu; Cunningham, Brian T.
2014-04-01
We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml-1) well below typical administered dosages (mg ml-1). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery.We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten
Haydari, Sakineh; Miladi-Gorji, Hossein; Mokhtari, Amin; Safari, Manouchehr
2014-08-22
Exposure to morphine during pregnancy produced long-term effects in offspring behaviors. Recent studies have shown that voluntary exercise decreases the severity of anxiety behaviors in both morphine-dependent and withdrawn rats. Thus, the aims of the present study were to examine whether maternal exercise decreases prenatal dependence-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with access to a running wheel that lasted at least 21 days. Then, anxiety-like behaviors using the elevated plus-maze (EPM) and voluntary consumption of morphine using a two-bottle choice paradigm (TBC) were tested in male rat pups. The results showed that the rat pups borne from exercising morphine-dependent mothers exhibited an increase in EPM open arm time (P<0.0001) and entries (P<0.05) as compared with the sedentary groups. In animal models of craving showed that voluntary consumption of morphine in the rat pups borne from exercising morphine-dependent mothers was less in the second (P<0.032) and third (P<0.014) periods of intake as compared with the sedentary group. This study showed that maternal exercise decreases the severity of the anxiogenic-like behaviors and voluntary consumption of morphine in rat pups. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Challenges of Using Methadone in the Indian Pain and Palliative Care Practice.
Viswanath, Vidya; Palat, Gayatri; Chary, Srini; Broderick, Ann
2018-01-01
Palliative care providers across India lobbied to gain access to methadone for pain relief and this has finally been achieved. Palliative care activists will count on the numerous strengths for introducing methadone in India, including the various national and state government initiatives that have been introduced recognizing the importance of palliative care as a specialty in addition to improving opioid accessibility and training. Adding to the support are the Non-Governmental Organizations (NGOs), the medical fraternity and the international interactive and innovative programs such as the Project Extension for Community Health Outcome. As compelling as the need for methadone is, many challenges await. This article outlines the challenges of procuring methadone and also discusses the challenges specific to methadone. Balancing the availability and diversion in a setting of opioid phobia, implementing the amended laws to improve availability and accessibility in a country with diverse health-care practices are the major challenges in implementing methadone for relief of pain. The unique pharmacology of the drug requires meticulous patient selection, vigilant monitoring, and excellent communication and collaboration with a multidisciplinary team and caregivers. The psychological acceptance of the patient, the professional training of the team and the place where care is provided are also challenges which need to be overcome. These challenges could well be the catalyst for a more diligent and vigilant approach to opioid prescribing practices. Start low, go slow could well be the way forward with caregiver education to prescribe methadone safely in the Indian palliative care setting.
Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.
Pan, Yinbing; Sun, Xiaodi; Jiang, Lai; Hu, Liang; Kong, Hong; Han, Yuan; Qian, Cheng; Song, Chao; Qian, Yanning; Liu, Wentao
2016-11-17
Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine. The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests. We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine
Methadone and oedema in the palliative care setting: a case report and review of the literature.
Dawson, Camilla; Paterson, Fiona; McFatter, Fiona; Buchanan, Deans
2014-05-01
Methadone is a synthetic opioid which is being used with increased frequency in the palliative care setting for management of complex pain. There have been cases published reporting the development of oedema with methadone maintenance therapy but no cases on the association with methadone and peripheral oedema in the palliative care setting. As yet, the underlying mechanisms are unclear. This case report describes a gentleman with ependymoma and difficult-to-control lower back pain and scrotal pain. This pain had failed to respond to other strong opioids. He was prescribed methadone and then subsequently developed bilateral peripheral oedema. Peripheral oedema resolved following cessation of methadone. This highlights an important potential adverse effect of methadone in a society of increased methadone prescription for pain control. The published literature to date is reviewed and possible underlying mechanisms explored.
McKenzie, Michelle; Nunn, Amy; Zaller, Nickolas D.; Bazazi, Alexander R.; Rich, Josiah D.
2010-01-01
More than 2.4 million people are currently incarcerated in the United States, many as a result of drug-related offenses. In addition, more than 200,000 active heroin addicts pass through the correctional system annually. New evidence suggests that both providing prisoners with referrals for community-based methadone programs and providing methadone prior to release reduces recidivism and adverse health and social consequences associated with drug use. This article reports the programmatic challenges associated with initiating methadone treatment in the Rhode Island correctional system. Significant obstacles to implementing methadone treatment include: stigma associated with pharmacological treatment, misconceptions regarding the nature of opioid addiction, logistics of control and storage of methadone, increased work load for nursing staff, and general safety and control concerns. The authors discuss strategies to address these barriers and conclude that providing methadone prior to inmate release is a feasible intervention with the potential to mitigate drug-related health and social harms. PMID:19736902
Cepeda, M Soledad; Fife, Daniel; Kihm, Mary A; Mastrogiovanni, Greg; Yuan, Yingli
2014-12-01
This study compared the risks of opioid shopping behavior and opioid abuse between tapentadol immediate release and oxycodone immediate release and, to validate the definition of shopping, examined the association between opioid shopping and opioid abuse further. This retrospective cohort study using linked dispensing and diagnosis databases followed opioid-naive patients for development of shopping behavior and/or opioid abuse during 1 year after initial exposure to tapentadol or oxycodone. Shopping was defined by having overlapping opioid prescriptions from >1 prescriber filled at ≥3 pharmacies; abuse by having International Classification of Diseases, 9th revision diagnoses reflecting opioid abuse, addiction, or dependence. To determine their association, we cross-tabulated shopping and opioid abuse and calculated odds ratios. Risks of developing each outcome were estimated using logistic regression. Among 277,401 participants initiating opioid use with tapentadol (39,524) or oxycodone (237,877), 0.6% developed shopping behavior, 0.75% developed abuse. Higher proportions of patients in the oxycodone group developed shopping behavior and abuse than in the tapentadol group (shopping: adjusted odds ratio [95% confidence interval], 0.45 [0.36-0.55]; abuse: 0.44 [0.37-0.54]). Shopping behavior and abuse were associated; of those with shopping behavior, 6.5% had abuse. Age (18 to 64 y), sex (male), prior benzodiazepine use, paying cash, and history (mood disorders, abuse of nonopioid medications, and back pain) were risk factors for developing either outcome. Shopping behavior and abuse measure complementary, but associated, constructs, which further validates the current definition of shopping. The risk of developing either is lower among patients who initiate opioid use with tapentadol than those who initiate opioid use with oxycodone.
McCarberg, Bill H; Kopecky, Ernest A; O'Connor, Melinda; Marseilles, Ann; Varanasi, Ravi K; Thompson, Christy; Fleming, Alison B
2016-12-01
Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose. To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes. A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration. There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size. Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.
Increases in body mass index following initiation of methadone treatment
Fenn, Jennifer M.; Laurent, Jennifer S.; Sigmon, Stacey C.
2014-01-01
Despite the clear efficacy of methadone for opioid dependence, one less desirable phenomenon associated with methadone may be weight gain. We examined changes in body mass index (BMI) among patients entering methadone treatment. A retrospective chart review was conducted for 96 patients enrolled in an outpatient methadone clinic for ≥6 months. The primary outcome of BMI was assessed at intake and a subsequent physical examination approximately 1.8±0.95 years later. Demographic, drug use and treatment characteristics were also examined. There was a significant increase in BMI following intake (p < 0.001). Mean BMIs increased from 27.2±6.8 to 30.1±7.7 kg/m2, translating to a 17.8-pound increase (10% increase in body weight) in the overall patient sample. Gender was the strongest predictor of BMI changes (p < 0.001), with significantly greater BMI increases in females than males (5.2 vs. 1.7 kg/m2, respectively). This translates to a 28-pound (17.5%) increase in females vs. a 12-pound (6.4%) increase in males. In summary, methadone treatment enrollment was associated with clinically significant weight gain, particularly among female patients. This study highlights the importance of efforts to help patients mitigate weight gain during treatment, particularly considering the significant health and economic consequences of obesity for individuals and society more generally. PMID:25441923
Chen, Yukun; Evola, Marianne
2013-01-01
Rationale Memantine is a N-methyl-d-aspartic acid receptor (NMDAR) channel blocker that binds to dizocilpine sites and appears well tolerated during chronic use. Published studies suggest NMDAR antagonists prevent development of tolerance to effects of morphine by blocking NMDAR hyperactivation. Objectives We sought to compare effects of memantine to those of the more frequently studied dizocilpine and to evaluate memantine as a potential adjunct to modify tolerance to mu-opioid receptor agonists. Methods Sprague–Dawley rats were trained to discriminate morphine (3.2 mg/kg) and saline under fixed ratio 15 schedules of food delivery. Potency and maximal stimulus or rate-altering effects of cumulative doses of morphine were examined 30 min after pretreatment with dizocilpine (0.032–0.1 mg/kg) or memantine (5–10 mg/kg) and after chronic treatment with combinations of dizocilpine or memantine and morphine, 10 mg/kg twice daily, for 6 to 14 days. Effects of dizocilpine or memantine on morphine antinociception were examined in a 55 °C water tail-withdrawal assay with drug treatments parallel to those in discrimination studies. Results Acutely, memantine attenuated while dizocilpine potentiated the stimulus and antinociceptive effects of morphine. Neither chronic dizocilpine nor memantine blocked tolerance to the stimulus effects of morphine. In contrast, combined-treatment with dizocilpine (0.1 mg/kg) blocked tolerance to antinociceptive effects of lower (0.1∼3.2 mg/kg) but not higher doses of morphine, whereas memantine did not block tolerance. Conclusions Memantine and dizocilpine interacted differently with morphine, possibly due to different NMDAR binding profiles. The lack of memantine-induced changes in morphine tolerance suggests memantine may not be a useful adjunct in chronic pain management. PMID:22864944
Nahata, M C; Miser, A W; Miser, J S; Reuning, R H
1984-02-01
Three children with terminal malignancy received a continuous subcutaneous infusion of morphine sulfate for the control of severe pain, the morphine dose being adjusted until the patient and/or parent reported complete freedom from pain. Analgesic plasma morphine concentrations at the steady state in these patients ranged from 12.9 to 57 ng/ml (median 19.6 ng/ml) while receiving morphine doses of 0.45-2.0 mg/h (0.034-0.06 mg/kg/h). One patient, who received 2 mg morphine per hour for 12 days demonstrated a 2-fold variation in steady-state plasma concentration during this period.
Mechanisms of morphine enhancement of spontaneous seizure activity.
Saboory, Ehsan; Derchansky, Miron; Ismaili, Mohammed; Jahromi, Shokrollah S; Brull, Richard; Carlen, Peter L; El Beheiry, Hossam
2007-12-01
High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors. Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons. Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 microM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 microM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective mu and kappa opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, delta opioid receptor ligands did not have an effect. The proseizure effect of morphine is mediated through selective stimulation of mu and kappa opiate receptors but not the activation of the delta receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.
Esmaeili-Mahani, Saeed; Rezaeezadeh-Roukerd, Maryam; Esmaeilpour, Khadije; Abbasnejad, Mehdi; Rasoulian, Bahram; Sheibani, Vahid; Kaeidi, Ayat; Hajializadeh, Zahra
2010-10-28
Olive (Olea europaea) leaves are used as anti-rheumatic, anti-inflammatory, antinociceptive, antipyretic, vasodilatory, hypotensive, antidiuretic and hypoglycemic agents in traditional medicine. Recently, it has been shown that olive leaf extract (OLE) has calcium channel blocker property; however, its influences on nociceptive threshold and morphine effects have not yet been clarified. All experiments were carried out on male Wistar rats. The tail-flick, hot-plate and formalin tests were used to assess the effect of OLE on nociceptive threshold. To determine the effect of OLE on analgesic and hyperalgesic effects of morphine, OLE (6, 12 and 25 mg/kg i.p.) that had no significant nociceptive effect, was injected concomitant with morphine (5 mg/kg and 1 μg/kg i.p., respectively). The tail-flick test was used to assess the effect of OLE on anti- and pro-nociceptive effects of morphine. The data showed that OLE (50-200 mg/kg i.p.) could produce dose-dependent analgesic effect on tail-flick and hot-plate tests. Administration of 200 mg/kg OLE (i.p.) caused significant decrease in pain responses in the first and the second phases of formalin test. In addition, OLE could potentiate the antinociceptive effect of 5 mg/kg morphine and block low-dose morphine-induced hyperalgesia. Our results indicate that olive leaf extract has analgesic property in several models of pain and useful influence on morphine analgesia in rats. Therefore, it can be used for the treatment and/or management of painful conditions. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Kim, Ki Jin; Lee, Sang Nam; Lee, Bong Hyo
2018-05-01
Morphine is a representative pain killer. However, repeated use tends to induce addiction. Music therapy has been gaining interest as a useful type of therapy for neuropsychiatric diseases. The present study examined whether Korean traditional music (KT) could suppress morphine-seeking behavior and anxiety-like behavior induced by extinction from chronic morphine use and additionally investigated a possible neuronal mechanism. Male Sprague-Dawley rats were trained to intravenously self-administer morphine hydrochloride (1.0 mg/kg) using a fixed ratio 1 schedule in daily 2 h session during 3 weeks. After training, rats who established baseline (variation less than 20% of the mean of infusion for 3 consecutive days) underwent extinction. Music was played twice a day during extinction. In the second experiment, the selective antagonists of GABA A and GABA B receptors were treated before the last playing to investigate the neuronal mechanism focusing on the GABA receptor pathway. Another experiment of elevated plus maze was performed to investigate whether music therapy has an anxiolytic effect at the extinction phase. KT but not other music (Indian road or rock music) reduced morphine-seeking behavior induced by a priming challenge with morphine. And, this effect was blocked by the GABA receptor antagonists. In addition, KT showed anxiolytic effects against withdrawal from morphine. Results of this study suggest that KT suppresses morphine-seeking behavior via GABA receptor pathway. In addition, KT showed to have anxiolytic effects, suggesting it has bi-directional effects on morphine. Copyright © 2018 Elsevier B.V. All rights reserved.
Romberg, Raymonda; Olofsen, Erik; Sarton, Elise; Teppema, Luc; Dahan, Albert
2003-10-01
Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing. In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean +/- SE. Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 +/- 0.2 h and C25 528 +/- 88 nm and for AHR were t1/2ke0 1.0 +/- 0.1 h and C25 873 +/- 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 +/- 0.9 h and C25 28 +/- 6 nm and for AHR were t1/2ke0 4.3 +/- 0.6 h and C25 16 +/- 2 nm. Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression
[Methadone and sleep apnea syndrome].
Durst, Philippe; Palazzolo, Jérôme; Peyrelong, Jean-Pierre; Berger, Michel; Chalabreysse, Michel; Billiard, Michel; Vialle, André
2005-03-01
Sleep apnea syndrome occurs when, during sleep, breathing stops for 10 seconds or longer, with an index of 5 times or more an hour. It is clinically characterized by loud snoring at night, continuous or interrupted by pauses followed by loud breathing. Sleep is fitful, broken by arousals, and yields little rest. There is daytime excessive sleepiness with repeated involuntary falling asleep, often unknown by the subject. In this article, we describe an observation of central sleep apnea syndrome in a female patient receiving an opiate replacement therapy. An analysis of the before and after methadone withdrawal polysomnograhic tracing was done for this patient. This diagnosis etiology and physiopathology are critically approached. Clinicians should be careful in treating induced sleep disorders in such patients. Prescribing benzodiazepines during an opiate withdrawal of the methadone type is not recommended when central apnea occurs.
Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.
Strain, E C; Bigelow, G E; Liebson, I A; Stitzer, M L
1999-03-17
Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. One hundred ninety-two eligible clinic patients. Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. Opioid-positive urinalysis results and retention in treatment. By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.
... tests Chest x-ray EKG (electrocardiogram, or heart tracing) Fluids through a vein (IV) Laxative Naloxone, a ... Toxicology Data Network. Morphine. Toxnet.nlm.nih.gov Web site. toxnet.nlm.nih.gov/cgi-bin/sis/ ...
Mantione, K; Zhu, W; Rialas, C; Casares, F; Cadet, P; Franklin, A L; Tonnesen, J; Stefano, G B
2002-03-01
We have previously demonstrated that Mytilus edulis pedal ganglia contain opiate alkaloids, i.e., morphine and morphine 6 glucuronide (M6G), as well as mu opiate receptor subtype fragments exhibiting high sequence similarity to those found in mammals. Now we demonstrate that M6G stimulates pedal ganglia constitutive nitric oxide (NO) synthase (cNOS)-derived NO release at identical concentrations and to similar peak levels as morphine. However, the classic opiate antagonist, naloxone, only blocked the ability of morphine to stimulate cNOS-derived NO release and not that of M6G. CTOP, a mu-specific antagonist, blocked the ability of M6G to induce cNOS-derived NO release as well as that of morphine, suggesting that a novel mu opiate receptor was present and selective toward M6G. In examining a receptor displacement analysis, both opiate alkaloids displaced [3H]-dihydromorphine binding to the mu opiate receptor subtype. However, morphine exhibited a twofold higher affinity, again suggesting that a novel mu opiate receptor may be present.
Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury
DOE Office of Scientific and Technical Information (OSTI.GOV)
He, Haiyan; Department of Pharmacology, Tianjin Medical University, Tianjin 300070; Huh, Jin
Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphinemore » reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine
Economic Cost of the Therapeutic Workplace Intervention Added to Methadone Maintenance
Knealing, Todd W.; Roebuck, M. Christopher; Wong, Conrad J.; Silverman, Kenneth
2008-01-01
The therapeutic workplace is a novel intervention that uses access to paid training and employment to reinforce drug abstinence within the context of standard methadone maintenance. We used the Drug Abuse Treatment Cost Analysis Program as a standard method of estimating the economic costs of this intervention. Over a one-year period, the therapeutic workplace served 122 methadone maintenance clients who had a median length of stay of 22 weeks. The workplace maintained a mean daily census of 48 clients. The combined cost of methadone maintenance and the therapeutic workplace was estimated at $362 per week. This cost is less than other treatments that might be used to promote abstinence in individuals who continue to use drugs during methadone treatment. Given prior evidence of effectiveness, these cost data may be useful to policymakers, social service agencies, and researchers interested in using or further developing the therapeutic workplace intervention. PMID:17614239
Donaldson, Síne R; Harding, Andrew M; Taylor, Simone E; Vally, Hassan; Greene, Shaun L
2017-08-01
The objective of this study was to evaluate the impact of an educational intervention on ED discharge opioid analgesic (OA) prescribing. A brief, one-on-one, educational intervention was delivered to ED OA prescribers by an ED clinical champion. The percentage of patients receiving (i) written advice regarding appropriate oxycodone use, (ii) written or verbal advice regarding appropriate post-discharge follow up and (iii) written general practitioner notification that oxycodone had been prescribed were determined pre- and post-intervention, through review of electronic patient records and structured patient telephone interviews conducted 3-7 days after ED attendance. Secondary outcomes included total amount prescribed and use of non-OA therapies. ED OA prescribers were surveyed to evaluate perceived effectiveness and intervention acceptability. A total of 30 ED OA prescribers received the 5-min intervention. Pre- and post-intervention, 80 and 81 patients were interviewed, respectively. Percentage of patients given written OA information increased from 10% to 22% (P = 0.04) and those receiving follow-up advice increased from 61 to 94% (P < 0.01). General practitioner notification of OA prescription increased from 15% to 88% (P < 0.01). Risk ratio for achieving all three end-points was 7.5 (95% confidence interval 1.8-32, P = 0.01). Median total amount of oxycodone prescribed/patient decreased from 100mg to 50mg (P = 0.04). Non-OA therapies were used by 49% of pre-intervention and 85% of post-intervention patients (P = <0.01). All ED OA prescribers agreed the intervention would change their prescribing practices; 70% deemed the intervention appropriate for delivery in their work environment. A brief, one-on-one educational intervention targeting ED OA prescribers was well received by clinicians and associated with improved quality of OA prescribing. © 2017 Australasian College for Emergency Medicine and Australasian Society for Emergency
Forensic Toxicology Perspectives of Methadone-associated Deaths in Tehran, Iran, a 7-year Overview.
Akhgari, Maryam; Amini-Shirazi, Noushin; Iravani, Fariba Sardari
2018-04-01
Methadone has a long history of pain relief and successful substitute for maintenance treatment in heroin and narcotic addiction. The aim of the study was to assess the trends of methadone-associated deaths in Tehran, Iran, in 2009-2015, from a forensic toxicology point of view. All methadone-associated deaths during this 7-year study period were evaluated according to demographic parameters and forensic toxicology analysis results. Results showed that 1274 cases of methadone-associated deaths were investigated during the study period. The incidence rate of methadone-associated deaths had risen 7.7 times in 2015 in comparison with 2009 (p < 0.05). The majority of cases were men (90.35%), aged from 20 to 40 years. About 80% of cases had shown positive results for other drugs and poisons in combination with methadone. Methamphetamine and tramadol were the most drugs detected in post-mortem samples. Death rates among methadone users in Tehran, Iran, increased year by year during 2009-2015. These findings raise the attention to the concomitant use of drugs with the need for changes in regulation and regulatory policy to restrict access and use of controlled drugs. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
Subcutaneous morphine infusion by syringe driver for terminally ill patients.
Cools, H J; Berkhout, A M; De Bock, G H
1996-05-01
The study aimed to find whether subcutaneous morphine administration by syringe driver for terminally ill patients in a Dutch nursing home led to higher morphine doses and earlier death than routine morphine administration. The data comprised the files of all patients dying over a 2 year period in a 355-bed nursing home in Delft in the Netherlands. Thirty-eight per cent of the patients had been given morphine, 29% by continuous subcutaneous syringe driver. In comparing the patients given morphine with and without a syringe driver no differences emerged in mean age, sex, length of admission, type of ward, diagnosis, duration of morphine administration and mean dose. The data indicate that subcutaneous morphine administration by syringe driver decreases dose frequency problems and improves the control of pain and other symptoms in the last week before death. There was no evidence that administration of morphine in this way shortens survival.
Zhang, Yong; Liang, Yupu; Levran, Orna; Randesi, Matthew; Yuferov, Vadim; Zhao, Connie; Kreek, Mary Jeanne
2017-08-01
Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain. The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice. Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration procedure (4 h/day, 0.25 mg/kg/infusion, FR1) and were euthanized 1 h after the last session. The dorsal and ventral striata were dissected, and total RNAs were extracted. Gene expressions were examined using RNA sequencing. We found that oxycodone self-administration exposure led to alterations of expression in numerous genes related to inflammation/immune functions in the dorsal striatum (54 upregulated genes and 1 downregulated gene) and ventral striatum (126 upregulated genes and 15 downregulated genes), with 38 upregulated genes identified in both brain regions. This study reveals novel neurobiological mechanisms underlying some of the effects of a commonly abused prescription opioid. We propose that inflammation/immune gene systems may undergo a major change during chronic self-administration of oxycodone.
Miller, Norman S; Greenfeld, Andrea
2004-01-01
The purpose of the study was to document the substantial increase in problematic use of hydrocodone and oxycodone in an addiction treatment population. Our study consisted of a retrospective review of medical records from all patients admitted and discharged in 2000 from Sparrow/St. Lawrence Addiction Detoxification Unit (N = 534). A literature review was conducted in medical journals, governmental groups, and reports including Drug Abuse Warning Network, Pharmacy Times, and National Household Survey on Drug Abuse. More than 144 patients (27%) were dependent on prescription opiate medications. The most frequently mentioned medication was Vicodin (hydrocodone) (53% of the users) followed by OxyContin (oxycodone) (19%). Physicians commonly prescribed these medications (75% of the cases). Predictors of dependence on opiate medications included substance-related diagnoses, positive toxicology for opiates, and other medical diagnoses. Patients under the care of physicians who have other drug dependence diagnoses and medical complaints appear at risk of developing dependence on prescription opiate medications. Proper evaluation and intervention can limit adverse consequences of prescription opiate medications.
PolyMorphine: an innovative biodegradable polymer drug for extended pain relief.
Rosario-Meléndez, Roselin; Harris, Carolyn L; Delgado-Rivera, Roberto; Yu, Lei; Uhrich, Kathryn E
2012-09-28
Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed "PolyMorphine", was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopies, and infrared spectroscopy. The weight-average molecular weight and the thermal properties were determined. The hydrolytic degradation pathway of the polymer was determined by in vitro studies, showing that free morphine is released. In vitro cytocompatibility studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. The animals retained full responsiveness to morphine after being subjected to an acute morphine challenge. Copyright © 2012 Elsevier B.V. All rights reserved.
Inhibiting social support from massage-like stroking increases morphine dependence.
