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  1. Quality of life under oxycodone/naloxone, oxycodone, or morphine treatment for chronic low back pain in routine clinical practice

    PubMed Central

    Ueberall, Michael A; Eberhardt, Alice; Mueller-Schwefe, Gerhard HH

    2016-01-01

    Objective To compare the quality of life of patients with moderate-to-severe chronic low back pain under treatment with the WHO-step III opioids oxycodone/naloxone, oxycodone, or morphine in routine clinical practice. Study design Prospective, 12-week, randomized, open-label, blinded end-point study in 88 medical centers in Germany. Patients and methods A total of 901 patients requiring around-the-clock pain treatment with a WHO-step III opioid were randomized to either morphine, oxycodone, or oxycodone/naloxone (1:1:1). Changes from baseline to week 12 in quality of life were assessed using different validated tools (EuroQoL-5 Dimensions [EQ-5D], Short Form 12 [SF-12], quality of life impairment by pain inventory [QLIP]). Results EQ-5D weighted index scores significantly improved over the 12-week treatment period under all three opioids (P<0.001) with significantly greater improvements under oxycodone/naloxone (65.2% vs 49.6% for oxycodone and 48.2% for morphine, P<0.001). The proportion of patients without EQ-5D complaints was also significantly higher under oxycodone/naloxone (P<0.001). Although quality of life ratings with the QLIP inventory showed significant improvements in all the three treatment arms, improvements were significantly higher under oxycodone/naloxone than under oxycodone and morphine (P<0.001): 90.7% of all oxycodone/naloxone patients achieved ≥30% improvements in quality of life, 72.8% had ≥50%, and 33.2% ≥70% improvements. Similarly, both physical and mental SF-12 component scores showed significantly greater improvements under oxycodone/naloxone with both scores close to the German population norm after 12 weeks. Conclusion Treatment with morphine, oxycodone, or oxycodone/naloxone under routine daily practice conditions significantly improved state of health and quality of life of patients with moderate-to-severe low back pain over a 12-week treatment period. Comparison between the treatment groups showed significantly greater

  2. Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment

    PubMed Central

    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

  3. Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain

    PubMed Central

    Thibault, Karine; Calvino, Bernard; Rivals, Isabelle; Marchand, Fabien; Dubacq, Sophie; McMahon, Stephen B.; Pezet, Sophie

    2014-01-01

    Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone. PMID:24618941

  4. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

    PubMed

    Pergolizzi, Joseph; Böger, Rainer H; Budd, Keith; Dahan, Albert; Erdine, Serdar; Hans, Guy; Kress, Hans-Georg; Langford, Richard; Likar, Rudolf; Raffa, Robert B; Sacerdote, Paola

    2008-01-01

    status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in

  5. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

    PubMed

    Pergolizzi, Joseph; Böger, Rainer H; Budd, Keith; Dahan, Albert; Erdine, Serdar; Hans, Guy; Kress, Hans-Georg; Langford, Richard; Likar, Rudolf; Raffa, Robert B; Sacerdote, Paola

    2008-01-01

    status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in

  6. Oxycodone

    MedlinePlus

    ... 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), ...

  7. Intravenous Oxycodone, Hydrocodone and Morphine in Recreational Opioid Users: Abuse Potential and Relative Potencies

    PubMed Central

    Stoops, William W.; Hatton, Kevin W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2010-01-01

    Rationale Nonmedical use and abuse of prescription opioids is an increasing public health problem. Intravenous (IV) administration of opioid analgesics intended for oral use is not uncommon, yet little is known about the relative abuse potential of these drugs when administered intravenously to recreational opioid abusers without physical dependence. Methods This inpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential of IV doses of oxycodone, hydrocodone and morphine. Nine healthy adult participants reporting recreational opioid use and histories of IV opioid use completed 11 experimental sessions, including one active-dose practice session. IV doses were infused over 5-min and included three identical doses of each opioid (5, 10 and 20 mg/10 ml) and saline placebo. Physiological, subjective and performance effects were collected before and for 6 h after drug administration. Results All three opioids produced prototypical mu agonist effects (e.g., miosis; increased ratings of liking) that were generally dose-related. Pharmacodynamic effects were observed within 5 min of IV administration. Physiological effects were more prolonged than subjective effects for all three drugs. While the magnitude of effects was generally comparable across drugs and qualitatively similar, valid potency assays indicated the following potency relationship: oxycodone > morphine > hydrocodone. Conclusions There were modest potency differences between oxycodone, hydrocodone and morphine, but their overall profile of effects was similar, indicating significant abuse potential when administered intravenously. PMID:20665209

  8. Comparison of epidural oxycodone and epidural morphine for post-caesarean section analgesia: A randomised controlled trial

    PubMed Central

    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

  9. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats.

    PubMed

    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.

  10. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats

    PubMed Central

    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

  11. Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors.

    PubMed

    Emery, Michael A; Bates, M L Shawn; Wellman, Paul J; Eitan, Shoshana

    2015-05-01

    Oxycodone and hydrocodone are opioids which are widely used for pain management and are also commonly misused and abused. The exposure to opioid analgesics has been associated with altered responses of D2-like dopamine receptors (D2DRs). Our recent results suggest that various opioids will differentially modulate the responses of D2DRs. The D2DRs are known to be involved in the pathology of addiction and other mental illnesses, indicating the need to improve our understanding of the effects of opioid analgesics on the responses of the D2DRs. Thus, in this study, we first established equianalgesic oral doses of oxycodone, hydrocodone, and morphine using the tail withdrawal assay. Then, mice were orally administered (gavage) with the various opioids or saline once daily for 6 days. Twenty-four hours later, the mice were tested for their locomotor response to quinpirole, a D2/D3 dopamine receptor agonist. Mice pretreated with oxycodone showed significantly greater locomotor supersensitivity to quinpirole than did morphine-pretreated mice, while hydrocodone-pretreated mice showed sensitivity in between that of mice treated with morphine and oxycodone. This finding suggests that various opioids differentially modulate the responses of D2DRs. It provides further evidence supporting of the notion that various opioids carry differential risks to the dopamine reward system. PMID:25617530

  12. Chronic methadone treatment shows a better cost/benefit ratio than chronic morphine in mice.

    PubMed

    Enquist, Johan; Ferwerda, Madeline; Milan-Lobo, Laura; Whistler, Jennifer L

    2012-02-01

    Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading μ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.

  13. Comparison of oxycodone and morphine on the proliferation, apoptosis and expression of related molecules in the A549 human lung adenocarcinoma cell line

    PubMed Central

    Tian, Mi; Jin, Li; Li, Renqi; Zhu, Sihai; Ji, Muhuo; Li, Weiyan

    2016-01-01

    The present study aimed to compare the effects of oxycodone and morphine hydrochloride on the proliferation, apoptosis and migration of A549 lung cancer cells. A549 human lung cancer cells were cultured in vitro and treated with oxycodone or morphine at various concentrations (10, 20 and 40 µg/ml). Cell migration was determined using a wound healing assay, whereas apoptosis was detected using flow cytometry. Reverse transcription quantitative-polymerase chain reaction was performed in order to assess the apoptosis-related gene expression levels, including p53, B-cell lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax). The levels of vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (uPA) were detected using enzyme-linked immunosorbent assays. The expression levels of intercellular cell adhesion molecule (ICAM)-1 were determined by immunofluorescence. In the present study, oxycodone and morphine induced apoptosis in A549 lung cancer cells with similar potency; however, >20 µg/ml oxycodone was more effective at inhibiting cell proliferation (P<0.05) and migration (P<0.05), as compared with morphine at the same concentration. Oxycodone induced a dose-dependent increase in the expression levels of p53 and Bax apoptosis-related genes, whereas it decreased the gene expression levels of Bcl-2. Furthermore, oxycodone decreased, whereas morphine increased, the expression levels of ICAM-1 in a concentration-dependent manner. In addition, at 40 µg/ml, the expression levels of VEGF and uPA in the morphine group were significantly higher than those demonstrated in the oxycodone group (P<0.05). In conclusion, oxycodone was more effective in inhibiting the proliferation and migration of A549 lung cancer cells, as compared with morphine. PMID:27446244

  14. Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

    PubMed

    Neelakantan, Harshini; Ward, Sara Jane; Walker, Ellen Ann

    2015-08-01

    The use of prescription opioids for clinical management of pain remains problematic because of concerns about addiction associated with opioid use. Another difficulty in pain management is the increasing evidence for sex differences in pain behavior and opioid-induced behavioral effects. However, few studies have documented the abuse potential of prescription opioids as a function of pain in rodents, with significant gaps in the literature pertaining to sex differences in the interaction between pain and opioid effects. The present study evaluated the effects of an experimentally induced acute pain state (acetic acid injections) on the potency of morphine and oxycodone to produce discriminative stimulus effects in male and female C57Bl/6 mice trained to discriminate 3.2 mg/kg morphine from saline. Acetic acid injections attenuated the stimulus potency of morphine by 2.2-fold but not the stimulus potency of oxycodone in male mice. Acetic acid injections did not alter the discriminative stimulus effects of either morphine or oxycodone in female mice. The antinociceptive effects of the 2 opioids were evaluated using the acetic acid-induced stretching test. For antinociceptive effects, morphine was 2.0-fold less potent relative to oxycodone in male mice, whereas morphine and oxycodone were equipotent in female mice. Taken together, these results indicate that acetic acid-induced acute pain differentially modulates the discriminative stimulus effects of morphine in male and female mice and that this change may be related to the variable antinociceptive effectiveness of these opioids across sexes.

  15. Effect of estrogen on morphine- and oxycodone-induced antinociception in a female femur bone cancer pain model.

    PubMed

    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.

  16. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

    PubMed

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2013-09-01

    This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3: 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3: 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  17. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts

    PubMed Central

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2014-01-01

    This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  18. Contrasting cardiovascular properties of the µ-opioid agonists morphine and methadone in the rat.

    PubMed

    Tung, Kenneth H; Angus, James A; Wright, Christine E

    2015-09-01

    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.

  19. Impact of morphine dependency and detoxification by methadone on male’s rat reproductive system

    PubMed Central

    Ghowsi, Mahnaz; Yousofvand, Namdar

    2015-01-01

    Background: One of the problems that addicts suffer from is decreased libido. Erectile dysfunction has been reported in men using opioids for treatment of heroin addiction. Objective: The study was performed to investigate the effects of morphine and detoxification with methadone as causes of sexual dysfunction in addiction. Methods and Methods: A total of 40 adult male rats (Wistar) were used. Animals were divided in to 4 groups. Control groups received saline for 30 days. Other 2 groups received 10 mg/kg morphine on day 1 and the morphine doses increased daily by 2 mg/kg increments per day until in day 30 a maximum of 68 mg/kg twice daily was achieved. Withdrawal syndrome sings were evaluated. At the end of period, one group of 2 morphine dependent groups was treated with methadone during 14 days. Animals in group 4 (saline solution+ methadone) received saline for 30 consecutive days and then detoxified with methadone during 14 days. Partial weights of seminal vesicles, testes, prostates, seminal vesicles content, concentrations of luteinizing hormone, follicle stimulating hormone, and testosterone in serum were determined. Results: In the dependent group serum levels of testosterone (p<0.001), folicle stimulating hormone (p=0.0097) and luteinizing hormone (p=0.0031) as well as the weights of testes (p=0.0051), partial weights of prostates, seminal vesicles and seminal vesicles contents (p<0.001) were reduced as compared with control group. In the morphine dependent animals detoxified with methadone, testosterone concentrations and seminal vesicles contents remained lower than levels in the control group (p<0.001). Conclusion: The results suggest that morphine dependence may impair the reproductive function in male rats. PMID:26221126

  20. Azole antifungal inhibition of buprenorphine, methadone and oxycodone in vitro metabolism.

    PubMed

    Moody, David E; Liu, Fenyun; Fang, Wenfang B

    2015-06-01

    Opioid-related mortality rates have escalated. Drug interactions may increase blood concentrations of the opioid. We therefore used human liver microsomes (HLMs) and cDNA-expressed human cytochrome P450s (rCYPs) to study in vitro inhibition of buprenorphine metabolism to norbuprenorphine (CYP3A4 and 2C8), oxycodone metabolism to noroxycodone (CYP3A4 and 2C18) and oxymorphone (CYP2D6), and methadone metabolism to R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP; CYP3A4 and 2B6). In this study, we have examined the inhibitory effect of 12 (mostly antifungal) azoles. These compounds have a wide range of solubility; to keep organic solvent ≤1%, there was an equally wide range of highest concentration tested (e.g., itraconazole 5 µM to fluconazole 1000 µM). Inhibitors were first incubated with HLMs at three concentrations with or without preincubation of inhibitor with reducing equivalents to also screen for time-dependent inhibition (TDI). Posaconazole displayed evidence of TDI; metronidazole and albendazole had no significant effect. Azoles were next screened at the highest achievable concentration for non-CYP3A4 pathways. IC50 values (µM) were determined for most CYP3A4 pathways (ranges) and other pathways as dictated by screen results: clotrimazole (0.30 - 0.35; others >30 µM); econazole (2.2 - 4.9; 2B6 R-EDDP - 9.5, S-EDDP - 6.8; 2C8 - 6.0; 2C18 - 1.0; 2D6 - 1.2); fluconazole (7.7 - 66; 2B6 - 313, 361; 2C8 - 1240; 2C18 - 17; 2D6 - 1000); itraconazole (2.5 to >5; others >5); ketoconazole (0.032 - 0.094; 2B6 - 12, 31; 2C8 - 78; 2C18 - 0.98; 2D6 - 182); miconazole (2.3 - 7.6; 2B6 - 2.8, 2.8; 2C8 - 5.3; 2C18 - 3.1; 2D6 - 5.9); posaconazole (3.4 - 20; 2C18 - 3.8; others >30); terconazole (0.48 to >10; 2C18 - 8.1; others >10) and voriconazole (0.40 - 15; 2B6 - 2.4, 2.5; 2C8 - 170; 2C18 - 13; 2D6 >300). Modeling based on estimated Ki values and plasma concentrations from the literature suggest that the orally administered azoles, particularly

  1. Popliteal Vein Blood Sampling and the Postmortem Redistribution of Diazepam, Methadone, and Morphine.

    PubMed

    Lemaire, Eric; Schmidt, Carl; Denooz, Raphael; Charlier, Corinne; Boxho, Philippe

    2016-07-01

    Postmortem redistribution (PMR) refers to the site- and time-related blood drug concentration variations after death. We compared central blood (cardiac and subclavian) with peripheral blood (femoral and popliteal) concentrations of diazepam, methadone, and morphine. To our knowledge, popliteal blood has never been compared with other sites. Intracardiac blood (ICB), subclavian blood (SB), femoral blood (FB), and popliteal blood (PB) were sampled in 30 cases. To assess PMR, mean concentrations and ratios were compared. Influence of postmortem interval on mean ratios was also assessed. Results show that popliteal mean concentrations were lower than those for other sites for all three drugs, even lower than femoral blood; mean ratios suggested that the popliteal site was less subject to PMR, and estimated postmortem interval did not influence ratios except for diazepam and methadone FB/PB. In conclusion, our study is the first to explore the popliteal site and suggests that popliteal blood is less prone to postmortem redistribution. PMID:27364283

  2. Methadone, Morphine, or Oxycodone in Treating Pain in Patients With Cancer

    ClinicalTrials.gov

    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

  3. Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence.

    PubMed

    Hämmig, Robert; Köhler, Wilfried; Bonorden-Kleij, Karin; Weber, Bernd; Lebentrau, Karin; Berthel, Toni; Babic-Hohnjec, Lucija; Vollmert, Christian; Höpner, Doris; Gholami, Najibulah; Verthein, Uwe; Haasen, Christian; Reimer, Jens; Ruckes, Christian

    2014-10-01

    Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n=95 group A, n=103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

  4. The biochemical analysis of methadone modulation on morphine-induced tolerance and dependence in the rat brain.

    PubMed

    He, Li; Whistler, Jennifer L

    2007-01-01

    We have recently demonstrated that the combination of methadone and morphine enhances the ability of morphine to induce mu-opioid peptide (MOP) receptor endocytosis. As a result, rats receiving both drugs show reduced morphine tolerance and dependence. In the present study, we identify the biochemical basis for the protective effect of the drug combination. In rats treated with morphine alone, the inhibitory effect of DAMGO on forskolin-stimulated adenylyl cyclase activity was significantly reduced in a brain-region-selective manner. Importantly, these reductions were prevented in animals receiving the drug combination. We found that these changes were not due to alterations in MOP receptor density, or MOP receptor-G protein coupling, as no significant change in these parameters was observed. Together these data demonstrate that neither changes in receptor number nor function are required for morphine tolerance and dependence. Rather, brain-region-selective changes in adenylyl cyclase signal transduction are critical, and both these biochemical changes and the behavioral effects are prevented by facilitating endocytosis of the MOP receptor.

  5. Physical compatibility of binary and ternary mixtures of morphine and methadone with other drugs for parenteral administration in palliative care.

    PubMed

    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. PMID:22252547

  6. Morphine

    MedlinePlus

    Morphine is used to relieve moderate to severe pain. Morphine extended-release tablets and capsules are only used ... controlled by the use of other pain medications. Morphine extended-release tablets and capsules should not be ...

  7. The effect of chronic morphine or methadone exposure and withdrawal on clock gene expression in the rat suprachiasmatic nucleus and AA-NAT activity in the pineal gland.

    PubMed

    Pačesová, D; Novotný, J; Bendová, Z

    2016-07-18

    The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine. PMID:27070740

  8. Validation of an extraction and gas chromatography-mass spectrometry quantification method for cocaine, methadone, and morphine in postmortem adipose tissue.

    PubMed

    Colucci, A P; Aventaggiato, L; Centrone, M; Gagliano-Candela, R

    2010-01-01

    Adipose tissue is a complex biological matrix that necessitates several pre-analytical preparation steps to separate drugs and metabolites from the lipophilic matrix. A novel, sensitive, and specific gas chromatographic-mass spectrometric (GC-MS) method for the determination of cocaine (metabolites), methadone, and morphine in postmortem adipose tissue was developed, optimized, and validated. The method involves the aqueous acid extraction of analytes, alkalinization of the extract, solid-phase extraction with chloroform, and derivatization with BSTFA before GC-MS analysis. Deuterated compounds were used as internal standards for determination and quantification of analytes. Limits of detection were 0.005 microg/g for cocaine and cocaethylene, 0.02 microg/g for benzoylecgonine, 0.01 microg/g for ecgoninemethylester, 0.005 microg/g for methadone, and 0.01 microg/g for morphine. Linearity ranged from 0.1 to 1.000 microg/g for all analytes. Intra- and interday accuracy ranged from 70.6 to 105%, and intra- and interday precisions were less than 8.2% and 8.6%, respectively, for all analytes. The method showed a good recovery. PMID:20663287

  9. Liposolubility and protein binding of oxycodone in vitro.

    PubMed

    Pöyhiä, R; Seppälä, T

    1994-01-01

    The liposolubility and protein-binding of oxycodone were studied in vitro and compared with other opioids. Liposolubility was assessed by three different methods: 1) the shake-flask method with n-octanol at pH 4-9, 2) measuring the retention time in reversed-phase high-performance liquid chromatography (RP-HPLC) with a LiChrosorb RP-18 and 3) studying the solubility in human epidural and subcutaneous fat. Human fat was obtained from patients undergoing surgery for herniated intervertebral disc. After incubation, pieces of fatty tissue immersed in a buffer solution containing oxycodone, morphine, pethidine or fentanyl for 10-40 min.; tissue pieces were homogenated, opioids extracted and opioid concentrations measured by gas- and high-performance liquid chromatography. The binding of oxycodone, morphine and fentanyl in plasma proteins was studied by ultrafiltration (Amicon-kit). The mean apparent partition coefficients Papp of oxycodone, morphine, pethidine and fentanyl in n-octanol at pH 7 were 0.7, 0.5, 10.5 and 399, respectively. The retention times in RP-HPLC for oxycodone, morphine, pethidine, fentanyl and buprenorphine were 0.6 min., 0.2 min., 2.4 min., 2.3 min. and 10.5 min., respectively. Only buprenorphine and fentanyl appeared to be highly lipophilic in the human fat tissue experiments; no difference was found between epidural or subcutaneous fat in this respect. The in vitro protein binding of oxycodone was 38%, of morphine 31% and of fentanyl 87% in average. It is concluded that, in terms of physiochemical properties, liposolubility and protein-binding, oxycodone resembles morphine more than it does fentanyl.

  10. An oxycodone conjugate vaccine elicits drug-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia.

    PubMed

    Pravetoni, M; Le Naour, M; Harmon, T M; Tucker, A M; Portoghese, P S; Pentel, P R

    2012-04-01

    Opioid conjugate vaccines have shown promise in attenuating the behavioral effects of heroin or morphine in animals. The goal of this study was to extend this approach to oxycodone (OXY), a commonly abused prescription opioid. Haptens were generated by adding tetraglycine (Gly)(4) or hemisuccinate (HS) linkers at the 6-position of OXY. Immunization of rats with OXY(Gly)(4) conjugated to the carrier proteins bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH) produced high-titer antibodies to OXY and its metabolite oxymorphone with substantially lower affinities for other structurally related opioid agonists and antagonists. There was no measurable binding of antibody by the (Gly)(4) linker alone or off-target opioids methadone and buprenorphine. OXY(HS) conjugates were less immunogenic despite achieving protein haptenation ratios comparable to OXY(Gly)(4)-BSA. In rats given a single intravenous dose of OXY, immunization with OXY(Gly)(4)-KLH increased OXY protein binding and retention in serum while decreasing its unbound (free) concentration in plasma and distribution to brain. Vaccine efficacy correlated with serum antibody titers, and it was greatest in rats given the lowest OXY dose (0.05 mg/kg) but was significant even after a larger OXY dose (0.5 mg/kg), equivalent to the high end of the therapeutic range in humans. These effects of OXY(Gly)(4)-KLH on drug disposition were comparable to those of nicotine or cocaine vaccines that are in clinical trials as addiction treatments. Immunization with OXY(Gly)(4)-KLH also reduced OXY analgesia in a thermal nociception test. These data support further study of vaccination with the OXY(Gly)(4)-KLH immunogen as a potential treatment option for OXY abuse or addiction.

  11. An Oxycodone Conjugate Vaccine Elicits Drug-Specific Antibodies that Reduce Oxycodone Distribution to Brain and Hot-Plate Analgesia

    PubMed Central

    Le Naour, M.; Harmon, T. M.; Tucker, A. M.; Portoghese, P. S.; Pentel, P. R.

    2012-01-01

    Opioid conjugate vaccines have shown promise in attenuating the behavioral effects of heroin or morphine in animals. The goal of this study was to extend this approach to oxycodone (OXY), a commonly abused prescription opioid. Haptens were generated by adding tetraglycine (Gly)4 or hemisuccinate (HS) linkers at the 6-position of OXY. Immunization of rats with OXY(Gly)4 conjugated to the carrier proteins bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH) produced high-titer antibodies to OXY and its metabolite oxymorphone with substantially lower affinities for other structurally related opioid agonists and antagonists. There was no measurable binding of antibody by the (Gly)4 linker alone or off-target opioids methadone and buprenorphine. OXY(HS) conjugates were less immunogenic despite achieving protein haptenation ratios comparable to OXY(Gly)4-BSA. In rats given a single intravenous dose of OXY, immunization with OXY(Gly)4-KLH increased OXY protein binding and retention in serum while decreasing its unbound (free) concentration in plasma and distribution to brain. Vaccine efficacy correlated with serum antibody titers, and it was greatest in rats given the lowest OXY dose (0.05 mg/kg) but was significant even after a larger OXY dose (0.5 mg/kg), equivalent to the high end of the therapeutic range in humans. These effects of OXY(Gly)4-KLH on drug disposition were comparable to those of nicotine or cocaine vaccines that are in clinical trials as addiction treatments. Immunization with OXY(Gly)4-KLH also reduced OXY analgesia in a thermal nociception test. These data support further study of vaccination with the OXY(Gly)4-KLH immunogen as a potential treatment option for OXY abuse or addiction. PMID:22262924

  12. Hydrocodone/oxycodone overdose

    MedlinePlus

    Hydrocodone and oxycodone belong to a class of narcotic medicines called opiates. These medicines are man-made ... medicines may also be combined with the non-narcotic medicine, acetaminophen (Tylenol).