Bates, M L Shawn; Emery, Michael A; Wellman, Paul J; Eitan, Shoshana
2017-12-01
Our previous studies showed that altering solely the drug experience of the cage mates with which rodents are housed affects the development of morphine dependence. In this study, we used designer receptors exclusively activated by designer drugs to artificially increase or decrease the activity of peripheral dorsal root ganglia sensory neurons expressing the G-protein-coupled receptor MRGPRB4. This is because sensory MRGPRB4-expressing neurons were shown to specifically detect the sensation of massage-like stroking resulting from social grooming, which is an important affiliative social behavior in the rodent. Blocking the sensation of social grooming in morphine-treated mice housed with drug-naive mice (i.e. morphine cage mates) significantly increased the display of jumping behavior in morphine-withdrawn animals. Activating the sensation of social grooming in morphine-treated animals housed solely with other morphine-treated animals (i.e. morphine only) did not significantly alter the display of jumping behavior in morphine-withdrawn animals. Repetitive jumping behaviors have been shown to correlate with morphine dependence. Thus, this study showed a role of social grooming in the protective effect of being housed with drug-naive mice on the development of morphine dependence. It further confirms a role of social support in the development of substance use problems.
Acupuncture at SI5 attenuates morphine seeking behavior after extinction.
Lee, Bong Hyo; Ma, Jeong Hun; In, Sunghyun; Kim, Hee Young; Yoon, Seong Shoon; Jang, Eun Young; Yang, Chae Ha
2012-10-31
Our previous studies have shown that acupuncture attenuates morphine self-administration and sensitization behavior as well as withdrawal signs. The present study was designed to investigate the role of acupuncture in the reinstatement of morphine seeking. Male Sprague-Dawley rats weighing 270-300 g were subjected to intravenous catheterization after food training. The animals were trained to self-administer morphine (1.0mg/kg, 3 weeks), followed by extinction (1 week). Extinction conditions were introduced by substituting saline for morphine. The rats were then tested for reinstatement of morphine self-administration by a priming injection of morphine (0.25mg/kg). To see whether acupuncture can reduce morphine reinstatement, acupuncture was performed at SI5 or LI5 for 1 min immediately before a morphine injection. To further test the involvement of gamma aminobutyric acid (GABA) receptors in acupuncture effects, GABA receptor antagonists were injected before acupuncture. In the present results, acupuncture at SI5, but not at control acupoint LI5 attenuated the reinstatement of morphine seeking behavior, which was blocked by the GABA receptor antagonists. It suggests that acupuncture can reduce the reinstatement of morphine seeking, possibly due to the mediation of GABA receptor system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Hayashi, Kanna; Ti, Lianping; Ayutthaya, Prempreeda Pramoj Na; Suwannawong, Paisan; Kaplan, Karyn; Small, Will; Kerr, Thomas
2017-09-07
Methadone maintenance therapy (MMT) is a mainstay for treating opioid use disorder and preventing and managing HIV among people who inject drugs (PWID). While previous research suggested low dosing of methadone and high rates of discontinuation of MMT among PWID in Thailand, little is known about patients' lived experiences with MMT in this setting. Therefore, we conducted a mixed-methods study to examine barriers to retention in MMT among PWID in Bangkok, Thailand, with particular attention to methadone dosing. Bivariate statistics were used to analyze quantitative survey data collected from methadone-treated PWID between July and October 2011. Qualitative data collected through semi-structured interviews with 16 methadone-treated PWID between July 2011 and June 2012 were analyzed thematically, with a focus on individual-level, social-structural, and environmental barriers to accessing MMT. Among 158 survey participants, a median dosage of methadone was 30 mg/day (interquartile range 20-50). Of these, 15.8% reported having acquired street methadone due to low prescribed dosages of methadone and 19.0% reported recent syringe sharing. Qualitative interview data indicated some methadone provider-related barriers, including discouraging patients from using methadone due to it being a Western medicine, difficulty negotiating higher doses of methadone, and abrupt dose reductions without patient consultation (involving the provision of non-medicated "syrup" in some cases). Social-structural and environmental barriers to optimal MMT access included intense police surveillance of methadone clinics; and frequent incarceration of PWID and a lack of access to methadone in prisons. Among our sample of methadone-treated PWID, methadone dosages were suboptimal according to the international guidelines. Poor adherence to international guidelines for opioid agonist therapies, aggressive law enforcement, and a lack of methadone in prisons need to be addressed to optimize MMT and
Nebulized naloxone gently and effectively reverses methadone intoxication.
Mycyk, Mark B; Szyszko, Amy L; Aks, Steven E
2003-02-01
A 46-year-old woman presented to the Emergency Department with lethargy and respiratory depression after ingesting methadone. Initial oxygen saturation of 61% on room air did not improve with supplemental oxygenation. As venous access was initially unobtainable, naloxone was administered by nebulizer. Within 5 min oxygen saturation was 100% and mental status was normal. The patient did not develop severe withdrawal symptoms. Naloxone hydrochloride has been administered by various routes to treat opioid toxicity. Our report describes the successful use of nebulized naloxone for methadone toxicity.
Kock, M; Thompson, E; Vulliet, P R; Brooks, D L
1994-10-01
Pharmacokinetic parameters of methadone were studied in adult dairy goats. Five goats were each given methadone hydrochloride as a single 0.2 mg/kg of body weight dosage by intramuscular (IM) administration. Plasma methadone concentrations were determined for 96 h after dosing. Plasma methadone concentrations after IM administration were best described by an open one-compartment model. Overall elimination half-life (t1/2) was 1.38 h. Peak plasma concentrations were reached 0.25 h after dosing, and the actual plasma concentration averaged 37.8 ng/ml (SD = 12.76) at that time. The data obtained from this study suggest that plasma concentrations, similar to those that are analgesic in humans, can be achieved after IM administration of methadone at a dose rate of 0.2 mg/kg of body weight. In addition, these plasma concentrations can be maintained for up to 3 h after a single injection and, therefore, may provide satisfactory analgesia for such period.
Increases in body mass index following initiation of methadone treatment.
Fenn, Jennifer M; Laurent, Jennifer S; Sigmon, Stacey C
2015-04-01
Despite the clear efficacy of methadone for opioid dependence, one less desirable phenomenon associated with methadone may be weight gain. We examined changes in body mass index (BMI) among patients entering methadone treatment. A retrospective chart review was conducted for 96 patients enrolled in an outpatient methadone clinic for ≥ 6 months. The primary outcome of BMI was assessed at intake and a subsequent physical examination approximately 1.8 ± 0.95 years later. Demographic, drug use and treatment characteristics were also examined. There was a significant increase in BMI following intake (p<0.001). Mean BMIs increased from 27.2 ± 6.8 to 30.1 ± 7.7 kg/m(2), translating to a 17.8-pound increase (10% increase in body weight) in the overall patient sample. Gender was the strongest predictor of BMI changes (p < 0.001), with significantly greater BMI increases in females than males (5.2 vs. 1.7 kg/m(2), respectively). This translates to a 28-pound (17.5%) increase in females vs. a 12-pound (6.4%) increase in males. In summary, methadone treatment enrollment was associated with clinically significant weight gain, particularly among female patients. This study highlights the importance of efforts to help patients mitigate weight gain during treatment, particularly considering the significant health and economic consequences of obesity for individuals and society more generally. Copyright © 2015 Elsevier Inc. All rights reserved.
Fife, Daniel; Kihm, Mary A.; Mastrogiovanni, Greg; Yuan, Yingli
2014-01-01
Objectives: This study compared the risks of opioid shopping behavior and opioid abuse between tapentadol immediate release and oxycodone immediate release and, to validate the definition of shopping, examined the association between opioid shopping and opioid abuse further. Materials and Methods: This retrospective cohort study using linked dispensing and diagnosis databases followed opioid-naive patients for development of shopping behavior and/or opioid abuse during 1 year after initial exposure to tapentadol or oxycodone. Shopping was defined by having overlapping opioid prescriptions from >1 prescriber filled at ≥3 pharmacies; abuse by having International Classification of Diseases, 9th revision diagnoses reflecting opioid abuse, addiction, or dependence. To determine their association, we cross-tabulated shopping and opioid abuse and calculated odds ratios. Risks of developing each outcome were estimated using logistic regression. Results: Among 277,401 participants initiating opioid use with tapentadol (39,524) or oxycodone (237,877), 0.6% developed shopping behavior, 0.75% developed abuse. Higher proportions of patients in the oxycodone group developed shopping behavior and abuse than in the tapentadol group (shopping: adjusted odds ratio [95% confidence interval], 0.45 [0.36-0.55]; abuse: 0.44 [0.37-0.54]). Shopping behavior and abuse were associated; of those with shopping behavior, 6.5% had abuse. Age (18 to 64 y), sex (male), prior benzodiazepine use, paying cash, and history (mood disorders, abuse of nonopioid medications, and back pain) were risk factors for developing either outcome. Discussion: Shopping behavior and abuse measure complementary, but associated, constructs, which further validates the current definition of shopping. The risk of developing either is lower among patients who initiate opioid use with tapentadol than those who initiate opioid use with oxycodone. PMID:24370606
Problem based review: The patient taking methadone.
Arora, Alok; Williams, Karen
2013-01-01
Methadone maintenance treatment (MMT) is an effective therapy for opioid-dependence; its use is based on a harm reduction philosophy and represents one of a range of treatment approaches for opioid-dependent individuals. The medical literature supports MMT as a well established and cost-effective treatment for opioid-dependence that allows a return-to-normal physiological, psychological and societal functioning. The effectiveness of MMT is enhanced by psycho-social interventions such as contingency management and addressing other co-existing health and social needs. MMT saves lives and reduces violent and non-violent crime, drug use and the transmission of HIV, hepatitis C and other communicable diseases. For some people, MMT may continue for life, while others may eventually be able to discontinue and remain abstinent. Methadone interacts with numerous drugs and prolongs the corrected QT interval (QTc) with risk of sudden cardiac death. It has a prolonged half-life and premature discharge of patients after methadone overdose may be fatal. Each patient must be assessed, treated and monitored on an individual basis. Successful outcomes through MMT require knowledge, experience, vigilance, and diligence on the part of the physician, the patient and all of those involved in treatment.
Opiate and non-opiate aspects of morphine induced seizures.
Frenk, H; Liban, A; Balamuth, R; Urca, G
1982-12-16
The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.
Access to Care for Methadone Maintenance Patients in the United States
ERIC Educational Resources Information Center
Hettema, Jennifer E.; Sorensen, James L.
2009-01-01
This policy commentary addresses a significant access to care issue that faces methadone maintenance patients seeking residential treatment in the United States. Methadone maintenance therapy (MMT) has demonstrated strong efficacy in the outpatient treatment of opiate dependence. However, many opiate dependent patients are also in need of more…
Eiden, Céline; Léglise, Yves; Bertomeu, Lisa; Clavel, Vivianne; Faillie, Jean-Luc; Petit, Pierre; Peyrière, Hélène
2013-01-01
A new formulation of methadone as capsules is marketed in France since 2008. Few data are available on the patient acceptability and the risk of misuse of this new formulation. To assess the patient acceptability after the switch methadone syrup/capsules and the diversion/misuse liability of the methadone capsule, a study through an anonymous questionnaire was conducted between March 2011 and May 2012 in two methadone centers of the region. Forty-one patients (men 75.6%) participated, with a median age of 37 years [IQR: 33-43 years]. The median duration of syrup methadone maintenance therapy was 1 year [IQR: 1-3 years]. A majority of patients (80.5%) described side-effects due to the syrup formulation. Median daily dose at the switch to methadone capsules was 75 mg [IQR: 42-105 mg]. Six patients described differences in the pharmacologic effect between the two formulations. Concerning the diversion and misuse liability of methadone capsules, 26.8% of patients reported that the medication was available at the "street market". Three patients have tried to solubilize and eight have tried to snooze it. All patients recognize the contribution of this new formulation concerning the use, side-effects and transport. None of them returned to the syrup. © 2013 Société Française de Pharmacologie et de Thérapeutique.
Factors Associated with Illegal Drug Use among Older Methadone Clients
ERIC Educational Resources Information Center
Rosen, Daniel
2004-01-01
Purpose. The overall aims of this study are to describe the life stressors of, exposure to illegal drug use of, and illegal drug use by older methadone clients. Design and Methods. The current study focuses on a sub-sample of the larger administrative data of a methadone clinic that is limited to African American and White clients over the age of…
Comparison of buprenorphine and methadone effects on opiate self-administration in primates.
Mello, N K; Bree, M P; Mendelson, J H
1983-05-01
The effects of ascending and descending doses of buprenorphine (0.014-0.789 mg/kg/day) and methadone (0.179-11.86 mg/kg/day) on opiate and food intake were studied in Macaque monkeys over 195 to 245 days. Food (1-g banana pellets) and i.v. drug self-administration (heroin 0.01 or 0.02 mg/kg/injection or Dilaudid 0.02 mg/kg/injection) were maintained on a second-order schedule of reinforcement [FR 4 (VR 16:S)]. Buprenorphine (0.282-0.789 mg/kg/day) produced a significant suppression of opiate self-administration at 2.5 to 7 times the dose shown to be effective in human opiate abusers (P less than .05-.001). Methadone (1.43-11.86 mg/kg/day) did not suppress opiate self-administration in four of five monkeys across a dose range equivalent to 100 to 800 mg/day in man. The distribution of opiate self-administration across drug sessions did not account for the absence of methadone suppression as monkeys took 43% of the total daily opiate injections during the first daily drug session, 2.5 hr after methadone administration. During buprenorphine maintenance, food intake remained stable or increased significantly above base-line levels. Methadone maintenance was associated with significant decrements in food intake in four of five monkeys. Buprenorphine appeared to be significantly more effective in suppressing opiate self-administration than methadone across the dose range studied. Buprenorphine had none of the toxic side effects (seizures, respiratory depression, profound psychomotor retardation) associated with high doses of methadone over 6 to 8 months of daily drug treatment. These data are consistent with clinical studies of buprenorphine effects on heroin self-administration in human opiate addicts.
Linardi, R L; Stokes, A M; Barker, S A; Short, C; Hosgood, G; Natalini, C C
2009-10-01
Methadone hydrochloride is a synthetic mu-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/mass spectrometry at predetermined time points for 24 h, and PK parameters were estimated using a noncompartmental model. Physical effects were observed and recorded by experienced clinicians. No drug toxicity, behavioural or adverse effects were observed in the horses. The disposition of methadone followed first order elimination and a biphasic serum profile with rapid absorption and elimination phases. The PK profile of methadone was characterized by high clearance (Cl/F), small volume of distribution (V(d)/F) and short elimination half-life (t(1/2)). The mean of the estimated t(1/2) (SD) for each dose (0.1, 0.2 and 0.4 mg/kg) was 2.2 (35.6), 1.3 (46.1) and 1.5 (40.8), and the mean for the estimated C(max) (SD) was 33.9 (6.7), 127.9 (36.0) and 193.5 (65.8) respectively.
Lintzeris, Nicholas; Monds, Lauren A; Rivas, Consuelo; Leung, Stefanie; Dunlop, Adrian; Newcombe, David; Walters, Carina; Galea, Susanna; White, Nancy; Montebello, Mark; Demirkol, Apo; Swanson, Nicola; Ali, Robert
Transfer from methadone to buprenorphine is problematic for many opioid-dependent patients, with limited documented evidence or practical clinical guidance, particularly for the range of methadone doses routinely prescribed for most patients (>50 mg). This study aimed to implement and evaluate recent national Australian guidelines for transferring patients from methadone to buprenorphine. A multisite prospective cohort study. Participants were patients who transferred from methadone to buprenorphine-naloxone at 1 of 4 specialist addiction centers in Australia and New Zealand. Clinicians were trained in the guidelines, and medical records were reviewed to examine process (eg, transfer setting, doses, and guideline adherence) and safety (precipitated withdrawal) measures. Participants completed research interviews before and after transfer-assessing changes in substance use, health outcomes, and side effects. In all, 33 participants underwent transfer, 9 from low methadone doses (<30 mg), 9 from medium doses (30-50 mg), and 15 from high doses (>50 mg). The majority of high-dose transfers occurred in inpatient settings. There was reasonable guideline adherence, and no complications identified in the low and medium-dose transfers. Three high-dose transfers (20%) experienced precipitated withdrawal, and 7/33 participants (21%) returned to methadone within 1 week of attempted transfer. Transfer is feasible in outpatient settings for those transferring from methadone doses below 50 mg; however, inpatient settings and specialist supervision is recommended for higher-dose transfers. The Australian clinical guidelines appear safe and feasible, although further research is required to optimize high-dose transfer procedures.
Effect of steady-state methadone on high fructose corn syrup consumption in rats.
Daniels, Stephen; Pratt, Mick; Zhou, Yan; Leri, Francesco
2018-02-01
Patients undergoing methadone maintenance treatment self-report enhanced preferences for, and excessive consumption of, foods rich in sugar. However, it is unclear whether these are direct pharmacological effects of methadone or the consequences of metabolic dysfunctions induced by addiction to illicit opiates. Hence, the current study in drug-naïve male Sprague-Dawley rats explored the effects of steady-state methadone delivered by osmotic mini-pumps (13 days; 0, 10, 30 mg/kg/day) on consumption of rat chow and a palatable, sweet, liquid high fructose corn syrup solution. Six days after the removal of the pumps, mRNA expression of genes involved in responses to stress and rewards were quantified: pro-opiomelanocortin in the hypothalamus, mu-opioid receptor in the nucleus accumbens, and dopamine D2 receptor in the dorsal striatum. Taste reactivity and locomotion tests were also performed throughout the study. It was found that methadone increased caloric intake from high fructose corn syrup and reduced caloric intake from chow, effects that could not be directly ascribed to changes in high fructose corn syrup taste reactivity or motor functions. However, the changes in caloric intake displayed significant tolerance, and mRNA expression analysis suggested that methadone attenuated the effect of high fructose corn syrup on pro-opiomelanocortin mRNA, and possibly on dopamine D2 receptor mRNA. These findings in rats suggest that the pharmacological effect of methadone, administered to achieve steady-state maintenance, may not be the primary cause of dietary alterations reported by patients maintained on methadone.
Oral Morphine Use in South India: A Population-Based Study
Karim, Safiya; Booth, Christopher M.
2017-01-01
Purpose Access to opioids for pain control is recognized as an urgent issue in low- and middle-income countries. Here we report temporal and regional trends in morphine use in Kerala, India. Methods Oral morphine use data for the State of Kerala (2012 to 2015) was used to describe temporal trends, regional variation, and provider characteristics. Total morphine use was calculated for each district of Kerala to derive an annual per capita use rate (milligrams per capita). Each provider was classified as government, private, nongovernment organization (NGO), or NGO partnership. Results Oral morphine use for Kerala was 1.32 mg/capita and increased over the study period 27% (from 1.23 mg/capita to 1.56 mg/capita). There was substantial variation in morphine use across districts (range, 0.49 mg/capita to 2.97 mg/capita; six-fold difference). This variation increased over time (19-fold difference in 2015). In 2015, 31% of morphine providers (51 of 167) were government institutions; they delivered 48% of total morphine in Kerala. Corresponding data for other providers are private institutions, 23% of centers and 13% of morphine; NGOs, 41% of centers and 34% of morphine; and NGO partnerships, 5% of centers and 4% of morphine. From 2012 to 2015, the total number of centers increased by 35%, from 124 to 167. Conclusion Oral morphine use has increased over time in Kerala but remains substantially lower than estimated need. There is significant geographic variation of use. Efforts are needed to improve palliative care in Kerala and to reduce regional disparities in access to opioids. PMID:29244992
Kitto, Kelley F; Fairbanks, Carolyn A
2006-04-24
We have determined the effect of intracerebroventricularly (i.c.v.) administered decarboxylated arginine (agmatine) on supraspinally induced chronic morphine analgesic tolerance. Mice pre-treated with a schedule of chronic i.c.v administration of morphine (10 nmol, b.i.d. 3 days) show a 12-fold reduction in the potency of acutely administered i.c.v morphine compared to saline injected controls. Co-administration of agmatine (10 nmol) with one of the two daily morphine injections completely prevents the reduction in i.c.v morphine analgesia. Mice injected with agmatine once daily (but no morphine) do not show a increase in morphine analgesic potency relative to saline controls, indicating that a mere potentiation of acute morphine analgesia cannot account for the agmatine-mediated anti-tolerance effect in those mice subjected to the morphine tolerance induction schedule. These observations agree with previous reports that systemically and intrathecally administered agmatine prevent opioid tolerance, and extend these results to include a supraspinal site of action.
Wang, Na; Wang, Yuantao; Pang, Lei; Wang, Jinguo
2015-01-01
Objective: To evaluate the efficacy of preemptive intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor. Methods: Sixty ASA I or II patients undergoing elective laparoscopic resection of ovarian tumor were randomly allocated to one of two groups: Group O (n=30) received intravenous oxycodone (0.1 mg·kg-1) 10 minutes before surgery over 2 minutes, and Group N (n=30) received an equivalent volume of normal saline. All patients received a standardized general anesthesia. MBP and HR at the time of arrival of the operating room (T1), 5 min before pneumoperitoneum (T2), 5 minutes (T3), 10 minutes (T4), and 15 minutes after pneumoperitoneum (T5), and VAS scores at postoperative 2, 4, 8, 12 and 24 hour were recorded. The tramadol consumption and side effects in 24 h after surgery were recorded. Results: VAS pain scores at 2, 4, 8 and 12 hour after operation were significantly lower in Group O (P<0.05). MBP and HR increased significantly due to pneumoperitoneum at T3, T4 and T5, compared with T1 and T2 within Group N, and were higher at T3, T4 and T5 in Group N than at the same time points in Group O. Tramadol consumption was statistically lower in Group O (P=0.0003). Conclusions: Preemptive intravenous oxycodone was an efficient and safe method to reduce intraoperative haemodynamic effect and postoperative pain. PMID:26101479
[Perioperative managements of the patients with cancer-pain receiving morphine].
Matsuda, M; Murakawa, K; Noma, K; Uemura, Y; Maeda, S; Tashiro, C
1998-09-01
In the patients receiving morphine preoperatively, it is preoperatively important to avoid withdrawal symptoms postoperatively and to suppress postoperative pain and to maintain an appropriate anesthetic depth during the operation. We experienced six patients who had been under preoperative pain control with oral and/or epidural morphine and undergone palliative operation for their cancer pain. Four of the patients were preoperatively administered with oral morphine ranging from 30 to 270 mg.day-1. One patient was given epidural morphine 10 mg.day-1. Another was with morphine 1800 mg.day-1 orally and 50 mg.day-1 epiduraly. In all cases, general anesthesia was maintained with inhalation anesthetics. Anesthetic supplementation and postoperative pain management were performed with continuous i.v. infusion of morphine (half dosage of daily oral dosage), or subcutaneous injection (one sixth dosage of daily oral morphine) while preoperative epidural morphine was continued throughout the perioperative period. We were able to manage these patients well and none of them developed withdrawal symptom or increased postoperative pain.
Internet-based survey of nonmedical prescription opioid use in the United States.
Katz, Nathaniel; Fernandez, Kathrine; Chang, Alan; Benoit, Christine; Butler, Stephen F
2008-01-01
Prescription opioid misuse is a growing problem in the United States. There are limited data to illuminate the nature of this issue. The Internet seems to be a novel approach in surveying populations of opioid users. An Internet-based survey of nonmedical opioid users visiting informational drug websites was used to measure rates of nonmedical use and characterize users. The prescription opioid module of the Addiction Severity Index Multimedia Version Connect was adapted to include variables such as favorite opioid. Links to the survey were posted on an informational drug website. Nonmedical use rates for KADIAN (morphine sulfate extended-release tablets), OxyContin (oxycodone HCl controlled-release tablets), Vicodin (hydrocodone bitartrate and acetaminophen tablets), and product-classes (morphine ER, oxycodone ER, and hydrocodone) were calculated. Descriptive statistics were calculated for remaining questions. During a 1-month recruitment period, 896 valid individuals completed the survey. Majority were white (78.3%) and male (72.4%). Participants were less likely to have used KADIAN in the past 30 days compared with OxyContin (P<0.0001) and Vicodin (P=0.0021). Additionally, participants were less likely to have used morphine ER in the previous 30 days than either oxycodone ER (P<0.0001) or hydrocodone (P<0.0001). Among OxyContin, Vicodin, and KADIAN users, OxyContin (43.8%), Dilaudid (15.6%), and fentanyl (9.4%) were the top 3 favorite opioids. This project demonstrates the feasibility of conducting product-specific, online surveys with rapid recruitment of participants from websites. This approach differentiates rates of nonmedical use of specific prescription opioids and provides other insights into individuals who nonmedically use opioids.
Imaging of subacute blood-brain barrier disruption after methadone overdose.
Huisa, Branko N; Gasparovic, Charles; Taheri, Saeid; Prestopnik, Jillian L; Rosenberg, Gary A
2013-07-01
Methadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins. To investigate the metabolic derangement of the white matter (WM) and blood-brain barrier (BBB) after DAL caused by methadone overdose. Case report of 2 patients with DAL after a single dose of "diverted" methadone used for pain control. In both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging ((1) H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired. Methadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods. Copyright © 2011 by the American Society of Neuroimaging.
Ardeshiri, Moslem; Jalali, Fahimeh
2016-06-01
In order to develop a fast and simple procedure for methadone analysis in biological fluids, a graphite paste electrode (GPE) was modified with the ion-pair of methadone-phosphotungstic acid, and multiwalled carbon nanotubes (MWCNTs). Optimized composition of the electrode with respect to graphite powder:paraffin oil:MWCNTs:ion pair, was 58:30:8:4 (w/w%). The electrode showed a near-Nernstian slope of 58.9 ± 0.3 mV/decade for methadone in a wide linear range of 1.0 × 10(-8)-4.6 × 10(-3)M, with a detection limit of 1.0 × 10(-8)M. The electrode response was independent of pH in the range of 5-11, with a fast response time (~4s) at 25 °C. The sensor showed high selectivity and was successfully applied to the determination of sub-micromolar concentrations of methadone in human blood serum and urine samples, with recoveries in the range of 95-99.8%. The average recovery of methadone from tablets (5 mg/tablet) by using the proposed method was 98%. The life time of the modified electrode was more than 5 months, due to the characteristic of GPE which can be cut off and fresh electrode surface be available. A titration procedure was performed for methadone analysis by using phosphotungstic acid, as titrating agent, which showed an accurate end point and 1:1 stoichiometry for the ion-pair formed (methadone:phosphotungstic acid). The simple and rapid procedure as well as excellent detection limit and selectivity are some of the advantages of the proposed sensor for methadone. Copyright © 2016 Elsevier B.V. All rights reserved.
Impulsivity in men with prescription of benzodiazepines and methadone in prison.
Moreno-Ramos, Luis; Fernández-Serrano, María José; Pérez-García, Miguel; Verdejo-García, Antonio
2016-06-14
Benzodiazepines and methadone use has been associated with various neuropsychological impairments. However, to the best of our knowledge, no studies have been carried out on the effect of these substances (either separately or combined) on impulsive personality, including studies in prisoners. The aim of this study is to examine the impulsive personality of a sample of 134 male prisoners using the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (Torrubia, Avila, Molto, & Caseras, 2001) and the UPPS-P Scale (Cyders et al., 2007). Some of these were methadone users, methadone and benzodiazepines users, polydrug users in abstinence and non-dependent drug users. The results showed that drug users have greater sensitivity to reward, positive urgency, negative urgency and sensation seeking than non-dependent users. Methadone users showed more sensitivity to punishment and lack of perseverance with respect to other users. No differences were found between methadone+benzodiazepines users and other groups. The secondary aim is to examine which impulsive personality dimensions are related to the two motivational systems proposed by Gray (BIS-BAS) using exploratory factor analysis. Results showed two different components. One component was defined by the subscales sensitivity to reinforcement, positive urgency, negative urgency and sensation seeking. The second component was defined by the subscales sensitivity to punishment, lack of perseverance and lack of premeditation.
Friesen, Claudia; Roscher, Mareike; Alt, Andreas; Miltner, Erich
2008-08-01
The therapeutic opioid drug methadone (d,l-methadone hydrochloride) is the most commonly used maintenance medication for outpatient treatment of opioid dependence. In our study, we found that methadone is also a potent inducer of cell death in leukemia cells and we clarified the unknown mechanism of methadone-induced cell killing in leukemia cells. Methadone inhibited proliferation in leukemia cells and induced cell death through apoptosis induction and activated apoptosis pathways through the activation of caspase-9 and caspase-3, down-regulation of Bcl-x(L) and X chromosome-linked inhibitor of apoptosis, and cleavage of poly(ADP-ribose) polymerase. In addition, methadone induced cell death not only in anticancer drug-sensitive and apoptosis-sensitive leukemia cells but also in doxorubicin-resistant, multidrug-resistant, and apoptosis-resistant leukemia cells, which anticancer drugs commonly used in conventional therapies of leukemias failed to kill. Depending on caspase activation, methadone overcomes doxorubicin resistance, multidrug resistance, and apoptosis resistance in leukemia cells through activation of mitochondria. In contrast to leukemia cells, nonleukemic peripheral blood lymphocytes survived after methadone treatment. These findings show that methadone kills leukemia cells and breaks chemoresistance and apoptosis resistance. Our results suggest that methadone is a promising therapeutic approach not only for patients with opioid dependence but also for patients with leukemias and provide the foundation for new strategies using methadone as an additional anticancer drug in leukemia therapy, especially when conventional therapies are less effective.
Csajka, Chantal; Crettol, Séverine; Guidi, Monia; Eap, Chin B
2016-12-01
Methadone is a μ-opioid agonist widely used for the treatment of pain, and for detoxification or maintenance treatment in opioid addiction. It has been shown to exhibit large pharmacokinetic variability and concentration-QTc relationships. In this study we investigated the relative influence of genetic polymorphism and other variables on the dose concentration-QTc relationship. A population model for methadone enantiomers in 251 opioid-dependent patients was developed using non-linear mixed effect modeling (NONMEM ® ). Various models were tested to characterize the pharmacokinetics of (R)- and (S)-methadone and the pharmacokinetic-pharmacodynamic relationship, while including demographics, physiological conditions, co-medications, and genetic variants as covariates. Model-based simulations were performed to assess the relative increase in QTc with dose upon stratification according to genetic polymorphisms involved in methadone disposition. A two-compartment model with first-order absorption and lag time provided the best model fit for (R)- and (S)-methadone pharmacokinetics. (S)-methadone clearance was influenced by cytochrome P450 (CYP) 2B6 activity, ABCB1 3435C>T, and α-1 acid glycoprotein level, while (R)-methadone clearance was influenced by CYP2B6 activity, POR*28, and CYP3A4*22. A linear model described the methadone concentration-QTc relationship, with a mean QTc increase of 9.9 ms and 19.2 ms per 1000 ng/ml of (R)- and (S)-methadone, respectively. Simulations with different methadone doses up to 240 mg/day showed that <8 % of patients presented with a QTc interval above 450 ms; however, this might reach 12 to 18 % for (R)- and (S)-methadone, respectively, in patients with a genetic status associated with a decreased methadone elimination at doses exceeding 240 mg/day. Risk factor assessment, electrocardiogram monitoring, and therapeutic drug monitoring are beneficial to optimize treatment in methadone patients, especially for those who have low
Crettol, Séverine; Monnat, Martine; Eap, Chin B
2007-01-01
In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected. PMID:17338832
Neurobiological Effects of Morphine after Spinal Cord Injury
Woller, Sarah A.; Bancroft, Eric; Aceves, Miriam; Funk, Mary Katherine; Hartman, John; Garraway, Sandra M.
2017-01-01
Abstract Opioids and non-steroidal anti-inflammatory drugs are used commonly to manage pain in the early phase of spinal cord injury (SCI). Despite its analgesic efficacy, however, our studies suggest that intrathecal morphine undermines locomotor recovery and increases lesion size in a rodent model of SCI. Similarly, intravenous (IV) morphine attenuates locomotor recovery. The current study explores whether IV morphine also increases lesion size after a spinal contusion (T12) injury and quantifies the cell types that are affected by early opioid administration. Using an experimenter-administered escalating dose of IV morphine across the first seven days post-injury, we quantified the expression of neuron, astrocyte, and microglial markers at the injury site. SCI decreased NeuN expression relative to shams. In subjects with SCI treated with IV morphine, virtually no NeuN+ cells remained across the rostral-caudal extent of the lesion. Further, whereas SCI per se increased the expression of astrocyte and microglial markers (glial fibrillary acidic protein and OX-42, respectively), morphine treatment decreased the expression of these markers. These cellular changes were accompanied by attenuation of locomotor recovery (Basso, Beattie, Bresnahan scores), decreased weight gain, and the development of opioid-induced hyperalgesia (increased tactile reactivity) in morphine-treated subjects. These data suggest that morphine use is contraindicated in the acute phase of a spinal injury. Faced with a lifetime of intractable pain, however, simply removing any effective analgesic for the management of SCI pain is not an ideal option. Instead, these data underscore the critical need for further understanding of the molecular pathways engaged by conventional medications within the pathophysiological context of an injury. PMID:27762659
Linking drugs of abuse in wastewater to contamination of surface and drinking water.
Rodayan, Angela; Afana, Shadi; Segura, Pedro A; Sultana, Tamanna; Metcalfe, Chris D; Yargeau, Viviane
2016-04-01
The concentrations of 17 drugs of abuse, including cocaine, several amphetamines, opioid drugs, and 2 metabolites--benzoylecgonine, a metabolite of cocaine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, a metabolite of methadone--were investigated in an urban watershed that is heavily impacted by discharges of municipal wastewater. The artificial sweetener sucralose was also monitored as a persistent tracer of contamination from municipal wastewater. Monitoring was conducted in a municipal wastewater treatment plant (WWTP) and at sites upstream and downstream of the WWTP discharge, as well as in a drinking water treatment plant (DWTP) located 19 km downstream of the WWTP discharge that withdraws raw water from the river. Drug concentrations were monitored with polar organic chemical integrative samplers deployed for 2 wk in the river and in the WWTP and DWTP. Several of the investigated compounds exhibited a decrease in concentration with distance downstream from the wastewater discharge into the river, but there was little attenuation of sucralose, cocaine, benzoylecgonine, morphine, acetylmorphine, acetylcodeine, and oxycodone. Heroin and methadone were not detected at any sample locations. Amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were not detected in the samples collected at the drinking water intake. Many of the drugs of abuse were not removed effectively in the DWTP, including cocaine, benzoylecgonine, methylenedioxyamphetamine, ephedrine, and several prescription opioids, most probably because the DWTP was operating at or above its rated treatment capacity. These data indicate that there can be transport of drugs of abuse from wastewater sources into drinking water in urban watersheds. © 2015 SETAC.
Morphine, but not Trauma, Sensitizes to Systemic Acinetobacter baumannii Infection
Breslow, Jessica M.; Monroy, M. Alexandra; Daly, John M.; Meissler, Joseph J.; Gaughan, John; Adler, Martin W.; Eisenstein, Toby K.
2014-01-01
Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 hr by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A−/− mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection. PMID:21826405
Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection.
Breslow, Jessica M; Monroy, M Alexandra; Daly, John M; Meissler, Joseph J; Gaughan, John; Adler, Martin W; Eisenstein, Toby K
2011-12-01
Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A(-/-) mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection.
Stress antagonizes morphine-induced analgesia in rats
NASA Technical Reports Server (NTRS)
Vernikos, J.; Shannon, L.; Heybach, J. P.
1981-01-01
Exposure to restraint stress resulted in antagonism of the analgesic effect of administered morphine in adult male rats. This antagonism of morphine-induced analgesia by restraint stress was not affected by adrenalectomy one day prior to testing, suggesting that stress-induced secretion of corticosteroids is not critical to this antagonism. In addition, parenteral administration of exogenous adrenocorticotropin (ACTH) mimicked the effect of stress in antagonizing morphine's analgesic efficacy. The hypothesis that ACTH is an endogenous opiate antagonist involved in modulating pain sensitivity is supported.
Lerner, Debra; Chang, Hong; Rogers, William H; Benson, Carmela; Chow, Wing; Kim, Myoung S; Biondi, David
2012-08-01
: To determine the impact of tapentadol extended release (ER) versus placebo or oxycodone controlled release (CR) on the work productivity of adults with chronic moderate to severe knee osteoarthritis pain. : Using clinical trial data on pain outcomes, a validated methodology imputed treatment group differences in at-work productivity and associated differences in productivity costs (assuming a $100,000 annual salary per participant). : Imputed improvements in at-work productivity were significantly greater for tapentadol ER compared with either placebo (mean, 1.96% vs 1.51%; P = 0.001) or oxycodone CR (mean, 1.96% vs 1.40%; P < 0.001). Mean net savings per participant were $450 (P < 0.01) for tapentadol ER versus placebo and $560 (P = 0.001) for tapentadol ER versus oxycodone CR. : Effective osteoarthritis pain treatment also may help employees to function better at work and reduce their employers' productivity costs.
Transcranial route of brain targeted delivery of methadone in oil.
Pathirana, W; Abhayawardhana, P; Kariyawasam, H; Ratnasooriya, W D
2009-05-01
The unique anatomical arrangement of blood vessels and sinuses in the human skull and the brain, the prevalence of a high density of skin appendages in the scalp, extracranial vessels of the scalp communicating with the brain via emissary veins and most importantly, the way that the scalp is used in Ayurvedic medical system in treating diseases associated with the brain show that a drug could be transcranially delivered and targeted to the brain through the scalp. The present study was to investigate by measuring the antinociceptive effect on rats whether the opioid analgesic methadone could be delivered and targeted to the brain by transcranial delivery route. A non aqueous solution of methadone base in sesame oil was used for the application on the scalp. Animal studies were carried out using six groups of male rats consisting of group 1, the oral control treated with distilled water 1 ml; group 2, the oral positive control treated with methadone hydrochloride solution 316.5 mug/ml; group 3, the negative control treated transcranially with the blank sesame oil 0.2 ml and three test groups 4, 5 and 6 treated with three different dose levels of the transcranial oil formulation of methadone base, 41.6 mug/0.2 ml, 104 mug/0.2 ml and 208 mug/0.2 ml, respectively. The antinociceptive effects were examined by subjecting the rats to the hot plate and tail flick tests. The two higher concentrations of the three transcranial methadone formulations yielded response vs time curves showing nearly equal maximum antinociceptive effects similar to that of the oral positive control. Maximum analgesic effect after transcranial administration was observed between 1st and 2nd h and declined up to 6th hour. The results indicate that the transcranial brain targeted delivery of methadone base in the form of an oil based non aqueous solution results in statistically significant antinociceptive effects under experimental conditions. Therefore, it is possible to deliver central nervous
A case of serotonin syndrome associated with methadone overdose.
Martinez, Terry T; Martinez, Daniel N
2008-01-01
A chronic pain patient prescribed 20 mg of methadone per day was seen at the Emergency Department within one hour following a witnessed intentional 200 mg ingestion. In addition, he was taking the serotonin re-uptake inhibitor antidepressant drugs, sertraline and venlafaxine as prescribed. Methadone is also a serotonin re-uptake inhibitor which has been involved in serotonin toxicity reactions. Initially, no symptoms of narcotic overdose (depressed central nervous system, respiration, or blood pressure) could be distinguished, and the standard narcotic urine screen was negative. No decontamination or antagonist therapy was given, and the patient was discharged to a psychiatric unit for observation. At 5 hours post-ingestion he presented in a panic with hallucinations and elevated blood pressure, pulse, and respiration. These symptoms are characteristic of serotonin syndrome which is often described as mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. At 10 hours post-ingestion the patient was found unconscious. He had aspirated stomach contents into his lungs. His respiration, blood pressure, and pulse were all severely depressed. He never regained conciousness, and he died 5 days later. The medical examiner's finding was probable acute methadone intoxication. In this case serotonin syndrome appears to have opposed and delayed typical narcotic symptoms. Methadone has additional pharmacologic and toxicologic properties which may complicate the assessment and treatment in overdose situations.
Patient perspectives on choosing buprenorphine over methadone in an urban, equal-access system.
Gryczynski, Jan; Jaffe, Jerome H; Schwartz, Robert P; Dušek, Kristi A; Gugsa, Nishan; Monroe, Cristin L; O'Grady, Kevin E; Olsen, Yngvild K; Mitchell, Shannon Gwin
2013-01-01
Recent policy initiatives in Baltimore City, MD significantly reduced access disparities between methadone and buprenorphine in the publicly funded treatment sector. This study examines reasons for choosing buprenorphine over methadone among patients with access to both medications. This study was embedded within a larger clinical trial conducted at two outpatient substance abuse treatment programs offering buprenorphine. Qualitative and quantitative data on treatment choice were collected for new patients starting buprenorphine treatment (n = 80). The sample consisted of predominantly urban African American (94%) heroin users who had prior experience with non-prescribed street buprenorphine (85%), and opioid agonist treatment (68%). Qualitative data were transcribed and coded for themes, while quantitative data were analyzed using descriptive and bivariate statistics. Participants typically conveyed their choice of buprenorphine treatment as a decision against methadone. Buprenorphine was perceived as a helpful medication while methadone was perceived as a harmful narcotic with multiple unwanted physical effects. Positive experiences with non-prescribed "street buprenorphine" were a central factor in participants' decisions to seek buprenorphine treatment. Differences in service structure between methadone and buprenorphine did not strongly influence treatment-seeking decisions in this sample. Personal experiences with medications and the street narrative surrounding them play an important role in treatment selection decisions. This study characterizes important decision factors that underlie patients' selection of buprenorphine over methadone treatment. Copyright © American Academy of Addiction Psychiatry.
Patient Perspectives on Choosing Buprenorphine over Methadone in an Urban Equal Access System
Gryczynski, Jan; Jaffe, Jerome H.; Schwartz, Robert P.; Dušek, Kristi A.; Gugsa, Nishan; Monroe, Cristin L.; O'Grady, Kevin E.; Olsen, Yngvild K.; Mitchell, Shannon Gwin
2014-01-01
Background Recent policy initiatives in Baltimore City, MD significantly reduced access disparities between methadone and buprenorphine in the publicly-funded treatment sector. Objectives This study examines reasons for choosing buprenorphine over methadone among patients with access to both medications. Methods This study was embedded within a larger clinical trial conducted at two outpatient substance abuse treatment programs offering buprenorphine. Qualitative and quantitative data on treatment choice were collected for new patients starting buprenorphine treatment (n=80). The sample consisted of predominantly urban African American (94%) heroin users who had prior experience with non-prescribed street buprenorphine (85%) and opioid agonist treatment (68%). Qualitative data were transcribed and coded for themes, while quantitative data were analyzed using descriptive and bivariate statistics. Results Participants typically conveyed their choice of buprenorphine treatment as a decision against methadone. Buprenorphine was perceived as a helpful medication while methadone was perceived as a harmful narcotic with multiple unwanted physical effects. Positive experiences with non-prescribed “street buprenorphine” were a central factor in participants’ decisions to seek buprenorphine treatment. Conclusions Differences in service structure between methadone and buprenorphine did not strongly influence treatment-seeking decisions in this sample. Personal experiences with medications and the street narrative surrounding them play an important role in treatment selection decisions. Scientific Significance This study characterizes important decision factors that underlie patients’ selection of buprenorphine over methadone treatment. PMID:23617873
Ginley, Meredith K; Rash, Carla J; Olmstead, Todd A; Petry, Nancy M
2017-11-01
Legal difficulties and cocaine use are prevalent in methadone maintenance patients, and they are related to one another, as well as to poor response to methadone treatment. Contingency management (CM) is efficacious for decreasing cocaine use, but the relation of CM treatment to criminal activities has rarely been studied. This study evaluated whether baseline legal problems are related to subsequent substance use and illegal activities for cocaine using methadone maintained patients and whether CM differentially improves outcomes depending on baseline legal problems. Using data from four randomized CM trials (N=323), we compared methadone maintained patients with legal problems at the start of study participation to those without initial legal problems. Overall, the addition of CM to standard methadone care improved substance use outcomes regardless of initial legal problems. Endorsement of legal problems within 30days of study initiation was associated with reduced proportion of negative samples submitted during the 12-week treatment period. A significant interaction effect of baseline legal problems and treatment condition was present for subsequent self-reports of illegal activities. Those with baseline legal problems who were assigned to CM had reduced self-reports of reengagement in illegal activity throughout a six month follow-up compared to their counterparts randomized to standard care. Adding CM to methadone treatment improves substance use outcomes and reduces subsequent illegal activity in cocaine-using methadone patients with legal problems. Copyright © 2017 Elsevier B.V. All rights reserved.
Effect of agmatine on long-term potentiation in morphine-treated rats.
Lu, Wei; Dong, Hua-Jin; Bi, Guo-Hua; Zhao, Yong-Qi; Yang, Zheng; Su, Rui-Bin; Li, Jin
2010-08-01
Agmatine is an endogenous amine derived from l-arginine that potentiates morphine analgesia and inhibits naloxone precipitated abstinent symptoms in morphine dependent rats. In this study, the effects of agmatine on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus (DG) on saline or morphine-treated rats were investigated. Population spikes (PS), evoked by stimulation of the LPP, was recorded from DG region. Acute agmatine (2.5-10mg/kg, s.c.) treatment facilitated hippocampal LTP. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and agmatine (10mg/kg, s.c.) restored the amplitude of PS that was attenuated by morphine. Chronic morphine treatment resulted in the enhancement of hippocampal LTP, agmatine co-administered with morphine significantly attenuated the enhancement of morphine on hippocampal LTP. Imidazoline receptor antagonist idazoxan (5mg/kg, i.p.) reversed the effect of agmatine. These results suggest that agmatine attenuated the effect of morphine on hippocampal LTP, possibly through activation of imidazoline receptor. Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.
Emergence of Methadone as a Street Drug in St. Petersburg, Russia
Heimer, Robert; Lyubimova, Aleksandra; Barbour, Russell; Levina, Olga S.
2015-01-01
Background The syndemic of opioid addiction, HIV, hepatitis, tuberculosis, imprisonment, and overdose in Russia has been worsened by the illegality of opioid substitution therapy. As part of on-going serial studies, we sought to explore the influence of opioid availability on aspects of the syndemic as it has affected the city of St. Petersburg. Methods We employed a sequential approach in which quantitative data collection and statistical analysis were followed by a qualitative phase. Quantitative data were obtained from a respondent-driven sample (RDS) of people who inject drugs (PWID) obtained in 2012–13. Individuals recruited by RDS were tested for antibodies to HIV and interviewed about drug use and injection practices, sociodemographics, health status, and access to medical care. Subsequently, we collected in-depth qualitative data on methadone use, knowledge, and market availability from PWID recruited at nine different locations within St. Petersburg. Results Analysis of interview data from the sample revealed he percentage of PWID injecting methadone in the 30 days prior to interview increased from 3.6% in 2010 to 53.3% in 2012–13. Injection of only methadone, as compared to injecting only heroin or both drugs, was associated with less frequent injection and reduced HIV-related injected risk, especially a lower rate of injecting with a previously used syringe. In-depth questioning of methadone injectors corroborated the finding from serial quantitative surveys of PWID that methadone’s black market availability is a recent phenomenon. Spatial analysis revealed widespread methadone availability but no concentration in any specific districts of the city. Conclusion Despite the prohibition of substitution therapy and demonization of methadone, the drug has emerged to rival heroin as the most commonly available opioid in St. Petersburg. Ironically, its use is associated with reduced injection-related HIV risk even when its use is illegal. PMID:26573380
Promethazine Misuse among Methadone Maintenance Patients and Community-Based Injection Drug Users
Shapiro, Brad J.; Lynch, Kara L.; Toochinda, Tab; Lutnick, Alexandra; Cheng, Helen Y.; Kral, Alex H.
2013-01-01
Objective Promethazine has been reported to be misused in conjunction with opioids in several settings. Promethazine misuse by itself or in conjunction with opioids may have serious adverse health effects. To date, no prevalence data for the nonmedical use of promethazine has been reported. This study examines the prevalence and correlates of promethazine use in two different populations in San Francisco, California, USA: methadone maintenance clinic patients and community-based injection drug users (IDUs). Methods We analyzed urine samples for the presence of promethazine and reviewed the clinical records for 334 methadone maintenance patients at the county methadone clinic. Separately, we used targeted sampling methods to recruit and survey 139 community-based opioid IDUs about their use of promethazine. We assessed prevalence and factors associated with promethazine use with bivariate and multivariate statistics. Results The prevalence of promethazine positive urine samples among the methadone maintenance patients was 26 percent. Only 15 percent of promethazine positive patients had an active prescription for promethazine. Among IDUs reporting injection of opiates in the community-based survey, 17 percent reported having used promethazine in the past month; 24 percent of the IDUs who reported being enrolled in methadone treatment reported using promethazine in the past month. Conclusions The finding that one quarter of methadone maintenance patients in a clinic or recruited in community settings have recently used promethazine provides compelling evidence of significant nonmedical use of promethazine in this patient population. Further research is needed to establish the extent and nature of nonmedical use of promethazine. PMID:23385449
Denson, D D; Crews, J C; Grummich, K W; Stirm, E J; Sue, C A
1991-03-01
The stability of methadone hydrochloride in 0.9% sodium chloride injection in flexible polyvinyl chloride containers was studied. Commercially available methadone hydrochloride 20 mg/mL and 25-mL single-dose bags of 0.9% sodium chloride injection were used. Six samples each were prepared at methadone hydrochloride concentrations of 1, 2, and 5 mg/mL. The solutions were stored at room temperature and were not protected from light. Immediately after preparation and after two, three, and four weeks of storage, each of the 18 samples was divided into three aliquots, each of which was analyzed in duplicate for methadone hydrochloride concentration by gas chromatography. There was less than 10% change in methadone hydrochloride concentration in any sample throughout the four-week study period. Methadone hydrochloride at concentrations of 1, 2, and 5 mg/mL prepared in commercially available flexible polyvinyl chloride containers of 0.9% sodium chloride injection and stored at room temperature without deliberate protection from light is stable for at least four weeks.