  13. Enhanced GABAergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model

    PubMed Central

    Takasu, Keiko; Ogawa, Koichi; Nakamura, Atsushi; Kanbara, Tomoe; Ono, Hiroko; Tomii, Takako; Morioka, Yasuhide; Hasegawa, Minoru; Shibasaki, Masahiro; Mori, Tomohisa; Suzuki, Tsutomu; Sakaguchi, Gaku

    2015-01-01

    Background and Purpose We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain. Experimental Approach We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model. Key Results The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input–output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir3.1 channels. Conclusion and Implications Our results demonstrate that Kir3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir3.1 channel activation. PMID:25521524

  14. Methadone overdose

    MedlinePlus

    ... strong painkiller. It is also used to treat heroin addiction. Methadone overdose occurs when someone accidentally or ... A.M. Editorial team. Related MedlinePlus Health Topics Heroin Pain Relievers Browse the Encyclopedia A.D.A. ...

  15. Optimum Methadone Compliance Testing

    PubMed Central

    2006-01-01

    Executive Summary Objective The objective of this analysis was to determine the diagnostic utility of oral fluid testing collected with the Intercept oral fluid collection device. Clinical Need: Target Population and Condition Opioids (opiates or narcotics) are a class of drugs derived from the opium poppy plant that typically relieve pain and produce a euphoric feeling. Methadone is a long-acting synthetic opioid used to treat opioid dependence and chronic pain. It prevents symptoms of opioid withdrawal, reduces opioid cravings and blocks the euphoric effects of short-acting opioids such as heroin and morphine. Opioid dependence is associated with harms including an increased risk of exposure to Human Immunodeficiency Virus and Hepatitis C as well as other health, social and psychological crises. The goal of methadone treatment is harm reduction. Treatment with methadone for opioid dependence is often a long-term therapy. The Ontario College of Physicians and Surgeons estimates that there are currently 250 physicians qualified to prescribe methadone, and 15,500 people in methadone maintenance programs across Ontario. Drug testing is a clinical tool whose purpose is to provide objective meaningful information, which will reinforce positive behavioral changes in patients and guide further treatment needs. Such information includes knowledge of whether the patient is taking their methadone as prescribed and reducing or abstaining from using opioid and other drugs of abuse use. The results of drug testing can be used with behavior modification techniques (contingency management techniques) where positive reinforcements such as increased methadone take-home privileges, sustained employment or parole are granted for drug screens negative for opioid use, and negative reinforcement including loss of these privileges for drug screens positive for opioid used. Body fluids including blood, oral fluid, often referred to as saliva, and urine may contain metabolites and the

  16. Oxycodone N-oxide.

    PubMed

    Sonar, Vijayakumar N; Parkin, Sean; Crooks, Peter A

    2012-11-01

    The title compound, (5R,9R,13S,14S,17R)-14-hydroxy-3-methoxy-17-methyl-4,5-epoxymorphinan-6-one N-oxide, C(18)H(21)NO(5), has been prepared in a diastereomerically pure form by the reaction of oxycodone with 3-chloroperbenzoic acid and subsequent crystallization of the product from chloroform. The crystal packing shows that the molecule exhibits intramolecular O-H···O [D···A = 2.482 (2) Å] hydrogen bonding. In addition, there are weak intermolecular C-H...O interactions which, along with van der Waals forces, stabilize the structure. The new chiral center at the 17-position is demonstrated to be R.

  17. 78 FR 19016 - Importer of Controlled Substances; Notice of Registration; Mylan Pharmaceuticals, Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-28

    ... FR 72409, Mylan Pharmaceuticals, Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, made...) II Oxycodone (9143) II Hydromorphone (9150) II Methadone (9250) II Morphine (9300) II Fentanyl...

  18. Opioid Use and Neural Tube Defects

    MedlinePlus

    ... study include codeine, oxycodone, hydrocodone, morphine, propoxyphene, meperidine, methadone, tramadol, hydromorphone, butorphanol, heroin, fentanyl, buprenorphine, nalbuphine, and diphenoxylate. Making Treatment Decisions When making treatment decisions just before or ...

  19. The use of methadone for cancer pain.

    PubMed

    Ripamonti, Carla; Bianchi, Mauro

    2002-06-01

    Methadone is not a new analgesic drug [69]. Several studies have demonstrated that methadone is a valid alternative to morphine, hydromorphone, and fentanyl for the treatment of cancer-related pain, and extensive reviews on the subject have been published in recent years [10,23,25,64,70,71]. Most people involved in pain therapy, however, are not well informed about the properties of methadone. The authors believe that the low cost of methadone paradoxically contributes to the limited knowledge of its characteristics and to the restricted therapeutic use of this drug. The low cost of methadone means there is little financial incentive for pharmaceutical companies to invest in research or to disseminate scientific information. Unfortunately, the lack of scientific information from pharmaceutical companies frequently results in a lack of knowledge on the part of physicians. Unless the existing approach changes, both culturally and politically, ignorance about methadone will persist among medical experts. The low cost of methadone, rather than being an advantage, will result in the limited exploitation of an effective drug.

  20. Morphine Rectal

    MedlinePlus

    Rectal morphine is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Rectal morphine comes as a suppository to insert in the rectum. It is usually inserted every 4 hours. Use ...

  1. Morphine Injection

    MedlinePlus

    Morphine injection is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Morphine injection comes as a solution (liquid) to inject intramuscularly (into a muscle) or intravenously (into a ...

  2. Topical methadone and meperidine analgesic synergy in the mouse

    PubMed Central

    Kolesnikov, Yuri A.; Oksman, Galina; Pasternak, Gavril W.

    2010-01-01

    Topical analgesics have many potential advantages over systemic administration. Prior work has shown potent analgesic activity of a number of topical opioids in the radiant heat tailflick assay. The current study confirms the analgesic activity of morphine and extends it to two other mu opioids, methadone and meperidine. Combinations of topical morphine and lidocaine are synergistic. Similarly, the combination of methadone and lidocaine is synergistic. While there appeared to be some potentiation with the combination of meperidine and lidocaine, it did not achieve significance. Systemically, prior studies have shown that co-administration of morphine and methadone was synergistic. The combination of morphine and methadone was also synergistic when given topically. In contrast, the combination of morphine and meperidine was not synergistic systemically and it was not synergistic topically. Thus, the pharmacology of topical opioids mimics that seen with systemic administration. Their activity in the topical model supports their potential utility while the local limitation of their actions offers the possibility of a reduced side-effect profile. PMID:20433826

  3. An opiate cocktail that reduces morphine tolerance and dependence.

    PubMed

    He, Li; Whistler, Jennifer L

    2005-06-01

    Morphine is an exceptionally effective analgesic whose utility is compromised by the development of tolerance and dependence to the drug. Morphine analgesia and dependence are mediated by its activity at the mu opioid peptide (MOP) receptor [1]. The MOP receptor is activated not only by morphine, but also by other opiate drugs such as methadone and endogenous opioids such as endorphins. Morphine, however, is a unique opioid agonist ligand because it fails to induce endocytic trafficking of the MOP receptor [2], whereas the endogenous ligands and methadone do facilitate endocytosis [3]. Using the unique pharmacology of the MOP receptor and its proposed existence as an oligomeric structure [4], we designed a pharmacological cocktail that facilitates endocytosis of the MOP receptor in response to morphine. This cocktail consists of morphine and a small dose of methadone. Importantly, this cocktail, while retaining full analgesic potency, does not promote morphine dependence. We further demonstrate that dependence is reduced, at least in part, because endocytosis of the MOP receptor in response to morphine prevents the upregulation of N-methyl-D-aspartate (NMDA) receptors.

  4. Neonatal abstinence syndrome

    MedlinePlus

    ... 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 ...

  5. Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and Oxycodone-Induced Brain Gene Expression in Rats

    PubMed Central

    Pravetoni, Marco; Pentel, Paul R.; Potter, David N.; Chartoff, Elena H.; Tally, Laura; LeSage, Mark G.

    2014-01-01

    Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination. PMID:25025380

  6. Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist

    PubMed Central

    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

  7. False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.

    PubMed

    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.

  8. Specific serum binding of morphine, levorphanol and heroin

    PubMed Central

    Herndon, B. L.; Baeder, D. H.; Ringle, D. A.

    1976-01-01

    Effects of repeated subcutaneous pellet implantation of a series of narcotic drugs on the serum binding of [14C]morphine was studied in rabbits. Three of the compounds, morphine, heroin and levorphanol, elicited production of a morphine-binding globulin in the implanted rabbits. This serum response did not occur with several other compounds tested, including the potent analgesic methadone, and the narcotic antagonist naloxone. The time course of production of this globulin response, as well as the specificity of the binding for the drug that induced the response are both characteristic of an immunological reaction.

  9. Use of Methadone for Prevention of Opioid Withdrawal in Critically Ill Children

    PubMed Central

    Jeffries, Sonia A; McGloin, Rumi; Pitfield, Alexander F; Carr, Roxane R

    2012-01-01

    Background Opioids are commonly administered to critically ill children for analgesia and sedation, but many patients experience opioid withdrawal upon discontinuation. The authors’ institution developed a protocol for using methadone to prevent opioid withdrawal in children who have received morphine by continuous IV infusion for 5 days or longer in the pediatric intensive care unit (PICU). Objectives The primary objectives were to determine if opioids were tapered according to the protocol and to determine the conversion ratio for IV morphine to oral methadone that was used. Secondary objectives were to describe the methadone dosage used and the clinical outcomes, to evaluate adjustments to methadone dosing, and to report the incidence of adverse effects. Methods A retrospective analysis of charts was conducted for pediatric patients who had received morphine by continuous IV infusion for 5 days or longer followed by methadone in the PICU between May 2008 and August 2009. Validated scoring systems (the Withdrawal Assessment Tool and the State Behavioral Scale) were used to assess symptoms of withdrawal and degree of sedation, respectively. Results Forty-three patients were included in the study, with median age of 8 months (range 0.25–201 months). For 31 patients (72%), the protocol was not used, and there were no patients for whom the protocol was followed to completion. The median duration of weaning was 10 days (range 0–91 days). The conversion ratio for IV morphine to oral methadone was 1:0.78 for anticipated 5-day weaning and 1:0.98 for anticipated 10-day weaning. During the first 10 days of weaning, 18 patients (42%) experienced withdrawal symptoms. The methadone dose was increased for 11 (26%) of the 43 patients. Patients were sedated for a median of 1 day (range 0–9 days), were comfortable for a median of 6.5 days (range 1–64 days), and were agitated for a median of 2.5 days (range 0–23 days). Naloxone was required for 2 patients. Conclusions

  10. Out-of-Hospital Mortality among Patients Receiving Methadone for Non-Cancer Pain

    PubMed Central

    Ray, Wayne A.; Chung, Cecilia P.; Murray, Katherine T.; Cooper, William O.; Hall, Kathi; Stein, C. Michael

    2014-01-01

    Importance Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone may increase risk for both lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. Objective To compare risk of out-of-hospital death in users of methadone for non-cancer pain to that for comparable users of sustained-release (SR) morphine. Design Retrospective cohort study. Setting Tennessee Medicaid, 1997 through 2009. Participants Cohort included current users of morphine SR or methadone 30–74 years of age without cancer or other life-threatening illness and not in a hospital or nursing home. At cohort entry, 32,742 and 6,014 had filled a prescription for morphine SR or methadone, respectively. The median age was 48 years, 58% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of patients received the opioid for either back or other musculoskeletal pain. The median daily doses prescribed for morphine SR and methadone were 90mg and 40mg, respectively. Main Outcomes and Measures The primary study endpoint was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. Results There were 477 deaths during 28,699 person years of followup, or 166 deaths per 10,000 person-years. After control for study covariates, current methadone users had a 46% increased risk of death during followup, with an adjusted hazard ratio (HR) of 1.46 (95% confidence interval 1.17–1.83, p = .0008), resulting in 72 (27–130) excess deaths per 10,000 person-years. Methadone users of doses ≤20mg/day, the lowest dose quartile, had increased risk (HR =1.59 [1.01–2.51], p = .0461) relative to a comparable dose of morphine SR (<60mg/day). Conclusions and Relevance The increased risk of death observed for users of methadone, even for low doses, supports recommendations that it

  11. Evaluation of poly-drug use in methadone-related fatalities using segmental hair analysis.

    PubMed

    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

  12. Evaluation of poly-drug use in methadone-related fatalities using segmental hair analysis.

    PubMed

    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

  13. The Methadone Illusion

    ERIC Educational Resources Information Center

    Lennard, Henry L.; And Others

    1972-01-01

    Methadone treatment for heroin addiction does not touch the roots of the drug problem" and to think that the use of another drug can solve the profound and complex task facing us is indeed an illusion." (Author/AL)

  14. Methadone for Pain Relief.

    PubMed

    Johnson, Joseph; Sheth, Samir

    2016-06-01

    Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. In reply to a question, the authors discuss the use of methadone for pain management, outline how the body processes methadone, list interactions and side effects, and emphasize the importance of taking the medication as prescribed. PMID:27159280

  15. Forensic drug testing for opiates. VI. Urine testing for hydromorphone, hydrocodone, oxymorphone, and oxycodone with commercial opiate immunoassays and gas chromatography-mass spectrometry.

    PubMed

    Smith, M L; Hughes, R O; Levine, B; Dickerson, S; Darwin, W D; Cone, E J

    1995-01-01

    Opiate testing for morphine and codeine is performed routinely in forensic urine drug-testing laboratories in an effort to identify illicit opiate abusers. In addition to heroin, the 6-keto-opioids, including hydromorphone, hydrocodone, oxymorphone, and oxycodone, have high abuse liability and are self-administered by opiate abusers, but only limited information is available on detection of these compounds by current immunoassay and gas chromatographic-mass spectrometric (GC-MS) methods. In this study, single doses of hydromorphone, hydrocodone, oxymorphone, and oxycodone were administered to human subjects, and urine samples were collected before and periodically after dosing. Opiate levels were determined in a quantitative mode with four commercial immunoassays, TDx opiates (TDx), Abuscreen radioimmunoassay (ABUS), Coat-A-Count morphine in urine (CAC), and EMIT d.a.u. opiate assay (EMIT), and by GC-MS. GC-MS assay results indicated that hydromorphone, hydrocodone, oxymorphone, and oxycodone administration resulted in rapid excretion of parent drug and O-demethylated metabolites in urine. Peak concentrations occurred within 8 h after drug administration and declined below 300 ng/mL within 24-48 h. Immunoassay testing indicated that hydromorphone, hydrocodone, and oxycodone, but not oxymorphone, were detectable in urine by TDx and EMIT (300-ng/mL cutoff) for 6-24 h. ABUS detected only hydrocodone, and CAC failed to detect any of the four 6-keto-opioid analgesics. Generally, immunoassays for opiates in urine displayed substantially lower sensitivities for 6-keto-opioids compared with GC-MS. Consequently, urine samples containing low to moderate concentrations of hydromorphone, hydrocodone, oxymorphone, and oxycodone will likely go undetected when tested by conventional immunoassays.

  16. Severe pruritus and myoclonus following intrathecal morphine administration in a dog.

    PubMed

    Iff, Isabelle; Valeskini, Karin; Mosing, Martina

    2012-09-01

    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.

  17. 77 FR 72409 - Importer of Controlled Substances, Notice of Application, Mylan Pharmaceuticals, Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-05

    ...). As noted in a previous notice published in the Federal Register on September 23, 1975, 40 FR 43745-46...) II Oxycodone (9143) II Hydromorphone (9150) II Methadone (9250) II Morphine (9300) II Fentanyl...

  18. 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…

  19. Sweat testing in addicts under methadone treatment: an Italian experience.

    PubMed

    Fucci, N; De Giovanni, N; Scarlata, S

    2008-01-30

    In the last years the interest in monitoring drug exposure with human sweat as alternative biological fluid, is increasing. Sweat collection is convenient, less invasive and difficult to adulterate compared to traditional specimens. The objective of this study was to determine the excretion profile of methadone and other drugs into human sweat. Pharmscope sweat patches (Medical Europe Diagnostic, Madrid, Spain) were used on heroin abusers under methadone treatment. Sweat patches were applied to 10 heroin addicts and 3 drug free volunteers admitted into the study. Sweat patches were worn for about 1 week; urine, saliva and hair samples were collected at the time of the removal of patches. After the extraction, sweat eluates were directly analyzed by GC/MS for the presence of nicotine, cotinine, caffeine, methadone, EDDP and cocaine. The extracts were subsequently derivatized to detect benzoylecgonine, ecgonine methyl ester, morphine, codeine and 6-acetylmorphine. No false positive results were obtained on the drug free samples. All the patches showed positive results for methadone. Cocaine was detected in two cases. Mainly the parent drug was identified rather than the metabolites. The results obtained show the usefulness of sweat as complementary specimen to saliva and urine providing a longer detection window. Moreover, sweat testing offers the advantage of being a non-invasive means of obtaining information about drug exposure.

  20. Fentanyl tolerance in the treatment of cancer pain: a case of successful opioid switching from fentanyl to oxycodone at a reduced equivalent dose.

    PubMed

    Sutou, Ichiro; Nakatani, Toshihiko; Hashimoto, Tatsuya; Saito, Yoji

    2015-06-01

    Opioids are not generally deemed to have an analgesic ceiling effect on cancer pain. However, there have been occasional reports of tolerance to opioid development induced by multiple doses of fentanyl. The authors report a case of suspected tolerance to the analgesic effect of opioid, in which an increasing dose of fentanyl failed to relieve the patient's cancer pain symptoms, but opioid switching to oxycodone injections enabled a dose reduction to below the equivalent dose conversion ratio. The patient was a 60-year-old man diagnosed with pancreatic body carcinoma with multiple metastases. The base dose consisted of 12 mg/day of transdermal fentanyl patches (equivalent to 3.6 mg/day, 150 μg/h fentanyl injection), and rescue therapy consisted of 10 mg immediate-release oxycodone powders. Despite the total daily dose of fentanyl reaching 5.6 mg (equivalent to 560 mg oral morphine), the analgesic effect was inadequate; thus, an urgent adjustment was necessary. Due to the moderate dose of fentanyl, the switch to oxycodone injection was done incrementally at a daily dose equivalent to 25% of the fentanyl injection. The total dose of oxycodone was replaced approximately 53.5% of the dose of fentanyl prior to opioid switching.

  1. 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…

  2. Relative abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers

    PubMed Central

    Comer, Sandra D; Sullivan, Maria A; Whittington, Robert A; Vosburg, Suzanne K; Kowalczyk, William J

    2013-01-01

    Abuse of prescription opioid medications has increased dramatically in the U.S. during the past decade, as indicated by a variety of epidemiological sources. However, few studies have systematically examined the relative reinforcing effects of commonly abused opioid medications. The current double-blind, placebo-controlled inpatient study was designed to compare the effects of intravenously delivered fentanyl (0, 0.0625, 0.125, 0.187, and 0.250 mg/70 kg), oxycodone (0, 6.25, 12.5, 25, and 50 mg/70 kg), morphine (0, 6.25, 12.5, 25, and 50 mg/70 kg), buprenorphine (0, 0.125, 0.5, 2, and 8 mg/70 kg), and heroin (0, 3.125, 6.25, 12.5, and 25 mg/70 kg) in morphine-maintained heroin abusers (N=8 completers maintained on 120 mg per day oral morphine in divided doses [30 mg q.i.d.]). All of the participants received all of the drugs tested; drugs and doses were administered in non-systematic order. All of the drugs produced statistically significant, dose-related increases in positive subjective ratings, such as “I feel a good drug effect” and “I like the drug.” In general, the order of potency in producing these effects, from most to least potent, was: fentanyl > buprenorphine ≥ heroin > morphine = oxycodone. In contrast, buprenorphine was the only drug that produced statistically significant increases in ratings of “I feel a bad drug effect” and it was the only drug that was not self-administered above placebo levels at any dose tested. These data suggest that the abuse liability of buprenorphine in heroin-dependent individuals may be low, despite the fact that it produces increases in positive subjective ratings. The abuse liabilities of fentanyl, morphine, oxycodone, and heroin, however, appear to be similar under these experimental conditions. PMID:17581533

  3. Morphine: Myths and Reality

    MedlinePlus

    ... and Families Take the Quiz Morphine: Myths and Reality February, 2013 The mere mention of “Morphine” can ... due to misinformation and lack of training. The reality is that Morphine (and other opiates that work ...

  4. Categorising methadone: Addiction and analgesia.

    PubMed

    Keane, Helen

    2013-11-01

    While methadone was first developed as an analgesic, and used for this purpose before it was adopted as a therapy for drug dependence, it is this latter use which has saturated its identity. Most of the literature and commentary on methadone discusses it in the context of methadone maintenance therapy (MMT). But one of the effects of the liberalization of opiate prescription for chronic pain which took place in the 1990s was the re-emergence of methadone as a painkiller. This article examines the relationship between methadone the painkiller and methadone the addiction treatment as it is constituted in recent medical research literature and treatment guidelines. It highlights the way medical discourse separates methadone into two substances with different effects depending on the problem that is being treated. Central to this separation is the classification of patients into addicts and non-addicts; and pain sufferers and non-pain sufferers. The article argues that despite this work of making and maintaining distinctions, the similarities in the way methadone is used and acts in these different medical contexts complicates these categories. The difficulties of keeping the 'two methadones' separate becomes most apparent in cases of MMT patients also being treated for chronic pain.

  5. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine

    PubMed Central

    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

  6. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.

    PubMed

    Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme

    2016-02-01

    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.