2014-01-01
Background Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. Results The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. Conclusion These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity. PMID:25017386
Rigo, Flavia Karine; Trevisan, Gabriela; Godoy, Maria C; Rossato, Mateus Fortes; Dalmolin, Gerusa D; Silva, Mariane A; Menezes, Mirian S; Caumo, Wolnei; Ferreira, Juliano
2017-03-01
Methadone and ketamine are used in neuropathic pain management. However, the benefits of both drugs association are uncertain in the treatment of neuropathic pain. Our primary objective was test the hypothesis that oral methadone combined with oral ketamine is more effective than oral methadone or ketamine alone in reducing neuropathic pain. We conducted a randomized, double blind, active-controlled parallel-group clinical trial. Forty-two patients with neuropathic pain refractory to conventional therapy were randomly assigned to receive oral methadone (n = 14), ketamine (n = 14), or methadone plus ketamine (n = 14) over a 3-month period. During these 90 days, we observed pain scores using a visual analogical scale (VAS), allodynia, burning/shooting pain, and some side effects. All treatments were effective in reducing pain scores by at least 40%. However, a significant improvement in pain was observed only in the ketamine alone group compared with both the methadone or methadone/ketamine groups. No significant differences were observed among the treatment groups for the reduction of burning or shooting pain, while ketamine alone was more effective than methadone or methadone/ketamine for the reduction of allodynia. Formal assessment for awareness of the allocation was not performed, some co-intervention bias may have occurred, our results could be only relevant to the patient population investigated and the use of VAS as the primary outcome detect changes in pain intensity but not to assess neuropathic pain symptoms. This study indicates that ketamine was better than methadone or methadone/ketamine for treating neuropathic pain.Key words: Multimodal analgesia, refractory pain, NMDA receptor, opioid.
Methadone maintenance and the problem with alcohol.
Siassi, I; Alston, D C
1976-01-01
There is a growing concern with the rapid pace of physical and psychosocial deterioration of methadone patients who abuse alcohol. The need for a sample method for determining the extent of the problem, as well as the presence of an alcohol problem in individual patients, led the authors to test the validity of the Michigan Alcoholism Sreen Test (MAST) in a small urban methadone maintenance clinic (N = 125). The MAST was administered to every patient by their counselors, and the nursing staff was asked to independently rate each patient according to Keller's definition of alcoholism. The authors compared the patients' MAST scores with the global ratings of the nursing staff. Forty-six percent (n = 58) of the patients scored in the alcoholism range of the MAST questionnaire, while 34% (n = 43) of the patients were diagnosed as alcoholics by the nursing staff. There was 75% (n = 94) agreement between the MAST findings and the nurses' global ratings (p less than .001). The authors suggest that the MAST could be an effective screening tool in the area of alcohol abuse in methadone clinics. Going beyond the data, the authors recommend reexamination by psychiatrists of their peripheral role in the treatment of these difficult and multihandicapped patients.
Gordon, Michael S; Kinlock, Timothy W; Schwartz, Robert P; O'Grady, Kevin E
2008-08-01
This study examined the effectiveness of methadone maintenance initiated prior to or just after release from prison at 6 months post-release. A three-group randomized controlled trial was conducted between September 2003 and June 2005. A Baltimore pre-release prison. Two hundred and eleven adult pre-release inmates who were heroin-dependent during the year prior to incarceration. Participants were assigned randomly to the following: counseling only: counseling in prison, with passive referral to treatment upon release (n = 70); counseling + transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n = 70); and counseling + methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n = 71). Addiction Severity Index at study entry and follow-up. Additional assessments at 6 months post-release were treatment record review; urine drug testing for opioids, cocaine and other illicit drugs. Counseling + methadone participants were significantly more likely than both counseling only and counseling + transfer participants to be retained in drug abuse treatment (P = 0.0001) and significantly less likely to have an opioid-positive urine specimen compared to counseling only (P = 0.002). Furthermore, counseling + methadone participants reported significantly fewer days of involvement in self-reported heroin use and criminal activity than counseling only participants. Methadone maintenance, initiated prior to or immediately after release from prison, increases treatment entry and reduces heroin use at 6 months post-release compared to counseling only. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.
Marteau, Dave
2015-01-01
Objective To examine the population-wide overdose risk emerging from the prescription of methadone and buprenorphine for opioid substitution treatment in England and Wales. Design Retrospective administrative data study. Setting National databases for England and Wales. Participants/cases Drug-related mortality data were drawn from the Office for National Statistics, and prescription data for methadone and buprenorphine were obtained from the National Health Service for the years 2007–2012. During this 6-year period, a total of 2366 methadone-related deaths and 52 buprenorphine-related deaths were registered, corresponding to 17 333 163 methadone and 2 602 374 buprenorphine prescriptions issued. The analysis encompassed poisoning deaths among members of the wider population of England and Wales who consumed, but were not prescribed these medications, in addition to patients prescribed methadone or buprenorphine. Main outcome measures Mortality risk: substance-specific overdose rate per 1000 prescriptions issued; relative risk ratio of methadone in relation to buprenorphine. Results During the years 2007–2012, the pooled overdose death rate was 0.137/1000 prescriptions of methadone, compared to 0.022/1000 prescriptions of buprenorphine (including buprenorphine-naloxone). The analysis generated a relative risk ratio of 6.23 (95% CI 4.79 to 8.10) of methadone in relation to buprenorphine. UK Borders Agency data were taken into consideration and revealed that only negligible amounts of methadone and buprenorphine were seized on entering UK territory between 2007 and 2012, suggesting domestic diversion. Conclusions Our analysis of the relative safety of buprenorphine and methadone for opioid substitution treatment reveals that buprenorphine is six times safer than methadone with regard to overdose risk among the general population. Clinicians should be aware of the increased risk of prescribing methadone, and tighter regulations are needed to prevent its
Jiang, Haibo; Cao, Xiaobin; Wang, Changhe; Luo, Wei; Li, Jianhua; Rou, Keming; Zhang, Bo; Fang, Yuehua; Li, Cong; Wu, Zunyou
2014-03-01
To describe the adherence and related determinants among HIV-positive methadone maintenance treatment(MMT)clients in Dali,Yunnan province from 2005 to 2013. Cases were selected from the "National MMT Information Management System". The main information included demographic, drug abuse behaviors prior to enrollment, MMT treatment and highly active antiretroviral therapy (HAART). Detailed medication records were collected to calculate the adherence to MMT. Multivariate unconditional logistic regression was conducted to analyze the impact factors of adherence. The MMT adherence rate of 480 subjects is 58.11%. Data from the multivariate unconditional logistic regression indicated that among those HIV-positive MMT clients that on HAART program (OR = 1.52, 95% CI:1.03-2.24), related factors as:having stable job(OR = 1.69, 95% CI:1.11-2.56), having compulsory history prior to enrollment in MMT (OR = 1.78, 95% CI:1.04-3.04) were likely to have higher rate on MMT adherence, whereas clients who showed positive result in the last urine morphine test (OR = 0.38, 95% CI:0.24-0.59) were associated with lower rate on MMT adherence. In order to improve the rate of adherence to MMT among those HIV-positive MMT clients, the coverage of HAART needed to be expanded and new approaches in combining MMT and HAART developed. Education and intervention efforts should be focused on clients who currently were jobless, those with last urine morphine testing as positive or had never received compulsory treatment.
ERIC Educational Resources Information Center
Stotts, Angela L.; Masuda, Akihiko; Wilson, Kelly
2009-01-01
Many clients who undergo methadone maintenance (MM) treatment for heroin and other opiate dependence prefer abstinence from methadone. Attempts at methadone detoxification are often unsuccessful, however, due to distressing physical as well as psychological symptoms. Outcomes from an MM client who voluntarily participated in an Acceptance and…
Wu, Hsin-Yu; Cunningham, Brian T
2014-05-21
We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml(-1)) well below typical administered dosages (mg ml(-1)). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery.
Torabi, Masoumeh; Pooriamehr, Alireza; Bigdeli, Imanollah; Miladi-Gorji, Hossein
2017-10-17
This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring. Copyright © 2017 Elsevier B.V. All rights reserved.
Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization
Dang, Vu C.; Williams, John T.
2013-01-01
Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1–2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-β-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised. PMID:15342737
Chronic morphine treatment reduces recovery from opioid desensitization.
Dang, Vu C; Williams, John T
2004-09-01
Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-beta-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.
Sadeghzadeh, Fatemeh; Babapour, Vahab; Haghparast, Abbas
2017-04-01
The high rate of relapse to drug use is one of the main problems in the treatment of addiction. Stress plays the essential role in drug abuse and relapse; nevertheless, little is known about the mechanisms underlying stress and relapse. Accordingly, the effects of intra-accumbal administration of Sulpiride, as a dopamine D2-like receptor antagonist, on an ineffective morphine dose + food deprivation(FD)- and morphine priming-induced reinstatement of conditioned place preference (CPP). About 104 adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannula into the nucleus accumbens (NAc). Subcutaneous (sc) injection of morphine (5 mg kg -1 ) was used daily during a 3-day conditioning phase. After a 24-hr "off" period following achievement of extinction criterion, rats were tested for FD- and priming-induced reinstatement of morphine CPP by an ineffective (0.5 mg kg -1 , sc) and priming (1 mg kg -1 , sc) dose of morphine, respectively. In the next experiments, animals received different doses of intra-accumbal Sulpiride (0.25, 1, and 4 µg/0.5 µL saline) bilaterally and were subsequently tested for morphine reinstatement. Our findings indicated that the 24-hr FD facilitated reinstatement of morphine CPP. Furthermore, the D2-like receptor antagonist attenuated the ineffective morphine dose+ FD- and priming-induced reinstatement of morphine CPP dose-dependently. Also, contribution of D2-like receptors in mediation of the ineffective morphine dose+ FD-induced reinstatement of CPP was greater than morphine priming-induced reinstatement of CPP. The role of dopaminergic system in morphine reinstatement through a neural pathway in the NAc provides the evidence that D2-like receptor antagonist can be useful therapeutic targets for reinstatement of morphine CPP. © 2016 Wiley Periodicals, Inc.
Desjardins, Stephane; Belkai, Emilie; Crete, Dominique; Cordonnier, Laurie; Scherrmann, Jean-Michel; Noble, Florence; Marie-Claire, Cynthia
2008-12-01
Chronic morphine treatment alters gene expression in brain structures. There are increasing evidences showing a correlation, in gene expression modulation, between blood cells and brain in psychological troubles. To test whether gene expression regulation in blood cells could be found in drug addiction, we investigated gene expression profiles in peripheral blood mononuclear (PBMC) cells of saline and morphine-treated rats. In rats chronically treated with morphine, the behavioral signs of spontaneous withdrawal were observed and a withdrawal score was determined. This score enabled to select the time points at which the animals displayed the mildest and strongest withdrawal signs (12 h and 36 h after the last injection). Oligonucleotide arrays were used to assess differential gene expression in the PBMCs and quantitative real-time RT-PCR to validate the modulation of several candidate genes 12 h and 36 h after the last injection. Among the 812 differentially expressed candidates, several genes (Adcy5, Htr2a) and pathways (Map kinases, G-proteins, integrins) have already been described as modulated in the brain of morphine-treated rats. Sixteen out of the twenty-four tested candidates were validated at 12 h, some of them showed a sustained modulation at 36 h while for most of them the modulation evolved as the withdrawal score increased. This study suggests similarities between the gene expression profile in PBMCs and brain of morphine-treated rats. Thus, the searching of correlations between the severity of the withdrawal and the PBMCs gene expression pattern by transcriptional analysis of blood cells could be promising for the study of the mechanisms of addiction.
Ristimaa, Johanna; Gergov, Merja; Pelander, Anna; Halmesmäki, Erja; Ojanperä, Ilkka
2010-09-01
Analysis of the major drugs of abuse in meconium has been established in clinical practice for detecting fetal exposure to illicit drugs, particularly for the ready availability of the sample and ease of collection from diapers, compared with neonatal hair and urine. Very little is known about the occurrence and detection possibilities of therapeutic and licit drugs in meconium. Meconium specimens (n = 209) were collected in delivery hospitals, from infants of mothers who were suspected to be drug abusers. A targeted analysis method by liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) was developed for abused drugs: amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, morphine, codeine, 6-monoacetylmorphine, oxycodone, methadone, tramadol, buprenorphine, and norbuprenorphine. A separate LC-MS/MS method was developed for 11-nor-∆(9)-tetrahydrocannabinol-9-carboxylic acid. A screening method based on LC coupled to time-of-flight MS was applied to a broad spectrum of drugs. As a result, a total of 77 different compounds were found. The main drug findings in meconium were as follows: local anesthetics 82.5% (n = 172), nicotine or its metabolites 61.5% (n = 129), opioids 48.5% (n = 101), stimulants 21.0% (n = 44), hypnotics and sedatives 19.0% (n = 40), antidepressants 18.0% (n = 38), antipsychotics 5.5% (n = 11), and cannabis 3.0% (n = 5). By revealing drugs and metabolites beyond the ordinary scope, the present procedure helps the pediatrician in cases where maternal denial is strong but the infant seems to suffer from typical drug-withdrawal symptoms. Intrapartum drug administration cannot be differentiated from gestational drug use by meconium analysis, which affects the interpretation of oxycodone, tramadol, fentanyl, pethidine, and ephedrine findings.
Effects of scopolamine on morphine-induced conditioned place preference in mice.
Tan, Hua; Liu, Ning; Wilson, Fraser A W; Ma, Yuanye
2007-09-01
It is well known that the cholinergic system plays a crucial role in learning and memory. Psychopharmacological studies in humans and animals have shown that a systemic cholinergic blockade may induce deficits in learning and memory. Accumulated studies have indicated that learning and memory play an important role in drug addition. In the present study, in order to get a further understanding about the functions of the cholinergic system in drug-related learning and memory, we examined the effects of scopolamine (0.5, 1.0 and 2.0 mg/kg) on morphine-induced conditioned place preference (CPP). Two kinds of morphine exposure durations (4 days and 12 days) were used. The main finding was that all doses of scopolamine enhanced the extinction of morphine-induced CPP in mice treated with morphine for 12 days. However, in mice treated with morphine for 4 days, all doses of scopolamine did not inhibit morphine-induced CPP. The highest dose (2.0 mg/kg) of scopolamine even significantly delayed the extinction of morphine-induced CPP. Our results suggest that the effects of a systemic cholinergic blockade on morphine-induced CPP depend on the morphine exposure time.
Imaging of Subacute Blood–Brain Barrier Disruption After Methadone Overdose
Huisa, Branko N.; Gasparovic, Charles; Taheri, Saeid; Prestopnik, Jillian L.; Rosenberg, Gary A.
2014-01-01
BACKGROUND Methadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins. OBJECTIVE To investigate the metabolic derangement of the white matter (WM) and blood–brain barrier (BBB) after DAL caused by methadone overdose. DESIGN, SETTING, AND PATIENTS Case report of 2 patients with DAL after a single dose of “diverted” methadone used for pain control. RESULTS In both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging (1H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired. CONCLUSIONS Methadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods. PMID:22211853
Plasma-Mediated Release of Morphine from Synthesized Prodrugs
2013-01-01
UPLC )9 (Waters Inc.) was utilized for measurements of morphine, PDA and PDB. UPLC has the capability to perform rapid (< 10 min) and reproducible...for UPLC versus ~30-50 µL for HPLC. The term “morphine” refers to the free morphine alkaloid base (Malinkrodt, etc.) unless otherwise stated...Baseline UPLC profiles were obtained for phosphate buffered saline (PBS), morphine and PDA in esterase de-activated plasma. Plasma was precipitated by the
Wang, Yi-lun; Li, Yu-sheng; Wei, Jie; Li, Hui; Yang, Tuo; Yang, Tu-bao; Lei, Guang-hua
2015-01-01
Objectives The purpose of this study was to compare the efficacy and safety of a single-dose intra-articular morphine plus bupivacaine versus morphine alone in patients undergoing arthroscopic knee surgery. Methods Randomized controlled trials comparing a combination of morphine and bupivacaine with morphine alone injected intra-articularly in the management of pain after knee arthrocopic surgery were retrieved (up to August 10, 2014) from MEDLINE, the Cochrane Library and Embase databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95% confidence intervals (CIs) were calculated using RevMan statistical software. Results Thirteen randomized controlled trials were included. Statistically significant differences were observed with regard to the VAS values during the immediate period (0-2h) (WMD -1.16; 95% CI -2.01 to -0.31; p = 0.007) and the time to first request for rescue analgesia (WMD = 2.05; 95% CI 0.19 to 3.92; p = 0.03). However, there was no significant difference in the VAS pain score during the early period (2-6h) (WMD -0.36; 95% CI -1.13 to 0.41; p = 0.35), the late period (6-48h) (WMD 0.11; 95% CI -0.40 to 0.63; p = 0.67), and the number of patients requiring supplementary analgesia (RR = 0.78; 95% CI 0.57 to 1.05; p = 0.10). In addition, systematic review showed that intra-articular morphine plus bupivacaine would not increase the incidence of adverse effects compared with morphine alone. Conclusion The present study suggested that the administration of single-dose intra-articular morphine plus bupivacaine provided better pain relief during the immediate period (0-2h), and lengthened the time interval before the first request for analgesic rescue without increasing the short-term side effects when compared with morphine alone. Level of Evidence Level I, meta-analysis of Level I studies. PMID:26474401
Methadone in combination with acepromazine as premedication prior to neutering in the cat.
Bortolami, Elisa; Murrell, Joanna C; Slingsby, Louisa S
2013-03-01
To investigate the safety, sedative and analgesic properties of methadone in combination with acepromazine prior to neutering in cats. Controlled clinical, block randomized, prospective, blinded study designed for regulatory purposes. 24 female and 21 male healthy cats. Cats received one of three opioids combined with acepromazine (0.05 mg kg(-1) ) intramuscularly (IM) for premedication: Group 1: buprenorphine (0.02 mg kg(-1) ), group 2: methadone (0.5 mg kg(-1) ), group 3 butorphanol (0.4 mg kg(-1) ). Sedation was assessed 30 minutes after premedication using a visual analogue scale (VAS) and simple descriptive scale. Anaesthesia was induced with alfaxalone and maintained with isoflurane in oxygen. Surgical ovariohysterectomy or castration was performed. Pain was assessed using an interactive VAS (IVAS) and mechanical nociceptive threshold (MNT) with a pressure rate onset device. Methadone (0.5 mg kg(-1) IM) and meloxicam (0.2 mg kg(-1) subcutaneously) were provided 6 and 8 hours after premedication respectively, or together as rescue analgesia (IVAS above 50). Sedation scores, induction agent dose, pain scores at all time points and rescue analgesia were not statistically different between groups. In methadone treated cats there was no significant variation in MNT over time, suggesting a possible anti-hyperalgesic action, whereas in the other two groups lower thresholds were recorded at various time points after surgery compared to baseline. No cats required rescue analgesia after the second dose of methadone. No perioperative adverse effects occurred. Methadone provided comparable sedation and analgesia to both buprenorphine and butorphanol when combined with acepromazine. Differences in analgesic efficacy between opioids might have been undetectable because of the surgical model and surgeon competency. Nevertheless, methadone is an effective analgesic in cats and its administration prior to feline neutering may be advantageous. © 2012 The Authors. Veterinary
Morphine Pharmacokinetics in Children With Down Syndrome Following Cardiac Surgery.
Goot, Benjamin H; Kaufman, Jon; Pan, Zhaoxing; Bourne, David W A; Hickey, Francis; Twite, Mark; Galinkin, Jeffrey; Christians, Uwe; Zuk, Jeannie; da Cruz, Eduardo M
2018-05-01
To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations. Morphine bolus dosing was used as needed, and total dose was tracked. Infusions were continued for 24 hours or until patients were extubated, whichever came first. Postinfusion, blood samples were continued for 24 hours for further evaluation of kinetics. If patients continued to require opioid, a nonmorphine alternative was used. Morphine concentrations were determined using a unique validated liquid chromatography tandem-mass spectrometry assay using dried blood spotting as opposed to large whole blood samples. Morphine concentration versus time data was modeled using population pharmacokinetics. A 16-bed cardiac ICU at an university-affiliated hospital. Forty-two patients (20 Down syndrome, 22 controls) were enrolled. None. The pharmacokinetics of morphine in pediatric patients with and without Down syndrome following cardiac surgery were analyzed. No significant difference was found in the patient characteristics or variables assessed including morphine total dose or time on infusion. Time mechanically ventilated was longer in children with Down syndrome, and regarding morphine pharmacokinetics, the covariates analyzed were age, weight, presence of Down syndrome, and gender. Only age was found to be significant. This study did not detect a significant difference in morphine pharmacokinetics between Down syndrome and non-Down syndrome children with congenital heart disease.
Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting.
Middleton, Paul M; Simpson, Paul M; Sinclair, Gary; Dobbins, Timothy A; Math, B; Bendall, Jason C
2010-01-01
To compare the effectiveness of intravenous (IV) morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane when administered by paramedics to patients with moderate to severe pain. We conducted a retrospective comparative study of adult patients with moderate to severe pain treated by paramedics from the Ambulance Service of New South Wales who received IV morphine, IN fentanyl, or inhaled methoxyflurane either alone or in combination between January 1, 2004, and November 30, 2006. We used multivariate logistic regression to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of > or = 30% of initial pain score using an 11-point verbal numeric rating scale (VNRS-11). The study population comprised 52,046 patients aged between 16 and 100 years with VNRS-11 scores of > or = 5. All analgesic agents were effective in the majority of patients (81.8%, 80.0%, and 59.1% for morphine, fentanyl, and methoxyflurane, respectively). There was very strong evidence that methoxyflurane was inferior to both morphine and fentanyl (p < 0.0001). There was strong evidence that morphine was more effective than fentanyl (p = 0.002). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Inhaled methoxyflurane, IN fentanyl, and IV morphine are all effective analgesic agents in the out-of-hospital setting. Morphine and fentanyl are significantly more effective analgesic agents than methoxyflurane. Morphine appears to be more effective than IN fentanyl; however, the benefit of IV morphine may be offset to some degree by the ability to administer IN fentanyl without the need for IV access.
The effect of IVPCA morphine on post-hysterectomy bowel function.
Chan, Kuang-Cheng; Cheng, Ya-Jung; Huang, Guang-Ta; Wen, Yuan-Jui; Lin, Chen-Jung; Chen, Li-Kuei; Sun, Wei-Zen
2002-06-01
Although morphine has been shown to induce bowel dysfunction in a dose-dependent fashion, in most relevant studies it was investigated in single bolus injection. Recently, intravenous morphine via patient-controlled analgesia (IVPCA) has been widely used to provide analgesia by divided bolus doses on patients' demand with satisfactory effects. This approach, by reducing the peak serum surge, largely resembles the pharmacokinetic and pharmacodynamic advantage of continuous infusion. There is yet no report on the investigation of its effect on post-operative bowel dysfunction. Fifty-one women who underwent abdominal total hysterectomy (ATH) due to uterine myoma were enrolled to investigate the association between the doses of morphine consumption by PCA and the time of first passage of flatus. In all patients morphine was administered intravenously via a PCA pump immediately after recovery from general anesthesia. We found that 49 out of 51 patients (96%) exhibited mild pain with IVPCA morphine. They had consumed an average dose of 16.9 mg morphine (range, 0-46 mg) upon the first passage of flatus which occurred 2036.4 min (average) post-operatively. There was no correlation between the dose of morphine and the time of first passage of flatus (r = 0.053, P > 0.05). The absence of suppression of bowel movement by IVPCA morphine for post-operative pain control suggests that favorable pharmacokinetic profile of IVPCA can help reduce the morphine-induced bowel dysfunction at its therapeutic level.
AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence.
Hu, Xiaoyu; Tian, Xuebi; Guo, Xiao; He, Ying; Chen, Haijun; Zhou, Jia; Wang, Zaijie Jim
2018-04-25
Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR PAMs). In mice treated with morphine (100 mg/kg, s.c.), acute morphine tolerance and dependence developed in 4-6 h. Treatment with aniracetam, a well-established AMPAR PAM, was able to completely prevent and reverse the development of acute antinociceptive tolerance to morphine. Partial, but significant, effects of aniracetam on acute morphine induced-physical dependence were also observed. Moreover, aniracetam significantly reversed the established morphine tolerance and dependence in a chronic model of morphine tolerance and dependence produced by intermittent morphine (10 mg/kg, s.c. for 5d). In addition, HJC0122, a new AMPAR PAM was found to have similar effects as aniracetam but with a higher potency. These previously undisclosed actions of AMPAR PAMs are intriguing and may shed lights on understanding the APMA signaling pathway in opioid addiction. Moreover, these data suggest that AMPAR PAMs may have utility in preventing and treating morphine tolerance and dependence. Copyright © 2018. Published by Elsevier Ltd.
Rectal methadone in cancer patients with pain. A preliminary clinical and pharmacokinetic study.
Ripamonti, C; Zecca, E; Brunelli, C; Rizzio, E; Saita, L; Lodi, F; De Conno, F
1995-10-01
Cancer pain can be treated in most cases with oral analgesics. However, during their clinical history, 53% to 70% of patients will need alternative routes of opioid administration. The rectal administration of opioids is a simple alternative route for many patients. There are no data in the literature regarding the pharmacodynamics and pharmacokinetics of rectal methadone. We evaluated the analgesia, tolerability and absorption profile of methadone hydrochloride in six opioid-naive cancer patients with pain. A blood sample was collected before administration of a single dose of drug (10 mg) and then again after fixed times. At these fixed times the patients were asked about pain, nausea and drowsiness by means of a visual analogue scale of 0-100 mm (VAS). Pain relief was statistically significant as early as 30 minutes and up to eight hours after methadone administration. None of the patients reported significant side effects. The pharmacokinetics of rectal methadone showed rapid and extensive distribution phases followed by a slow elimination phase. Rectal methadone can be considered an effective analgesic therapy for patients with cancer pain for whom oral and/or parenteral opioids are not indicated or available.
The Impact of Morphine After a Spinal Cord Injury
Hook, Michelle A.; Liu, Grace T.; Washburn, Stephanie N.; Ferguson, Adam R.; Bopp, Anne C.; Huie, John R.; Grau, James W.
2007-01-01
Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury. PMID:17383022
NASA Astrophysics Data System (ADS)
Tavakol, Hossein; Esfandyari, Maryam; Taheri, Salman; Heydari, Akbar
2011-08-01
In this work, two important opioid antagonists, naltrexone and oxycodone, were prepared from thebaine and were characterized by IR, 1H NMR and 13C NMR spectroscopy. Moreover, computational NMR and IR parameters were obtained using density functional theory (DFT) at B3LYP/6-311++G** level of theory. Complete NMR and vibrational assignment were carried out using the observed and calculated spectra. The IR frequencies and NMR chemical shifts, determined experimentally, were compared with those obtained theoretically from DFT calculations, showed good agreements. The RMS errors observed between experimental and calculated data for the IR absorptions are 85 and 105 cm -1, for the 1H NMR peaks are 0.87 and 0.17 ppm and for those of 13C NMR are 5.6 and 5.3 ppm, respectively for naltrexone and oxycodone.
Xiang, Xiaobing; Yuan, Xiaohong; Lian, Yanhong; Fang, Jun; Wu, Yingli
2018-02-01
Problems like postoperative pain are still common phenomena after general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid with a safe and excellent therapeutic effect on visceral pain. Flurbiprofen axetil has the efficacy of targeted analgesia. We hypothesize that different doses of oxycodone hydrochloride combined with flurbiprofen axetil would generate great results on postoperative intravenous analgesia in lower abdominal patients. In the clinical trial, 90 American Society of Anesthesiologists I or II patients scheduled for elective general anesthesia were randomly divided into 3 groups, 30 cases in each group. Group I: oxycodone hydrochloride 0.5 mg/kg + flurbiprofen axetil 150 mg, group II: oxycodone hydrochloride 0.75 mg/kg + flurbiprofen axetil 150 mg, group III: oxycodone hydrochloride 1.0 mg/kg + flurbiprofen axetil 150 mg. Dilute them with 0.9% saline to 150 mL, respectively, with the background dose of 2 mL/h, patient-controlled analgesia 2 mL per time, with an interval of 10 min, and the loading dose of 0.1 mL/kg. Record the preoperative situation, 24 h (T0) before surgery, postoperative situation, 1 h (T1), 4 h (T2), 8 h (T3), 12 h (T4), 24 h (T5), 48 h (T6), 72 h (T7) after the surgery, including the mean arterial pressure, heart rate, saturation of pulse oximetry, static and dynamic pain rating (NRS) and Ramsay sedation score, effective pressing and total pressing ratio (referred to as the pressing ratio), patient satisfaction, and occurrence of adverse reactions. There was no significant statistic difference in mean arterial blood pressure, heart rate, arterial oxygen saturation, and adverse reactions among the 2 groups at each time point (P > .05). Compared with group I, the static NRS rating in group II and group III were significantly lower than that in group I (P < .05) from T1 to T5. The dynamic NRS rating of group II from T1 to T4 and that of group III from T1 to T5 were significantly lower (P
Cooperman, Nina A; Richter, Kimber P; Bernstein, Steven L; Steinberg, Marc L; Williams, Jill M
2015-04-01
Over 80% of people in methadone treatment smoke cigarettes, and existing smoking cessation interventions have been minimally effective. To develop an Information-Motivation-Behavioral Skills (IMB) Model of behavior change based smoking cessation intervention for methadone maintained smokers, we examined smoking cessation related IMB factors in this population. Current or former smokers in methadone treatment (n = 35) participated in focus groups. Ten methadone clinic counselors participated in an individual interview. A content analysis was conducted using deductive and inductive approaches. Commonly known IMB factors related to smoking cessation were described. These factors included: the health effects of smoking and treatment options for quitting (information); pregnancy and cost of cigarettes (motivators); and coping with emotions, finding social support, and pharmacotherapy adherence (behavioral skills). IMB factors specific to methadone maintained smokers were also described. These factors included: the relationship between quitting smoking and drug relapse (information), the belief that smoking is the same as using drugs (motivator); and coping with methadone clinic culture and applying skills used to quit drugs to quitting smoking (behavioral skills). IMB strengths and deficits varied by individual. Methadone maintained smokers could benefit from research on an IMB Model based smoking cessation intervention that is individualized, addresses IMB factors common among all smokers, and also addresses IMB factors unique to this population.
Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas
2015-07-25
Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals' risk behaviours and engagement with post-release treatment programmes. In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care--forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution's standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from
Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas
2015-01-01
Summary Background Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals’ risk behaviours and engagement with post-release treatment programmes. Methods In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care—forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution’s standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose ≤100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance
Xiao, Y; Smith, R D; Caruso, F S; Kellar, K J
2001-10-01
The opioid agonist properties of (+/-)-methadone are ascribed almost entirely to the (-)-methadone enantiomer. To extend our knowledge of the pharmacological actions of methadone at ligand-gated ion channels, we investigated the effects of the two enantiomers of methadone and its metabolites R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium perchlorate (EDDP) and R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride (EMDP), as well as structural analogs of methadone, including (-)-alpha-acetylmethadol hydrochloride (LAAM) and (+)-alpha-propoxyphene, on rat alpha3beta4 neuronal nicotinic acetylcholine receptors (nAChRs) stably expressed in a human embryonic kidney 293 cell line, designated KXalpha3beta4R2. (+/-)-methadone inhibited nicotine-stimulated 86Rb+ efflux from the cells in a concentration-dependent manner with an IC50 value of 1.9 +/- 0.2 microM, indicating that it is a potent nAChR antagonist. The (-)- and (+)-enantiomers of methadone have similar inhibitory potencies on nicotine-stimulated 86Rb+ efflux, with IC50 values of approximately 2 microM. EDDP, the major metabolite of methadone, is even more potent, with an IC50 value of approximately 0.5 microM, making it one of the most potent nicotinic receptor blockers reported. In the presence of (+/-)-methadone, EDDP, or LAAM, the maximum nicotine-stimulated 86Rb+ efflux was markedly decreased, but the EC50 value for nicotine stimulation was altered only slightly, if at all, indicating that these compounds block alpha3beta4 nicotinic receptor function by a noncompetitive mechanism. Consistent with a noncompetitive mechanism, (+/-)-methadone, its metabolites, and structural analogs have very low affinity for nicotinic receptor agonist binding sites in membrane homogenates from KXalpha3beta4R2 cells. We conclude that both enantiomers of methadone and its metabolites as well as LAAM and (+)-alpha-propoxyphene are potent noncompetitive antagonists of alpha3beta4 nAChRs.
[Behavioural studies during the gestational-lactation period in morphine treated rats].
Sobor, Melinda; Timár, Júlia; Riba, Pál; Király, Kornél P; Al-Khrasani, Mahmoud; Gyarmati, Zsuzsanna; Fürst, Zsuzsanna
2013-12-01
Opioids impair the maternal behaviour of experimental animals. The effect of morphine on maternal behaviour in rat dams treated chronically with morphine during the whole pregnancy and lactation has not been yet analysed systematically. The aim of our work was to investigate the behavioural effects of moderate dose morphine administered constantly in the whole perinatal period in rats. Nulliparous female rats were treated with 10 mg/kg morphine s.c. once daily, from the day of mating. Maternal behaviour was observed, the effects of acute morphine treatment on the maternal behaviour and whether this effect could be antagonised by naloxone were also investigated. Physical and other behavioural (anxiety-like signals in elevated plus maze, changes in locomotor activity) withdrawal signs precipitated by naloxone were registered. After weaning sensitivity to the rewarding effect of morphine was measured by conditioned place preference and to the aversive effect of naloxone by conditioned place aversion tests. Antinociceptive test on tail-flick apparatus was performed to investigate the changes in morphine antinociceptive effects due to chronic morphine treatment. Maternal behaviour was significantly impaired in morphine-treated dams. This effect of morphine lasted c.a. 2-3 hours a day, it showed dose-dependency and was enhanced in MO-treated group (sensitisation). Only weak physical and no other behavioural (anxiety-like behaviour or hypolocomotion) withdrawal signs were precipitated by naloxone. The positive reinforcing effect of morphine and aversive effect of naloxone were markedly increased on conditioned place paradigm. Significant antinociceptive tolerance was not seen. Although human drug abuse can be hardly modelling under experimental circumstances, our constant, relatively moderate dose morphine treatment administered once daily during the whole pregnancy and lactation resulted in several subtle behavioural changes in dams. In perinatally opioid
Endogenous Cholinergic Neurotransmission Contributes to Behavioral Sensitization to Morphine
Bajic, Dusica; Soiza-Reilly, Mariano; Spalding, Allegra L.; Berde, Charles B.; Commons, Kathryn G.
2015-01-01
Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg), a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter) in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg) dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg. PMID:25647082
Methadone Maintenance: The Addict's Family Recreated.
ERIC Educational Resources Information Center
Schwartzman, John; Bokos, Peter
1979-01-01
A study of four methadone clinics, the addicts treated at these clinics, and their families, reveals basic dissonances in treatment ideology and professional-paraprofessional relationships which, combined with the addict's particular mode of functioning, make significant change in his behavior improbable. (Author)
Khalil-Khalili, Masoumeh; Rashidy-Pour, Ali; Bandegi, Ahmad Reza; Yousefi, Behpoor; Jorjani, Hassan; Miladi-Gorji, Hossein
2018-03-06
This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) on the severity of physical and psychological dependence and morphine-induced locomotor sensitization, the ventral tegmental area (VTA)-nucleus accumbens (NAc) BDNF levels in morphine-dependent and withdrawn rats. Rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 10 days. Then, rats were tested for naloxone-precipitated morphine withdrawal signs, the anxiety (the elevated plus maze-EPM) after the last morphine injection and injection of ANA12 (ip). Also, morphine-induced locomotor sensitization was evaluated after morphine challenge followed by an injection of ANA-12 in morphine-withdrawn rats. The VTA-NAc BDNF levels were assessed in morphine-dependent and withdrawn rats. The overall Gellert-Holtzman score was significantly higher in morphine-dependent rats receiving ANA-12 than in those receiving saline. Also, the percentage of time spent in the open arms in control and morphine-dependent rats receiving ANA-12 were higher compared to the Cont/Sal and D/Sal rats, respectively. There was no significant difference in the locomotor activity and the VTA-NAc BDNF levels between D/Sal/morphine and D/ANA-12/morphine groups after morphine withdrawal. We conclude that the systemic administration of ANA-12 exacerbates the severity of physical dependence on morphine and partially attenuates the anxiety-like behavior in morphine-dependent rats. However, ANA-12 did not affect morphine-induced locomotor sensitization and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats. Copyright © 2017 Elsevier B.V. All rights reserved.
Intrathecal morphine for analgesia in children undergoing selective dorsal rhizotomy.
Dews, T E; Schubert, A; Fried, A; Ebrahim, Z; Oswalt, K; Paranandi, L
1996-03-01
Selective dorsal root rhizotomy is performed for relief of spasticity in children with cerebral palsy. Postoperative pain relief can be provided by intrathecal morphine administered at the time of the procedure. We sought to define an optimal dose of intrathecal morphine in children undergoing selective rhizotomy, through a randomized, double-blinded prospective trial. After institutional approval and parental written informed consent, 27 patients, ages 3-10 years, were randomized to receive 10, 20, or 30 micrograms.kg-1 (Groups A, B, and C, respectively) of preservative-free morphine administered intrathecally by the surgeon after dural closure. Postoperatively, vital signs, pulse oximetry, and pain intensity scores were recorded hourly for 24 hr. Supplemental intravenous morphine was administered postoperatively according to a predetermined schedule based on pain scores. There was considerable individual variability in the time to initial morphine dosing and cumulative supplemental morphine dose. Time to first supplemental morphine dose was not different between groups. When compared to Groups A and B, cumulative 6-hr supplemental morphine dose was significantly lower in Group C (38.6 +/- 47 micrograms versus 79.1 +/- 74 and 189.6 +/- 126 for Groups A and B, respectively). By 12 hr, cumulative supplemental morphine dose was similar in Groups A and C. Group B consistently had a higher supplemental dose requirement than Groups A and C at 6, 12, and 18 hr. By 24 hr, there was no difference in cumulative dose among groups. Postoperative pain scores and the incidence of respiratory events, nausea, vomiting and pruritus were comparable among groups. These data suggest that intrathecal morphine at 30 micrograms.kg-1 provides the most intense analgesia at 6 hr following selective dorsal root rhizotomy, but was otherwise comparable to the 10 micrograms.kg-1 dose.
Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish
Khor, Beng-Siang; Amar Jamil, Mohd Fadzly; Adenan, Mohamad Ilham; Chong Shu-Chien, Alexander
2011-01-01
A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway. PMID:22205946
Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C
2013-12-01
Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes.
Wan, Li; Bi, Jiangjiang; Li, Jun; Zuo, Zhiyi
2017-03-06
Glutamate transporters (EAAT) have been implicated in the drug addiction behavior. We determined whether EAAT type 3 (EAAT3) played a role in morphine addiction. Six- to eight-week-old EAAT3 knockout (EAAT3 -/- ) mice and their wild-type littermates received 3 intraperitoneal injections of 10mg/kg morphine, each on an alternative day, to induce conditioned place preference (CPP). Two days after the place preference returned to baseline, mice received 2.5mg/kg morphine to induce reinstatement. Some mice received intraperitoneal injection of 4mg/kg riluzole, an EAAT activator, 30min before morphine or saline injection. Hippocampus, medial prefrontal cortex, nucleus accumbens and ventral tegmental area were harvested for Western analysis 24h after the last dose of morphine was injected. Morphine induced CPP in wild-type and EAAT3 -/- mice. Gender is not a statistically significant factor to influence this behavior. This conditioned behavior extinguished after morphine administration was stopped for 8-9days in wild-type mice, while this extinction occurred 6days after discontinuation of morphine injection in EAAT3 -/- mice. A small dose of morphine similarly reinstated the conditioned behavior in the wild-type and EAAT3 -/- mice. Riluzole abolished morphine-induced CPP during the initial place preference. Morphine increased EAAT3 expression in the plasma membrane of medial prefrontal cortex, nucleus accumbens and ventral tegmental area but did not affect EAAT3 expression in the hippocampus. These results suggest that EAAT3 delays the extinction of morphine-induced CPP. EAAT activation may prevent the formation of morphine-induced CPP. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Wan, Li; Bi, Jiangjiang; Li, Jun; Zuo, Zhiyi
2017-01-01
Glutamate transporters (EAAT) have been implicated in the drug addiction behavior. We determined whether EAAT type 3 (EAAT3) played a role in morphine addiction. Six- to eight-week old EAAT3 knockout (EAAT3−/−) mice and their wild-type littermates received 3 intraperitoneal injections of 10 mg/kg morphine, each on an alternative day, to induce conditioned place preference (CPP). Two days after the place preference returned to baseline, mice received 2.5 mg/kg morphine to induce reinstatement. Some mice received intraperitoneal injection of 4 mg/kg riluzole, an EAAT activator, 30 min before morphine or saline injection. Hippocampus, medial prefrontal cortex, nucleus accumbens and ventral tegmental area were harvested for Western analysis 24 h after the last dose of morphine was injected. Morphine induced CPP in wild-type and EAAT3−/− mice. Gender is not a statistically significant factor to influence this behavior. This conditioned behavior extinguished after morphine administration was stopped for 8 to 9 days in wild-type mice, while this extinction occurred 6 days after discontinuation of morphine injection in EAAT3−/− mice. A small dose of morphine similarly reinstated the conditioned behavior in the wild-type and EAAT3−/− mice. Riluzole abolished morphine-induced CPP during the initial place preference. Morphine increased EAAT3 expression in the plasma membrane of medial prefrontal cortex, nucleus accumbens and ventral tegmental area but did not affect EAAT3 expression in the hippocampus. These results suggest that EAAT3 delays the extinction of morphine-induced CPP. EAAT activation may prevent the formation of morphine-induced CPP. PMID:28049029
When to Use Methadone for pain: A Case-Based Approach.
Palat, Gayatri; Vallath, Nandini; Chary, Srini; Broderick, Ann
2018-01-01
The case studies are written in this article to illustrate how methadone might be used for pain in the Indian context. These cases might be used for discussion in a multidisciplinary team, or for individual study. It is important to understand that pain requires a multidisciplinary approach as opioids will assist only with physical, i.e. neuropathic and nociceptive pain, but not emotional, spiritual, or relational pain or the pain of immobility. The social determinants of pain were included to demonstrate how emotional, relational, and psychological dimensions of pain amplify the physical aspects of pain. The case studies follow a practical step-wise approach to pain while undergoing cancer treatment, pain toward the end-of-life and needing longer acting opioid. Methadone in children, and methadone in conditions of opioid toxicity or where there is a need for absorption in the proximal intestine cases are included.
QT Interval Screening in Methadone Maintenance Treatment: Report of a SAMHSA Expert Panel
Martin, Judith A.; Campbell, Anthony; Killip, Thomas; Kotz, Margaret; Krantz, Mori J.; Kreek, Mary Jeanne; McCarroll, Brian A.; Mehta, Davendra; Payte, J. Thomas; Stimmel, Barry; Taylor, Trusandra; Wilford, Bonnie B.
2014-01-01
In an effort to enhance patient safety in Opioid Treatment Programs (OTPs), the Substance Abuse and Mental Health Services Administration (SAMHSA) convened a multi-disciplinary Expert Panel on the Cardiac Effects of Methadone. Panel members reviewed the literature, regulatory actions, professional guidances, and OTPs’ experiences regarding adverse cardiac events associated with methadone. The Panel concluded that, to the extent possible, every OTP should have a universal Cardiac Risk Management Plan (incorporating clinical assessment, ECG assessment, risk stratification, and prevention of drug interactions) for all patients, and should strongly consider patient-specific risk minimization strategies (such as careful patient monitoring, obtaining ECGs as indicated by a particular patient’s risk profile, and adjusting the methadone dose as needed) for patients with identified risk factors for adverse cardiac events. The Panel also suggested specific modifications to informed consent documents, patient education, staff education, and methadone protocols. PMID:22026519
Scheidel, Bernhard; Maritz, Martina A; Gschwind, Yves J; Steigerwald, Kerstin; Guth, Volker; Kovacs, Peter; Rey, Helene
2017-11-01
To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (Cmax), and plasma concentrations at the end of the dosing interval (Cτ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and
Picrotoxin-induced seizures modified by morphine and opiate antagonists.
Thomas, J; Nores, W L; Kenigs, V; Olson, G A; Olson, R D
1993-07-01
The effects of naloxone, Tyr-MIF-1, and MIF-1 on morphine-mediated changes in susceptibility to picrotoxin-induced seizures were studied. Rats were pretreated with naloxone, MIF-1, Tyr-MIF-1, or saline. At 15-min intervals, they received a second pretreatment of morphine or saline and then were tested for seizures following a convulsant dose of picrotoxin. Several parameters of specific categories of seizures were scored. Morphine increased the number of focal seizure episodes, duration of postseizure akinesis, and incidence of generalized clonic seizures. Naloxone tended to block the morphine-mediated changes in susceptibility. Tyr-MIF-1 had effects similar to naloxone on duration of postseizure immobility but tended to potentiate the effects of morphine on focal seizure episodes. The effects of morphine and the opiate antagonists on focal seizure episodes and postseizure duration suggest the general involvement of several types of opiate receptors in these picrotoxin-induced behaviors. However, the observation of antagonistic effects for Tyr-MIF-1 on immobility but agonistic effects for focal seizures suggests that the type of effect exerted by opiate agents may depend upon other neuronal variables.
Functional Impact of ABCB1 Variants on Interactions between P-Glycoprotein and Methadone
Hung, Chin-Chuan; Chiou, Mu-Han; Teng, Yu-Ning; Hsieh, Yow-Wen; Huang, Chieh-Liang; Lane, Hsien-Yuan
2013-01-01
Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp’s interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates. PMID:23527191
Examining variation in treatment costs: a cost function for outpatient methadone treatment programs.
Dunlap, Laura J; Zarkin, Gary A; Cowell, Alexander J
2008-06-01
To estimate a hybrid cost function of the relationship between total annual cost for outpatient methadone treatment and output (annual patient days and selected services), input prices (wages and building space costs), and selected program and patient case-mix characteristics. Data are from a multistate study of 159 methadone treatment programs that participated in the Center for Substance Abuse Treatment's Evaluation of the Methadone/LAAM Treatment Program Accreditation Project between 1998 and 2000. Using least squares regression for weighted data, we estimate the relationship between total annual costs and selected output measures, wages, building space costs, and selected program and patient case-mix characteristics. Findings indicate that total annual cost is positively associated with program's annual patient days, with a 10 percent increase in patient days associated with an 8.2 percent increase in total cost. Total annual cost also increases with counselor wages (p<.01), but no significant association is found for nurse wages or monthly building costs. Surprisingly, program characteristics and patient case mix variables do not appear to explain variations in methadone treatment costs. Similar results are found for a model with services as outputs. This study provides important new insights into the determinants of methadone treatment costs. Our findings concur with economic theory in that total annual cost is positively related to counselor wages. However, among our factor inputs, counselor wages are the only significant driver of these costs. Furthermore, our findings suggest that methadone programs may realize economies of scale; however, other important factors, such as patient access, should be considered.
ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals.
Coller, Janet K; Barratt, Daniel T; Dahlen, Karianne; Loennechen, Morten H; Somogyi, Andrew A
2006-12-01
The most common treatment for opioid dependence is substitution therapy with another opioid such as methadone. The methadone dosage is individualized but highly variable, and program retention rates are low due in part to nonoptimal dosing resulting in withdrawal symptoms and further heroin craving and use. Methadone is a substrate for the P-glycoprotein transporter, encoded by the ABCB1 gene, which regulates central nervous system exposure. This retrospective study aimed to investigate the influence of ABCB1 genetic variability on methadone dose requirements. Genomic deoxyribonucleic acid was isolated from opioid-dependent subjects (n = 60) and non-opioid-dependent control subjects (n = 60), and polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction were used to determine the presence of single nucleotide polymorphisms at positions 61, 1199, 1236, 2677, and 3435. ABCB1 haplotypes were inferred with PHASE software (version 2.1). There were no significant differences in the allele or genotype frequencies of the individual single nucleotide polymorphisms or haplotypes between the 2 populations. ABCB1 genetic variability influenced daily methadone dose requirements, such that subjects carrying 2 copies of the wild-type haplotype required higher doses compared with those with 1 copy and those with no copies (98.3 +/- 10.4, 58.6 +/- 20.9, and 55.4 +/- 26.1 mg/d, respectively; P = .029). In addition, carriers of the AGCTT haplotype required significantly lower doses than noncarriers (38.0 +/- 16.8 and 61.3 +/- 24.6 mg/d, respectively; P = .04). Although ABCB1 genetic variability is not related to the development of opioid dependence, identification of variant haplotypes may, after larger prospective studies have been performed, provide clinicians with a tool for methadone dosage individualization.
[Effects of odor cue on morphine-induced dependence and craving in mice].
Liu, Xiao-Fen; Yang, Guang; Yang, Rui; Jia, Qiang; Guan, Su-Dong
2012-04-01
The olfactory system may play a pivotal role in drug addiction. To clarify the issues, we investigated the morphine dependence and psychological craving in morphine addicted mice using the conditioned place preference (CPP) paradigm by taking an only odor cue as the conditioned stimulus (CS). The results showed that by pairing morphine with odor, the CPP could be induced in mice. When the morphine addicted mice were exposed to a novel environment during morphine withdrawal, they spent significantly longer time in the chamber with morphine-paired odor than in the control chamber. The effects of odor cue on the morphine CPP were blocked by the administration of dopamine D1 or D2 antagonists. The studies indicated that olfactory system plays an important role in drug addiction.