  7. A multicenter, primary-care-based, open-label study to assess the success of converting opioid-experienced patients with chronic moderate-to-severe pain to morphine sulfate and naltrexone hydrochloride extended-release capsules using a standardized conversion guide

    PubMed Central

    Setnik, Beatrice; Roland, Carl L; Sommerville, Kenneth W; Pixton, Glenn C; Berke, Robert; Calkins, Anne; Goli, Veeraindar

    2015-01-01

    Objective 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. Methods 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. Results 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. Conclusion 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. PMID:26185466

  8. Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment

    PubMed Central

    Shiran, Mohammad-Reza; Lennard, Martin S; Iqbal, Mohammad-Zafar; Lagundoye, Oldwale; Seivewright, Nicholas; Tucker, Geoffrey T; Rostami-Hodjegan, Amin

    2009-01-01

    AIMS To investigate the influence of different cytochrome P450 (CYP) activities and other potential covariates on the disposition of methadone in patients on methadone maintenance therapy (MMT). METHODS Eighty-eight patients (58 male; 21–55 years; 84 White) on MMT were studied. CYP2D6 activity [3 h plasma metabolic ratio of dextromethorphan (DEX) to dextrorphan (DOR)] was determined in 44 patients (29 male; 24–55 years), CYP1A2 activity (salivary caffeine elimination half-life) in 44 patients (21 male; 24–55 years) and CYP3A activity (oral clearance of midazolam) in 49 patients (33 male; 23–55 years). Data on all three CYPs were obtained from 32 subjects. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by LC/MS. Population pharmacokinetics and subsequent multiple regression analysis were used to calculate methadone oral clearance and to identify its covariates. RESULTS Between 61 and 68% of the overall variation in total plasma trough concentrations of (RS)-, (R)- and (S)-methadone was explained by methadone dose, duration of addiction before starting MMT, CYP3A activity and illicit morphine use. CYP3A activity explained 22, 16, 15 and 23% of the variation in unbound (R)-, unbound (S)-, total (RS)- and total (S)-methadone clearances, respectively. Neither CYP2D6 nor CYP1A2 activity was related to methadone disposition. CONCLUSIONS CYP3A activity has a modest influence on methadone disposition. Inhibitors and inducers of this enzyme should be monitored in patients taking methadone. PMID:19133059

  9. Evaluation of the analgesic effect of subcutaneous methadone after cesarean section

    PubMed Central

    Jabalameli, Mitra; Kalantari, Forough

    2014-01-01

    Background: Inadequate pain control has a significant role in maternal and neonatal health in early post-partum period which interferes with breastfeeding and has a negative influence on child normal growth. The aim of this study is evaluation of subcutaneous methadone effectiveness on post-operative pain control. Materials and Methods: Double blind randomized prospective clinical trial involving 60 term pregnancy patients through 2008 to 2009 Undergo cesarean. Inclusion criteria: Prime gravid candidate of elective cesarean and spinal anesthesia class 1 or 2. Known case of drug allergy and methadone interaction, addiction, uncontrolled medical disease excluded. Case group injected 10 mg of subcutaneous methadone in the site of incision before final suture. Morphine was a pain reliever in follow up examination. Data include mean of pain, nausea and vomiting, MAP, etc., collected and analyzed by independent-T test and Man Whitney test. Results: Although mean usage of morphine between groups was not significant statistically but the mean pain severity (P value < 0.05) and mean satisfactory (P value = 0.02) was statistically significant between groups. Other parameters were not statistically significant. Conclusion: We suggest subcutaneous methadone as a safe pain reliever in post cesarean section patients. PMID:25337527

  10. Serotonin syndrome probably triggered by a morphine-phenelzine interaction.

    PubMed

    Mateo-Carrasco, Hector; Muñoz-Aguilera, Eva María; García-Torrecillas, Juan Manuel; Abu Al-Robb, Hiba

    2015-06-01

    Serotonin syndrome is a potentially life-threatening condition caused by excessive central and peripheral stimulation of serotonin brainstem receptors, usually triggered by inadvertent interactions between agents with serotonergic activity. Evidence supporting an association between nonserotonergic opiates, such as oxycodone or morphine, and serotonin syndrome is very limited and even contradictory. In this case report, we describe a patient who developed serotonergic-adverse effects likely precipitated by an interaction between morphine and phenelzine. A 57-year-old woman presented to the emergency department with complaints of increasing visual hallucinations, restlessness, photophobia, dizziness, neck stiffness, occipital headache, confusion, sweating, tachycardia, and nausea over the previous week. On admission, her blood pressure was 185/65 mm Hg, and clonus was noted in the lower extremities. The patient was hospitalized 10 days earlier for cellulitis of the left breast secondary to a left mastectomy 5 months earlier, and a short course of oral morphine was prescribed for pain control. Her routine medications consisted of aspirin, atorvastatin, bisoprolol, clopidogrel, gabapentin, omeprazole, phenelzine, and ramipril. Supportive measures were initiated on admission. Phenelzine and morphine were discontinued immediately, leading to a progressive resolution of symptoms over the next 48 hours. Phenelzine was restarted on discharge without further complications. Use of the Drug Interaction Probability Scale indicated a probable relationship (score of 6) between the patient's development of serotonin syndrome and the combination of morphine and phenelzine. The mechanism underlying this interaction, however, remains unclear and warrants further investigation. Clinicians should carefully weigh the risk and benefits of initiating morphine in patients taking monoamine oxidase inhibitors or any other serotonin-enhancing drugs.

  11. Factors Associated with Methadone Treatment Duration: A Cox Regression Analysis

    PubMed Central

    Peng, Ching-Yi; Chao, En; Lee, Tony Szu-Hsien

    2015-01-01

    This study examined retention rates and associated predictors of methadone maintenance treatment (MMT) duration among 128 newly admitted patients in Taiwan. A semi-structured questionnaire was used to obtain demographic and drug use history. Daily records of methadone taken and test results for HIV, HCV, and morphine toxicology were taken from a computerized medical registry. Cox regression analyses were performed to examine factors associated with MMT duration. MMT retention rates were 80.5%, 68.8%, 53.9%, and 41.4% for 3, 6, 12, and 18 months, respectively. Excluding 38 patients incarcerated during the study period, retention rates were 81.1%, 73.3%, 61.1%, and 48.9% for 3 months, 6 months, 12 months, and 18 months, respectively. No participant seroconverted to HIV and 1 died during the 18-months follow-up. Results showed that being female, imprisonment, a longer distance from house to clinic, having a lower methadone dose after 30 days, being HCV positive, and in the New Taipei city program predicted early patient dropout. The findings suggest favorable MMT outcomes of HIV seroincidence and mortality. Results indicate that the need to minimize travel distance and to provide programs that meet women’s requirements justify expansion of MMT clinics in Taiwan. PMID:25875531

  12. Illicit Heroin and Methamphetamine Use among Methadone Maintenance Treatment Patients in Dehong Prefecture of Yunnan Province, China

    PubMed Central

    Duan, Song; Ye, Runhua; Yang, Yuecheng; Wang, Jibao; Tang, Renhai; Gao, Meiyang; He, Na

    2015-01-01

    Objective 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. Methods 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. Results 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. Conclusion 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. PMID:26196394

  13. Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain.

    PubMed

    Holtman, Joseph R; Crooks, Peter A; Johnson-Hardy, Jaime; Wala, Elzbieta P

    2010-12-01

    Mu-opioids (i.e. morphine, oxycodone, hydrocodone) are considered to be the primary drugs for treatment of moderate to severe acute, chronic and cancer pain. Despite their analgesic effectiveness they have several clinically significant side-effects (cognitive, motor, respiratory, cardiovascular, gastrointestinal). They also have a limited spectrum of action, being more effective for nociceptive than neuropathic pain. In an effort to identify other opioid analgesics with greater effectiveness in mixed pain states and with a better side-effect profile compared to the classical mu-opioid agonist, morphine, a relatively little-known morphine derivative, morphine-6-O-sulfate, was characterized using a range of well-established rodent pain models. The present data demonstrated that morphine-6-O-sulfate was efficacious after several routes of administration, including neuroaxial (intrathecal), parenteral (intraperitoneal) and oral in the rat. It showed potent, dose-related, analgesic activities against acute nociceptive pain (the tail flick test), neuropathic pain (chronic constriction nerve injury hyperalgesia and allodynia) and inflammatory pain (formalin test). It had a good separation based on dose (at least 10-fold) between side-effects (incoordination, hypolocomotion, inhibition of gastrointestinal motility) and analgesia in all models of pain tested. In addition, morphine-6-O-sulfate had a more favorable potency ratio for delay of gastrointestinal transit and analgesia when compared to morphine. These preclinical findings suggest that morphine-6-O-sulfate is a potential candidate for development as a novel opioid for management of nociceptive, neuropathic and mixed pain states.

  14. Enhanced development of dispositional tolerance to methadone by desipramine given together with methadone

    SciTech Connect

    Liu, S.J.; Wang, R.I.H.

    1985-02-25

    Rats given 2-day oral administration of methadone (15 mg/kg, twice on day 1 and once on day 2) by gastric tube developed dispositional tolerance to methadone analgesia as demonstrated by a decrease in analgesic response and by an increase in methadone metabolism. The increased metabolism of methadone was evidenced by a decrease in brain concentration of /sup 14/C-methadone and increases in the percentages of total /sup 14/C in liver or urine as /sup 14/C-water-soluble metabolites (/sup 14/C-WSM) after the rats were challenged with a test dose of /sup 14/C-methadone. Two-day pretreatment with a combination of desipramine (DMI) (10 mg/kg, ip) and methadone (15 mg/kg, po) enhanced the development of dispositional tolerance to methadone analgesia which was evidenced by a greater decrease in the brain concentration of methadone and a greater increase in methadone metabolism as compared to those changes in rats pretreated with only methadone. Repeated treatment with DMI alone neither decreased the analgesic effect of methadone nor stimulated methadone metabolism. It is suggested that DMI given together with methadone promoted the induction of methadone metabolism in the liver by prolonging the enzyme-stimulating state of methadone, thus enhancing the development of dispositional tolerance to methadone. 20 references, 1 figure, 1 table.

  15. Methadone Induced Sensorineural Hearing Loss

    PubMed Central

    Saifan, Chadi; Barakat, Iskandar; El-Sayegh, Suzanne

    2013-01-01

    Background. Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL. PMID:23983704

  16. The demedicalization of methadone maintenance.

    PubMed

    Rosenbaum, M

    1995-01-01

    The institution of methadone maintenance as a treatment modality for heroin addiction in the mid-1960s was part of the growing medicalization of social problems in the United States. The definition of deviance as "sickness" rather than "badness" set the stage for America's first harm-reduction strategy. By the 1970s methadone maintenance was seen as a way to reduce drug-related crime, and federally funded programs proliferated. Accompanying methadone's phenomenal expansion was increased regulation, bureaucratization, and criticism. The early 1980s brought the Reagan era, fiscal austerity, the new "just say no" abstinence morality, and demedicalization of methadone maintenance. By the time needle-sharing was recognized as a major contributing factor in the spread of HIV, methadone had been transformed into a largely fee-for-service, short-term, begrudgingly tolerated treatment modality. Ironically, while other countries were able to use methadone to curb the spread of AIDS, the United States refused to facilitate its expansion, and in fact impeded it. To the frustration of proponents and consumers, this original harm-reduction tool, with the potential to impact the epidemic, was demedicalized and remains marginalized. PMID:7562261

  17. 75 FR 44287 - Manufacturer of Controlled Substances; Notice of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-28

    ... 16, 2010, and published in the Federal Register on March 24, 2010, (75 FR 14189), Siegfried (USA), 33... Codeine (9050) II Oxycodone (9143) II Hydromorphone (9150) II Hydrocodone (9193) II Methadone (9250) II Methadone intermediate (9254) II Dextropropoxyphene, bulk (non-dosage forms) II (9273). Morphine (9300)...

  18. Selection of the initial methadone regimen for the management of iatrogenic opioid abstinence syndrome in critically ill children.

    PubMed

    Johnson, Peter N; Boyles, Krystal A; Miller, Jamie L

    2012-02-01

    Iatrogenic opioid abstinence syndrome (IOAS) is a common complication in critically ill infants and children receiving prolonged exposure to continuous infusions of opioids. Although no guidelines are available regarding management of IOAS in children, several treatment options are available, including clonidine, morphine, and methadone. Methadone is commonly prescribed due to its long half-life and antagonism of the N-methyl-d-aspartate receptor. Different approaches, such as weight-based and formula-based methods, have been used to determine the initial methadone dosing regimen. Because of the vast differences in the recommended dosing regimen from these sources, we conducted a literature search to identify articles evaluating the initial methadone dosing regimen for prevention and/or treatment of IOAS in children. Specifically, we evaluated the reported frequency of withdrawal and oversedation after initiation of methadone treatment. Our literature search was limited to English-language articles in the MEDLINE (1950-March 2011), EMBASE (1988-March 2011), International Pharmaceutical Abstracts (1970-March 2011), and Cochrane Library (1996-March 2011) databases. Relevant abstracts and reference citations were also reviewed. A total of eight reports representing 183 patients were included in the analysis. There was wide discrepancy in the initial methadone dosing regimen. Approximately one-third of all patients experienced withdrawal after starting methadone, and there did not appear to be a difference between weight-based and formula-based regimens. Seven patients experienced oversedation; however, not all articles reported this complication. It appears that a standard approach to initial methadone dosing does not exist because withdrawal occurred despite the regimen started. Therefore, it seems best to begin with the lowest dose possible and titrate to the child's response to avoid complications such as oversedation. Routine monitoring should be performed in all

  19. The offset of morphine tolerance in rats and mice.

    PubMed

    Cox, B M; Ginsburg, M; Willis, J

    1975-03-01

    1. In rats and mice made tolerant to morphine by pretreatment with the drug, the shift to the right of the log dose/analgesic response line for in naive animals occurs without significant change in slope provided that sufficient time is allowed for elimination of pretreatment drug. 2. Responsiveness to the analgesic effects of morphine, given together with cycloheximide to prevent reinforcement of tolerance, was measured in rats (paw pressure method) and mice (hot plate method) at intervals during 1-23 days following cessation of a variety of regimens of tolerance-inducing drug treatments. 3. A biphasic pattern of recovery of responsiveness was observed, which was independent of the regimen or the drug (morphine, methadone or diamorphine) used to induce tolerance. Estimates of the rates of the first, fast phase are imprecise but the rate of the second phase of offset, from 4th day after cessation of pretreatment had, in rats, a mean half-time of 13.2 plus or minus 0.53 days-for all pretreatments combined, there being no significant differences between the various pretreatment regimens employed. In mice, similarly, a biphasic recovery of analgesic responsiveness was seen after morphine pretreatment, the mean half-time of the slower phase being 17.4 days. 4. Precipitation of an acute withdrawal syndrome in rats by naloxone HCl given 6 h after the final injection of a tolerance-inducing treatment with morphine did not affect the subsequent rate of recovery from tolerance. 5. During the period following a tolerance-inducing pretreatment with morphine in mice, the rate of attenuation of the naloxone-evoked jumping response was faster than the rate of offset of tolerance. PMID:1169082

  20. Can an immunoassay become a standard technique in detecting oxycodone and its metabolites?

    PubMed

    Abadie, Jude M; Allison, Kim H; Black, David A; Garbin, James; Saxon, Andrew J; Bankson, Daniel D

    2005-01-01

    Opiate toxicology testing is routinely performed in the hospital setting to identify abusers and/or to determine those patients who are not taking prescribed opiate analgesics such as oxycodone. Commercially available assays for opiate detection in urine have decreased sensitivity for oxycodone, which contributes to a high false-negative rate. Functioning as a beta site, our Veterans Affairs hospital evaluated a new enzyme immunoassay, DRI Oxycodone Assay, for its use in the qualitative and semiquantitative detection of oxycodone in urine. We hypothesize that an immunoassay for oxycodone with superior sensitivity and specificity, when compared to the traditional opiate assays, would reduce the need for more expensive and time-consuming confirmatory testing. We used the new liquid homogenous enzyme immunoassay to determine oxycodone results in a total of 148 urine samples from 4 different sample groups. Gas chromatography-mass spectroscopy was subsequently used to confirm the presence or absence of oxycodone (or its primary metabolite, noroxycodone). We also evaluated within-run, between-run, and linearity studies and conducted a crossover study to establish a cutoff value for oxycodone. In our patient population, we used the new DRI immunoassay to evaluate 17,069 urine samples to estimate oxycodone misuse profiles (patients not taking prescribed oxycodone or taking oxycodone without a prescription) during a 4-month period. The sensitivity and specificity of the new oxycodone immunoassay were 97.7% and 100%, respectively, at the cutoff concentration of 300 ng/mL. The assay linearity was 1,250 ng/mL, and the sensitivity was 10 ng/mL. Within-run precision and between-run coefficient of variation were 2.3% and 1.8%, respectively. None of the 15 compounds that we evaluated for interference had crossover significant enough to produce a positive oxycodone result when using 300 ng/mL as the cutoff value. None of the 17,069 oxycodone immunoassays was followed with a request

  1. Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome.

    PubMed

    Harper, R G; Solish, G; Feingold, E; Gersten-Woolf, N B; Sokal, M M

    1977-10-15

    The relationship between the quantity of methadone ingested by the pregnant mother, the quantity of methadone in maternal and neonatal body fluids, and the subsequent neonatal withdrawal course was studied. The severity of the neonatal withdrawal syndrome was found to be related to the total dose of methadone ingested by the mother during the last 12 weeks of pregnancy (p less than 0.02), the maternal dose of methadone at delivery (p less than 0.01), and the intrapartum serum methadone levels (p less than 0.01). The cord blood levels of methadone were consistently lower than the maternal serum levels. Amniotic fluid methadone levels were not constantly related to maternal or neonatal serum methadone levels. Concentrations of methadone 10 to 60 times greater than that of cord blood were found in neonatal urine.

  2. Methadone and its role in drug-related fatalities in Cologne 1989-2000.

    PubMed

    Grass, H; Behnsen, S; Kimont, H-G; Staak, M; Käferstein, H

    2003-04-01

    All drug-associated deaths from 1989 to 2000 were analysed at the Institute of Forensic Medicine in Cologne. Information concerning sex, gender, drug consumption, time, place and circumstances of death were analysed. A number of 605 cases were recorded; in 518 cases a toxicological analysis was possible and in 171 an autopsy was performed. When it was possible to determine the cause of death form the information available, acute drug intoxication was recorded in 65%. Heroin head the list of identified substances. Sixty-three percent of the specimens showed a combination of several substances, especially a combination of morphine, benzodiazepines, other medications and alcohol. In comparison with other studies the percentage of methadone-positive specimens is low, even though the proportion of specimens positive for methadone increased from 1989 to 2000. This analysis is discussed using background information concerning the management of substitution therapy and the available literature.

  3. A Study of the Sexual Function, Sleep, and Weight Status of Patients after 6 Months of Methadone Maintenance Treatment

    PubMed Central

    Parvaresh, Noushin; Sabahi, Abdol Reza; Mazhari, Shahrzad; Gilani, Hoda

    2015-01-01

    Background Methadone is a synthetic opioid and receptor agonist morphine; thus, its consumption has the effects and side effects of opioid. Methadone maintenance treatment (MMT) is used as an alternative treatment for people who are suffering from substance abuse and do not have the ability to withdraw. Despite its benefits, this drug also has side effects. The purpose of this study was to investigate the effects of methadone treatment on sexual function, sleep, and weight after 6 months. Methods The study subjects consisted of 200 patients who had referred to the Methadone Clinic of Shahid Beheshti Training Hospital, Kerman, Iran, during a 6-month period and were treated using MMT. Data collection tools consisted of the demographic questionnaire, Pittsburgh sleep quality index (PSQI), and Arizona sexual experience scale (ASEX). The questionnaires were completed by the participants before and 6 months after the treatment. Findings The results of this study showed that methadone consumption has significant effects on sexual dysfunction, sleep disorders, and weight gain. Conclusion The consideration of the side effects of MMT can result in consumers’ commitment to the treatment. PMID:26322207

  4. Characterization and validation of a pharmacokinetic model for controlled-release oxycodone.

    PubMed

    Mandema, J W; Kaiko, R F; Oshlack, B; Reder, R F; Stanski, D R

    1996-12-01

    1. Oxycodone is a strong opioid agonist that is currently available in immediate-release (IR) formulations for the treatment of moderate to severe pain. Recently, controlled-release (CR) oxycodone tablets were developed to provide the benefits of twice-a-day dosing to patients treated with oxycodone. The purpose of this investigation was to develop and validate a pharmacokinetic model for CR oxycodone tablets in comparison with IR oxycodone solution. 2. Twenty-four normal male volunteers were enrolled in a single-dose, randomized, analytically blinded, two-way crossover study designed to compare the pharmacokinetics of two 10 mg CR oxycodone tablets with 20 mg IR oxycodone oral solution. Pharmacokinetic models describing the oxycodone plasma concentration vs time profiles of CR tablets and IR solution were derived using NONMEM version IV. The predictive performance of the models was assessed by comparison of predicted oxycodone plasma concentrations with actual oxycodone plasma concentrations observed in a separate group of 21 volunteers who received repeated doses of IR and CR oxycodone for 4 days. 3. The unit impulse disposition function of oxycodone was best described by a one-compartment model. Absorption rate of the IR solution was best described by a mono-exponential model with a lag time, whereas absorption rate of the CR tablet was best described using a bi-exponential model. The absorption profile of the CR tablets was characterized by a rapid absorption component (t1/2abs = 37 min) accounting for 38% of the available dose and a slow absorption phase (t1/2abs = 6.2 h) accounting for 62% of the available dose. Two 10 mg tablets of oral CR oxycodone hydrochloride were 102.7% bioavailable relative to 20 mg of IR oxycodone hydrochloride oral solution. The population model derived after administration of a single dose accurately predicted both the mean and range of oxycodone concentrations observed during 4 days of repeated dosing. The mean prediction error was

  5. Foucault on methadone: beyond biopower.

    PubMed

    Keane, Helen

    2009-09-01

    This essay reviews four texts which critically analyse methadone maintenance therapy using Foucault as a key theoretical framework: [Friedman, J., & Alicea, M. (2001). Surviving heroin: Interviews with women in methadone clinics. Florida: University Press of Florida], [Bourgois, P. (2000). Disciplining addictions: The bio-politics of methadone and heroin in the United States. Culture Medicine and Psychiatry, 24, 165-195], [Bull, M. (2008). Governing the heroin trade: From treaties to treatment. Ashgate: Aldershot], and [Fraser, S., & valentine, k. (2008). Substance & substitution: Methadone subjects in liberal societies. New York: Palgrave Macmillan]. Taken together these works demonstrate one trajectory in the development of critical drug studies over the past decade. While all four view MMT as a regulatory technology which aims to create productive and obedient subjects, their understandings of the power relations of the clinic are quite distinct. The first two texts emphasise the social control of drug users, the third, issues of governmentality and liberal political practice, while the fourth engages with ontological questions about substances themselves. Thus while Foucauldian analysis has become familiar in social studies of drugs and alcohol, new uses for its conceptual tools continue to emerge.

  6. Breastfeeding and Methadone Therapy: The Maternal Experience

    PubMed Central

    Demirci, Jill R.; Bogen, Debra L.; Klionsky, Yael

    2014-01-01

    Background Despite evidence of low transfer of methadone into breast milk and the potential physical and psychological benefits that breastfeeding offers for methadone-exposed mothers and infants, the rate of breastfeeding initiation in this population is about half that reported nationally. This study describes the perceptions surrounding breastfeeding decisions and management among pregnant and postpartum women taking methadone. Methods Seven pregnant women and four postpartum women enrolled in methadone maintenance programs participated in semi-structured, audio-taped interviews and focus groups, respectively, about their breastfeeding experiences. Transcripts were analyzed and coded using qualitative content analysis. Results Three major content categories were indentified: (1) fears, barriers and misconceptions about breastfeeding while taking methadone; (2) motivation and perceived benefits of breastfeeding; and (3) sources of information, support, and anxiety about general breastfeeding management and breastfeeding while taking methadone. Lack of support from the healthcare community and misinformation about the dangers of combining breastfeeding and methadone therapy represented significant, yet modifiable, barriers to breastfeeding success in methadone-exposed women. Conclusions Interventions to increase the prevalence of breastfeeding among women taking methadone should address identified logistical, educational, and psychological barriers and consider inclusion of women themselves, partners, peers, and clinicians. In particular, clinicians who care for methadone-exposed mothers and infants should be educated on therapeutic communication, up-to-date breastfeeding contraindications, and the health benefits of breastfeeding in this population. PMID:24702686

  7. Drug Abuse: Methadone Becomes the Solution and the Problem

    ERIC Educational Resources Information Center

    Bazell, Robert J.