Paris, Andrew; Kozma, Chris M.; Chow, Wing; Patel, Anisha M.; Mody, Samir H.; Kim, Myoung S.
2013-01-01
Background Few studies have estimated the economic effect of using an opioid that is associated with lower rates of gastrointestinal (GI) adverse events (AEs) than another opioid for postsurgical pain. Objective To estimate the number of postsurgical GI events and incremental hospital costs, including potential savings, associated with lower GI AE rates, for tapentadol immediate release (IR) versus oxycodone IR, using a literature-based calculator. Methods An electronic spreadsheet–based cost calculator was developed to estimate the total number of GI AEs (ie, nausea, vomiting, or constipation) and incremental costs to a hospital when using tapentadol IR 100 mg versus oxycodone IR 15 mg, in a hypothetical cohort of 1500 hospitalized patients requiring short-acting opioids for postsurgical pain. Data inputs were chosen from recently published, well-designed studies, including GI AE rates from a previously published phase 3 clinical trial of postsurgical patients who received these 2 opioids; GI event–related incremental length of stay from a large US hospital database; drug costs using wholesale acquisition costs in 2011 US dollars; and average hospitalization cost from the 2009 Healthcare Cost and Utilization Project database. The base case assumed that 5% (chosen as a conservative estimate) of patients admitted to the hospital would shift from oxycodone IR to tapentadol IR. Results In this hypothetical cohort of 1500 hospitalized patients, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100-mg use predicted reductions in the total number of GI events from 1095 to 1085, and in the total cost of GI AEs from $2,978,400 to $2,949,840. This cost reduction translates to a net savings of $22,922 after factoring in drug cost. For individual GI events, the net savings were $26,491 for nausea; $12,212 for vomiting; and $7187 for constipation. Conclusion Using tapentadol IR in place of a traditional μ-opioid shows the potential for reduced GI events and
Melichar, Jan K; Hume, Susan P; Williams, Tim M; Daglish, Mark R C; Taylor, Lindsay G; Ahmad, Rabia; Malizia, Andrea L; Brooks, David J; Myles, Judith S; Lingford-Hughes, Anne; Nutt, David J
2005-01-01
Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.
Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression.
Lin, Sheng-Hsiung; Huang, Ya-Ni; Kao, Jen-Hsin; Tien, Lu-Tai; Tsai, Ru-Yin; Wong, Chih-Shung
2016-05-01
Melatonin has been reported to attenuate opioid tolerance. In this study, we explored the possible mechanism of melatonin in diminishing morphine tolerance. Two intrathecal (i.t.) catheters were implanted in male Wistar rats for drug delivery. One was linked to a mini-osmotic pump for morphine or saline infusion. On the seventh day, 50μg of melatonin or vehicle was injected through the other catheter instantly after discontinuation of morphine or saline infusion; 3h later, 15μg of morphine or saline was injected. The antinociceptive response was then measured using the tail-flick test every 30min for 120min. The results showed that chronic morphine infusion elicited antinociceptive tolerance and upregulated heat shock protein 27 (HSP27) expression in the dorsal horn of the rat spinal cord. Melatonin pretreatment partially restored morphine's antinociceptive effect in morphine-tolerant rats and reversed morphine-induced HSP27 upregulation. In addition, chronic morphine infusion induced microglial cell activation and was reversed by melatonin treatment. The present study provides evidence that melatonin, acting via inhibiting morphine-induced neuroinflammation, can be useful as a therapeutic adjuvant for patients under long-term opioid treatment for pain relief. Copyright © 2016 Elsevier Inc. All rights reserved.
George, Rani; Haywood, Alison; Good, Phillip; Hennig, Stefanie; Khan, Sohil; Norris, Ross; Hardy, Janet
2017-09-01
Methadone is a potent analgesic used to treat refractory cancer pain. It is administered as a racemic mixture, with the l-enantiomer being primarily a μ-receptor agonist, whereas the d-enantiomer is an N-methyl-d-aspartate antagonist and inhibits serotonin and norepinephrine reuptake. Dose requirements vary greatly among patients to achieve optimal pain control and to avoid the risk of adverse effects. The relationship between plasma and saliva methadone enantiomer concentrations was investigated to determine if saliva could be a substitute for plasma in pharmacodynamic and pharmacokinetic studies for clinical monitoring and dose optimization of methadone in patients with advanced cancer. Patients with advanced cancer who were prescribed varying doses of oral methadone for pain management were recruited to obtain paired plasma and saliva samples. Pain scores were recorded at the time of sampling. The total and unbound plasma and saliva concentrations of the l- and d-enantiomers of methadone were quantified by using an HPLC-MS/MS method. The relationship between plasma (total and unbound) and saliva concentrations were compared. The saliva-to-plasma concentration ratio was compared versus the dose administered and the time after dosing for both enantiomers. The association of methadone concentrations with reported pain scores was compared by using a Mann-Whitney U test for significance. Fifty patients receiving a mean dose of 11mg/d of methadone provided 151 paired plasma and saliva samples. The median age of the population was 61 years with an interquartile range of 53-71 years with total body weight ranging from 59-88 kg. Median (interquartile) total plasma concentrations for l- and d-methadone were 50.78 ng/mL (30.6-113.0 ng/mL) and 62.0 ng/mL (28.7-116.0 ng/mL), respectively. Median (interquartile range) saliva concentrations for l- and d-methadone were 81.5 ng/mL (28.0-203.2 ng/mL) and 44.2 (16.2-149.7 ng/mL). No relationship could be established between
Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C.
2013-01-01
Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes. PMID:24653586
Ziegler, M; Poustka, F; von Loewenich, V; Englert, E
2000-09-01
In a retrospective case control study at the University of Frankfurt, Germany, 101 babies born to opiate-addicted mothers were identified from birth charts from 1988 to 1995. After birth, they developed a withdrawal syndrome (neonatal abstinence syndrome). Fifty control infants and their mothers were selected from neonatal wards. The group of opiate-exposed babies was subdivided into a group born to mothers without methadone treatment (n = 48) and a group born to mothers who were enrolled in a methadone program (n = 51). The methadone infants had a significantly higher mean birth weight (2822 g) than children in the group without methadone (2471 g). The abstinence syndrome was much more intense in the methadone group (convulsions 47.1%) than in heroin-exposed babies without methadone treatment (convulsions 27.1%). Women in methadone maintenance programs lived in more stable socioeconomic conditions than opiate-addicted women without methadone substitution. Moreover, they cared significantly better for their babies: 81.3% of the methadone mothers visited their children on a regular basis and 90.9% cared adequately. The data emphasize the need in future research to look more closely at the role of methadone treatment programs in the development of opiate-exposed babies.
Liaw, Wen-Jinn; Tsao, Cheng-Ming; Huang, Go-Shine; Wu, Chin-Chen; Ho, Shung-Tai; Wang, Jhi-Joung; Tao, Yuan-Xiang; Shui, Hao-Ai
2014-01-01
Introduction Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. Methods To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal cord level by giving them twice-daily injections of morphine (20 µg/10 µL) for 4 days. We confirmed tolerance by measuring paw withdrawal latencies and maximal possible analgesic effect of morphine on day 5. We then carried out phosphoproteomic analysis to investigate the global phosphorylation of spinal proteins associated with morphine tolerance. Finally, pull-down assays were used to identify phosphorylated types and sites of 14-3-3 proteins, and bioinformatics was applied to predict biological networks impacted by the morphine-regulated proteins. Results Our proteomics data showed that repeated morphine treatment altered phosphorylation of 10 proteins in the spinal cord. Pull-down assays identified 2 serine/threonine phosphorylated sites in 14-3-3 proteins. Bioinformatics further revealed that morphine impacted on cytoskeletal reorganization, neuroplasticity, protein folding and modulation, signal transduction and biomolecular metabolism. Conclusions Repeated morphine administration may affect multiple biological networks by altering protein phosphorylation. These data may provide insight into the mechanism that underlies the development of morphine tolerance. PMID:24392096
Methadone disrupts performance on the working memory version of the Morris water task.
Hepner, Ilana J; Homewood, Judi; Taylor, Alan J
2002-05-01
The aim of the study was to examine if administration of the mu-opiate agonist methadone hydrochloride resulted in deficits in performance on the Morris water tank task, a widely used test of spatial cognition. To this end, after initial training on the task, Long-Evans rats were administered saline or methadone at either 1.25, 2.5 or 5 mg/kg ip 15 min prior to testing. The performance of the highest-dose methadone group was inferior to that of the controls on the working memory version of the Morris task. There were also differences between the groups on the reference memory version of the task, but this result cannot be considered reliable. These data show that methadone has its most profound effect on cognition in rats when efficient performance on the task requires attention to and retention of new information, in this case, the relationship between platform location and the extramaze cues.
Interaction of prenatal stress and morphine alters prolactin and seizure in rat pups.
Saboory, Ehsan; Ebrahimi, Loghman; Roshan-Milani, Shiva; Hashemi, Paria
2015-10-01
Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylenetetrazol (PTZ) induced epileptic behaviors and prolactin blood level (PBL) was investigated in rat offspring. Pregnant Wistar rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, pregnant rats were placed in 25°C water on gestation days 17, 18 and 19 (GD17, GD18 and GD19) for 30 min. In the morphine/saline group, pregnant rats received morphine (10, 12 and 15 mg/kg, IP, on GD17, GD18 and GD19, respectively) or saline (1 ml, IP). In the morphine/saline-stressed group, the rats received morphine or saline and then exposed to stress. On postnatal days 6 and 15 (P6 and P15), blood samples were obtained and PBL was determined. At P15 and P25, the rest of the pups was injected with PTZ to induce seizure. Then, epileptic behaviors of each rat were observed individually. Latency of first convulsion decreased in control-morphine and stressed-saline groups while increased in stressed-morphine rats compared to control-saline group on P15 (P=0.04). Number of tonic-clonic seizures significantly increased in control-morphine and stressed-saline rats compared to control-saline group at P15 (P=0.02). PBL increased in stressed-saline, control-morphine and stress-morphine groups compared to control-saline rats. It can be concluded that prenatal exposure of rats to forced-swim stress and morphine changed their susceptibility to PTZ-induced seizure and PBL during infancy and prepubertal period. Co-administration of morphine attenuated effect of stress on epileptic behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.
Fleming, Alison B; Carlson, Douglas R; Varanasi, Ravi K; Grima, Michael; Mayock, Stephen P; Saim, Said; Kopecky, Ernest A
2016-03-01
Patients who have chronic pain with dysphagia (difficulty swallowing) (CPD) often have difficulty taking oral medication and, as such, alter their medications by crushing or chewing in an attempt to make it easier to swallow. Such manipulation of currently marketed, extended-release (ER) opioid analgesics can significantly alter the pharmacokinetic (PK) properties of the formulations, resulting in poor treatment outcome or serious adverse events. There is an unmet medical need for oral ER opioid formulations suitable for patients with CPD. The primary objectives of this study were to conduct in vitro studies to evaluate alternate means of administration of a new, extended-release (ER), abuse-deterrent, microsphere-in-capsule formulation of oxycodone for patients with CPD. Specifically, these studies investigated the in vitro equivalence of drug release rates from Oxycodone DETERx® ER intact capsules (control condition) and administration via alternate modes-opening the capsule and sprinkling the microspheres onto soft foods or administration through enteral tubes. Secondary objectives were to compare alternate modes of administration of Oxycodone DETERx® to a commercially available ER-morphine product. Soft food study: Oxycodone DETERx® microspheres were sprinkled onto and mixed with several soft foods (ie, applesauce, vanilla pudding, strawberry jam, yogurt, and vanilla ice cream); the effect of drug contact time (0, 30, and 60 minutes) on drug release was studied. Enteral tube study: Oxycodone DETERx® microspheres were administered through varying sizes of nasogastric (10 and 12 Fr.) tubes and a 16 Fr. gastrostomy tube using 5 different delivery vehicles (ie, water, liquid nutritional feeds [Jevity®, Ensure®], and milk [whole milk and 2% milk]). Drug release rate was characterized using a standard in vitro dissolution methodology; dissolution of intact Oxycodone DETERx® capsules served as the control for both the soft food and enteral tube studies
Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats.
Chou, Kuang-Yi; Tsai, Ru-Yin; Tsai, Wei-Yuan; Wu, Ching-Tang; Yeh, Chun-Chang; Cherng, Chen-Hwan; Wong, Chih-Shung
2013-12-01
As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine. Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 μg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 μl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 μl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 μg in 5 μl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45-52°C, respective). Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine. This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management. Copyright © 2013. Published by Elsevier B.V.
Eizadi-Mood, Nastaran; Naeini, Seyed Amir Hossein Madani; Hedaiaty, Mahrang; Sabzghabaee, Ali Mohammad; Moudi, Maryam
2016-01-01
Methadone poisoning is common in our society, mainly in drug addicts. One of its lethal complications is pulmonary edema. Therefore, we evaluated the prevalence of pulmonary edema in the deceased cases with methadone poisoning and its possible relationship with some medical variables. In this cross-sectional study which was done in 2014, we have investigated the deceased patients with methadone toxicity who underwent autopsy at Isfahan Forensic Medicine Department (Iran). All variables including age, gender, and autopsy findings were recorded and analyzed. Demographic characteristics and medical complications of the patients were compared between the patients with or without pulmonary edema in the autopsy findings. There were 64 cases who died with methadone poisoning during the 1-year study period. The average age of cases (±standard deviation) was 32.1 ± 10.29 years, among which 92.2% were male. Based on the autopsy findings, 64.1% were diagnosed with pulmonary edema. There was no statistically significant relationship between pulmonary edema and age, gender, history of addiction, and hepatic or cardiovascular complications. Pulmonary edema is a common finding in deceased methadone poisoning cases and must be considered and ruled out in patients with acute methadone toxicity.
Biliary and pancreatic ductal dilation in patients on methadone maintenance therapy.
Bates, David D B; Tamayo-Murillo, Dorathy; Kussman, Steven; Luce, Adam; LeBedis, Christina A; Soto, Jorge A; Anderson, Stephan W
2017-03-01
To determine whether the diameter of intrahepatic and extrahepatic bile ducts and pancreatic ducts in patients on methadone maintenance therapy is increased when compared with control subjects. Between January 1, 2000 and March 15, 2013, a total of 97 patients (mean age 49.9, range 22-79, 65 male, 32 female) were identified who were receiving chronic methadone maintenance therapy (MMT) when they underwent imaging with abdominal MRI or a contrast-enhanced abdominopelvic CT. A group of 97 consecutive non-MMT control patients (mean age 51.4, range 21-86, 45 male, 52 female) who underwent imaging with abdominal MRI or contrast-enhanced abdominopelvic CT were identified. Patients with known pancreaticobiliary pathology that may confound biliary ductal measurements were excluded. Blinded interpretation was performed, documenting the diameters of the intrahepatic and extrahepatic bile ducts and pancreatic ducts. Descriptive statistics were performed. Patients on MMT demonstrated increased bile duct diameter, with an average increase in duct diameter of 2.39 mm for the common bile duct (p < 0.001; 95% CI 1.88-2.90 mm), 1.43 mm for the intrahepatic bile ducts (p < 0.001; 95% CI 1.12-1.74 mm), and 0.90 mm for the pancreatic duct (p < 0.001; 95% CI 0.64-1.16 mm). No statistically significant correlation was found between ductal diameters and the daily dose of methadone. Patients on methadone maintenance therapy demonstrate significantly increased intra- and extrahepatic bile duct and pancreatic duct diameter when compared with controls. There was no correlation between the dose of methadone and ductal diameter.
Kang, Soo-Kyung; Lee, Yeon-Hee; Park, Hyeji; Ro, Jin Y; Auh, Q-Schick
2018-06-19
This placebo-controlled randomized double-blinded clinical study assessed the analgesic efficacy of intramuscular morphine in TMD patients with myofascial pain and sex dependent responses of the morphine treatment. Men and women with TMD were treated with morphine (1.5 or 5 mg), lidocaine or saline in the masseter muscle. VAS of pain intensity, PPT and PPtol were compared between treatment groups and gender. An additional group was treated with morphine in the trapezius muscle to evaluate the systemic effect of morphine that may reduce pain in the masseter muscle. There was a significant difference in VAS scores between the morphine 5 mg group and the saline group favoring morphine, but not between the morphine 5 mg and lidocaine. Morphine 1.5 mg and 5 mg treatments led to consistently and significantly elevated PPT and PPtol measures in men, but not in women. Morphine administered in the trapezius muscle did not affect the outcome measures. A single dose intramuscular morphine produced analgesic effects up to 48 hrs in patients with myofascial pain. Intramuscular morphine elevated mechanical pain threshold and tolerance in the masseter only in male patients, suggesting sex differences in local morphine effects. No systemic effect of intramuscular morphine was detected. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Neonatal morphine exposure in very preterm infants-cerebral development and outcomes.
Steinhorn, Rachel; McPherson, Christopher; Anderson, Peter J; Neil, Jeffrey; Doyle, Lex W; Inder, Terrie
2015-05-01
To investigate the association of morphine exposure in very preterm infants with cerebral volumes and neurodevelopmental outcome from birth through middle childhood. Observational study of very preterm infants in the Victorian Infant Brain Study cohort. A total of 230 infants born <30 weeks' gestational age or <1250 g were recruited from all admissions to the neonatal intensive care unit of the Royal Women's Hospital. Fifty-seven (25%) infants received morphine analgesia during their neonatal intensive care unit stay at the attending physician's discretion. Primary outcomes were regional brain volumes at term and 7 years; neurobehavioral performance at term; and cognitive, motor, emotional, behavioral, communication, and executive function scores at age 2 and 7 years. Linear regressions were used to compare outcomes between participants who did and did not receive morphine. At term, preterm infants who received morphine had similar rates of gray matter injury to no-morphine infants, but a trend toward smaller cortical volumes in the orbitofrontal (Pleft=.002, Pright=.01) and subgenual (Pleft=.01) regions. At 7 years, cortical volumes did not differ between groups. At 2 years, morphine-exposed children were more likely to show behavioral dysregulation (P=.007) than no-morphine children, but at 7 years no detrimental impacts of morphine on neurobehavioral outcome were observed. Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. Copyright © 2015 Elsevier Inc. All rights reserved.
Gomes, Tara; Paterson, J Michael; Juurlink, David N; Dhalla, Irfan A; Mamdani, Muhammad M
2012-01-01
In August 2010, a tamper-resistant formulation of controlled-release oxycodone (OxyContin-OP) was introduced in the United States but not in Canada. Our objective was to determine whether introduction of OxyContin-OP in the United States influenced prescription volumes for the original controlled-release oxycodone formulation (OxyContin) at Canadian pharmacies near the international border. We conducted a population-based, serial, cross-sectional study of prescriptions dispensed from pharmacies in the 3 cities with the highest volume of US-Canada border crossings in Ontario: Niagara Falls, Windsor and Sarnia. We analyzed data on all outpatient prescriptions for OxyContin dispensed by Canadian pharmacies near each border crossing between 2010 Apr. 1 and 2012 Feb. 29. We calculated and compared monthly prescription rates, adjusted per 1000 population and stratified by tablet strength. The number of tablets dispensed near 4 border crossings in the 3 Canadian cities remained stable over the study period. However, the rate of dispensing at pharmacies near the Detroit-Windsor Tunnel increased roughly 4-fold between August 2010 and February 2011, from 505 to 1969 tablets per 1000 population. By April 2011, following warnings to prescribers and pharmacies regarding drug-seeking behaviour, the dispensing rate declined to 1683 tablets per 1000 population in this area. By November 2011, the rate had returned to levels observed in early 2010. Our analyses suggest that 242 075 excess OxyContin tablets were dispensed near the Detroit-Windsor Tunnel between August 2010 and October 2011. Prescribing of the original formulation of controlled-release oxycodone rose substantially near a major international border crossing following the introduction of a tamper-resistant formulation in the United States. It is possible that the restriction of this finding to the area surrounding the Detroit-Windsor Tunnel reflects specific characteristics of this border crossing, including its high
Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A
2010-03-01
Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.
Ontogenesis of morphine-induced behavior in the cat.
Burgess, J Wesley; Villablanca, Jaime R
2007-02-23
We analyzed the behavioral responses to a single dose of morphine in kittens at postnatal (P) ages 7, 15, 30, 60, 90, and 120 days. Each kitten received 0.5 or 3.0 mg/kg i.p. of morphine sulphate or saline vehicle. An average of 6.5 kittens were studied at each dose and age. An ethogram was constructed, based on morphine effects in adult cats, to score appropriate behaviors from direct observation and video sampling. After injection behaviors were sampled for periods of 2 min every 15-30 min for a total of 4 h. The frequency of each selected behavior was scored at 2 s intervals during each of the 2 min periods and it was expressed as a percent of all time samples scored for the 4 h period. Statistical comparisons were made with control (saline) littermates. At P7-15 the drug's main effect was behavioral depression; i.e., kittens, away from the litter, laid sprawled as if with no muscle tonus; Nursing was suppressed and Vocalization was distressed. Mainly with the higher dose, at P30, morphine-specific behaviors appeared for the first time. With the kitten in a Sitting position, these included stereotypical Head and Paw Movements and body Torsion. At P60 other drug-elicited behaviors emerged, including Spinning, Retching, and Vomiting. By P90-120 the frequency of Head (16.0%) and Paw (16.9%) Movements doubled relative to P30-60. Morphine significantly changed frequencies of newly matured behaviors (in control kittens) including Sniffing and Licking (increased), and Grooming (decreased/blocked). Retching and Vomiting increased to adult levels. Morphine-induced hyperthermia was first detected at P60 and peaked by P90-P120. The early behavioral depression shifted to a pattern of increasing activity starting at P30 and peaking at P90-120, at which time Sleep was absent and Laying was reduced, while Walking and Sitting were increased. We concluded that the maturation of the stereotypical behavioral responses to morphine in cats begins at about P30 and is completed
Cooperman, Nina A.; Richter, Kimber P.; Bernstein, Steven L.; Steinberg, Marc L.; Williams, Jill M.
2015-01-01
Background Over 80% of people in methadone treatment smoke cigarettes, and existing smoking cessation interventions have been minimally effective. Objective To develop an Information-Motivation-Behavioral Skills (IMB) Model of behavior change based smoking cessation intervention for methadone maintained smokers, we examined smoking cessation related information, motivation, and behavioral skills in this population. Methods Current or former smokers in methadone treatment (n=35) participated in focus groups. Ten methadone clinic counselors participated in an individual interview. A content analysis was conducted using deductive and inductive approaches. Results Commonly known information, motivation, and behavioral skills factors related to smoking cessation were described. These factors included: the health effects of smoking and treatment options for quitting (information); pregnancy and cost of cigarettes (motivators); and coping with emotions, finding social support, and pharmacotherapy adherence (behavioral skills). Information, motivation, and behavioral skills factors specific to methadone maintained smokers were also described. These factors included: the relationship between quitting smoking and drug relapse (information), the belief that smoking is the same as using drugs (motivator); and coping with methadone clinic culture and applying skills used to quit drugs to quitting smoking (behavioral skills). Information, motivation, and behavioral skills strengths and deficits varied by individual. Conclusions Methadone maintained smokers could benefit from research on an IMB Model based smoking cessation intervention that is individualized, addresses IMB factors common among all smokers, and also addresses IMB factors unique to this population. PMID:25559697
Idrisov, Bulat; Murphy, Sean M; Morrill, Tyler; Saadoun, Mayada; Lunze, Karsten; Shepard, Donald
2017-01-20
Opioid agonist therapy using methadone, an effective treatment of opioid use disorders (OUD) for people who inject drugs (PWID), is recommended by the World Health Organization as essential to curtail the growing HIV epidemic. Yet, despite increasing prevalence of OUD and HIV, methadone therapy has not yet been implemented in Russia. The aim of this modeling study was to estimate the cost-effectiveness of methadone therapy for Russian adults with a diagnosed OUD. We modeled the projected program implementation costs and estimated disability-adjusted life years (DALYs) averted over a 10-year period, associated with the provision of methadone therapy for a hypothetical, unreplenished cohort of Russian adults with an OUD (n = 249,000), in comparison to the current therapies at existing addiction treatment facilities. Our model compared four distinct scenarios of treatment coverage in the cohort ranging from 3.1 to 55%. Providing methadone therapy to as few as 3.1% of adults with an OUD amounted to an estimated almost 50,000 DALYs averted over 10 years at a cost of just over USD 17 million. Further expanding service coverage to 55% resulted in an estimated almost 900,000 DALYs averted, at a cost of about USD 308 million. Our study indicated that implementing opioid agonist therapy with methadone to treat OUD at existing facilities in Russia is highly cost-effective.
Disciplining addictions: the bio-politics of methadone and heroin in the United States.
Bourgois, P
2000-06-01
Biomedical understanding of methadone as a magic-bullet pharmacological block to the euphoric effects of heroin is inconsistent with epidemiological and clinical data. An ethnographic perspective on the ways street-based heroin addicts experience methadone reveals the quagmire of power relations that shape drug treatment in the United States. The phenomenon of the methadone clinic is an unhappy compromise between competing discourses: A criminalizing morality versus a medicalizing model of addiction-as-a-brain-disease. Treatment in this context becomes a hostile exercise in disciplining the unruly misuses of pleasure and in controlling economically unproductive bodies. Most of the biomedical and epidemiological research literature on methadone obscures these power dynamics by technocratically debating dosage titrations in a social vacuum. A foucaultian critique of the interplay between power and knowledge might dismiss debates over the Swiss experiments with heroin prescription as merely one more version of biopower disciplining unworthy bodies. Foucault's ill-defined concept of the specific intellectual as someone who confronts power relations on a practical technical level, however, suggests there can be a role for political as well as theoretical engagement with debates in the field of applied substance abuse treatment. Meanwhile, too many heroin addicts who are prescribed methadone in the United States suffer negative side effects that range from an accentuated craving for polydrug abuse to a paralyzing sense of impotence and physical and emotional discomfort.
Analgesic tolerance to morphine is regulated by PPARγ
de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Stopponi, Serena; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto
2014-01-01
Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. Experimental Approach We monitored analgesia on alternate days using the tail immersion test. Key Results Daily administration of morphine (30 mg·kg−1, bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg−1, bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg−1, bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg−1, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. Conclusions and Implications Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse. PMID:25048682
Effects of Shilajit on the development of tolerance to morphine in mice.
Tiwari, P; Ramarao, P; Ghosal, S
2001-03-01
Effects of concomitant administration of Processed Shilajit (PS, 0.1 and 1 mg/kg, i.p.), in Swiss mice were evaluated on the development of tolerance to morphine induced analgesia in the hot plate test. Chronic administration of morphine (10 mg/kg, i.p., b.i.d.) to mice over a duration of 10 days resulted in the development of tolerance to the analgesic effect of morphine. Concomitant administration of PS with morphine, from day 6 to day 10, resulted in a significant inhibition of the development of tolerance to morphine (10 mg/kg, i.p.) induced analgesia. Processed Shilajit per se, in the doses used, did not elicit any significant analgesia in mice; nor did the chronic concomitant administration of Processed Shilajit alter the morphine-induced analgesia. These findings with Processed Shilajit indicate its potential as a prospective modifier of analgesic tolerance to morphine. Copyright 2001 John Wiley & Sons, Ltd.
Pregabalin role in inhibition of morphine analgesic tolerance and physical dependency in rats.
Hasanein, Parisa; Shakeri, Saeed
2014-11-05
Pregabalin is recently proposed as analgesic or adjuvant in pain management. While previous preclinical investigations have evaluated pregabalin-opioid interactions, the effect of pregabalin on opioid tolerance and dependency has not yet been studied. Here we evaluated the effects of different doses of pregabalin (50, 100 and 200mg/kg, s.c.) on morphine-induced tolerance and dependency in rats. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10mg/kg, s.c.) twice daily for 7 days. To develop morphine dependence, rats were given escalating doses of morphine. To determine the effect of pregabalin on the development of morphine tolerance and dependence, different doses of pregabalin were administrated before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate the degree of tolerance and dependence, respectively. Chronic morphine-injected rats showed significant decrements in the percentage maximum possible effect (%MPE) of morphine on the days 5 and 7 (32.5%±3.5, 21.5%±4, respectively) compared to the first day (100%) which showed morphine tolerance. Pregabalin 200mg/kg completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with pregabalin attenuated almost all of the naloxone-induced withdrawal signs which include weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor. These data show that pregabaline has a potential anti-tolerant/anti-dependence property against chronic usage of morphine. Therefore, pregabalin appears to be a promising candidate for the treatment of opioid addiction after confirming by future clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.
Bajic, Dusica; Berde, Charles B.; Commons, Kathryn G.
2012-01-01
The development of tolerance to the antinociceptive effects of morphine has been associated with networks within ventrolateral periaqueductal gray (vlPAG) and separately, nitric oxide signaling. Furthermore, it is known that the mechanisms that underlie tolerance differ with age. In this study, we used a rat model of antinociceptive tolerance to morphine at two ages, postnatal day (PD) 7 and adult, to determine if changes in the vlPAG related to nitric oxide signaling produced by chronic morphine exposure were age-dependent. Three pharmacological groups were analyzed: control, acute morphine, and chronic morphine group. Either morphine (10 mg/kg) or equal volume of normal saline was given subcutaneously twice daily for 6 ½ days. Animals were analyzed for morphine dose-response using Hot Plate test, and for the expression of several genes associated with nitric oxide metabolism was evaluated using rtPCR. In addition, the effect of morphine exposure on immunohistochemistry for Fos, and nNOS as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) reaction at the vlPAG were measured. In both age groups acute morphine activated Fos in the vlPAG, and this effect was attenuated by chronic morphine, specifically in the vlPAG at the level of the laterodorsal tegmental nucleus (LDTg). In adults, but not PD7 rats, chronic morphine administration was associated with activation of nitric oxide function. In contrast, changes in the gene expression of PD7 rats suggested superoxide and peroxide metabolisms may be engaged. These data indicate that there is supraspinal neuroplasticity following morphine administration as early as PD7. Furthermore, oxidative stress pathways associated with chronic morphine exposure appear age-specific. PMID:22999971
Morphine-induced kinetic alterations of choline acetyltransferase of the rat caudate nucleus
Datta, K.; Wajda, I. J.
1972-01-01
1. In order to explain the decrease of choline acetyltransferase (2.3.1.6.) activity observed in the caudate nucleus of morphine-treated rats, partially purified preparations of the enzyme were used in kinetic studies, with choline as substrate. 2. The apparent Michaelis constant for the enzyme obtained from normal rats was found to be 0·9 mM choline; this value doubled when the animals were killed one hour after a single injection of morphine (30 mg/kg). When the rats were injected daily for 4 or 15 days, and killed one hour after the last injection, the apparent Km value was 2·1 mM in each case. Prolonged daily treatment with morphine, followed by 48 h withdrawal, or by administration of 4 mg/kg of naloxone (given half an hour after the last injection of morphine) resulted in apparent Km values of 1·3-1·5 mM of choline, suggesting a gradual return to the lower, normal substrate requirement. Vmax changes were insignificant. 3. The effect of morphine added in vitro to different enzyme preparations was also studied. The Km values of 0·9 mM, in the enzyme isolated from normal rats, increased to 2·0 after incubation in vitro with 12·5 mM morphine. Similar increases were found in enzymes obtained from rats 48 h after the withdrawal of morphine or from rats injected with naloxone after prolonged morphine treatment. The high apparent Km values, found in enzyme obtained from animals killed one hour after the last dose of morphine, did not change upon incubation with 12·5 mM morphine. A similar pattern of Km changes was noticed after incubation with 25 mM acetylcholine. 4. An increase of 32% in acetylcholine (ACh) level was found in the caudate nucleus one hour after subcutaneous injection of 30 mg/kg of morphine. Return to normal values was observed when morphine was administered daily. After two to three weeks of daily treatment and subsequent withdrawal from morphine for 48 h, the levels of ACh were normal. If the daily treated rats were given naloxone within
Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration
Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.
2014-01-01
Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine and 3.1mg codeine, 8h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography tandem mass spectrometry (1μg/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32h after the first dose. All specimens screened positive 0.5h after dosing and remained positive for 0.5-13h at Draeger 20μg/L morphine cutoff. Maximum OF morphine and codeine concentrations (Cmax) were 177 and 32.6μg/L, with times to Cmax (Tmax) of 0.5-1h and 0.5-2.5h post-dose, respectively. Windows of detection after the second dose extended at least 24h for morphine and to 18h for codeine. After both doses, the last morphine positive OF result was 1h with 40μg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cutoff, and 0.5h with 95μg/L cutoff, recently recommended by the Driving Under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1h after ingestion of 15.7mg of morphine in raw poppy seeds, depending upon the cutoff employed. PMID:25345619
Object relations and differential treatment response to methadone maintenance.
Nicholson, B; Treece, C
1981-07-01
The authors report results from a psychiatric study of narcotic addicts in which the relationship between specified aspects of object relations development and treatment response to methadone maintenance was examined. Two groups were defined as high and low drug users (in addition to the prescribed methadone dose) depending upon the frequency and intensity of additional drug use; a middle group was excluded. Thirty subjects participated. The dimensions of separation/individuation, narcissistic development, and self and object representations were measured by 12 scaled variables; scores of the high and low drug users were compared by t-test. In all cases, the high use group was found to be more impaired than the low use group. However, the dimensions differed greatly in their ability to differentiate the groups. The strongest group differences were found in the area of narcissistic development, with the high user group significantly more impaired than the low user group. The strength of these findings lends empirical support to the notion that an addict population can be differentiated on diagnostic and ego psychological measures. This has important implications for methadone maintenance treatment programs, and, possibly, for drug programs in general.
Narp regulates long-term aversive effects of morphine withdrawal
Reti, Irving M.; Crombag, Hans S.; Takamiya, Kogo; Sutton, Jeffrey M.; Guo, Ning; Dinenna, Megan L.; Huganir, Richard L.; Holland, Peter C.; Baraban, Jay M.
2008-01-01
Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. As Narp is an immediate early gene product that is secreted at synaptic sites and binds to AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, we found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, we evaluated whether long-term aversive effects of morphine withdrawal are altered in Narp KO mice. We found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than WT controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction. PMID:18729628
Withdrawal of repeated morphine enhances histamine-induced scratching responses in mice.
Abe, Kenji; Kobayashi, Kanayo; Yoshino, Saori; Taguchi, Kyoji; Nojima, Hiroshi
2015-04-01
An itch is experientially well known that the scratching response of conditions such as atopic dermatitis is enhanced under psychological stress. Morphine is typical narcotic drug that induces a scratching response upon local application as an adverse drug reaction. Although long-term treatment with morphine will cause tolerance and dependence, morphine withdrawal can cause psychologically and physiologically stressful changes in humans. In this study, we evaluated the effects of morphine withdrawal on histamine-induced scratching behavior in mice. Administration of morphine with progressively increasing doses (10-50 mg/kg, i.p.) was performed for 5 consecutive days. At 3, 24, 48, and 72 hr after spontaneous withdrawal from the final morphine dose, histamine was intradermally injected into the rostral part of the back and then the number of bouts of scratching in 60 min was recorded and summed. We found that at 24 hr after morphine withdrawal there was a significant increase in histamine-induced scratching behavior. The spinal c-Fos positive cells were also significantly increased. The relative adrenal weight increased and the relative thymus weight decreased, both significantly. Moreover, the plasma corticosterone levels changed in parallel with the number of scratching bouts. These results suggest that morphine withdrawal induces a stressed state and enhances in histamine-induced scratching behavior. Increased reaction against histamine in the cervical vertebrae will participate in this stress-induced itch enhancement.
Experiences of Opium Dependents from Performance of Methadone Centers of Kerman, Iran
Banazadeh Mahani, Nabi; Kheradmand, Ali; Abedi, Heidarali
2009-01-01
Background: To assess patients' satisfaction and to evaluate methadone therapy program, it is important to understand the experiences of opium dependents during the treatment period in methadone centers and determine the quality of this program and revise standards based on that. This study aimed to describe the nature and structure of patients' experiences during treatment in methadone centers. Methods: This was a qualitative method using phenomenology. Sampling was purposive and the participants were selected from opium dependents referred to Kerman methadone centers during 2007. Sampling continued until data saturation and the sample size was 32. Colaizzi's method was applied for data analysis. Findings: The findings of this study included 27 codes categorized in four main groups: experiences of structure, personnel, patients, and regulations. These four categories showed the main structure of experiences in methadone centers. Conclusion: Lack of treatment centers in near-by cities or the problems of those centers suggest that it is necessary to establish new centers or solve the problems of centers in near-by cities. The type of patients referring to the centers plays a role in treatment process. The regular presence of physicians and other personnel and their concerns and care for patients as well as longer working hours of the centers have roles in patients' satisfaction and increase of consistency with treatment. Discussing the rules and regulations of the center with patients including the obligatory of daily reference to the center to obtain medicine and injections sound necessary. Also, it is necessary to find ways for solving problems of urine tests. PMID:24494087
Blum, Kenneth; Oscar-Berman, Marlene; Femino, John; Waite, Roger L; Benya, Lisa; Giordano, John; Borsten, Joan; Downs, William B; Braverman, Eric R; Loehmann, Raquel; Dushaj, Kristina; Han, David; Simpatico, Thomas; Hauser, Mary; Barh, Debmalya; McLaughlin, Thomas
2013-04-23
While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.
Naltrexone implants compared to methadone: outcomes six months after prison release.
Lobmaier, Philipp P; Kunøe, Nikolaj; Gossop, Michael; Katevoll, Tormod; Waal, Helge
2010-01-01
After prison release, offenders with heroin use problems are at high risk of relapse and overdose death. There is a particular need for treatments that can be initiated in prison and continued after release into the community. Methadone maintenance treatment has been shown to reduce heroin use, criminality and mortality. Naltrexone implant treatment has not previously been evaluated in prison settings. This study compares the effects of naltrexone implants and methadone treatment on heroin and other illicit drug use, and criminality among heroin-dependent inmates after release from prison. Forty-six volunteers were randomly allocated to naltrexone implants or methadone before release. Intention-to-treat analyses showed reductions in both groups in frequency of use of heroin and benzodiazepines, as well as criminality, 6 months after prison release. Naltrexone implants may be a valuable treatment option in prison settings. 2010 S. Karger AG, Basel.
Hsieh, Ming-Chi; Panchangam, Sri Chandana; Lai, Webber Wei-Po; Lin, Angela Yu-Chen
2018-06-12
Free chlorine sunlight photolysis (sunlight/FC) markedly enhances the degradation rate of methadone, a synthetic opioid used medically, over that obtained using sunlight alone. The pseudo-first-order rate constants of methadone degradation under acidic conditions ([methadone] = 0.2 μM, [free chlorine] = 4 μM, and pH = 4) for sunlight/FC and sunlight photolysis are 7.0 ± 1.1 × 10 -2 min -1 and 1.4 ± 0.2 × 10 -2 min -1 , respectively. The improved methadone degradation can be attributed to the production of HO and reactive chlorine species (RCS) during sunlight/FC photolysis. HO and RCS predominantly accounted for degradation during sunlight/FC photolysis under acidic and neutral conditions, while direct photolysis was the major contributor towards methadone degradation in alkaline conditions. The initial pH (pH 4-11) and free chlorine concentration (1-6 μM) significantly influenced the overall degradation efficiency of methadone. The presence of HCO 3 - , Cl - and dissolved organic matters, which may competitively react with HO and RCS, retard the degradation of methadone in synthetic wastewater. Consequently, a 50% lower methadone degradation rate was observed when deionized (DI) water was replaced with tap water. These results emphasize the need to consider different water matrices when applying sunlight/FC photolysis for water treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.
Sublingual and oral morphine administration. Review and new findings.
Robison, J M; Wilkie, D J; Campbell, B
1995-12-01
Clinical reports rave about the efficacy of sublingual morphine, but most research data suggest that sublingual morphine lacks the necessary physical characteristics to be absorbed through sublingual tissues. This article clarifies these assertions by reviewing the clinical literature that supports sublingual administration, the theories relevant to sublingual morphine administration, and the pharmacokinetic research that supports or negates the benefit of this route. Recommendations for clinical nursing practice are provided to guide decision-making in care of patients with cancer pain.
Gordon, Andrea L; Lopatko, Olga V; Somogyi, Andrew A; Foster, David J R; White, Jason M
2010-01-01
AIMS The aim of this study was to compare the transfer of buprenorphine and methadone between maternal and cord blood in women under chronic dosing conditions and to determine if differences exist in the transfer of the two methadone enantiomers. METHODS Maternal and cord blood samples were collected at delivery from women maintained on methadone (35, 25–140 mg day−1) (median; range) or buprenorphine (6.00, 2–20 mg day−1) during pregnancy. Plasma concentration ratios are presented as an indicator of foetal exposure relative to the mother. RESULTS Methadone was quantified in all samples, with cord : maternal plasma methadone concentration ratios (n = 15 mother-infant pairs) being significantly higher (P < 0.0001; mean difference (MD) 0.07; 95% confidence interval (CI) 0.048, 0.092) for the active (R)-methadone enantiomer (0.41; 0.19, 0.56) (median; range) compared with (S)-methadone (0.36; 0.15, 0.53). (R)- : (S)-methadone concentration ratios were also significantly higher (P < 0.0001; MD 0.24 95% CI 0.300, 0.180) for cord (1.40; 0.95, 1.67) compared with maternal plasma (1.16; 0.81, 1.38). Half the infant buprenorphine samples were below the assay lower limit of quantification (LLOQ) (0.125 ng ml−1). The latter was four-fold lower than the LLOQ for methadone (0.50 ng ml−1). The cord : maternal plasma buprenorphine concentration ratio (n = 9 mother-infant pairs) was 0.35; 0.14, 0.47 and for norbuprenorphine 0.49; 0.24, 0.91. CONCLUSIONS The transfer of the individual methadone enantiomers to the foetal circulation is stereoselective. Infants born to buprenorphine maintained women are not exposed to a greater proportion of the maternal dose compared with methadone and may be exposed to relatively less of the maternal dose compared with infants born to women maintained on methadone during pregnancy. PMID:21175445
Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping
2015-07-24
One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.
Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons
Llorente, Javier; Withey, Sarah; Rivero, Guadalupe; Cunningham, Margaret; Cooke, Alex; Saxena, Kunal; McPherson, Jamie; Oldfield, Sue; Dewey, William L.; Bailey, Chris P.; Kelly, Eamonn; Henderson, Graeme
2013-01-01
Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in μ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance. PMID:23716621
Simeone, Claire; Shapiro, Brad; Lum, Paula J
2017-08-22
Persons living with HIV and unhealthy substance use are often less engaged in HIV care, have higher morbidity and mortality and are at increased risk of transmitting HIV to uninfected partners. We developed a quality-improvement tracking system at an urban methadone clinic to monitor patients along the HIV care continuum and identify patients needing intervention. To evaluate patient outcomes along the HIV Care Continuum at an urban methadone clinic and explore the relationship of HIV primary care site and patient demographic characteristics with retention in HIV treatment and viral suppression. We reviewed electronic medical record data from 2015 for all methadone clinic patients with known HIV disease, including age, gender, race, HIV care sites, HIV care visit dates and HIV viral load. Patients received either HIV primary care at the methadone clinic, an HIV specialty clinic located in the adjacent building, or a community clinic. Retention was defined as an HIV primary care visit in both halves of the year. Viral suppression was defined as an HIV viral load <40 copies/ml at the last lab draw. The population (n = 65) was 63% male, 82% age 45 or older and 60% non-Caucasian. Of these 65 patients 77% (n = 50) were retained in care and 80% (n = 52) were virologically suppressed. Viral suppression was significantly higher for women (p = .022) and patients 45 years or older (p = .034). There was a trend towards greater retention in care and viral suppression among patients receiving HIV care at the methadone clinic (93, 93%) compared to the HIV clinic (74, 79%) or community clinics (62, 62%). Retention in HIV care and viral suppression are high in an urban methadone clinic providing integrated HIV services. This quality improvement analysis supports integrating HIV primary care with methadone treatment services for this at-risk population.
Coller, Janet K; Michalakas, Jennifer R; James, Heather M; Farquharson, Aaron L; Colvill, Joel; White, Jason M; Somogyi, Andrew A
2012-11-01
Management of pain in opioid dependent individuals is problematic due to numerous issues including cross-tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative. Methadone inhibits CYP2D6 in vivo and in vitro. We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O-demethylation (CYP2D6) to the opioid-active metabolite M1 and N-demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control. Compared with subjects on buprenorphine, methadone reduced the clearance of tramadol to active O-desmethyl-tramadol (M1) but had no effect on N-desmethyltramadol (M2) formation. Similar to other analgesics whose active metabolites are formed by CYP2D6 such as codeine, reduced formation of O-desmethyltramadol (M1) is likely to result in reduced analgesia for subjects maintained on methadone. Hence alternative analgesics whose metabolism is independent of CYP2D6 should be utilized in this patient population. To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects. METHODS Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites. The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012-0.103)] compared with those taking buprenorphine [0.192 (0.108-0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower
Carrieri, Patrizia Maria; Michel, Laurent; Lions, Caroline; Cohen, Julien; Vray, Muriel; Mora, Marion; Marcellin, Fabienne; Spire, Bruno; Morel, Alain; Roux, Perrine
2014-01-01
Methadone coverage is poor in many countries due in part to methadone induction being possible only in specialized care (SC). This multicenter pragmatic trial compared the effectiveness of methadone treatment between two induction models: primary care (PC) and SC. In this study, registered at ClinicalTrials.Gov (NCT00657397), opioid-dependent individuals not on methadone treatment for at least one month or receiving buprenorphine but needing to switch were randomly assigned to start methadone in PC (N = 155) or in SC (N = 66) in 10 sites in France. Visits were scheduled at months M0, M3, M6 and M12. The primary outcome was self-reported abstinence from street-opioids at 12 months (M12) (with an underlying 15% non-inferiority hypothesis for PC). Secondary outcomes were abstinence during follow-up, engagement in treatment (i.e. completing the induction period), retention and satisfaction with the explanations provided by the physician. Primary analysis used intention to treat (ITT). Mixed models and the log-rank test were used to assess the arm effect (PC vs. SC) on the course of abstinence and retention, respectively. In the ITT analysis (n = 155 in PC, 66 in SC), which compared the proportions of street-opioid abstinent participants, 85/155 (55%) and 22/66 (33%) of the participants were classified as street-opioid abstinent at M12 in PC and SC, respectively. This ITT analysis showed the non-inferiority of PC (21.5 [7.7; 35.3]). Engagement in treatment and satisfaction with the explanations provided by the physician were significantly higher in PC than SC. Retention in methadone and abstinence during follow-up were comparable in both arms (p = 0.47, p = 0.39, respectively). Under appropriate conditions, methadone induction in primary care is feasible and acceptable to both physicians and patients. It is as effective as induction in specialized care in reducing street-opioid use and ensuring engagement and retention in treatment for opioid dependence. Number Eudract
Pain in methadone patients: Time to address undertreatment and suicide risk (ANRS-Methaville trial)
Nordmann, Sandra; Vilotitch, Antoine; Lions, Caroline; Michel, Laurent; Mora, Marion; Spire, Bruno; Maradan, Gwenaelle; Bendiane, Marc-Karim; Morel, Alain; Roux, Perrine; Carrieri, Patrizia
2017-01-01
Background Pain in opioid-dependent patients is common but data measuring the course of pain (and its correlates) using validated scales in patients initiating methadone treatment are sparse. We aimed to assess pain and its interference in daily life, associated correlates, and undertreatment before and during methadone treatment. Methods This is a secondary analysis using longitudinal data of a randomized trial comparing two methadone initiation models. We assessed the effect of methadone initiation and other correlates on pain intensity and interference (using the Brief Pain Inventory) at months 0, 6 and 12 using a mixed multinomial logistic regression model. Results The study group comprised 168 patients who had data for either pain intensity or interference for at least one visit. Moderate to severe pain was reported in 12.9% of patients at M0, 5.4% at M6 and 7.3% at M12. Substantial interference with daily functioning was reported in 36.0% at M0, 14.5% at M6 and 17.1% at M12. Of the 98 visits where patients reported moderate to severe pain or substantial interference, 55.1% reported no treatment for pain relief, non-opioid analgesics were reported by 34.7%, opioid analgesics by 3.1% and both opioid and non-opioid analgesics by 7.1%. Methadone was associated with decreased pain intensity at 6 months (OR = 0.29, p = 0.04) and 12 months (OR = 0.30, p = 0.05) of follow-up and tended to be associated with substantial pain interference. Suicide risk was associated with both pain intensity and pain interference. Conclusions Methadone in opioid-dependent patients can reduce pain. However, undertreatment of pain in methadone patients remains a major clinical concern. Patients with pain are at higher risk of suicide. Adequate screening and management of pain in this population is a priority and needs to be integrated into routine comprehensive care. PMID:28520735
Pharmacotherapy in the Treatment of Addiction: Methadone
Kreek, Mary Jeanne; Borg, Lisa; Ducat, Elizabeth; Ray, Brenda
2010-01-01
Methadone maintenance treatment is the most widely available pharmacotherapy for opioid addiction and has been shown over a period of 40 years to be an effective and safe treatment. While women comprise approximately 40% of clients currently being treated in MMT programs, comparatively little research geared specifically toward this group has been published. This article begins with an overview of neurobiological studies on opioid addiction, including a discussion of gender differences, followed by a review of the pharmacology of methadone The authors then examine the particular needs and differences of women being treated in MMTs, including co-dependence with other substances, women’s health issues and psychosocial needs unique to this population. In conclusion, research shows that women have different substance abuse treatment needs in comparison to their male counterparts. One New York City MMT program that has attempted to address these differences is highlighted. PMID:20407977
Scala, Christopher; Marsot, Amélie; Limoges, Marie-Josée; Locatelli, Yann; Simon, Nicolas; Alvarez, Jean-Claude
2015-03-01
To assess the population pharmacokinetics of methadone in deer. Prospective non-randomized experimental trial. Twelve healthy adult sika deer (nine males and three females). Deer received intramuscular administration of racemic methadone hydrochloride at 0.5 mg kg(-1) or 1 mg kg(-1) . Plasma methadone and its metabolite 2-Ethylidene-1,5-Dimethyl-3,3-Diphenyl-Pyrolidine (EDDP) concentrations were determined by validated liquid chromatography coupled to tandem mass spectrometry methods, at times 0, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours. Population pharmacokinetics analysis was undertaken using a non-linear mixed effects modelling (NONMEM). A two-compartment linear disposition model best described observed time-concentration profiles of methadone and EDDP. Population parameter estimates of methadone were elimination clearance (17.3 L hour(-1) ), metabolic clearance (34.6 L hour(-1) ), volume of distribution of compartment 1 (216.0 L) and volume of distribution of compartment 2 (384.0 L). Population parameter estimates of EDDP were elimination clearance (121.0 L hour(-1) ), volume of distribution of compartment 3 (1.08 L) and volume of distribution of compartment 4 (499.5 L). The total clearance and total volume of distribution of methadone and EDDP were 51.9 L hour(-1) , 121.0 L hour (-1) , 600.0 L and 500.6 L, respectively. The methadone terminal elimination half-life was 8.19 hours. No adverse effects were observed after methadone administration. Following intramuscular injection, methadone was characterized by a large total volume of distribution, high systemic clearance and intermediate terminal half-life in sika deer. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.