    1973-01-01

    Methadone is used to divert heroin addicts from using stronger drugs. Rate of crimes committed by drug addicts has fallen considerably after putting them on methadone. Despite criticisms, methadone use seems to be encouraging for the future. (PS)

  8. ROLE OF MENINGEAL MAST CELLS IN INTRATHECAL MORPHINE EVOKED GRANULOMA FORMATION

    PubMed Central

    Yaksh, Tony L.; Allen, Jeffery W.; Veesart, Samantha L.; Horais, Kjersti A; Malkmus, Shelle A.; Scadeng, Miriam; Steinauer, Joanne J.; Rossi, Steve S

    2013-01-01

    Background Intrathecal morphine forms granulomas that arise from the adjacent arachnoid membrane. We propose that these inflammatory cells exit the meningeal vasculature secondary to meningeal mast cell degranulation. Methods Three sets of experiments were accomplished in dogs. 1) Ex vivo Meningeal mast cell degranulation. Histamine release was measured ex vivo from canine dura incubated with opiates. 2) In vivo cutaneous mast cell degranulation. Flare areas on the dog abdomen were measured after subcutaneous opiates. 3) In vivo granuloma pharmacology. Dogs with lumbar intrathecal catheters received infusion of intrathecal saline or intrathecal morphine. Intrathecal morphine dogs received: i) No other treatment (Control); ii) Twice daily subcutaneous naltrexone; iii) Intrathecal co-infusion of cromolyn; or, iv) Twice daily subcutaneous cromolyn for the 24–28 day study course. Results 1) Morphine but not fentanyl evoked dural histamine release, which was blocked by cromolyn but not naloxone. 2) Wheal/flare was produced by subcutaneous morphine, methadone, hydromorphone, but not fentanyl, and was unaffected by naltrexone but prevented by cromolyn. 3) Granulomas occurred in all dogs receiving intrathecal morphine (15/15); subcutaneous naltrexone had no effect on granulomas (6/6), but was reduced by concurrent intrathecal cromolyn (0/5) or twice daily subcutaneous cromolyn (1 of 5). Conclusions The pharmacology of cutaneous/dural MC degranulation and intrathecal granulomas are comparable, not mediated by opioid receptors, and reduced by agents preventing MC degranulation. If an agent produces cutaneous MC degranulation at concentrations produced by intrathecal delivery, the agent may initiate granulomas. PMID:23426209

  9. A new therapeutic option for postoperative pain management with oxycodone HCI injection

    PubMed Central

    2016-01-01

    Fentanyl is the most commonly used opioid analgesic in intravenous patient-controlled analgesia (IV PCA) in Korea. IV oxycodone was approved for postoperative IV PCA by the Ministry of Food and Drug Safety of Korea in 2013. The approved dosage regimen for postoperative pain relief with IV oxycodone is IV bolus loading of 2 mg followed by PCA composed of demand boluses of 1 mg and no background infusion with an oxycodone concentration of 1 mg/ml. However, a simulation study indicated that the minimum effective analgesic concentration (MEAC, as indicated by relief of pain by administering rescue analgesics) of oxycodone was reached most quickly with a higher loading dose of 0.1 mg/kg and IV PCA with background infusion. Oxycodone is a therapeutic option as an analgesic for postoperative pain management. It is necessary to reduce the analgesic dose of oxycodone in elderly patients because metabolic clearance decreases with age. PMID:27274364

  10. Efficacy of methadone versus methadone and guanfacine in the detoxification of heroin-addicted patients.

    PubMed

    San, L; Fernandez, T; Cami, J; Gossop, M

    1994-01-01

    In a randomized double-blind study, the clinical efficacy of methadone vs. methadone and guanfacine was assessed in terms of evolution of opioid withdrawal symptoms during inpatient detoxification. A total of 144 patients were included and randomly allocated to three different treatment groups: methadone alone, and two combined treatment schedules (methadone plus 3 or 4 mg of guanfacine). No differences were observed among the three groups with regard to retention rate throughout the study period. Both therapies, methadone and methadone plus guanfacine, determined a slight increase in withdrawal scores when methadone was discontinued. However, guanfacine was unable to effectively control methadone-associated withdrawal symptoms. These results indicate that guanfacine does not effectively reduce the opioid withdrawal symptoms.

  11. Premature Discharge from Methadone Treatment

    PubMed Central

    Reisinger, Heather Schacht; Schwartz, Robert P.; Mitchell, Shannon Gwin; Peterson, James A.; Kelly, Sharon M.; O’Grady, Kevin E.; Marrari, Erica A.; Brown, Barry S.; Agar, Michael H.

    2008-01-01

    Longer retention in drug abuse treatment is associated with better patient outcomes and research indicates the first 12 months of methadone treatment are critical to patient success. Nevertheless, large-scale multi-site longitudinal studies over the past three decades indicate that the majority of patients drop out during the first year of methadone treatment. Through an examination of 42 qualitative interviews with patients prematurely discharged from six methadone treatment programs in Baltimore, this paper highlights factors patients describe as contributing to their reasons for being discharged within the first 12 months of the treatment. The two most consistent themes are program-related factors and incarceration. The former factors are richly described through patients’ words and underscore the ways in which patients’ perceptions of control exerted by the program and by the medication and misunderstandings of program structure can lead to premature discharge. Patients’ reasons for discharge were compared to counselors’ reasons as indicated in discharge summary forms. An analysis of the patterns of agreement and disagreement are presented. Patient-centered program and policy implications are discussed. PMID:19999682

  12. Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation†

    PubMed Central

    Sessler, Nelson E; Downing, Jerod M; Kale, Hrishikesh; Chilcoat, Howard D; Baumgartner, Todd F; Coplan, Paul M

    2014-01-01

    Purpose Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fatalities. The effect of making opioid tablets harder to crush/dissolve on opioid-related fatalities has not been assessed. The objective of this study was to assess the impact of introducing extended-release oxycodone (ERO [OxyContin®]) tablets containing physicochemical barriers to crushing/dissolving (reformulated ERO) on deaths reported to the manufacturer. Methods All spontaneous adverse event reports of death in the US reported to the manufacturer between 3Q2009 and 3Q2013 involving ERO were used. The mean numbers of deaths/quarter in the 3 years after reformulated ERO introduction were compared with the year before. Changes in the slope of trends in deaths were assessed using spline regression. Comparison groups consisted of non-fatal reports involving ERO and fatality reports involving ER morphine. Results Reports of death decreased 82% (95% CI: −89, −73) from the year before to the third year after (131 to 23 deaths per year) reformulation; overdose death reports decreased 87% (95% CI: −93, −78) and overdose deaths with mention of abuse-related behavior decreased 86% (95% CI:−92, −75). In contrast, non-fatal ERO reports did not decrease post-reformulation, and reported ER morphine fatalities remained unchanged. The ratio of ERO fatalities to all oxycodone fatalities decreased from 21% to 8% in the year pre-reformulation to the second year post-reformulation. Conclusions These findings, when considered in the context of previously published studies using other surveillance systems, suggest that the abuse-deterrent characteristics of reformulated ERO have decreased the fatalities associated with its misuse/abuse. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd. PMID:24916486

  13. 77 FR 40069 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-06

    ... Oxycodone is an opioid drug that is primarily used as an analgesic to relieve ] moderate to severe pain... pain where the use of an opioid analgesic is appropriate. In October 2010, FDA approved NDA 200534 for... chronic pain where the use of an opioid analgesic is appropriate, and NDA 200535, oxycodone oral...

  14. 21 CFR 862.3620 - Methadone test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Methadone test system. 862.3620 Section 862.3620....3620 Methadone test system. (a) Identification. A methadone test system is a device intended to measure methadone, an addictive narcotic pain-relieving drug, in serum and urine. Measurements obtained by...

  15. 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…

  16. Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice.

    PubMed

    Yang, Pao-Pao; Yeh, Geng-Chang; Yeh, Teng-Kuang; Xi, Jinghua; Loh, Horace H; Law, Ping-Yee; Tao, Pao-Luh

    2016-09-01

    Oxycodone has been used clinically for over 90 years. While it is known that it exhibits low affinity for the multiple opioid receptors, whether its pharmacological activities are due to oxycodone activation of the opioid receptor type or due to its active metabolite (oxymorphone) that exhibits high affinity for the mu-opioid receptors remains unresolved. Ross and Smith (1997) reported the antinociceptive effects of oxycodone (171nmol, i.c.v.) are induced by putative kappa-opioid receptors in SD rat while others have reported oxycodone activities are due to activation of mu- and/or delta-opioid receptors. In this study, using male mu-opioid receptor knock-out (MOR-KO) mice, we examined whether delta-opioid receptor was involved in oxycodone antinociception. Systemic subcutaneous (s.c.) administration of oxycodone (above 40mg/kg) could induce a small but significant antinociceptive effect in MOR-KO mice by the tail flick test. Delta-opioid receptor antagonist (naltrindole, 10mg/kg or 20mg/kg, i.p.) could block this effect. When oxycodone was injected directly into the brain of MOR-KO mice by intracerebroventricular (i.c.v.) route, oxycodone at doses of 50nmol or higher could induce similar level of antinociceptive responses to those observed in wild type mice at the same doses by i.c.v. Delta-opioid receptor antagonists (naltrindole at 10nmol or ICI 154,129 at 20μg) completely blocked the supraspinal antinociceptive effect of oxycodone in MOR-KO mice. Such oxycodone antinociceptive responses were probably not due to its active metabolites oxymorphone because (a) the relative low level of oxymorphone was found in the brain after systemically or centrally oxycodone injection using LC/MS/MS analysis; (b) oxymorphone at a dose that mimics the level detected in the mice brain did not show any significant antinocieption effect; (c) oxycodone exhibits equal potency as oxymorphone albeit being a partial agonist in regulating [Ca(2+)]I transients in a clonal cell line

  17. Methadone Medical Maintenance: An Early 21st-Century Perspective.

    PubMed

    Novick, David M; Salsitz, Edwin A; Joseph, Herman; Kreek, Mary Jeanne

    2015-01-01

    Methadone medical maintenance is the treatment of stable methadone-maintained patients in primary care physicians' offices under an exemption from federal methadone regulations. Reports from seven such programs in six states show high retention and low frequencies of illicit drug use. Patients and physicians indicate high levels of satisfaction. Although methadone maintenance has a long history of safety and efficacy, most methadone medical maintenance programs are no longer operating or accepting new patients. Federal regulations for standard methadone clinics allow some features of methadone medical maintenance, and advocacy for state approval of these changes is strongly recommended. PMID:26110221

  18. Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats.

    PubMed

    Leri, Francesco; Burns, Lindsay H

    2005-10-01

    Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and alleviate opioid tolerance and dependence. Our present studies in male Sprague-Dawley rats assessed the abuse potential of oxycodone+ultra-low-dose naltrexone (NTX) versus oxycodone alone. The lowest NTX dose (1 pg/kg/infusion), but not slightly higher doses (10 and 100 pg/kg/infusion), enhanced oxycodone (0.1 mg/kg/infusion) intravenous self-administration, suggesting a reduced rewarding potency per infusion. During tests of reinstatement performed in extinction conditions, co-self-administration of any of these three NTX doses significantly reduced drug-seeking precipitated by priming injections of oxycodone (0.25 mg/kg, s.c.), a drug-conditioned cue, or foot-shock stress. During self-administration on a progressive-ratio schedule, animals self-administering oxycodone (0.1 mg/kg/infusion)+NTX (1 pg/kg/infusion) reached a "break-point" sooner and showed a trend toward less responding compared to rats self-administering oxycodone alone (0.1 mg/kg/infusion). In the final experiment, the addition of ultra-low-dose NTX (10 pg/kg, s.c.) enhanced the acute stimulatory effect of oxycodone (1 mg/kg, s.c.), as well as locomotor sensitization produced by repeated oxycodone administration (7 x 1 mg/kg, s.c.). In summary, this work shows that ultra-low-dose NTX co-treatment augments the locomotor effects of oxycodone as it enhances opioid analgesia, but reduces oxycodone's rewarding potency and subsequent vulnerability to relapse.

  19. Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series

    PubMed Central

    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

  20. Relapsing thrombotic microangiopathy and intravenous sustained-release oxycodone

    PubMed Central

    Nataatmadja, Melissa; Divi, Dakshinamurthy

    2016-01-01

    Thrombotic microangiopathy (TMA) associated with injecting sustained-release oxymorphone, an opioid intended for oral use, has previously been reported. We report a case of TMA secondary to intravenous use of sustained-release oxycodone, and the first case to demonstrate relapsing disease due to persistent intravenous opioid use. In cases such as these, TMA is suspected to be due to a polyethylene oxide (PEO) coating found on these drugs, and the disease is likely due to a directly toxic effect of PEO to endothelial cells. We hypothesize that there are unidentified genetic predispositions causing some persons to be susceptible to developing this disease. PMID:27478601

  1. The combination of morphine and minocycline may be a good treatment for intractable post-herpetic neuralgia.

    PubMed

    Chen, Suchang; Hui, Hui; Zhang, Deren; Xue, Yanzhi

    2010-12-01

    Post-herpetic neuralgia (PHN) is a devastating complication of shingles. The treatment of PHN with traditional pharmaceutical agents has various side effects. Therefore, the treatment of intractable PHN is often very time consuming, mainly because the available treatments often lead to intolerable side effects before the efficient dose can be reached. Opioids such as morphine and oxycodone are the most widely used drugs for the alleviation for severe chronic pain. A number of high quality studies demonstrated that opioids are effective in relieving neuropathic pain including PHN. Yet concerns of misuse, abuse and tolerance of opioids have, however, severely influenced their contribution to neuropathic pain, especially the tolerance that resulted in a loss of drug effect or the necessity for escalating doses to produce pain relief. The glia cells, particularly microglia and astrocytes are thought to play an important role in central sensitization. It is known that activated microglia cells produce NO, cytokines, and cyclooxygenase. All of these chemicals regulate synaptic transmissions in the central nervous system. Additionally, glia modulations showed antiallodynic and antihyperalgesic properties in various experimental pain models. Minocycline, a semisynthetic, second-generation tetracycline can potently inhibit microglial activation and proliferation. Also, the growing body of recent evidence indicates that minocycline attenuates morphine tolerance in neuropathic mice with a mechanism related to microglia. The combination of morphine and minocycline has synergetic effect. This can prevent the development of intractable PHN and attenuate morphine antinociceptive tolerance and further improve the efficacy of morphine and therefore reducing its dosage and side effects. We thereby hypothesize that the combination of morphine and minocycline may produce a duel effect of morphine antinociceptive and minocycline selectively inhibiting the activation of microglia. PMID

  2. Markers for detection of supplementation in narcotic programs--deuterium-labeled methadone.

    PubMed

    Hsia, J C; Tam, J C; Giles, H G; Leung, C C; Marcus, H; Marshman, J A; Leblanc, A E

    1976-08-01

    Specific deuterium labeling of methadone and use of gas chromatography-mass spectroscopy technique permits rapid and quanitative determination of the ratio of the labeled to unlabeled drug in body fluids. A trideuertiomethadone (methadone-d3) was shown to have exactly the same analgesic activity and toxicity in mice as methadone. The rates of absorption, distribution, and excretion of methadone-d3 and methadone were identical in rats. These observations suggest that methadone-d3 may be used as an in vivo marker for monitoring methadone intake of patients, and thus may improve the effectiveness of methadone treatment programs. PMID:941022

  3. Cholestatic hepatitis as a possible new side-effect of oxycodone: a case report

    PubMed Central

    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

  4. Stability and compatibility of morphine.

    PubMed

    Vermeire, A; Remon, J P

    1999-09-30

    Morphine is a widely used analgesic for the treatment of severe cancer pain. For a large number of terminally ill patients oral administration is no longer possible and morphine is administered parenterally using portable pumps allowing comfortable treatment of the patient at home. In this situation the storage of pre-filled reservoirs and/or the administration over a longer period of time are daily practices and require data on the stability of morphine solutions. As most of these patients suffer from several other symptoms, the administration of admixtures with other drugs is common and requires information on the compatibility of morphine. Morphine degrades in aqueous solutions with the formation of mainly pseudomorphine, to a lesser extent morphine-N-oxide and probably apomorphine. From the study of the kinetics of morphine degradation it was concluded that the degradation of morphine is accelerated in the presence of oxygen and at higher pH of the solution, whereas temperature and light have only a minor influence on the degradation rate. The data reported on the stability of morphine infusion solutions kept under ambient conditions indicated that oxygen, light, the type of reservoir, the type of diluent, the salt form and the concentration of morphine do not affect the stability of morphine solutions stored for up to 3 months. Morphine solutions should preferably be stored at room temperature in order to avoid precipitation at low temperatures and water evaporation at higher temperatures causing increase in morphine concentration when stored in polymer reservoirs. Analyzing the data available on the compatibility of morphine infusion solutions revealed that differences in the formulation of the drug solutions (drug concentration, salt form, type and concentration of additives) and diluent, as well as temperature and order and ratio of mixing might affect the compatibility. Only few reports provide all necessary information, limiting the information useful for

  5. Methadone's effect on nAChRs--a link between methadone use and smoking?

    PubMed

    Talka, Reeta; Tuominen, Raimo K; Salminen, Outi

    2015-10-15

    Methadone is a long-acting opioid agonist that is frequently prescribed as a treatment for opioid addiction. Almost all methadone maintenance patients are smokers, and there is a correlation between smoking habit and use of methadone. Methadone administration increases tobacco smoking, and heavy smokers use higher doses of methadone. Nevertheless, methadone maintenance patients are willing to quit smoking although their quit rates are low. Studies on nicotine-methadone interactions provide an example of the bedside-to-bench approach, i.e., observations in clinical settings have been studied experimentally in vivo and in vitro. In vivo studies have revealed the interplay between nicotine and the endogenous opioid system. At the receptor level, methadone has been shown to be an agonist of human α7 nAChRs and a non-competitive antagonist of human α4β2 and α3* nAChRs. These drugs do not have significant interactions at the level of drug metabolism, and thus the interaction is most likely pharmacodynamic. The net effect of the interaction may depend on individual characteristics because pharmacogenetic factors influence the disposition of both methadone and nicotine. PMID:26231941

  6. Methadone Maintenance as Law and Order

    ERIC Educational Resources Information Center

    Heyman, Florence

    1972-01-01

    Argues that substitution of methadone for heroin would not rehabilitate the drug addict, but it may be used as a method of tranquilizing a potentially troublesome ghetto and poor white population. (RJ)

  7. Randomized, double-blind, placebo-controlled and active-controlled study to assess the relative abuse potential of oxycodone HCl-niacin tablets compared with oxycodone alone in nondependent, recreational opioid users

    PubMed Central

    Webster, Lynn R; Rolleri, Robert L; Pixton, Glenn C; Sommerville, Kenneth W

    2012-01-01

    Background Abuse-deterrent formulations attempt to address public health and societal concerns regarding opioid abuse. Oxycodone HCl-niacin tablets combine oxycodone HCl with niacin and functional inactive excipients to create potential barriers to oral, intranasal, and intravenous abuse. This study compared the relative abuse potential of oral immediate-release oxycodone HCl-niacin with that of oral immediate-release oxycodone HCl and placebo in nondependent, recreational opioid users. Methods Forty-nine participants received oxycodone HCl-niacin 40/240 mg and 80/480 mg, oxycodone 40 mg and 80 mg, and placebo in a randomized, double-blind, placebo-controlled and active-controlled, five-way crossover study. Primary endpoints based on a bipolar 100 mm visual analog scale for drug liking were area under effect curve (AUE0–1h, AUE0–2h, AUE0–3h), peak disliking, and effect at 0.5 hours post-dose (E0.5h). Other endpoints included take drug again assessment, overall drug liking, and pupillometry. Results There were statistically significant differences between oxycodone HCl-niacin and oxycodone HCl doses for all primary endpoints (P < 0.0001, all comparisons), suggesting reduced abuse potential with oxycodone HCl-niacin. Take drug again and overall drug liking showed greater liking of oxycodone alone. Oxycodone HCl-niacin 80/480 mg had consistently lower liking assessments than oxycodone HCl-niacin 40/240 mg, suggesting a dose-response to the aversive effects of niacin. Opioid-related adverse events were similar for equivalent oxycodone doses. The treatment-emergent adverse events most specifically associated with oxycodone HCl-niacin (ie, skin-burning sensation, warmth, and flushing) were consistent with the expected vasocutaneous effects of niacin. No serious adverse events were reported. Conclusion Oxycodone HCl-niacin tablets may, in a dose-dependent manner, decrease the potential for oral abuse of oxycodone without unexpected adverse events or clinically

  8. [Breast feeding during methadon- and buprenorphin therapy].

    PubMed

    Müller, M J; Lange, M; Paul, T; Seeliger, S

    2011-12-01

    The number of opiate addicted patients treated with opioid replacement therapy is continuously increasing. In Germany, 57.7% of these patients are treated with methadone and 18.6% with buprenorphine. This maintenance therapy provides several advantages while addicted pregnant women and their foetus have a high benefit from appropriate replacement therapy. However, the recommendations concerning breast feeding during an opioid replacement therapy are discussed controversially, because methadone as well as buprenorphine accumulate in breast milk. This accumulation might cause damages to the newborn's health; so, child benefits of breast feeding have to be balanced with possible health risks.This review provides an overview of a selective literature search based on the PubMed-database and german consensus recommendations. Used search terms included: (methadone*) AND (breastfeeding OR lactation), (methadone*) AND (human milk), (buprenorphine*) AND (breastfeeding OR lactation) and (buprenorphine*) AND (human milk).According to the available literature, addicted women, substinated with methadone or buprenorphine are allowed to breast feed their newborns. The advantages of breast feeding prevail the risks of an infant opiate intoxication caused by methadone or buprenorphine.

  9. Manifest and Latent Components in Methadone Maintenance: The Methadone Maintenance Game

    ERIC Educational Resources Information Center

    King, Charles H.

    1975-01-01

    This paper discusses various difficulties which arise when the staff of a methadone maintenance clinic must come to grips with the manifest and latent issues in service delivery. A solution is suggested which involves severing the tie between methadone and the behaviors which are reinforced by its use. (Author)

  10. The Correlation between Methadone Dosage and Comorbid Psychiatric Disorders in Patients on Methadone Maintenance Treatment

    PubMed Central

    Parvaresh, Nooshin; Masoudi, Arman; Majidi-Tabrizi, Shiva; Mazhari, Shahrzad

    2012-01-01

    Background Methadone Maintenance Treatment is a useful method for opioid dependents, which results in harm reduction and increased quality of life in opioid dependents. The prevalence of psychiatric disorders in addicts is higher than in the general population which can interfere with the course and treatment of substance dependents and decrease the efficacy of treatment. Methods This descriptive, cross-sectional study was aimed to determine the correlation between psychiatric disorders and methadone dosage. It was performed on 154 patients of Kerman Shahid Beheshti Hospital’s Methadone Clinic during a six month period from Dec 2010 to Jul 2011. The study population was chosen by convenience sampling. The searching tools were Socio-Demographic Questionnaire, psychiatric structured interview based on DSM-IV-TR, Beck Depression Inventory, Young Mania Rating Scales, and Anxiety and Depression Rating Scales. Findings Significant correlations were observed between increased methadone dosage and antisocial personality disorder. In addition, significant positive correlations were observed between increased methadone dosage and Hamilton anxiety scores, Hamilton depression scores and Young Mania scores. Conclusion High methadone dosage may be a marker of coexisting psychiatric disorders in patients on methadone maintenance treatment which indicates the necessity of devoting further attention to this group. Psychiatric services should be open and accessible to the patients, especially those who seek treatment voluntarily. Early diagnosis and treatment of patients with coexisting psychiatric disorders may increase the efficacy of methadone maintenance treatment. PMID:24494130

  11. The hyperglycaemic effect of morphine

    PubMed Central

    Feldberg, W.; Shaligram, S. V.

    1972-01-01

    1. In the unanaesthetized cat, an injection of 0·75 mg of morphine into a lateral cerebral ventricle produced strong hyperglycaemia; on intravenous injection, 10 to 30 times larger doses were required. Other effects produced with both injections were shivering, pupillary dilatation, opening of the eyes, miaowing, periods of excitation, and analgesia. Between the periods of excitation the cat did not react to objects moving in front of its eyes and it had a vacant stare. 2. Noradrenaline, adrenaline, and 5-hydroxytryptamine (5-HT) injected intraventricularly (250 μg, twice) depressed the hyperglycaemia due to intraventricular morphine, and noradrenaline also depressed the hyperglycaemia due to intravenous morphine. Adrenaline produced the strongest and 5-HT the weakest depression. 5-HT did not depress the other effects of morphine, but the catecholamines depressed most of them; only analgesia and the vacant stare appeared to be unaffected. 3. Reserpine injected intraventricularly (0·5 mg, twice) greatly accentuated the hyperglycaemia as well as the other effects produced by intraventricular morphine, but pupillary dilatation and opening of the eyes no longer occurred; the protrusion of the nictitating membranes produced by the reserpine persisted. 4. Pentobarbitone sodium injected intraperitoneally in an anaesthetizing dose practically abolished the morphine hyperglycaemia, but injected intraventricularly in a dose of a few milligrammes, it had a two fold effect: depression followed by enhancement of the morphine hyperglycaemia. The enhancement may be due to sensitization of the effect of the adrenaline released by morphine, since adrenaline hyperglycaemia was enhanced as well. 5. Morphine did not seem to act on structures in the walls of either the lateral or third ventricle when producing its hyperglycaemic effect on intraventricular injection. The action may therefore be on more caudally situated parts of the neuro-axis, on the central grey, on structures in

  12. A comparison of oxycodone and fentanyl in intravenous patient-controlled analgesia after laparoscopic hysterectomy

    PubMed Central

    Kim, Nan-Seol; Yoo, Sie Hyeon; Chung, Jin Hun; Chung, Ji-Won; Seo, Yonghan; Chung, Ho-Soon; Jeon, Hye-Rim; Gong, Hyung Youn; Lee, Hyun-Young; Mun, Seong-Taek

    2015-01-01

    Background We planned to compare the effect of intravenous oxycodone and fentanyl on post-operative pain after laparoscopic hysterectomy. Methods We examined 60 patients were randomized to postoperative pain treatment with either oxycodone (n = 30, Group O) or fentanyl (n = 30, Group F). The patients received 10 mg oxycodone/100 µg fentanyl with ketorolac 30 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 h postoperatively. Results The accumulated oxycodone consumption was less than fentanyl during 8, 24 and 48 h postoperatively. Numeric rating score of Group O showed significantly lower than that of Group F during 30 min, 2, 4, 8 and 24 h postoperatively. The incidences of adverse reactions were similar in the two groups, though the incidence of nausea was higher in the Group O during the 24 and 48 h postoperative period. Conclusions Oxycodone IV-PCA was more advantageous than fentanyl IV-PCA for laparoscopic hysterectomy in view of accumulated oxycodone consumption, pain control and cost beneficial effect. However, patient satisfaction was not good in the group O compared to group F. PMID:26045929

  13. Blockade of morphine-induced behavioral sensitization by a combination of amisulpride and RB101, comparison with classical opioid maintenance treatments

    PubMed Central

    Cordonnier, L; Sanchez, M; Roques, B P; Noble, F

    2007-01-01

    Background and purpose: Maintenance treatments with methadone or buprenorphine are more or less efficient procedures for helping heroin addicts to stop or reduce drug abuse. Another approach to treat opiate dependence could be to target the endogenous opioid system by enhancing the effects of enkephalins by protecting them from enzymic degradation by the dual peptidase inhibitor RB101. Experimental approach: As chronic treatment with the dopamine D2 antagonist amisulpride facilitates RB101-induced behavioral effects, we chose in this study to treat mice previously sensitized to the hyperlocomotor effects induced by morphine with a combination of amisulpride and RB101. Key results: Expression of morphine-induced locomotor sensitization was abolished after combined treatment with amisulpride (20 mg.kg−1, i.p.) and RB101 (80 mg.kg−1, i.p.), whereas these drugs were not effective when used alone. We then compared these results with the effects of amisulpride combined with buprenorphine (0.1 mg.kg−1, i.p.) or methadone (2.5 mg.kg−1, i.p.) upon morphine-induced behavioral sensitization. Whereas the combination of amisulpride and buprenorphine partially blocked the expression of morphine sensitization, amisulpride+methadone was not effective in this paradigm. Conclusions and implications: The combination of amisulpride+RB101 appears to be very efficient in blocking the expression of morphine-induced behavioral sensitization. This could reflect a reinstatement of a balance between the function of the dopamine and opioid systems and could represent a new approach in maintenance treatments for opiate addiction. PMID:17351659

  14. Methadone

    MedlinePlus

    ... mL (4 ounces) of water, orange juice, Tang®, citrus flavors of Kool-Aid®, or a citrus fruit drink to dissolve. Drink the entire mixture ... Nuedexta); fluvoxamine (Luvox); medications for glaucoma, irritable bowel disease, Parkinson's disease, ulcers, and urinary problems; certain medications ...

  15. Hyperphagia in neonates withdrawing from methadone

    PubMed Central

    Martinez, A.; Kastner, B.; Taeusch, H

    1999-01-01

    AIMS—To examine whether hyperphagia is a clinically significant problem in infants born to women receiving methadone maintenance.
METHODS—The volume of feeds, changes in infant body weight, as well as occurrence of adverse clinical effects in infants withdrawing from methadone were studied during the first month of life. A retrospective chart review was conducted for all infants at San Francisco General between 1992 and 1995, born to women receiving methadone maintenance during their pregnancy. Forty four infants were identified and the data obtained from hospital medical records. The daily oral intake of these infants was recorded during the first month of life. The incidence of hyperphagia (oral intake> 190 cc/kg/day) was measured. Associations between infant oral intake and maternal methadone dose were studied using correlation analysis as well as Anova for repeated measures. Adverse clinical symptoms were also recorded. A subset of premature infants was studied separately.
RESULTS—The incidence of hyperphagia was 26% by day 8 and 56% by day 16 of life in the infants. Hyperphagia was not associated with maternal methadone dose or with infant withdrawal scores. Infants who were hyperphagic lost significantly more weight during the first week of life than those who were not. Despite significantly greater intake, the hyperphagic infants did not gain weight more rapidly during the first month of life compared with those infants with lower oral intake. Infants who were hyperphagic (maximum intake of 290 cc/kg/day) did not experience increased vomiting, aspiration, diarrhoea, or abdominal distention.
CONCLUSIONS—Hyperphagia is commonly found in infants withdrawing from methadone and can be persistent in a significant number. Hyperphagia was not associated with either increased neonatal weight gain or with adverse gastrointestinal consequences. Hyperphagia may occur in infants withdrawing from methadone who have high metabolic demands due to clinical

  16. Methadone toxicity in a poisoning referral center

    PubMed Central

    Taheri, Fatemeh; Yaraghi, Ahmad; Sabzghabaee, Ali Mohammad; Moudi, Maryam; Eizadi-Mood, Nastaran; Gheshlaghi, Farzad; Farajzadegan, Ziba

    2013-01-01

    Objective: Methadone poisoning can occur accidentally or intentionally for suicide or homicide purposes. The aim of this study was to evaluate the epidemiological and clinical manifestations of Methadone poisoning. Methods: A descriptive analytical study was performed from 2010 to 2012 in the poisoning emergency and clinical toxicology departments of Noor hospital affiliated with Isfahan University of Medical Sciences (Isfahan, Iran). All patients with Methadone poisoning within this period of time were investigated. Different variables were recorded in a checklist. Findings: A total of 385 patients were studied. About 85.7% had ingested only Methadone and 14.3% had ingested other medications with Methadone. Mean ± standard deviation of the age was 32.1 ± 15 years (range: 1-90). Most of the patients were male (76.4%). Nearly 40% of the patients were narcotic addicts, 25.5% were addicts under surveillance of Methadone maintenance therapy centers and 34.5% were non-addicts. Intentional poisoning was observed in most of the patients (57.7%). Most of the patients had a low level of consciousness on admission (58.2%). Respiratory depression and hypotension was observed in 35.6% and 12.7% of the cases as the most common symptoms. Regarding vital signs, there was a significant difference in respiratory rate on admission among different evaluated groups (P = 0.02). Length of hospital stay was 18.79 ± 0.72 h (range: 4-240 h, median: 15 h). About 57 patients (25.8%) from the intentionally poisoned patients and 19 patients (12.3%) from the unintentionally poisoned patients had a history of psychiatric disorder (P = 0.001). Most of the patients survived without complications. Conclusion: Addiction, age, gender, attempt to suicide and a history of psychiatric disorder were of the most important factors effective in Methadone poisoning, which should be considered in the public training and prevention of poisoning. PMID:24991620

  17. Going Through the Changes: Methadone in New York City

    ERIC Educational Resources Information Center

    Agar, Michael

    1977-01-01

    Methadone has been defined as an agent to draw addicts out of the street life into "straight" society. However, the complementary perspective of the streets sees methadone as a new, widely available drug to be integrated into a subculture previously dominated by heroin. This article discusses the adaptation to methadone and its implications. (NQ)

  18. 21 CFR 862.3620 - Methadone test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Methadone test system. 862.3620 Section 862.3620...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3620 Methadone test system. (a) Identification. A methadone test system is a device intended to...

  19. 21 CFR 862.3620 - Methadone test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Methadone test system. 862.3620 Section 862.3620...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3620 Methadone test system. (a) Identification. A methadone test system is a device intended to...

  20. 21 CFR 862.3620 - Methadone test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Methadone test system. 862.3620 Section 862.3620...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3620 Methadone test system. (a) Identification. A methadone test system is a device intended to...

  1. 21 CFR 862.3620 - Methadone test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Methadone test system. 862.3620 Section 862.3620...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3620 Methadone test system. (a) Identification. A methadone test system is a device intended to...

  2. Work Adjustment of the Methadone-Maintained Corporate Employee

    ERIC Educational Resources Information Center

    Yankowitz, Robert; Randell, Joan

    1977-01-01

    The work adjustment of 26 methadone-maintained corporate employees was evaluated. Results indicated: (a) relative to their nonmethadone-maintained coworkers, the methadone-maintained employees had comparable job performance and superior punctuality and attendance; and (b) the methadone-maintained skilled laborers were satisfied with their…

  3. Systematic knockdown of morphine pathway enzymes in opium poppy using virus-induced gene silencing.

    PubMed

    Wijekoon, Champa P; Facchini, Peter J

    2012-03-01

    Opium poppy (Papaver somniferum) remains the sole commercial source for several pharmaceutical alkaloids including the narcotic analgesics codeine and morphine, and the semi-synthetic drugs oxycodone, buprenorphine and naltrexone. Although most of the biosynthetic genes have been identified, the post-transcriptional regulation of the morphinan alkaloid pathway has not been determined. We have used virus-induced gene silencing (VIGS) as a functional genomics tool to investigate the regulation of morphine biosynthesis via a systematic reduction in enzyme levels responsible for the final six steps in the pathway. Specific gene silencing was confirmed at the transcript level by real-time quantitative PCR (polymerase chain reaction), and at the protein level by immunoblot analysis using antibodies raised against salutaridine synthase (SalSyn), salutaridine reductase (SalR), salutaridine 7-O-acetyltransferase (SalAT), thebaine 6-O-demethylase (T6ODM), codeinone reductase (COR), and codeine O-demethylase (CODM). In some cases, silencing a specific biosynthetic gene resulted in a predictable accumulation of the substrate for the corresponding enzyme. Reduced SalSyn, SalR, T6ODM and CODM protein levels correlated with lower morphine levels and a substantial increase in the accumulation of reticuline, salutaridine, thebaine and codeine, respectively. In contrast, the silencing of genes encoding SalAT and COR resulted in the accumulation of salutaridine and reticuline, respectively, which are not the corresponding enzymatic substrates. The silencing of alkaloid biosynthetic genes using VIGS confirms the physiological function of enzymes previously characterized in vitro, provides insight into the biochemical regulation of morphine biosynthesis, and demonstrates the immense potential for metabolic engineering in opium poppy.

  4. A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats.

    PubMed

    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.

  5. Characterization of (+/-)-methadone uptake by rat lung.

    PubMed Central

    Chi, C H; Dixit, B N

    1977-01-01

    1. By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (+/-)-methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (+/-)-methadone against a concentration gradient. 2. This phenomenon was investigated in vitro with rat lung slices incubated in Krebs-Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio). 3. The principal observations were: (i) Studies on the time-course of the uptake showed that the T/M ratios of (+/-)-methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (+/-)-methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.5; (iii) When the concentration of (+/-)-methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self-saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4. These results suggested that at low concentrations, (+/-)-methadone was transported predominantly by a self-saturable process while at higher concentrations it was transported by a process of simple diffusion. 5. At low concentrations (0.01 mM) the uptake of (+)-methadone was higher than that of (-)-isomer indicating stereo-specificity of the uptake process. The uptake of (+/-)-methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (approximately 100 degrees C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM). 6. Kinetic analysis of data showed that the diffusion constant

  6. Profile of Clients Attending a Methadone Clinic

    PubMed Central

    JACOB, Sabrina Anne; MOHAMMED, Fauziah; HASSALI, Mohamed Azmi Ahmad

    2015-01-01

    Background: Client characteristics provide useful information for designing programs that target individuals with risk factors for substance use and for determining client retention. Therefore, this study examined the profiles of clients attending a methadone clinic. Methods: A cross-sectional analysis of clients of a methadone clinic was conducted through a survey to obtain a profile of methadone clients. Results: Of the 51 patients who responded (response rate: 66.2%), the mean (SD) age at which they started substance use was 19.8 (5.1) years. Friends were cited as the most regular source of drugs (82.4%), and heroin was the most commonly used drug (98%). Daily substance use was reported by 72.5% of the respondents; 23.5% admitted to having stolen money to purchase drugs; 92.2% tried quitting substance use on their own and 98% stated that the main reason for registering at the clinic was that they wanted to stop their drug dependence. Approximately 60% of clients were receiving methadone doses of less than 60 mg/day. Conclusion: Heroin is still the most popular drug of abuse and most clients still receive methadone doses below the recommended level, despite evidence of poor patient retention rates associated with these low doses. PMID:25892951

  7. Controlled-Release Oxycodone Versus Naproxen at Home After Ambulatory Surgery: A Randomized Controlled Trial

    PubMed Central

    Stessel, Björn; Theunissen, Maurice; Fiddelers, Audrey A.; Joosten, Elbert A.; Kessels, Alfons G.; Gramke, Hans-Fritz; Marcus, Marco A.

    2014-01-01

    Background Strong opioids in the home setting after ambulatory surgery have rarely been studied for fear of hazardous adverse effects such as respiratory depression. Objectives We compared the efficacy of paracetamol/controlled-release (CR) oxycodone and paracetamol/naproxen for treatment of acute postoperative pain at home after ambulatory surgery. Secondary outcomes were adverse effects of study medication, treatment satisfaction, and postoperative analgesic compliance. Methods Patients undergoing ambulatory knee arthroscopy or inguinal hernia repair surgery (n = 105) were randomized into 3 groups: Group1 paracetamol/naproxen (n = 35), Group 2 paracetamol/CR oxycodone for 24 hours (n = 35), and Group 3 paracetamol/CR oxycodone for 48 hours (n = 35). Pain intensity at movement and at rest using a visual analog scale as well as satisfaction with postoperative analgesia and side effects were recorded for up to 48 hours postoperatively. Compliance with study medication was also assessed. Results For pain at movement and at rest, no significant differences were found between the paracetamol/naproxen group and either the paracetamol/CR oxycodone for 24 hours group (β = 2.6 [4.9]; P = 0.597) or the paracetamol/CR oxycodone for 48 hours (β = –1.7 [5.1]; P = 0.736). No major adverse effects of study medication were registered and satisfaction with postoperative pain treatment was high in all groups. Compliance was comparable across the groups. Despite clear instructions, 8 patients with the lowest pain scores did not use any of the prescribed pain medication. Conclusions Paracetamol/CR oxycodone and paracetamol/naproxen are equally effective in treatment of acute postoperative pain at home after ambulatory surgery with comparable patient satisfaction level. We suggest paracetamol/CR oxycodone to be a valuable alternative for the current paracetamol/naproxen gold standard, particularly in patients with a contraindication for nonsteroidal anti-inflammatory drugs

  8. The genetic influences on oxycodone response characteristics in human experimental pain.

    PubMed

    Olesen, Anne E; Sato, Hiroe; Nielsen, Lecia M; Staahl, Camilla; Droney, Joanne; Gretton, Sophy; Branford, Ruth; Drewes, Asbjørn M; Arendt-Nielsen, Lars; Riley, Julia; Ross, Joy

    2015-08-01

    Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.

  9. Pharmacogenomics of methadone maintenance treatment.

    PubMed

    Somogyi, Andrew A; Barratt, Daniel T; Ali, Robert L; Coller, Janet K

    2014-05-01

    Methadone is the major opioid substitution therapy for opioid dependence. Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines. Nevertheless many genetic factors have been investigated including those affecting its metabolism (CYP2B6-consistent results), efflux transport (P-gp-inconsistent results), target μ-opioid receptor (μ-opioid receptor-inconsistent results) and a host of other receptors (DRD2) and signaling elements (GIRK2 and ARRB2; not replicated). None by themselves have been able to substantially explain dosage variation (the major but not sole end point). When multiple genes have been combined such as ABCB1, CYP2B6, OPRM1 and DRD2 a greater contribution to dosage variation was found but not as yet replicated. As stabilization of dosage needs to be made rapidly, it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed, which may or may not tailor to different ethnic groups and each country's policy towards an outcome that benefits all.

  10. Body Composition Changes Associated With Methadone Treatment

    PubMed Central

    Sadek, Gamal E.; Chiu, Simon; Cernovsky, Zack Z.

    2016-01-01

    Background: Methadone is associated with a statistically significant increase in BMI in the first 2 years of treatment. Objectives: To evaluate the changes of body composition (bone mass, % fat, % muscle mass, % water, and basal metabolic rate) related to this increase. Patients and Methods: Changes in body composition were monitored, via bioelectrical impedance, in 29 patients in methadone treatment for opiate dependency (age 18 to 44, mean = 29.3, SD = 7.0, 13 men, 16 women). Results: Within one year from admission to treatment, a statistically significant (t-tests, P < 0.05) increase was noted in their body mass index (BMI), % of body fat, average body mass, and average basal metabolic rate, and relative decrease in their % of muscle mass and % of bone mass. Neither absolute bone mass nor muscle mass changed significantly. Conclusions: Physicians involved in care of methadone patients should recommend dietary and lifestyle changes to improve their overall health. PMID:27162765

  11. [Impact of slow-release oral morphine on drug abusing habits in Austria].

    PubMed

    Beer, Beate; Rabl, Walter; Libiseller, Kathrin; Giacomuzzi, Salvatore; Riemer, Yvonne; Pavlic, Marion

    2010-01-01

    A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is

  12. Effects of different dosages of oxycodone and fentanyl on the hemodynamic changes during intubation

    PubMed Central

    Park, Ki-Bum; Ann, Junggun; Lee, Haemi

    2016-01-01

    Objectives: To investigate the effectiveness of oxycodone compared with fentanyl for attenuating the hemodynamic response during endotracheal intubation. Methods: This study was conducted from June 2014 to February 2015 on healthy adults undergoing general anesthesia at the Yeungnam University Hospital, Daegu, Republic of Korea. Ninety-five patients were randomly assigned to one of 3 groups to receive the following drugs; Group F: fentanyl 2 µg/kg; Group O/70: oxycodone 140 µg/kg; Group O/100: oxycodone 200 µg/kg. Five minutes after injection of the study drug, general anesthesia was induced with propofol 1.5 mg/kg and rocuronium 0.8 mg/kg. The mean blood pressure (MBP), heart rate (HR), peripheral oxygen saturation (SpO2), and bispectral index (BIS) were compared before administration of the study drug (T1), just before endotracheal intubation (T2), one minute after endotracheal intubation (T3), and 7.5 minutes after endotracheal intubation (T4). Complications were assessed. Results: The 2 oxycodone groups showed no significant differences in MBP, HR, SpO2, and BIS compared to Group F at the time points assessed. The incidence of complications was comparable among the groups. Conclusions: Oxycodone could successfully be used to attenuate the sympathetic response during anesthetic induction. The hemodynamic profiles and incidence of complications were clinically similar among the groups, but Group O/70 tended to show a lower rate of complications of apnea. PMID:27464860

  13. Separate and combined psychopharmacological effects of alprazolam and oxycodone in healthy volunteers

    PubMed Central

    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

  14. Morphine suppression of ethanol withdrawal in mice.

    PubMed

    Blum, K; Wallace, J E; Schwerter, H A; Eubanks, J D

    1976-01-15

    The acute administration of morphine, alcohol or dopamine results in a pronounced suppression of the convulsions produced by alcohol in mice. The suppressive action of morphine on alcohol withdrawal in the mouse apparently is not a product of morphine intoxication, but rather to some other specific interaction between alcohol and morphine in the central nervous system. The conclusion suggest that dopamine may play a significant role as a modulator in convulsions produced during alcohol withdrawal.

  15. The Disposition of Oxycodone and Metabolite in Human Hair.

    PubMed

    Reisfield, Gary M; Jones, Joseph T

    2015-01-01

    The disposition of oxycodone (OC) and metabolites in hair remains poorly characterized. We present a case involving a pharmacist in an impaired professionals' monitoring program in whom hair testing yielded OC on two occasions. On both occasions, his hair was negative for the oxymorphone (OM) metabolite at the cutoff concentration of 100 pg/mg. He claimed that, absent the detection of metabolite, the OC necessarily represented external contamination. This prompted a review of the laboratory's OC-positive hair results for the quarter April-June 2014. Overall, 466 specimens contained OC, with a mean (median) concentration of 2,375 (1,060) pg/mg. Of these OC-positive specimens, only 47 (10%) contained detectable OM. When OC was present at or below the mean (median) concentration, only 2.2% (1.3%) of specimens were OM-positive. In the setting of OC administration, the detection of OM in hair is unlikely at a cutoff concentration of 100 pg/mg. More consistent demonstration of OC metabolite(s) in hair will require the validation of methods to detect OM at lower concentrations and/or methods to detect noroxycodone.

  16. Methadone, Cocaine, Opiates and Metabolite Disposition in Umbilical Cord and Correlations to Maternal Methadone Dose and Neonatal Outcomes

    PubMed Central

    de Castro, Ana; Jones, Hendreé E.; Johnson, Rolley E.; Gray, Teresa R; Shakleya, Diaa M; Huestis, Marilyn A

    2011-01-01

    Objectives To explore methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) umbilical cord disposition, correlate with maternal methadone dose and neonatal outcomes, and evaluate the window of drug detection in umbilical cord of in utero illicit drug exposure. Methods Subjects, 19 opioid-dependent pregnant women from two clinical studies, one comparing methadone and buprenorphine pharmacotherapy for opioid-dependence treatment, and the second examining monetary reinforcement schedules to maintain drug abstinence. Correlations were calculated for methadone and EDDP umbilical cord concentrations and maternal methadone dose, and neonatal outcomes. Cocaine- and opiate-positive umbilical cord concentrations were compared to those in placenta and meconium, and urine specimens collected throughout gestation. Results Significant positive correlations were found for umbilical cord methadone concentrations and methadone mean daily dose, mean dose during the 3rd trimester and methadone cumulative daily dose. Umbilical cord EDDP concentrations and EDDP/methadone concentration ratios were positively correlated to newborn length, peak neonatal abstinence syndrome (NAS) score and time-to-peak NAS score. Methadone concentrations and EDDP/methadone ratios in umbilical cord and placenta were positively correlated. Meconium identified many more cocaine and opiate positive specimens than umbilical cord. Conclusion Umbilical cord methadone concentrations were correlated to methadone doses. Also, our results indicate that methadone and EDDP concentrations might help to predict NAS severity. Meconium proved to be more suitable than umbilical cord to detect in utero exposure to cocaine and opiates; however, umbilical cord could be useful when meconium is unavailable due to in utero or delayed expulsion. PMID:21743375

  17. Methadone maintenance and drug-related crime.

    PubMed

    Bell, J; Mattick, R; Hay, A; Chan, J; Hall, W

    1997-01-01

    Using data from an evaluation of methadone maintenance treatment, this study investigated factors associated with continued involvement in crime during treatment, and in particular whether there appeared to be differences in effectiveness of treatment between different methadone clinics. The methodology was an observational study, in which 304 patients attending three low-intervention, private methadone clinics in Sydney were interviewed on three occasions over a twelve month period. Outcome measures were self-reported criminal activity and police department records of convictions. By self-report, crime dropped promptly and substantially on entry to treatment, to a level of acquisitive crime about one-eighth that reported during the last addiction period. Analysis of official records indicated that rates of acquisitive convictions were significantly lower in the in-treatment period compared to prior to entry to treatment, corroborating the changes suggested by self-report. Persisting involvement in crime in treatment was predicted by two factors: the cost of persisting use of illicit drugs, particularly cannabis, and ASPD symptom count. Treatment factors also were independently predictive of continued involvement in crime. By both self-report and official records, and adjusting for subject factors, treatment at one clinic was associated with greater involvement in crime. This clinic operated in a chaotic and poorly organized way. It is concluded that crime during methadone treatment is substantially lower than during street addiction, although the extent of reduction depends on the quality of treatment being delivered.