Relative bioavailability of methadone hydrochloride administered in chewing gum and tablets.
Christrup, L L; Angelo, H R; Bonde, J; Kristensen, F; Rasmussen, S N
1990-01-01
Methadone administered in chewing gum in doses of 16.7-22.6 mg to seven patients in a study using an open balanced cross-over design, was compared with 20 mg of methadone given perorally as tablets. There was no significant difference in the AUC/D obtained after administration of chewing gum and tablets (p greater than 0.05). It is concluded that the chewing gum formulation should be considered for further testing with respect to suppression of abstinence syndrome in narcotic addicts.
Shimizu, Norifumi; Kishioka, Shiroh; Maeda, Takehiko; Fukazawa, Yohji; Dake, Yoshihiro; Yamamoto, Chizuko; Ozaki, Masanobu; Yamamoto, Hiroyuki
2004-08-01
Morphine's analgesic actions are thought to be mediated through both the central and peripheral nervous systems. L-type calcium channel blockers have been reported to potentiate the analgesic effects of morphine, but the locus of this interaction is not known. In this experiment, we examined the site of verapamil-induced potentiation of morphine analgesia in mice using the quaternary opioid receptor antagonist naloxone-methiodide (NLX-M). Subcutaneous injections of morphine increased locomotor activity and serum corticosterone level, which are mediated by the central nervous system. These central effects were not antagonized by 0.1 mg/kg of NLX-M, whereas this dose of NLX-M partially antagonized the analgesic effect of morphine. Treatment with verapamil potentiated morphine analgesia in a dose-dependent manner. The verapamil-induced potentiation of morphine analgesia was abolished by pretreatment with NLX-M (0.1 and 1 mg/kg). These findings suggest that peripheral mechanisms partially contribute to morphine analgesia and mediate the potentiation of morphine analgesia by verapamil.
ERIC Educational Resources Information Center
Havens, Jennifer R.; Talbert, Jeffrey C.; Walker, Robert; Leedham, Cynthia; Leukefeld, Carl G.
2006-01-01
Context: Prescription opioid abuse has emerged as a public health problem, particularly in rural America. Purpose: To examine temporal and geographic trends in rates of controlled-release oxycodone (OxyContin) prescribing for Kentucky Medicaid recipients. Methods: A cross-sectional analysis was completed in which the state was divided into 3…
Electromechanical coupling in rat basilar artery in response to morphine.
Waters, A; Harder, D R
1983-12-01
Force development, intracellular membrane potential (Em), and voltage vs. current curves were measured in rat basilar artery to help elucidate the mechanism of action of morphine sulfate and a synthetic narcotic, meperidine hydrochloride, on this preparation. Morphine sulfate caused a dose-dependent contraction of these vessels, which was reversible with naloxone. Electrical studies show that morphine may act upon this vascular smooth muscle preparation by decreasing potassium conductance (gk). This hypothesis is supported by the findings that morphine sulfate depolarized these cells and increased the input resistance (rin) determined by the application of rectangular hyperpolarizing and depolarizing current pulses through the microelectrode during impalement and recording of the associated voltage changes (delta V). Meperidine hydrochloride had significantly less effect on this preparation than morphine sulfate. Further studies show that the vehicular medium used for the commercially available preparation of naloxone (viz. the methyl and propyl esters of p-hydroxybenzoic acid in a ratio of 9:1) is, in vitro, a vasodilator of cerebral vascular smooth muscle.
Chericoni, S; Stefanelli, F; Iannella, V; Giusiani, M
2014-02-15
Opiates play a relevant role in forensic toxicology and their assay in urine or blood is usually performed for example in workplace drug-testing or toxicological investigation of drug impaired driving. The present work describes two new methods for detecting morphine, codeine and 6-monoacethyl morphine in human urine or blood using a single step derivatisation in aqueous phase. Propyl chloroformate is used as the dramatizing agent followed by liquid-liquid extraction and gas-chromatography-mass spectroscopy to detect the derivatives. The methods have been validated both for hydrolysed and unhydrolysed urine. For hydrolysed urine, the LOD and LOQ were 2.5ng/ml and 8.5ng/ml for codeine, and 5.2ng/ml and 15.1ng/ml for morphine, respectively. For unhydrolysed urine, the LOD and LOQ were 3.0ng/ml and 10.1ng/ml for codeine, 2.7ng/ml and 8.1ng/ml for morphine, 0.8ng/ml and 1.5ng/ml for 6-monoacetyl morphine, respectively. In blood, the LOD and LOQ were 0.44ng/ml and 1.46ng/ml for codeine, 0.29ng/ml and 0.98ng/ml for morphine, 0.15ng/ml and 0.51ng/ml for 6-monoacetyl morphine, respectively. The validated methods have been applied to 50 urine samples and 40 blood samples (both positive and negative) and they can be used in routine analyses. Copyright © 2013 Elsevier B.V. All rights reserved.
Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients.
Bendall, Jason C; Simpson, Paul M; Middleton, Paul M
2011-01-01
To compare the effectiveness of intravenous morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane for managing moderate to severe pain in pediatric patients in the out-of-hospital setting. We conducted a retrospective comparative study of 3,312 pediatric patients aged between 5 and 15 years who had moderate to severe pain (pain score ≥ 5) and who received intravenous morphine, IN fentanyl, or inhaled methoxyflurane, either alone or in combination, between January 1, 2004, and November 30, 2006. Multivariate logistic regression was used to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of ≥ 30% of initial pain score using an 11-point verbal numeric rating scale. Effective analgesia was achieved in 82.5% of cases overall. All analgesic agents were effective in the majority of patients (87.5%, 89.5%, and 78.3% for morphine, fentanyl, and methoxyflurane, respectively). There was evidence that methoxyflurane was less effective than both morphine (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.36-0.74) and fentanyl (OR 0.43; 95% CI 0.29-0.62; p < 0.0001). There was no clinical or statistical evidence of difference in the effectiveness of fentanyl and morphine in this population (OR 1.22; 95% CI 0.74-2.01). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Intranasal fentanyl and intravenous morphine are equally effective analgesic agents in pediatric patients with moderate to severe acute pain in the out-of-hospital setting. Methoxyflurane is less effective in comparison with both morphine and fentanyl, but is an effective analgesic in the majority of children.
Mansouri, Mohammad Taghi; Khodayar, Mohammad Javad; Tabatabaee, Amirhossein; Ghorbanzadeh, Behnam; Naghizadeh, Bahareh
2015-10-01
Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.
Narp regulates long-term aversive effects of morphine withdrawal.
Reti, Irving M; Crombag, Hans S; Takamiya, Kogo; Sutton, Jeffrey M; Guo, Ning; Dinenna, Megan L; Huganir, Richard L; Holland, Peter C; Baraban, Jay M
2008-08-01
Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. Because Narp is an immediate early gene product that is secreted at synaptic sites and binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, the authors found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, the authors evaluate whether long-term aversive effects of morphine withdrawal are altered in Narp knockout (KO) mice. The authors found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than do wild type (WT) controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction.
Protective Effect of Bacoside-A against Morphine-Induced Oxidative Stress in Rats.
Sumathi, T; Nathiya, V C; Sakthikumar, M
2011-07-01
In the present study, we investigated the protective effect of bacoside-A the active principle isolated from the plant Bacopa monniera against oxidative damage induced by morphine in rat brain. Morphine intoxicated rats received 10-160 mg/kg b.w. of morphine hydrochloride intraperitoneally for 21 days. Bacoside-A pretreated rats were administered with bacoside-A (10 mg/kg b.w/day) orally, 2 h before the injection of morphine for 21 days. Pretreatment with bacoside-A has shown to possess a significant protective role against morphine induced brain oxidative damage in the antioxidant status (total reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and lipid peroxidation) and membrane bound ATP-ases(Na(+)/K(+)ATPase. Ca(2+) and Mg(2+) ATPases) activities in rat. The results of the present study indicate that bacoside-A protects the brain from oxidative stress induced by morphine.
Coller, Janet K; Michalakas, Jennifer R; James, Heather M; Farquharson, Aaron L; Colvill, Joel; White, Jason M; Somogyi, Andrew A
2012-01-01
AIMS To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects. METHODS Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites. RESULTS The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012–0.103)] compared with those taking buprenorphine [0.192 (0.108–0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.044–0.093) and 0.126 (0.069–0.187), respectively, P= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.033–0.085) and 0.033 (0.014–0.049), respectively, P= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.635–1.30) and 0.685 (0.347–1.04), respectively, P= 0.35, probability score 0.65). CONCLUSIONS Methadone inhibited the CYP2D6-mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol. PMID:22369095
Prescription histories and dose strengths associated with overdose deaths.
Hirsch, Anne; Proescholdbell, Scott K; Bronson, William; Dasgupta, Nabarun
2014-07-01
Misuse, abuse, and diversion of prescription drugs are large and growing public health problems that have resulted in an overdose epidemic. We investigated whether short-acting or extended-release opioids were more frequently prescribed to those who died of an overdose and whether there was a linear relationship between dose strength and associated overdose deaths. The study population was North Carolina residents in 2010. We conducted a retrospective, population-based, descriptive study of medication histories of overdose decedents using data from vital statistics, medical examiner records, and a prescription drug monitoring program. Unintentional or undetermined drug overdoses were responsible for 892 deaths. Out of 191 deaths involving methadone, only two were patients in opioid treatment programs. Immediate-release oxycodone was involved in the greatest number of opioid-related deaths. Out of 221 oxycodone deaths, 134 (61%) of the decedents filled a prescription for oxycodone in the 60 days prior to death. The most common strength dispensed within 60 days to a decedent who died of an oxycodone overdose was 10 mg for immediate-release (72 prescriptions). Immediate-release oxycodone products (rho = 1.00, P < 0.01) and extended-release fentanyl products (rho = 1.00, P < 0.01) showed strong increasing linear trends between dose strength and proportion of prescriptions dispensed to decedents. A significant proportion of overdose decedents had been prescribed the same type of drugs that contributed to their death, especially for decedents who died from overdoses involving oxycodone, hydrocodone, and alprazolam. Higher dose strengths for certain opioids had higher associated mortality, and certain immediate-release opioids may be considered for public health prevention efforts.
Yang, Liling; Wang, Shuxing; Lim, Grewo; Sung, Backil; Zeng, Qing; Mao, Jianren
2008-12-01
Glutamate transporters play a crucial role in physiological glutamate homeostasis and neurotoxicity. Recently, we have shown that downregulation of glutamate transporters after chronic morphine exposure contributed to the development of morphine tolerance. In the present study, we examined whether regulation of the glutamate transporter expression with the proposed proteasome inhibitor MG-132 would contribute to the development of tolerance to repeated intrathecal (twice daily x 7 days) morphine administration in rats. The results showed that MG-132 (5 nmol) given intrathecally blocked morphine-induced glutamate transporter downregulation and the decrease in glutamate uptake activity within the spinal cord dorsal horn. Co-administration of morphine (15 nmol) with MG-132 (vehicle=1<2.5<5=10 nmol) also dose-dependently prevented the development of morphine tolerance in rats. These findings suggest that prevention of spinal glutamate transporter downregulation may regulate the glutamatergic function that has been implicated in the development of morphine tolerance. The possible relationship between MG-132-mediated regulation of glutamate transporters, ubiquitin-proteasome system, and the cellular mechanisms of morphine tolerance is discussed in light of these findings.
Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats.
Mattioli, Theresa-Alexandra M; Milne, Brian; Cahill, Catherine M
2010-04-16
The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance. Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration. Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone
Effects of morphine on brain plasticity.
Beltrán-Campos, V; Silva-Vera, M; García-Campos, M L; Díaz-Cintra, S
2015-04-01
Morphine shares with other opiates and drugs of abuse the ability to modify the plasticity of brain areas that regulate the morphology of dendrites and spines, which are the primary sites of excitatory synapses in regions of the brain involved in incentive motivation, rewards, and learning. In this review we discuss the impact of morphine use during the prenatal period of brain development and its long-term consequences in murines, and then link those consequences to similar effects occurring in human neonates and adults. Repeated exposure to morphine as treatment for pain in terminally ill patients produces long-term changes in the density of postsynaptic sites (dendrites and spines) in sensitive areas of the brain, such as the prefrontal cortex, the limbic system (hippocampus, amygdala), and caudate nuclei and nucleus accumbens. This article reviews the cellular mechanisms and receptors involved, primarily dopaminergic and glutamatergic receptors, as well as synaptic plasticity brought about by changes in dendritic spines in these areas. The actions of morphine on both developing and adult brains produce alterations in the plasticity of excitatory postsynaptic sites of the brain areas involved in limbic system functions (reward and learning). Doctors need further studies on plasticity in dendrites and spines and on signaling molecules, such as calcium, in order to improve treatments for addiction. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Bitti, Flavia S; Campagnol, Daniela; Rangel, Julia Pp; Nunes Junior, Juarez S; Loureiro, Bárbara; Monteiro, Eduardo R
2017-03-01
To evaluate the sedative and cardiopulmonary effects of three methadone doses, combined with acepromazine, in dogs. Prospective, randomized, complete block study. Six healthy, adult, cross-bred dogs weighing 17.2±4.4 kg (mean±standard deviation). Each dog was administered four treatments: acepromazine (0.05 mg kg -1 ) alone or acepromazine (same dose) in combination with methadone (0.25, 0.50 or 0.75 mg kg -1 ). All drugs were administered intramuscularly. Sedation was scored by a numeric descriptive scale (NDS, range 0-3) and a simple numerical scale (SNS, range 0-10). Heart rate, invasive blood pressure, arterial blood gases and rectal temperature were measured at 15 to 30 minute intervals for 120 minutes. According to NDS scores, mild to moderate sedation (NDS=1-2) was observed in most dogs in the acepromazine treatment, with only one out of six dogs scored as exhibiting intense sedation (NDS=3). All treatments with methadone resulted in significantly higher SNS scores compared with acepromazine alone. In these treatments, most dogs exhibited intense sedation (NDS=3). Increasing the dose of methadone from 0.25 to 0.50 or 0.75 mg kg -1 prolonged sedation in a dose-related manner, but did not influence the degree of sedation. The main adverse effects following administration of acepromazine-methadone treatments were decreased blood pressure, mild respiratory acidosis and decreased rectal temperature. These effects were well tolerated and resolved without treatment. In this study in six dogs, acepromazine-methadone administration resulted in intense sedation in most dogs. The results are interpreted to indicate that a low dose of methadone (0.25 mg kg -1 ) administered in combination with acepromazine (0.05 mg kg -1 ) will induce short-term sedation in dogs, whereas higher doses of methadone should be administered when prolonged sedation is desired. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia
Vallecillo, Gabriel; Robles, María José; Torrens, Marta; Samos, Pilar; Roquer, Albert; Martires, Paula K; Sanvisens, Arantza; Muga, Roberto; Pedro-Botet, Juan
2018-01-02
Observational studies have reported a high prevalence of obesity and diabetes in subjects on methadone therapy; there are, however, limited data about metabolic syndrome. The aim of the study was to evaluate the prevalence of metabolic syndrome and related factors in individuals with heroin use disorder on methadone therapy. A cross-sectional study in individuals with heroin use disorder on methadone therapy at a drug abuse outpatient center. Medical examinations and laboratory analyses after a 12-hour overnight fast were recorded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. One hundred and twenty-two subjects were included, with a mean age of 46.1 ± 9 years, a median body mass index (BMI) of 25.3 kg/m 2 (interquartile range [IQR]: 21.2-28), and 77.9% were men. Median exposure to methadone therapy was 13 years (IQR: 5-20). Overweight and obesity were present in 29.5% and 17.2% of the participants, respectively. Metabolic syndrome components were low high-density lipoprotein (HDL) cholesterol (51.6%), hypertriglyceridemia (36.8%), high blood pressure (36.8%), abdominal obesity (27.0%), and raised blood glucose levels (18.0%). Abdominal obesity was more prevalent in women (52% vs. 20%, P = >0.01) and high blood pressure more prevalent in men (41.1% vs. 22.2%, P = .07). Prevalence of metabolic syndrome was 29.5% (95% confidence interval [CI]: 16.6-31.8). In the multivariate logistic regression analysis, BMI (per 1 kg/m 2 increase odds ratio [OR]: 1.49, 95% CI: 1.27-1.76) and exposure time to methadone therapy (per 5 years of treatment increase OR: 1.38, 95% CI: 1.28-1.48) were associated with metabolic syndrome. Overweight and metabolic syndrome are prevalent findings in individuals with heroin use disorder on methadone therapy. Of specific concern is the association of methadone exposure with metabolic syndrome. Preventive measures and clinical routine screening should be
Kukanich, Butch; Borum, Stacy L
2008-05-01
To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. 6 healthy Greyhounds, 3 male and 3 female. Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.
Fan, Yaodong; Niu, Haichen; Rizak, Joshua D; Li, Ling; Wang, Guimei; Xu, Liqi; Ren, He; Lei, Hao; Yu, Hualin
2012-10-01
It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor (NMDAR), play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (ceftriaxone) are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone. A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory (acquisition, extinction, and reinstatement of morphine preference) in rats. A low dose of neither MK-801 (0.05 mg/kg, i.p.) nor ceftriaxone (25 mg/kg, i.p.) alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP. The combined action of a low dose of an NMDAR antagonist (MK-801) and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.
Xu, Jia; Sun, Jinling; Xue, Zhaoxia; Li, Xinwang
2014-06-18
This study investigated the relationships among an enriched environment, stress levels, and drug addiction. Mice were divided randomly into four treatment groups (n=12 each): enriched environment without restraint stress (EN), standard environment without restraint stress (SN), enriched environment with restraint stress (ES), and standard environment with restraint stress (SS). Mice were reared in the respective environment for 45 days. Then, the ES and SS groups were subjected to restraint stress daily (2 h/day) for 14 days, whereas the EN and SN groups were not subjected to restraint stress during this stage. The stress levels of all mice were tested in the elevated plus maze immediately after exposure to restraint stress. After the 2-week stress testing period, mice were administered acute or chronic morphine (5 mg/kg) treatment for 7 days. Then, after a 7-day withdrawal period, the mice were injected with saline (1 ml/kg) or morphine (5 mg/kg) daily for 2 days to observe locomotor activity. The results indicated that the enriched environment reduced the stress and locomotor activity induced by acute morphine administration or saline after chronic morphine treatment. However, the enriched environment did not significantly inhibit locomotor activity induced by morphine challenge. In addition, the stress level did not mediate the effect of the enriched environment on drug-induced locomotor activity after acute or chronic morphine treatment.
Drug interactions between buprenorphine, methadone and hepatitis C therapeutics.
Ogbuagu, Onyema; Friedland, Gerald; Bruce, R Douglas
2016-07-01
People who inject drugs (PWID) and other individuals with opioid use disorders have a dramatically higher prevalence of hepatitis C virus (HCV) infection than the general population. The availability of novel direct acting antivirals (DAAs) for the treatment of HCV infection with very high efficacy, improved tolerability and shortened treatment durations have led to global efforts to ramp up treatment for all HCV-infected individuals to prevent or delay complications of the disease. Individuals with opioid use disorders, including those on medication-assisted therapy such as methadone or buprenorphine, are a key demographic group that can benefit from HCV treatment given their high HCV prevalence; however, pharmacokinetic and pharmacodynamic drug interactions could blunt their utility. We performed a comprehensive literature review of published and unpublished data from PubMed database, relevant conference abstracts/proceedings and FDA approved drug package inserts, to review the pharmacokinetic (PK) profile and drug interactions between currently approved HCV DAAs and methadone and buprenorphine. The paper highlights specific drug combinations which result in altered opioid drug levels including telaprevir/methadone, daclatasvir/buprenorphine, and Abbvie 3D combination regimen (paritaprevir, ritonavir, ombitasvir and dasabuvir)/buprenorphine. However, concurrent pharmacodynamics assessments did not reveal significant signs and symptoms of opioid withdrawal or toxicity that would preclude concurrent administration.
Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury
Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W.
2009-01-01
Abstract Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 μg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-μg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 μg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord. PMID:19388818
Effect of Bacopasides on acquisition and expression of morphine tolerance.
Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Badshah, Amir; Ullah, Ihsan; Ullah, Sami
2011-07-15
Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance. Copyright © 2011 Elsevier GmbH. All rights reserved.
GORDON, MICHAEL S.; KINLOCK, TIMOTHY W.; COUVILLION, KATHRYN A.; SCHWARTZ, ROBERT P.; O’GRADY, KEVIN
2014-01-01
The present report is an intent-to-treat analysis involving secondary data drawn from the first randomized clinical trial of prison-initiated methadone in the United States. This study examined predictors of treatment entry and completion in prison. A sample of 211 adult male prerelease inmates with preincarceration heroin dependence were randomly assigned to one of three treatment conditions: counseling only (counseling in prison; n= 70); counseling plus transfer (counseling in prison with transfer to methadone maintenance treatment upon release; n= 70); and counseling plus methadone (methadone maintenance in prison, continued in a community-based methadone maintenance program upon release; n= 71). Entered prison treatment (p <. 01), and completed prison treatment (p< .001) were significantly predicted by the set of 10 explanatory variables and favored the treatment conditions receiving methadone. The present results indicate that individuals who are older in age and have longer prison sentences may have better outcomes than younger individuals with shorter sentences, meaning they are more likely to enter and complete prison-based treatment. Furthermore, implications for the treatment of prisoners with prior heroin dependence and for conducting clinical trials may indicate the importance of examining individual characteristics and the possibility of the examination of patient preference. PMID:25392605
Gordon, Michael S; Kinlock, Timothy W; Couvillion, Kathryn A; Schwartz, Robert P; O'Grady, Kevin
2012-05-01
The present report is an intent-to-treat analysis involving secondary data drawn from the first randomized clinical trial of prison-initiated methadone in the United States. This study examined predictors of treatment entry and completion in prison. A sample of 211 adult male prerelease inmates with preincarceration heroin dependence were randomly assigned to one of three treatment conditions: counseling only (counseling in prison; n= 70); counseling plus transfer (counseling in prison with transfer to methadone maintenance treatment upon release; n= 70); and counseling plus methadone (methadone maintenance in prison, continued in a community-based methadone maintenance program upon release; n= 71). Entered prison treatment (p <. 01), and completed prison treatment (p< .001) were significantly predicted by the set of 10 explanatory variables and favored the treatment conditions receiving methadone. The present results indicate that individuals who are older in age and have longer prison sentences may have better outcomes than younger individuals with shorter sentences, meaning they are more likely to enter and complete prison-based treatment. Furthermore, implications for the treatment of prisoners with prior heroin dependence and for conducting clinical trials may indicate the importance of examining individual characteristics and the possibility of the examination of patient preference.
Synthetic substances with morphine-like effect
Eddy, Nathan B.; Halbach, H.; Braenden, Olav J.
1957-01-01
A review of effects in man of morphine-like drugs which have been brought under international narcotics control is presented in the form of individual monographs. These are based on controlled observations with quantitative data and significant reports of results obtained in medical practice. In a summarizing section, the drugs are compared with respect to effectiveness, side-effects and addiction liability. Morphine-like drugs of natural and synthetic origin now cover a wide range of potency (analgesic, antitussive), not necessarily paralleled by incidence of side-effects or addiction liability. PMID:13511135