  18. Employment Patterns of Methadone Maintenance Clients

    ERIC Educational Resources Information Center

    Bloch, Harriet I.; And Others

    1977-01-01

    Analysis of employment patterns of methadone maintenance clients had indicated that the majority were not employed at time of program admission. At time of evaluation, 70 percent of the sample were employed; 88 percent of these clients had previous work histories and brought marketable skills with them. (Author)

  19. 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)

  20. Profile of extended-release oxycodone/acetaminophen for acute pain.

    PubMed

    Bekhit, Mary Hanna

    2015-01-01

    This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER) formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA)-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone) with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen), are available solely in immediate-release (IR) formulations. PMID:26527898

  1. Profile of extended-release oxycodone/acetaminophen for acute pain

    PubMed Central

    Bekhit, Mary Hanna

    2015-01-01

    This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER) formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA)-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone) with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen), are available solely in immediate-release (IR) formulations. PMID:26527898

  2. Quantitation of methadone and metabolite in patients under maintenance treatment.

    PubMed

    Diong, Shiau Hui; Mohd Yusoff, Nor Shuhadah; Sim, Maw Shin; Raja Aziddin, Raja Elina; Chik, Zamri; Rajan, Poppy; Abdul Rashid, Rusdi; Chemi, Norliza; Mohamed, Zahurin

    2014-01-01

    Gas chromatography-mass spectrometry quantitative method was developed to monitor concentrations of methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in plasma and urine of patients. The developed method was simple, accurate and reproducible to quantify methadone and EDDP in plasma and urine samples in the concentration range of 15-1,000 and 50-2,000 ng/mL, respectively. The proposed analytical method was applied to plasma and urine samples obtained from 96 patients undergoing methadone maintenance treatment (MMT) with daily methadone doses of 2-120 mg/day. Urinary methadone excretion was observed to be significantly affected by pH, in which the ratio of methadone to EDDP was two times higher in acidic urine (P = 0.029). The findings of this study further enhance the guidelines for monitoring of methadone treatment among outpatients. Methadone-to-EDDP ratio in urine was found to be consistent at 24 and 4 h, hence suggesting the possibility that outpatients may be monitored with single urine sample in order to check for compliance. This study which provides data on peak concentrations of methadone and EDDP as well as the ratio of both compounds has added to the body of knowledge regarding pharmacokinetic properties of methadone among heroin-dependent patients under MMT.

  3. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

    PubMed Central

    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

  4. Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.

    PubMed

    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. PMID:26061355

  5. Characteristics of methadone-related fatalities in Norway.

    PubMed

    Bernard, Jean-Paul; Khiabani, Hassan Z; Hilberg, Thor; Karinen, Ritva; Slørdal, Lars; Waal, Helge; Mørland, Jørg

    2015-11-01

    There are currently over 7000 patients enrolled in opioid maintenance treatment (OMT) programs in Norway. A rise in methadone-related deaths proportional to increasing methadone sales over the period 2000-2006 has been observed, but the causative factors for these fatalities have been elusive. In the present study, individual characteristics, methadone concentrations and additional toxicological findings were analyzed. Methadone intoxication deaths (n = 264) were divided into 3 groups according to toxicological findings in whole blood: group 1 - methadone detected alone, or together with one additional drug at low or therapeutic levels, or a low concentration of ethanol (<1 g/L) (n = 21); group 2 - multiple additional drugs/substances detected below lethal levels (n = 175); group 3 - one or more additional drugs/substances detected at lethal levels, or ethanol >3 g/L (n = 55). Methadone blood concentrations in decedents who had been enrolled in OMT were higher than for decedents not in treatment, in all groups. Blood methadone concentrations around 1 mg/L were present in fatal multi-drug intoxications in OMT patients. Results suggest that some patients may be at risk of dying when combining therapeutic concentrations of methadone with other psychoactive substances. Somatic disease was a common finding among deceased OMT patients. Concentrations in methadone users not enrolled in OMT were predominantly between 0.3 and 0.4 mg/L and were not related to the presence of other drugs. However, methadone concentrations below 0.1 mg/L may be associated with intoxication following methadone use, both alone and in combination with other drugs. Younger male users (mean age 34 years) seemed to have a higher susceptibility to methadone intoxication.

  6. Characteristics of methadone-related fatalities in Norway.

    PubMed

    Bernard, Jean-Paul; Khiabani, Hassan Z; Hilberg, Thor; Karinen, Ritva; Slørdal, Lars; Waal, Helge; Mørland, Jørg

    2015-11-01

    There are currently over 7000 patients enrolled in opioid maintenance treatment (OMT) programs in Norway. A rise in methadone-related deaths proportional to increasing methadone sales over the period 2000-2006 has been observed, but the causative factors for these fatalities have been elusive. In the present study, individual characteristics, methadone concentrations and additional toxicological findings were analyzed. Methadone intoxication deaths (n = 264) were divided into 3 groups according to toxicological findings in whole blood: group 1 - methadone detected alone, or together with one additional drug at low or therapeutic levels, or a low concentration of ethanol (<1 g/L) (n = 21); group 2 - multiple additional drugs/substances detected below lethal levels (n = 175); group 3 - one or more additional drugs/substances detected at lethal levels, or ethanol >3 g/L (n = 55). Methadone blood concentrations in decedents who had been enrolled in OMT were higher than for decedents not in treatment, in all groups. Blood methadone concentrations around 1 mg/L were present in fatal multi-drug intoxications in OMT patients. Results suggest that some patients may be at risk of dying when combining therapeutic concentrations of methadone with other psychoactive substances. Somatic disease was a common finding among deceased OMT patients. Concentrations in methadone users not enrolled in OMT were predominantly between 0.3 and 0.4 mg/L and were not related to the presence of other drugs. However, methadone concentrations below 0.1 mg/L may be associated with intoxication following methadone use, both alone and in combination with other drugs. Younger male users (mean age 34 years) seemed to have a higher susceptibility to methadone intoxication. PMID:26439870

  7. Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect.

    PubMed

    Nakazawa, Yusuke; Okura, Takashi; Shimomura, Keita; Terasaki, Tetsuya; Deguchi, Yoshiharu

    2010-01-01

    To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [(3)H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [(3)H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [(3)H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentration-dependent manner by amitriptyline, fluvoxamine and mexiletine with K(i) values of 13, 65, and 44 microM, respectively. These K(i) values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations. PMID:19499573

  8. Methadone-related deaths. A ten year overview.

    PubMed

    Vignali, Claudia; Stramesi, Cristiana; Morini, Luca; Pozzi, Fulvia; Groppi, Angelo

    2015-12-01

    Over the last 10 years we have registered in our district (about 500,000 inhabitants) 36 cases of fatal methadone poisoning, involving both patients on treatment and naive subjects: this is a significant increase of deaths due to methadone use, misuse or abuse compared with previous years. Twenty-four patients (66.7%) were on methadone maintenance programs for heroin detoxification, while 12 (33.3%) were taking the drug without a medical prescription. The average blood concentration of methadone in patients undergoing a maintenance program was 1.06 mg/L (0.21-3.37 mg/L), against 0.79 mg/L (0.2-3.15 mg/L) in those taking the non-prescribed drug. Since 111 heroin-related deaths were recorded in our district in the same period, the fact that there appear to be many methadone deaths (about a third of heroin-related deaths) cannot be overlooked. The aim of this work is to understand the possible reasons for such a large number of methadone-related deaths. On this subject, we have noticed that risks associated with methadone intake are often underestimated by clinicians prescribing the drug: sometimes methadone is prescribed without taking into account patient's tolerance to opiates, and a large number of subjects enrolled in methadone maintenance programs in Italy, have also been given take-home doses, thus increasing the risk of abuse and diversion.

  9. Eating behavior reveals rats' preference for morphine.

    PubMed

    Yanaura, S; Suzuki, T; Kawai, T

    1980-04-01

    Using an automatic food intake measuring apparatus ("food intakometer"), we recorded the approach behavior to food, eating behavior and food intake of morphine dependent rats and examined the relationship among these factors and morphine dependence. Morphine dependent rats were produced by the drug-admixed food (DAF) method. In the choice trial of free feeding group, morphine dependent rats showed only the approach behavior both to drug-free diet and to morphine-admixed food, then ate the morphine-admixed food and approached the drug-free diet at the same period. Eating behavior in the case of morphine-admixed food was observed not only at night but also during thee feeding group, morphine dependent rats showed only the approach behavior both to drug-free diet and to morphine-admixed food, then ate the morphine-admixed food and approached the drug-free diet at the same period. Eating behavior in the case of morphine-admixed food was observed not only at night but also during the day time in the morphine dependent rats. In the choice trial of the limited feeding group, preference for morphine rapidly increased in every choice trial of each session and the preference rate became stable at about 60%. Eating patterns of these rats were similar to these in the free feeding group. When these rats were given morphine prior to the choice trial, eating behavior of those on the morphine-admixed food was inhibited dose-dependently, while eating behavior of these on the drug-free diet was enhanced dose-dependently. When these rats were allowed free access to drug-free diet for 1 hour previously to the choice trial, eating behavior of the rats on the morphine-admixed food in the choice trial was markedly enhanced. Thus, the rats clearly showed drug-seeking behavior and seemed to be able to distinguish between the need for morphine and satisfaction without it. Morphine dependent rats apparently can control their required maintenance dose.

  10. Satisfaction With Methadone Among Heroin-Dependent Patients With Current Substance Use Disorders During Methadone Maintenance Treatment.

    PubMed

    Perez de Los Cobos, Jose; Trujols, Joan; Siñol, Núria; Duran-Sindreu, Santiago; Batlle, Francesca

    2016-04-01

    Methadone maintenance treatment (MMT) has long been used to treat heroin-dependent patients. However, satisfaction with methadone in this patient population is unknown. The aim of this cross-sectional case-control study was to evaluate satisfaction with methadone in heroin-dependent patients with current substance use disorders (SUDs). Cases included 152 methadone-maintained patients with current SUD, requiring inpatient detoxification treatment, and controls included 33 methadone-maintained patients in sustained full remission for SUD. Satisfaction with methadone as a medication to treat heroin addiction was measured by using the Scale to Assess Satisfaction with Medications for Addiction Treatment-methadone for heroin addiction (SASMAT-METHER). The SASMAT-METHER subscales assess the following domains: personal functioning and well-being, antiaddictive effect on heroin, and antiaddictive effect on other substances. Compared with patients with remitted SUD, patients with current SUD scored lower on all SASMAT-METHER assessments. In such patients, overall SASMAT-METHER scores were independently and negatively associated with downward desired adjustment of methadone dose and days of heroin use during last month; although various sets of factors were independently associated with each of the SASMAT-METHER subscales, the only determinant of dissatisfaction on all subscales was the desire for downward adjustment of methadone dose. In summary, MMT patients with current SUD are less satisfied with methadone than MMT patients with remitted SUD. In patients with current SUD, downward desired adjustment of methadone dose and days of heroin use during last month are independently associated with overall dissatisfaction with methadone. PMID:26825608

  11. 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…

  12. Oxycodone lengthens reproductions of suprasecond time intervals in human research volunteers

    PubMed Central

    Gooch, Cynthia M.; Rakitin, Brian C.; Cooper, Ziva D; Comer, Sandra D.; Balsam, Peter D

    2011-01-01

    Oxycodone, a popularly used opioid for treating pain, is widely abused. Other drugs of abuse have been shown to affect time perception, which in turn may affect sensitivity to future consequences. This may contribute to continued use. The current study evaluated the effect of oxycodone on time perception in normal healthy volunteers. For this within-subject, double-blind design study, participants performed a temporal reproduction task before and after receiving placebo or oxycodone (15 mg, po) over 6 outpatient sessions. Participants were first trained with feedback to reproduce three standard intervals (1.1, 2.2, and 3.3 s) in separate blocks by matching response latency from a start signal to the duration of that block’s standard interval. During testing participants were instructed to reproduce the three intervals from memory without feedback before and after drug administration . Oxycodone significantly lengthened time estimations for the two longer intervals relative to placebo. These results suggest that opioids alter temporal processing for intervals greater than one second, raising questions about the effect of these drugs on valuation of future consequences. PMID:21750426

  13. Design and in vivo evaluation of oxycodone once-a-day controlled-release tablets

    PubMed Central

    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

  14. Effects of methadone hydrochloride on the growth of organotypic cerebellar cultures prepared from methadone-tolerant and control rats.

    PubMed

    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.

  15. Pharmacotherapy in the treatment of addiction: methadone.

    PubMed

    Kreek, Mary Jeanne; Borg, Lisa; Ducat, Elizabeth; Ray, Brenda

    2010-04-01

    Methadone maintenance treatment (MMT) is the most widely available pharmacotherapy for opioid addiction and has been shown to be an effective and safe treatment over a period of 40 years. Although 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. 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.

  16. Pharmacotherapy in the Treatment of Addiction: Methadone

    PubMed Central

    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

  17. Prenatal oxycodone exposure impairs spatial learning and/or memory in rats.

    PubMed

    Davis, Chris P; Franklin, La'tonya M; Johnson, Gabriel S; Schrott, Lisa M

    2010-09-01

    Recent changes in demographic patterns of drug use have resulted in the increased non-medical use of prescription opiates. These users are younger and more likely to be female, which has the potential for increasing rates of in utero exposure. Therefore, we developed a rat model that simulates a prescription opiate-dependent woman who becomes pregnant. Adult female Sprague-Dawley rats were treated for 30 days via oral gavage with ascending doses of oxycodone HCl up to a final dose of 15mg/kg/day, which was maintained during breeding and gestation. Controls were treated with water. The adult male offspring of these treated dams were tested on the radial arm maze, the Morris water maze (with a short and a long intertrial interval), and a spatial T-maze. Prenatal oxycodone exposure led to a deficit in the radial arm maze characterized by a greater number of reference memory errors, especially in the beginning of testing. In contrast, in the T-maze, prenatal oxycodone-exposed rats learned the task as well as well as the prenatal water controls. However, they had a modest deficit in retention of the task when assessed 5 days after acquisition training ended. For the Morris water maze, the intertrial interval affected the pattern of learning. While there was no deficit when the training had a short intertrial interval, when there was a long intertrial interval, prenatal oxycodone-exposed rats had poorer acquisition. The spatial learning deficit was characterized by and increased latency to find and a greater distance traveled to the platform in the prenatal oxycodone-exposed rats. These data were corroborated by analysis of the behavioral search strategy, which showed a decreased use of spatial strategies and an increase in non-spatial strategies, especially wall-hugging, in prenatal oxycodone-exposed rats as compared to prenatal water control rats on day 2 of acquisition. These results indicate that prenatal oxycodone exposure consistently impairs learning and memory in

  18. Trends in Methadone Distribution for Pain Treatment, Methadone Diversion, and Overdose Deaths - United States, 2002-2014.

    PubMed

    Jones, Christopher M; Baldwin, Grant T; Manocchio, Teresa; White, Jessica O; Mack, Karin A

    2016-01-01

    Use of the prescription opioid methadone for treatment of pain, as opposed to treatment of opioid use disorder (e.g., addiction), has been identified as a contributor to the U.S. opioid overdose epidemic. Although methadone accounted for only 2% of opioid prescriptions in 2009 (1), it was involved in approximately 30% of overdose deaths. Beginning with 2006 warnings from the Food and Drug Administration (FDA), efforts to reduce methadone use for pain have accelerated (2,3). The Office of the Assistant Secretary for Planning and Evaluation of the U.S. Department of Health and Human Services and CDC analyzed methadone distribution, reports of diversion (the transfer of legally manufactured methadone into illegal markets), and overdose deaths during 2002-2014. On average, the rate of grams of methadone distributed increased 25.1% per year during 2002-2006 and declined 3.2% per year during 2006-2013. Methadone-involved overdose deaths increased 22.1% per year during 2002-2006 and then declined 6.5% per year during 2006-2014. During 2002-2006, rates of methadone diversion increased 24.3% per year; during 2006-2009, the rate increased at a slower rate, and after 2009, the rate declined 12.8% per year through 2014. Across sex, most age groups, racial/ethnic populations, and U.S. Census regions, the methadone overdose death rate peaked during 2005-2007 and declined in subsequent years. There was no change among persons aged ≥65 years, and among persons aged 55-64 years the methadone overdose death rate continued to increase through 2014. Additional clinical and public health policy changes are needed to reduce harm associated with methadone use for pain, especially among persons aged ≥55 years. PMID:27387857

  19. Immunomodulation by morphine and marijuana.

    PubMed

    Yahya, M D; Watson, R R

    1987-12-01

    The immunomodulatory effects of morphine and the active components of marijuana, particularly tetrahydrocannabinol, on various aspects of the host immune parameters include alterations in humoral, cell-mediated and innate immunity. Most studies have shown immunosuppressive effects due to use of these abused substances, although there are reports that they may not produce any deleterious effect and may even enhance some aspects of host immunity. They reduce resistance to cancer growth and microbial pathogens in animals.

  20. 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…

  1. Multimodality Approach to Methadone Treatment of Narcotic Addicts

    ERIC Educational Resources Information Center

    Brill, Leon; Chambers, Carl D.

    1971-01-01

    This multimodality approach is geared primarily to the goal of abstinence. For addicts who cannot achieve this goal, methadone maintenance is suggested as the next step. The modalities described range from low-dose maintenance for clinic outpatients to intensive rehabilitation in a methadone maintenance residential center facility. (Author)

  2. Methadone Diversion: Experiences and Issues. Services Research Monograph Series.

    ERIC Educational Resources Information Center

    Inciardi, James A.

    This report is a description of the phenomenon of methadone diversion as it exists now and places it in the context of prior research in this area. The intent here is to clarify issues around methadone diversion and to provide guidance to treatment administrators and program planners regarding efforts they can initiate to monitor this significant…

  3. Implosive Therapy Treatment of Heroin Addicts during Methadone Detoxification.

    ERIC Educational Resources Information Center

    Hirt, Michael; Greenfield, Heywood

    1979-01-01

    Examined effectiveness of implosive therapy with heroin addicts during detoxification from methadone. Treatment groups received 12 sessions of implosive therapy or eclectic counseling and were followed for a six-week period. The implosive therapy group were the only ones to significantly reduce their methadone level during treatment and follow-up.…

  4. Decreasing Methadone Dose Via Anxiety Reduction: A Treatment Manual.

    ERIC Educational Resources Information Center

    Kushner, Marlene; And Others

    This manual describes a Relaxation-Information Presentation program based on the clinical observation that anxiety is a serious barrier to detoxification for many methadone clients, and on experimental evidence indicating that expectations may play a greater role in the discomfort experienced during detoxification than the actual methadone dose.…

  5. Effects of methadone on human cigarette smoking and subjective ratings.

    PubMed

    Chait, L D; Griffiths, R R

    1984-06-01

    In order to study possible interactions between opioids and cigarette smoking, we examined the effects of oral methadone administration on the smoking behavior of five male methadone-maintenance patients. Isolated subjects smoked their regular brand of cigarettes ad libitum in a naturalistic laboratory environment while reading or watching television. Ninety minutes before each daily 2-hr smoking session subjects received either placebo, dextromethorphan (a taste blind) or one of three doses of methadone, 0.5, 1.0 or 2.0 times their regular maintenance dose (40-60 mg). Each subject received each treatment five times, in a mixed order across days. Methadone pretreatment resulted in a dose-related increase in the number of cigarettes smoked per session (from a mean of 2.8 after placebo to 5.6 after the high dose of methadone). The total time spent puffing during the session increased from a mean of 27 sec after placebo to 74 sec after the high dose of methadone. CO levels in expired air (a measure of actual smoke inhalation) showed corresponding dose-related increases. Methadone administration also resulted in dose-related decreases in pupil diameter and increases in subjective ratings of smoking satisfaction and dose-strength. Dextromethorphan had no significant effects on any measure of smoking behavior or subjective response. The results demonstrate that methadone can produce substantial increases in cigarette smoking and may have implications regarding the proposed role of endogenous opioids in the smoking process.

  6. 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…

  7. Behavioral Treatments During Outpatient Methadone Maintenance: A Controlled Evaluation.

    ERIC Educational Resources Information Center

    Bigelow, George; And Others

    The Treatment Evaluation Project was established to evaluate the feasibility of using behavioral treatment in conjunction with methadone maintenance to improve the effectiveness of methadone treatment. Over 100 outpatients were accepted into treatment and randomly assigned to one of four behavioral treatment modalities in addition to the usual…

  8. Intravenous oxycodone for pain relief in the first stage of labour--maternal pharmacokinetics and neonatal exposure.

    PubMed

    Kokki, Merja; Franco, Maria Gonzalez; Raatikainen, Kaisa; Välitalo, Pyry; Sankilampi, Ulla; Heinonen, Seppo; Neuvonen, Pertti J; Kokki, Hannu

    2012-09-01

    Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open-labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1 mg i.v., up to a cumulative dose of 5 mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half-life of 2.6 hr (range, 1.8-2.8). Oxycodone concentrations in the umbilical plasma 2.7 μg/l (0.3-14.5) were similar as in maternal plasma 2.4 (0.1-14.8) μg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half-life of i.v. oxycodone was significantly shorter than that reported in non-pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure.

  9. Concentrations of Methadone in Breast Milk and Plasma in the Immediate Perinatal Period

    PubMed Central

    Jansson, Lauren M.; Choo, Robin E.; Harrow, Cheryl; Velez, Martha; Schroeder, Jennifer R.; Lowe, Ross; Huestis, Marilyn A.

    2009-01-01

    This study evaluates concentrations of methadone in breast milk and plasma among a sample of methadone-maintained women in the immediate perinatal period. Twelve methadone-maintained, lactating women provided blood and breast milk specimens 1, 2, 3, and 4 days after delivery. Specimens were collected at the time of trough (just before methadone dose) and peak (3 hours after dosing) maternal methadone levels. Paired specimens of foremilk (prefeed) and hindmilk (postfeed) were obtained at each sampling time. Although there was a significant increase in methadone concentration in breast milk over time for the peak postfeed sampling time, t(22) = 2.40, P = .0255, methadone concentrations in breast milk were small, ranging from 21 to 314 ng/mL, and were unrelated to maternal methadone dose. Results obtained from this study contribute to the recommendation of breastfeeding for methadone-maintained women regardless of methadone dose. PMID:17478871

  10. Development and validation of a solid-phase extraction gas chromatography–mass spectrometry method for the simultaneous quantification of methadone, heroin, cocaine and metabolites in sweat

    PubMed Central

    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

  11. Slow-release oral morphine for opioid maintenance treatment: a systematic review

    PubMed Central

    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

  12. Simultaneous determination of opiates, methadone, buprenorphine and metabolites in human urine by superficially porous liquid chromatography tandem mass spectrometry.

    PubMed

    Lin, Huei-Ru; Chen, Chin-Lun; Huang, Chieh-Liang; Chen, Shao-Tsu; Lua, Ahai-Chuang

    2013-04-15

    For monitoring compliance of methadone or buprenorphine maintenance patient, a method for the simultaneous determination of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), buprenorphine, norbuprenorphine, opiates (morphine, codeine, 6-monoacetylmorphine) in urine by superficially porous liquid chromatography tandem mass spectrometry was developed and validated. After enzyme digestion and liquid-liquid extraction, reverse-phase separation was achieved in 5.2 min and quantification was performed by multiple reaction monitoring. Chromatographic separation was performed at 40 °C on a reversed phase Poroshell column with gradient elution. The mobile phase consisted of water and methanol, each containing 0.1% formic acid, at a flow rate of 0.32 mL/min. Intra-day and inter-day precision were less than 12.1% and accuracy was between -9.8% and 13.7%. Extraction efficiencies were more than 68%. Although ion suppression was detected, deuterated internal standards compensated for these effects. Carryover was minimal, less than 0.20%. All analytes were stable at room temperature for 16 h, 4 °C for 72 h, and after three freeze-thaw cycles. The assay also fulfilled compound identification criteria in accordance with the European Commission Decision 2002/657/EC. We analyzed 62 urine samples from patients received maintenance therapy and found that 54.8% of the patient samples tested were detected for morphine, codeine, or 6-monoacetylmorphine. This method provides a reliable and simultaneous quantification of opiates, maintenance drugs, and their metabolites in urine samples. It facilitates the routine monitoring in individuals prescribed the drug to ensure compliance and help therapeutic process. PMID:23507455

  13. Effects of cold pressor pain on the abuse liability of intranasal oxycodone in male and female prescription opioid abusers

    PubMed Central

    Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2012-01-01

    Background Approximately 1.9 million persons in the U.S. have prescription opioid use disorders often with concomitant bodily pain, but systematic data on the impact of pain on abuse liability of opioids is lacking. The purpose of this study was to determine whether pain alters the intranasal abuse liability of oxycodone, a commonly prescribed and abused analgesic, in males and females. Methods Sporadic prescription opioid abusers (10 females, 10 males) participated in this mixed (between and within-subject), randomized inpatient study. Experimental sessions (n=6) tested intranasal placebo, oxycodone 15 or 30 mg/70 kg during cold pressor testing (CPT) and a warm water control. Observer- and subject-rated drug effect measures, analgesia, physiologic and cognitive effects were assessed. Results The CPT significantly increased blood pressure, heart rate, pain, stress, and “opiate desire” compared to the no-pain control but did not alter opioid liking, high or street value. Intranasal oxycodone produced effects within 10 minutes, significantly decreasing pain and significantly increasing subjective measures of abuse liability (e.g., high). Females had higher ratings of street value, high, and liking for one or both active doses. Conclusions The CPT was a reliably painful and stressful stimulus that did not diminish the abuse liability of intranasal Oxycodone®. Females were more sensitive to oxycodone on several abuse liability measures that warrant further follow-up. Snorting oxycodone rapidly produced psychoactive effects indicative of substantial abuse liability. PMID:22209386

  14. Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats.

    PubMed

    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.

  15. The pattern of intravenous drug use and associated criminal activity in patients on a methadone treatment waiting list.

    PubMed

    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. PMID:16203481

  16. Cognitive impairment in methadone maintenance patients.

    PubMed

    Mintzer, Miriam Z; Stitzer, Maxine L

    2002-06-01

    Few well-controlled studies have examined psychomotor and cognitive performance in methadone maintenance patients (MMP). In the present study, performance of 18 opioid-dependent MMP was evaluated relative to that of 21 control participants without substance abuse histories. The MMP and control groups were balanced with respect to gender, race, age, years of education, current employment status, current reading level, and estimated IQ score. Recent drug abstinence was verified by urine testing. Participants with a urine screen positive for benzodiazepines or a breathalyzer test positive for alcohol prior to performance testing were excluded. To avoid testing under conditions of acute heroin or cocaine intoxication, but without testing under conditions of acute withdrawal, participants with current use of heroin or cocaine were only required to abstain for 24 h prior to performance testing. MMP exhibited impairment relative to controls in psychomotor speed (digit symbol substitution and trail-making tests), working memory (two-back task), decision making (gambling task), and metamemory (confidence ratings on a recognition memory test); results also suggested possible impairment in inhibitory mechanisms (Stroop color-word paradigm). MMP did not exhibit impairment in time estimation, conceptual flexibility or long-term memory. The wide range of impaired functions is striking, and may have important implications for daily functioning in MMP. Further research is necessary to determine the clinical significance of the impairments in laboratory-based tests for daily performance in the natural environment, as well as to differentiate impairments due to acute methadone dosing, chronic methadone maintenance, chronic poly-drug abuse, and other factors. PMID:12062778

  17. Cognitive impairment in methadone maintenance patients.

    PubMed

    Mintzer, Miriam Z; Stitzer, Maxine L

    2002-06-01

    Few well-controlled studies have examined psychomotor and cognitive performance in methadone maintenance patients (MMP). In the present study, performance of 18 opioid-dependent MMP was evaluated relative to that of 21 control participants without substance abuse histories. The MMP and control groups were balanced with respect to gender, race, age, years of education, current employment status, current reading level, and estimated IQ score. Recent drug abstinence was verified by urine testing. Participants with a urine screen positive for benzodiazepines or a breathalyzer test positive for alcohol prior to performance testing were excluded. To avoid testing under conditions of acute heroin or cocaine intoxication, but without testing under conditions of acute withdrawal, participants with current use of heroin or cocaine were only required to abstain for 24 h prior to performance testing. MMP exhibited impairment relative to controls in psychomotor speed (digit symbol substitution and trail-making tests), working memory (two-back task), decision making (gambling task), and metamemory (confidence ratings on a recognition memory test); results also suggested possible impairment in inhibitory mechanisms (Stroop color-word paradigm). MMP did not exhibit impairment in time estimation, conceptual flexibility or long-term memory. The wide range of impaired functions is striking, and may have important implications for daily functioning in MMP. Further research is necessary to determine the clinical significance of the impairments in laboratory-based tests for daily performance in the natural environment, as well as to differentiate impairments due to acute methadone dosing, chronic methadone maintenance, chronic poly-drug abuse, and other factors.

  18. Brain Reward Circuits in Morphine Addiction

    PubMed Central

    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

  19. Contingent methadone delivery: effects on illicit-opiate use.

    PubMed

    Higgins, S T; Stitzer, M L; Bigelow, G E; Liebson, I A

    1986-07-01

    This study examined the effects of contingent vs. non-contingent delivery of a methadone dose supplement on relapse to illicit opiate use in the context of a methadone outpatient detoxification program. Following a 3-week methadone stabilization period on 30 mg, patients (N = 39) were randomly assigned to a contingent, a non-contingent, or a control treatment group. All patients received identical gradual reductions in their assigned methadone dose. During the dose reduction period (weeks 4-11), members of the contingent (N = 13) and non-contingent groups (N = 13) could obtain daily methadone-dose supplements up to 20 mg, but contingent group members could obtain supplements only if their most recent urinalysis results were opiate negative. Control subjects (N = 13) did not have dose increases available. The contingent group presented significantly lower opiate-positive urines during weeks 8-11 (14% positive) of the detox than the non-contingent (38% positive) or control (50% positive) groups. Additionally, the availability of extra methadone improved treatment retention and increased clinic attendance above levels observed in the control group. The potential for further use of methadone's reinforcing properties in the treatment of opiate dependence is discussed.

  20. A systematic review of the cardiotoxicity of methadone

    PubMed Central

    Alinejad, Samira; Kazemi, Toba; Zamani, Nasim; Hoffman, Robert S.; Mehrpour, Omid

    2015-01-01

    Methadone is one of the most popular synthetic opioids in the world with some favorable properties making it useful both in the treatment of moderate to severe pain and for opioid addiction. Increased use of methadone has resulted in an increased prevalence of its toxicity, one aspect of which is cardiotoxicity. In this paper, we review the effects of methadone on the heart as well as cardiac concerns in some special situations such as pregnancy and childhood. Methods: We searched for the terms methadone, toxicity, poisoning, cardiotoxicity, heart, dysrhythmia, arrhythmia, QT interval prolongation, torsade de pointes, and Electrocardiogram (ECG) in bibliographical databases including TUMS digital library, PubMed, Scopus, and Google Scholar. This review includes relevant articles published between 2000 and 2013. The main cardiac effects of methadone include prolongation of QT interval and torsade de pointes. Other effects include changes in QT dispersion, pathological U waves, Taku-Tsubo syndrome (stress cardiomyopathy), Brugada-like syndrome, and coronary artery diseases. The aim of this paper is to inform physicians and health care staff about these adverse effects. Effectiveness of methadone in the treatment of pain and addiction should be weighed against these adverse effects and physicians should consider the ways to lessen such undesirable effects. This article presents some recommendations to prevent heart toxicity in methadone users. PMID:26869865

  1. Respiratory and ventilatory effects of methadone in healthy women.

    PubMed

    Olsen, G D; Wilson, J E; Robertson, G E

    1981-03-01

    The effects of oral methadone on respiration, ventilation, pupillary diameter, and plasma concentrations of estrone, estradiol, and progesterone were investigated in healthy nonpregnant women, 21 to 29 yr old. All women were in the follicular phase of the menstrual cycle. The study design was a randomized, double-blind, placebo-controlled trial. Six women received 15 mg methadone . HCl, and six received placebo. Alveolar ventilation and oxygen consumption before treatments correlated with plasma progesterone concentration (r2 = 0.85 and 0.68) but the slope and x-intercept of the ventilatory response to carbon dioxide curve did not. Female sex steroids in plasma were not affected by methadone. Mean elimination half-life of methadone from serum was 19 hr. Methadone-induced respiratory depression and miosis lasted more than 48 hr. The intensity of these changes was a linear function of the logarithm of the serum methadone concentration. Plasma progesterone concentration is an important determinant of resting ventilation and metabolism in the follicular phase of the menstrual cycle but endogenous progesterone does not protect women from the respiratory depressant effects of methadone. PMID:6781808

  2. Contingent methadone delivery: effects on illicit-opiate use.

    PubMed

    Higgins, S T; Stitzer, M L; Bigelow, G E; Liebson, I A

    1986-07-01

    This study examined the effects of contingent vs. non-contingent delivery of a methadone dose supplement on relapse to illicit opiate use in the context of a methadone outpatient detoxification program. Following a 3-week methadone stabilization period on 30 mg, patients (N = 39) were randomly assigned to a contingent, a non-contingent, or a control treatment group. All patients received identical gradual reductions in their assigned methadone dose. During the dose reduction period (weeks 4-11), members of the contingent (N = 13) and non-contingent groups (N = 13) could obtain daily methadone-dose supplements up to 20 mg, but contingent group members could obtain supplements only if their most recent urinalysis results were opiate negative. Control subjects (N = 13) did not have dose increases available. The contingent group presented significantly lower opiate-positive urines during weeks 8-11 (14% positive) of the detox than the non-contingent (38% positive) or control (50% positive) groups. Additionally, the availability of extra methadone improved treatment retention and increased clinic attendance above levels observed in the control group. The potential for further use of methadone's reinforcing properties in the treatment of opiate dependence is discussed. PMID:3757767

  3. Endogenous formation of morphine in human cells.

    PubMed

    Poeaknapo, Chotima; Schmidt, Jürgen; Brandsch, Matthias; Dräger, Birgit; Zenk, Meinhart H

    2004-09-28

    Morphine is a plant (opium poppy)-derived alkaloid and one of the strongest known analgesic compounds. Studies from several laboratories have suggested that animal and human tissue or fluids contain trace amounts of morphine. Its origin in mammals has been believed to be of dietary origin. Here, we address the question of whether morphine is of endogenous origin or derived from exogenous sources. Benzylisoquinoline alkaloids present in human neuroblastoma cells (SH-SY5Y) and human pancreas carcinoma cells (DAN-G) were identified by GC/tandem MS (MS/MS) as norlaudanosoline (DAN-G), reticuline (DAN-G and SH-SY5Y), and morphine (10 nM, SH-SY5Y). The stereochemistry of reticuline was determined to be 1-(S). Growth of the SH-SY5Y cell line in the presence of (18)O(2) led to the [(18)O]-labeled morphine that had the molecular weight 4 mass units higher than if grown in (16)O(2), indicating the presence of two atoms of (18)O per molecule of morphine. Growth of DAN-G cells in an (18)O(2) atmosphere yielded norlaudanosoline and (S)-reticuline, both labeled at only two of the four oxygen atoms. This result clearly demonstrates that all three alkaloids are of biosynthetic origin and suggests that norlaudanosoline and (S)-reticuline are endogenous precursors of morphine. Feeding of [ring-(13)C(6)]-tyramine, [1-(13)C, N-(13)CH(3)]-(S)-reticuline and [N-CD(3)]-thebaine to the neuroblastoma cells led each to the position-specific labeling of morphine, as established by GC/MS/MS. Without doubt, human cells can produce the alkaloid morphine. The studies presented here serve as a platform for the exploration of the function of "endogenous morphine" in the neurosciences and immunosciences.

  4. PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice.

    PubMed

    Smith, Forrest L; Javed, Ruby R; Smith, Paul A; Dewey, William L; Gabra, Bichoy H

    2006-12-01

    Male Swiss Webster mice exhibited antinociception, hypothermia and Straub tail 3h following a 75mg morphine pellet implantation. These signs disappeared by 72h, and the morphine-pelleted mice were indistinguishable from placebo-pelleted ones, although brain morphine concentrations ranged from 200 to 400ng/gm. We previously demonstrated that chemical inhibitors of protein kinase C (PKC) and A (PKA) are able to reverse morphine tolerance in acutely morphine-challenged mice. However, it was not known whether the reversal of tolerance was due to the interaction of kinase inhibitors with the morphine released from the pellet, the acutely injected morphine to challenge tolerant mice, or both. The present study aimed at determining the interaction between the PKC and PKA inhibitors and the morphine released "solely" from the pellet to reinstate the morphine-induced behavioral and physiological effects, 72h after implantation of morphine pellets. Placebo or 75mg morphine pellets were surgically implanted, and testing was conducted 72h later. Our results showed that the intracerebroventricular (i.c.v.) administration of the PKC inhibitors, bisindolylmaleimide I and Gö-6976 as well as the PKA inhibitors, 4-cyano-3-methylisoquinoline and KT-5720, restored the morphine-induced behaviors of antinociception, Straub tail and hypothermia in morphine-pelleted mice to the same extent observed 3h following the pellet implantation. The tail withdrawal and the hot plate reaction time expressed as percent maximum possible effect (%MPE) was increased to 80-100 and 41-90%, respectively, in PKC and PKA inhibitor-treated morphine tolerant mice compared to 2-10% in non-treated mice. Similarly, a significant hypothermia (1.3-4.0 degrees C decrease in body temperature) was detected in PKC and PKA inhibitor-treated morphine tolerant mice compared to an euthermic state in non-treated morphine tolerant mice. Finally, the Straub tail score was increased to 1.1-1.6 in PKC and PKA inhibitor

  5. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  6. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  7. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  8. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  9. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  10. The combination of mitragynine and morphine prevents the development of morphine tolerance in mice.

    PubMed

    Fakurazi, Sharida; Rahman, Shamima Abdul; Hidayat, Mohamad Taufik; Ithnin, Hairuszah; Moklas, Mohamad Aris Mohd; Arulselvan, Palanisamy

    2013-01-01

    Mitragynine (MG) is the major active alkaloid found in Mitragyna speciosa Korth. In the present study, we investigated the enhancement of analgesic action of MG when combined with morphine and the effect of the combination on the development of tolerance towards morphine. Mice were administered intraperitoneally with a dose of MG (15 and 25 mg/kg b.wt) combined with morphine (5 mg/kg b.wt) respectively for 9 days. The antinociceptive effect was evaluated by a hot plate test. The protein expression of cyclic adenosine monophosphate (cAMP) and cAMP response element binding (CREB) was analyzed by immunoblot. Toxicological parameters especially liver and kidney function tests were assessed after the combination treatment with MG and morphine. The concurrent administration of MG and morphine showed significant (p < 0.05) increase in latency time when compared to morphine alone group and the outstanding analgesic effects in the combination regimens were maintained until day 9. For the protein expression, there was a significant increment of cAMP and CREB levels (p < 0.05) in group treated with 5 mg/kg morphine but there was no significant change of these protein expressions when MG was combined with morphine. There was a significant changes in toxicological parameters of various treated groups. The combination treatment of MG and morphine effectively reduce the tolerance due to the chronic administration of morphine. PMID:23292329

  11. Direct Injection LC-MS-MS Analysis of Opiates, Methamphetamine, Buprenorphine, Methadone and Their Metabolites in Oral Fluid from Substitution Therapy Patients.

    PubMed

    Liu, Hsiu-Chuan; Lee, Hsi-Tzu; Hsu, Ya-Ching; Huang, Mei-Han; Liu, Ray H; Chen, Tai-Jui; Lin, Dong-Liang

    2015-01-01

    A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed, validated and applied to simultaneous analysis of oral fluid samples for the following 10 analytes: methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), buprenorphine, norbuprenorphine, morphine, codeine, 6-acetylmorphine, 6-acetylcodeine, amphetamine, and methamphetamine. The oral fluid sample was briefly centrifuged and the supernatant was directly injected into the LC-MS-MS system operated under reverse-phase chromatography and electrospray ionization (ESI). Deuterated analogs of the analytes were adopted as the internal standards and found to be effective (except for buprenorphine) to compensate for potential matrix effects. Each analytical run took <10 min. Linearity range (r(2) > 0.99) established for buprenorphine and the other nine analytes were 5-100 and 1-100 ng/mL. Intra- and interday precision (% CV) ranges for the 10 analytes were 0.87-12.2% and 1.27-12.8%, while the corresponding accuracy (%) ranges were 91.8-113% and 91.9-111%. Limits of detection and quantitation established for these 10 analytes were in the ranges of 0.1-1.0 and 0.25-1.0 ng/mL (5 ng/mL for buprenorphine). The method was successfully applied to the analysis of 62 oral fluid specimens collected from patients participating in methadone and buprenorphine substitution therapy programs. Analytical results of methadone and buprenorphine were compared with data derived from GC-MS analysis and found to be compatible. Overall, the direct injection LC-MS-MS method performed well, permitting rapid analysis of oral fluid samples for simultaneous quantification of methadone, buprenorphine, opiate and amphetamine drug categories without extensive sample preparation steps. PMID:25935159

  12. Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

    PubMed Central

    Klepstad, Pål; Hilton, Priscilla; Moen, Jorunn; Kaasa, Stein; Borchgrevink, Petter C; Zahlsen, Kolbjørn; Dale, Ola

    2004-01-01

    Background The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. Methods We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100). Results The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). Conclusion These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine. PMID:15461818

  13. Comparison of relative oxycodone consumption in surgical pleth index-guided analgesia versus conventional analgesia during sevoflurane anesthesia

    PubMed Central

    Won, Young Ju; Lim, Byung Gun; Lee, So Hyun; Park, Sangwoo; Kim, Heezoo; Lee, Il Ok; Kong, Myoung Hoon

    2016-01-01

    Abstract Background: The surgical pleth index (SPI) is proposed for titration of analgesic drugs during general anesthesia. Several reports have investigated the effect of SPI on the consumption of opioids including remifentanil, fentanyl, and sufentanil during anesthesia, but there are no reports about oxycodone. We aimed to investigate intravenous oxycodone consumption between SPI-guided analgesia and conventional analgesia practices during sevoflurane anesthesia in patients undergoing thyroidectomy. Methods: Forty-five patients undergoing elective thyroidectomy were randomly assigned to an SPI group (SPI-guided analgesia group, n = 23) or a control group (conventional analgesia group, n = 22). Anesthesia was maintained with sevoflurane to achieve bispectral index values between 40 and 60. In the SPI group, oxycodone 1 mg was administered intravenously at SPI values over 50; in the control group, oxycodone 1 mg was administered intravenously at the occurrence of tachycardia or hypertension event. Intraoperative oxycodone consumption and extubation time were recorded. The number of hemodynamic and somatic movement events was recorded, as were postoperative pain and recovery scores. Results: Patients’ characteristics were comparable between the groups. Intraoperative oxycodone consumption in the SPI group was significantly lower than the control group (3.5 ± 2.4 vs 5.1 ± 2.4 mg; P = 0.012). Extubation time was significantly shorter in the SPI group (10.6 ± 3.5 vs 13.4 ± 4.6 min; P = 0.026). Hemodynamic and somatic movement events during anesthesia were comparable between the groups, as were numeric rating scales for pain and modified Aldrete scores at postanesthesia care unit. Conclusions: SPI-guided analgesia reduces intravenous oxycodone consumption and extubation time compared with conventional analgesia based on clinical parameters during sevoflurane anesthesia in patients undergoing thyroidectomy. PMID:27583920

  14. Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats.

    PubMed

    Wiebelhaus, Jason M; Walentiny, D Matthew; Beardsley, Patrick M

    2016-01-01

    Incidence of prescription opioid abuse and overdose, often led by oxycodone, continues to increase, producing twice as many overdose deaths as heroin. Surprisingly, preclinical reports relevant to oxycodone's abuse-related effects are relatively sparse considering its history and patient usage. The goal of this study was to characterize dose- and time-dependent effects of acute and repeated oxycodone administration in a frequency-rate intracranial self-stimulation (ICSS) procedure, an assay often predictive of drug-related reinforcing effects, in male Sprague-Dawley rats. We hypothesized that oxycodone would produce a biphasic profile of rate-increasing and rate-decreasing effects maintained by ICSS similar to μ-opioid receptor agonists. Oxycodone (0.03, 0.3, 1, and 3 mg/kg, s.c.) produced dose- and time-dependent alterations on ICSS, with the predicted biphasic profile of rate-increasing effects at lower stimulation frequencies followed by rate-decreasing effects at higher frequencies. Peak effects were observed between 30 and 60 minutes, which were reversed by naloxone pretreatment (30 minutes). Tolerance to rate-decreasing effects was observed over a 5-day period when rats were treated with 1 mg/kg oxycodone twice a day. Subsequently, the dosing regimen was increased to 3 mg/kg twice a day over 10 days, although further marked tolerance did not develop. When then challenged with 10 mg/kg naloxone, a significant suppression below baseline levels of ICSS-maintained responding occurred indicative of dependence that recovered to baseline within 5 hours. The results of this study provide the first report of acute and chronic effects of oxycodone on responding maintained by ICSS presentation and the use of ICSS-maintained responding to characterize its tolerance and dependence effects.

  15. Social influences on morphine sensitization in adolescent rats.

    PubMed

    Hofford, Rebecca S; Schul, Destri L; Wellman, Paul J; Eitan, Shoshana

    2012-05-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examines the effects of social interactions on morphine sensitization in both adolescent and adult rats. Rats treated with morphine (twice daily, 6 days, 2.5-10 mg/kg, subcutaneously, s.c.) or saline were group-housed in two different conditions. Thus, four experimental groups were examined for each age group: (1) morphine-treated rats housed physically and visually separate from saline-injected rats ('morphine only'); (2) morphine-treated rats housed together with saline-injected rats ('morphine cage-mates'); (3) saline-injected rats housed together with morphine-treated rats ('saline cage-mates'); and (4) saline-injected rats housed physically and visually separate from morphine-treated rats ('saline only'). Starting 9 days following the last morphine injection, rats were individually examined once daily for 5 consecutive days for their locomotor response to 2.5 mg/kg of morphine. For both age groups, there were no significant differences in morphine-induced hyper-locomotion between saline cage-mates and saline only rats. Morphine only rats exhibited morphine locomotor sensitization as compared to both the saline only and saline cage-mates rats. Notably, a significant difference was observed between the adolescent morphine cage-mates and morphine only rats. The adolescent morphine cage-mates did not exhibit the enhanced locomotor response as compared to the saline only and saline cage-mate rats. A trend of reduced morphine locomotor sensitization was observed in the adult morphine cage-mates as compared to morphine only but it did not reach statistical significance. Thus, this study demonstrates social influences on morphine sensitization which are more prevalent in adolescents as compared to adults.

  16. Pregnancies exposed to methadone, methadone and other illicit substances, and poly-drugs without methadone: A comparison of fetal neurobehaviors and infant outcomes

    PubMed Central

    Jansson, L.M.; Di Pietro, J.A.; Elko, A.; Williams, E.L.; Milio, L.; Velez, M.

    2011-01-01

    BACKGROUND It is suspected that there is a continuum of impairment among prenatally drug-exposed infants, such that opioid and/or poly-drug exposure confers the highest risk for adverse neonatal outcomes than other classes of substances or single substance exposures. Suitable control groups are difficult to identify. This study compared fetal neurobehavioral development and infant outcomes in offspring of three groups of pregnant women in drug treatment. Exposure groups include: Methadone + other illicit substances (MM+Poly) and two groups currently abstinent for poly drug exposures: Methadone only (MM/A) and Non-methadone (NM/A). METHODS Forty-nine women (19 MM+Poly, 18 MM/A, and 12 NM/A) underwent fetal monitoring at 36 weeks gestation at peak and trough levels of methadone (MM+Poly; MM/A) or at comparable morning and afternoon times (NM/A). Fetal heart rate (FHR), heart rate variability (FHRV) and motor activity (FM) data were collected. Infant measures included birth outcomes and Neonatal Abstinence Syndrome (NAS) assessment. RESULTS As compared to the NM/A group, cardiac measures were decreased in methadone-exposed fetuses at peak levels. FHR was significantly more suppressed in the MM+Poly group. FM was significantly lower in the MM/A versus the NM/A group at both peak and trough, indicative of more persistent exposure effects. The MM+Poly group delivered one week earlier and required NAS pharmacological treatment twice as often as the MM/A group. CONCLUSIONS Results support the notion that poly-drug exposure may potentiate the effects of methadone on the fetus and infant and highlights the need for intensified treatment for methadone-maintained women who abuse other substances. PMID:22041255

  17. Photoaffinity labeling of opioid receptor with morphine-7,8-oxide (morphine epoxide)

    SciTech Connect

    Takayanagi, I.; Shibata, R.; Miyata, N.; Hirobe, M.

    1982-05-01

    The opioid receptor mediating inhibitory action of morphine in the electrically stimulated guinea pig ileum was irreversibly photoinactivated by morphine epoxide (3 X 10(-6) M). Morphine epoxide (up to 3 X 10(-5) M) did not influence the responses of rat vas deferens (epsilon-receptor) or rabbit vas deferens (kappa-receptor) to electrical stimulation. Effective concentrations of morphine epoxide were much lower in the guinea pig ileum (mu-receptor) than in the mouse vas deference (delta-receptor). The inhibitory action of (Met)-enkephalin on the twitch responses of the rat vas deferens and mouse vas deferens to electrical stimulation were not influenced after irradiation in the presence of morphine epoxide (3 X 10(-6) M). Therefore, morphine epoxide is probably a useful probe for photoaffinity labeling of the mu-receptor in vitro.

  18. Morphine effects on striatal transcriptome in mice

    PubMed Central

    Korostynski, Michal; Piechota, Marcin; Kaminska, Dorota; Solecki, Wojciech; Przewlocki, Ryszard

    2007-01-01

    Background Chronic opiate use produces molecular and cellular adaptations in the nervous system that lead to tolerance, physical dependence, and addiction. Genome-wide comparison of morphine-induced changes in brain transcription of mouse strains with different opioid-related phenotypes provides an opportunity to discover the relationship between gene expression and behavioral response to the drug. Results Here, we analyzed the effects of single and repeated morphine administrations in selected inbred mouse strains (129P3/J, DBA/2J, C57BL/6J, and SWR/J). Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts. Through ontologic classification, we linked particular sets of genes to biologic functions, including metabolism, transmission of nerve impulse, and cell-cell signaling. We identified numerous novel morphine-regulated genes (for instance, Olig2 and Camk1g), and a number of transcripts with strain-specific changes in expression (for instance, Hspa1a and Fzd2). Moreover, transcriptional activation of a pattern of co-expressed genes (for instance, Tsc22d3 and Nfkbia) was identified as being mediated via the glucocorticoid receptor (GR). Further studies revealed that blockade of the GR altered morphine-induced locomotor activity and development of physical dependence. Conclusion Our results indicate that there are differences between strains in the magnitude of transcriptional response to acute morphine treatment and in the degree of tolerance in gene expression observed after chronic morphine treatment. Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait. The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine. PMID:17598886

  19. Methadone-induced rigid-chest syndrome after substantial overdose.

    PubMed

    Lynch, Robert E; Hack, Richard A

    2010-07-01

    We report here the case of an infant who developed life-threatening rigid-chest syndrome after receiving an accidental overdose of methadone. The child responded to narcotic reversal. Pediatric physicians should be aware of this possible complication.

  20. The effect of parole on methadone patient behavior.

    PubMed

    Anglin, M D; McGlothlin, W H; Speckart, G

    1981-01-01

    A 7-year followup of three male samples of 1971-1973 methadone maintenance admissions was conducted: a random sample of 100; a sample of 136 who had a minimum of 30 months remaining on civil addict parole status at the time of methadone entry; and a matched sample of 136 not on parole. Ninety percent of those not decreased were interviewed. The overall sample spent 58% of the nonincarcerated follow-up interval on methadone. This resulted in a large decline in daily heroin use and associated criminal behavior measures. The addition of parole supervision with urine testing resulted in only marginal improvements in behavior over that attributable to maintenance alone; however, the parole status did significantly reduce the length of intervals of daily heroin use both prior and subsequent to methadone entry.

  1. Simultaneous determination of opiates, methadone, amphetamines, cocaine, and metabolites in human placenta and umbilical cord by LC-MS/MS.

    PubMed

    de Castro, Ana; Díaz, Ariana; Piñeiro, Beatriz; Lendoiro, Elena; Cruz, Angelines; López-Rivadulla, Manuel; Concheiro, Marta

    2013-05-01

    LC-MS/MS methods for the quantification of morphine, morphine-3-glucuronide, morphine-6-glucuronide, codeine, 6-acetylmorphine, cocaine, benzoylecgonine, ecgonine methyl ester, hydroxybenzoylecgonine, cocaethylene, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), methadone, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in human placenta and umbilical cord were developed and validated. Specimens (1 ± 0.02 g) were homogenized with the Ultra-Turrax T8 disperser and centrifuged, and the supernatant was submitted to solid-phase extraction with Oasis MCX cartridges. Chromatographic separation was performed using an Atlantis T3 analytical column (100 × 2.1 mm, 3 μm) and a gradient of 0.1 % formic acid and acetonitrile. Selectivity was verified in 10 different blank specimens. The method was linear from 1-5 to 100-500 ng/g, depending on the analyte. Limits of detection and quantification ranged from 0.5 to 2.5 ng/g and 1 to 5 ng/g, respectively. Method imprecision was ≤15.3 %, except for MDMA at low quality control (18.1 %); accuracy, 87.1 to 114 %; extraction efficiency, 16.3 to 154.0 % (%CV = 1.8-39.4 %); matrix effect, -75.7 to 449.9 % (%CV = 3.5-50 %); and process efficiency, 8.7 to 316.0 %. The method was applied to authentic placenta and umbilical cord specimens from drug-user pregnant women. PMID:23397092

  2. Intrathecal PLC(β3) oligodeoxynucleotides antisense potentiates acute morphine efficacy and attenuates chronic morphine tolerance.

    PubMed

    Quanhong, Zhou; Ying, Xue; Moxi, Chen; Tao, Xu; Jing, Wang; Xin, Zhang; Li, Wang; Derong, Cui; Xiaoli, Zhang; Wei, Jiang

    2012-09-01

    Morphine is a mainstay for chronic pain treatment, but its efficacy has been hampered by physical tolerance. The underlying mechanism for chronic morphine induced tolerance is complicated and not well understood. PLC(β3) is regarded as an important factor in the morphine tolerance signal pathway. In this study, we determined intrathecal (i.t.) administration of an antisense oligodeoxynucleotide (ODN) of PLC(β3) could quicken the on-set antinociceptive efficacy of acute morphine treatment and prolong the maximum effect up to 4h. The antisense could also attenuate the development of morphine-induced tolerance and left shift the ED50 after 7 day of coadministration with morphine. These results probably were contributed by the PLC(β3) antisense ODN as they successfully knocked down protein expression levels and reduced activity of PLC(β3) in spinal cord in rats. The mismatch group had no such effects. The results confirmed the important involvement of PLC(β3) in both acute morphine efficacy and chronic morphine tolerance at spinal level in rats. This study may provide an idea for producing a novel adjuvant for morphine treatment.

  3. Topical application of a novel oxycodone gel formulation (tocopheryl phosphate mixture) in a rat model of peripheral inflammatory pain produces localized pain relief without significant systemic exposure.

    PubMed

    Smith, Maree T; Wyse, Bruce D; Edwards, Stephen R; El-Tamimy, Mahmoud; Gaetano, Giacinto; Gavin, Paul

    2015-07-01

    This study was designed to assess the analgesic efficacy and systemic exposure of oxycodone administered topically in a novel tocopheryl phosphate mixture (TPM) gel formulation, to the inflamed hindpaws in a rat model of inflammatory pain. Unilateral hindpaw inflammation was induced in male Sprague-Dawley rats by intraplantar (i.pl.) injection of Freund's complete adjuvant (FCA). Mechanical hyperalgesia and hindpaw inflammation were assessed by measuring paw pressure thresholds and hindpaw volume, respectively, just prior to i.pl. FCA and again 5-6 days later. The analgesic effects of oxycodone administered topically (1 mg in TPM gel) or by i.pl. injection (50 μg), were assessed. Systemic oxycodone exposure was assessed over an 8-h postdosing interval following topical application. Skin permeation of oxycodone from the gel formulation was assessed in vitro using Franz diffusion cells. Oxycodone administered topically or by i.pl. injection produced significant (p < 0.05) analgesia in the inflamed hindpaws. Systemic oxycodone exposure was insignificant after topical dosing. The in vitro cumulative skin permeation of oxycodone was linearly related to the amount applied. Topical TPM/oxycodone gel formulations have the potential to alleviate moderate to severe inflammatory pain conditions with minimal systemic exposure, thereby avoiding central nervous system (CNS)-mediated adverse effects associated with oral administration of opioid analgesics.

  4. Study on the sampling of methadone from exhaled breath.

    PubMed

    Beck, Olof; Sandqvist, Sören; Böttcher, Michael; Eriksen, Paul; Franck, Johan; Palmskog, Göran

    2011-06-01

    This study aimed at develop and validate the procedure for collecting exhaled breath for drug testing. Patients receiving methadone maintenance treatment were recruited for the study. Methadone levels were measured using liquid chromatography- electrospray-tandem mass spectrometry. The sampling device was based on a 47-mm C(18) filter and used under pressure to aid flow through the filter. The mouth was rinsed before sampling, and the device was constructed to protect against any saliva contamination. Methadone was present in breath samples before and after the daily intake of methadone. The mean (± SD) pre-dose level was found to be 135 ± 109 pg/min (n = 48, median 121). The exhaled methadone increased after dose intake. Saliva levels of methadone were high in comparison with exhaled breath levels. Saliva contamination was suspected in about 10% of the collected samples. Similar results were obtained using 1, 3, and 10 min sampling times. The inter- and intraindividual variability were found to be similar and in the order of 50%. Alternative sampling using XAD-2 beads and solid-phase microextraction fiber was found to be possible and enables sampling with low back pressure and with no need for pump assistance. The presented results confirm that breath testing is a new possibility for the detection of drugs of abuse.

  5. Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy

    PubMed Central

    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. Method: 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. Results: 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. Conclusion: 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. PMID:26106330

  6. The Source of Methadone in Overdose Deaths in Western Virginia in 2004

    PubMed Central

    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

  7. Opioid pharmacokinetic drug-drug interactions.

    PubMed

    Overholser, Brian R; Foster, David R

    2011-09-01

    Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.

  8. Abuse-related effects of mu opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure

    PubMed Central

    Altarifi, Ahmad A.; Rice, Kenner C.; Negus, S. Stevens

    2013-01-01

    Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be rapidly varied to maintain a wide range of baseline response rates, and drugs effects can be simultaneously evaluated on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS “facilitation” denotes drug-induced increases in low ICSS rates and is often interpreted as an abuse-related effect, whereas ICSS “depression” denotes decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of drug efficacy and of prior mu agonist exposure as determinants of mu agonist effects on ICSS in rats with electrodes implanted in the medial forebrain bundle. The high-, intermediate- and low-efficacy mu agonists methadone, fentanyl and nalbuphine were tested during escalating regimens of morphine exposure (Vehicle, 3.2, 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose-dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that mu agonist exposure increases expression of abuse-related ICSS facilitation by mu agonists with a broad range of efficacies at mu receptors. PMID:23881045

  9. Abuse-related effects of µ-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure.

    PubMed

    Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens

    2013-09-01

    Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be varied rapidly to maintain a wide range of baseline response rates, and drugs' effects can be evaluated simultaneously on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS 'facilitation' indicates drug-induced increases in low ICSS rates and is often considered an abuse-related effect, whereas ICSS 'depression' indicates decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of µ-agonist efficacy and of previous µ-agonist exposure as determinants of µ-agonist effects on ICSS in rats with electrodes implanted into the medial forebrain bundle. The high-efficacy, intermediate-efficacy, and low-efficacy µ agonists methadone, fentanyl, and nalbuphine were tested during escalating regimens of morphine exposure (vehicle, 3.2, and 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that µ-agonist exposure increases the expression of abuse-related ICSS facilitation by µ agonists with a broad range of efficacies at µ receptors.

  10. Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats

    PubMed Central

    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

  11. Eating pattern of morphine dependent rats.

    PubMed

    Yanaura, S; Suzuki, T

    1979-10-01

    To analyze the drug ingestion patterns of rats in the course of dependence development while on the drug-admixed food (DAF) method, an automatic food intake measuring apparatus was developed. Rats were put on morphine-admixed food, and the food ingestion patterns were recorded with the apparatus in the course of dependence development, during drug withdrawal and at the time of challenge with levallorphan. The naive rats ate the regular diet intermittently at night, and the eating time of morphine-treated rats was longer than that of naive rats. The treated rats also exhibited a frequent eating behavior after 4--5 days on the morphine treatment. During morphine withdrawal, the animal gradually ate the regular diet at about 1-hour intervals, even after evolvement of abstinence signs. When the morphine-dependent rats were given levallorphan, they neither ate nor approached to the food for the first 2--3 hours, but after this time, showed abrupt increases in these activities. Thus, the drug intake pattern of rats in the course of morphine dependence development suggests a correlation between the stage of development of physical dependence and the stage when the animals frequently eat the drug-admixed food.

  12. Pavlovian conditioning analysis of morphine tolerance.

    PubMed

    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.

  13. Oxycodone alters temporal summation but not conditioned pain modulation: preclinical findings and possible relations to mechanisms of opioid analgesia.

    PubMed

    Suzan, Erica; Midbari, Ayelet; Treister, Roi; Haddad, May; Pud, Dorit; Eisenberg, Elon

    2013-08-01

    Opioid analgesia is mediated primarily by modulating (inhibiting and enhancing) pain mechanisms at the spinal and supraspinal levels. Advanced psychophysical paradigms of temporal summation (TS) and conditioned pain modulation (CPM) likely represent pain mechanisms at both levels. Therefore, the study of opioid effects on TS and CPM can shed light on their analgesic mechanisms in humans. The current randomized, double-blind study tested the effects of oxycodone on the magnitude of both TS and CPM in 40 healthy subjects. TS was tested by measuring increments in pain intensity in response to 10 repetitive painful phasic heat stimuli. CPM was assessed by subtracting the response to a painful phasic heat stimulus administrated simultaneously with a conditioning cold pain stimulus from a painful phasic heat stimulus alone. These paradigms were tested before and at 60, 120, and 180 minutes after administration of a single oral dose of either oxycodone or an active placebo. Repeated-measures analysis of variance revealed significant effects of oxycodone, but not placebo, on the magnitude of TS (F=7.196, P<.001). Pairwise comparisons revealed that relative to baseline, TS was significantly reduced at 60 minutes (P=.008) and at 180 minutes (P=.017) after oxycodone administration. In contrast, no significant effects of either oxycodone (F=0.871, P=.458) or placebo (F=2.086, P=.106) on the magnitude of CPM were found. These results suggest that under the current experimental conditions, oxycodone exerted spinal, rather than supraspinal, analgesic effects. Furthermore, compared with CPM, TS seems more suitable for studying the mechanisms of opioid analgesia in humans.

  14. A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats

    PubMed Central

    Kosten, Therese A.; Shen, Xiaoyun Y.; O'Malley, Patrick W.; Kinsey, Berma M.; Lykissa, Ernest D.; Orson, Frank M.; Kosten, Thomas R.

    2013-01-01

    Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC–MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence. PMID:23739535

  15. The nature of methadone diversion in England: a Merseyside case study

    PubMed Central

    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

  16. Intractable restless legs syndrome: role of prolonged-release oxycodone-naloxone.

    PubMed

    de Biase, Stefano; Valente, Mariarosaria; Gigli, Gian Luigi

    2016-01-01

    Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs accompanied by uncomfortable sensations that occur at night or at time of rest. Pharmacological therapy should be limited to patients who suffer from clinically relevant symptoms. Chronic RLS is usually treated with either a dopamine agonist (pramipexole, ropinirole, rotigotine) or an α2δ calcium-channel ligand (gabapentin, gabapentin enacarbil, pregabalin). Augmentation is the main complication of long-term dopaminergic treatment, and frequently requires a reduction of current dopaminergic dose or a switch to non-dopaminergic medications. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a recent Phase III trial, oxycodone-naloxone prolonged release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatments. The adverse-event profile was consistent with the safety profile of opioids. The most frequent adverse events were fatigue, constipation, nausea, headache, hyperhidrosis, somnolence, dry mouth, and pruritus. Adverse events were usually mild or moderate in intensity. No cases of augmentation were reported. Oxycodone-naloxone PR is approved for the second-line symptomatic treatment of adults with severe to very severe idiopathic RLS after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone-naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and α2δ ligands are needed. PMID:26966363

  17. Using Acceptance and Commitment Therapy during Methadone Dose Reduction: Rationale, Treatment Description, and a Case Report

    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…

  18. Methadone Maintenance: The Experience of Four Programs. The Drug Abuse Council Manuscript Series, No. 1.

    ERIC Educational Resources Information Center

    Danaceau, Paul

    Methadone maintenance is a relatively new method for treating heroin addiction. Controversy and questions remain about the drug itself and its use of methadone. The author was engaged by The Drug Abuse Council to prepare these descriptions of four methadone programs and the accompanying summary. The evolution of these programs is examined, and the…

  19. Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

    PubMed

    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.

  20. Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

    PubMed

    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. PMID:26222257

  1. Increases in body mass index following initiation of methadone treatment

    PubMed Central

    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

  2. Characterization of methadone overdose: clinical considerations and the scientific evidence.

    PubMed

    Wolff, Kim

    2002-08-01

    Overdosing with methadone is a growing phenomenon in Britain and other countries due to the increase in prescription and the availability of this compound. Little is known of the circumstances surrounding methadone death due to some extent to the difficulty of defining drug-related death and also the difficulty of collecting clinical and biographical data in a predominantly illegal and marginal milieu. However, the evidence points to highest risk at night (to this end manifestations of its toxicity often go unrecognized) in those whose usual tolerance has been reduced and occurring some considerable time after ingestion. Further investigations are needed to elucidate fully the mechanism and spectrum of methadone overdose. Death from methadone is eminently preventable more so because of the long-term nature of the clinical sequelae. Indeed the key issue with methadone that sets it apart from other opioids is its potential for delayed toxicity. Consequently steps should be taken to disseminate the salient facts to all those who come into contact with the drug.

  3. The effect of different durations of morphine exposure on mesencephalic dopaminergic neurons in morphine dependent rats.

    PubMed

    Shi, Weibo; Ma, Chunling; Qi, Qian; Liu, Lizhe; Bi, Haitao; Cong, Bin; Li, Yingmin

    2015-12-01

    Mesencephalic dopaminergic neurons are heavily involved in the development of drug dependence. Thyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, plays an important role in the survival of dopaminergic neurons. Therefore, this study investigated TH changes in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN), as well as the morphine effects on dopaminergic neurons induced by different durations of morphine dependence. Models of morphine dependence were established in rats, and paraffin-embedded sections, immunohistochemistry and western blotting were used to observe the changes in the expression of TH protein. Fluoro-Jade B staining was used to detect degeneration and necrosis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) detected the apoptosis of mesencephalic dopaminergic nerve cells. Immunohistochemistry and western blotting showed that the number of TH positive cells and the protein levels in the VTA and SN were significantly decreased in the rats with a long period of morphine dependency. With prolonged morphine exposure, the dopaminergic nerve cells in the VTA and SN showed degeneration and necrosis, while apoptotic cells were not observed. The number of VTA and SN dopaminergic nerve cells decreased with increasing periods of morphine dependence, which was most likely attributable to the degeneration and necrosis of nerve cells induced by morphine toxicity.

  4. Trends in Controlled-Release Oxycodone (Oxycontin[R]) Prescribing among Medicaid Recipients in Kentucky, 1998-2002. Research Note

    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…

  5. A specific immunoassay for the determination of morphine and its glucuronides in human blood.

    PubMed

    Beike, J; Blaschke, G; Mertz, A; Köhler, H; Brinkmann, B

    1998-01-01

    The development of specific antisera for immunochemical determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide is described. Morphine was N-demethylated to normorphine and N-alkylated to give N-aminopropyl-normorphine as hapten for antisera against morphine. As haptens for antisera against morphine-3-glucuronide and morphine-6-glucuronide, N-aminopropyl-nor-morphine was glucuronidated in position 3 or 6 respectively. Each of these three haptens were coupled to BSA employing the glutaraldehyde method to obtain three different immunogens. Immunisation of rabbits with these conjugates gave anti-morphine, anti-morphine-3-glucuronide and anti-morphine-6-glucuronide antisera, which were tested in a competitive, heterogeneous radioimmunoassay. Tracers for this radioimmunoassay procedure were synthesised by substitution of morphine and morphine-6-glucuronide in position 2 with 125I and indirect iodination of the morphine-3-glucuronide hapten according to the method of Bolton and Hunter. The resulting antisera show very specific reactions with morphine, morphine-3-glucuronide and morphine-6-glucuronide. Cross reactivities of each antiserum with structurally related opiates and opioides are very low. The cross reactivities of the anti-morphine antiserum against morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine were less than 0.3%, the anti-morphine-3-glucuronide antiserum against morphine, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine less than 0.1% and the anti-morphine-6-glucuronide antiserum against morphine, morphine-3-glucuronide, codeine or dihydrocodeine less than 0.1%, against codeine-6-glucuronide less than 2.3%. The determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in blood samples (limit of detection= 3, 1, 0.5 ng/g) of nine cases of fatal heroin overdose with this radioimmunoassay method and the comparison with a GC/MS method is described.

  6. Simultaneous analysis of buprenorphine, methadone, cocaine, opiates and nicotine metabolites in sweat by liquid chromatography tandem mass spectrometry.

    PubMed

    Concheiro, Marta; Shakleya, Diaa M; Huestis, Marilyn A

    2011-04-01

    A liquid chromatography tandem mass spectrometry method for buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine, ecgonine methyl ester (EME), morphine, codeine, 6-acetylmorphine, heroin, 6-acetylcodeine, cotinine, and trans-3'-hydroxycotinine quantification in sweat was developed and comprehensively validated. Sweat patches were mixed with 6 mL acetate buffer at pH 4.5, and supernatant extracted with Strata-XC-cartridges. Reverse-phase separation was achieved with a gradient mobile phase of 0.1% formic acid and acetonitrile in 15 min. Quantification was achieved by multiple reaction monitoring of two transitions per compound. The assay was a linear 1-1,000 ng/patch, except EME 5-1,000 ng/patch. Intra-, inter-day and total imprecision were <10.1%CV, analytical recovery 87.2-107.7%, extraction efficiency 35.3-160.9%, and process efficiency 25.5-91.7%. Ion suppression was detected for EME (-63.3%) and EDDP (-60.4%), and enhancement for NBUP (42.6%). Deuterated internal standards compensated for these effects. No carryover was detected, and all analytes were stable for 24 h at 22 °C, 72 h at 4 °C, and after three freeze/thaw cycles. The method was applied to weekly sweat patches from an opioid-dependent BUP-maintained pregnant woman; 75.0% of sweat patches were positive for BUP, 93.8% for cocaine, 37.5% for opiates, 6.3% for methadone and all for tobacco biomarkers. This method permits a fast and simultaneous quantification of 14 drugs and metabolites in sweat patches, with good selectivity and sensitivity. PMID:21125263

  7. Simultaneous analysis of buprenorphine, methadone, cocaine, opiates and nicotine metabolites in sweat by liquid chromatography tandem mass spectrometry

    PubMed Central

    Concheiro, Marta; Shakleya, Diaa M.

    2013-01-01

    A liquid chromatography tandem mass spectrometry method for buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine, ecgonine methyl ester (EME), morphine, codeine, 6-acetylmorphine, heroin, 6-acetylcodeine, cotinine, and trans-3′-hydroxycotinine quantification in sweat was developed and comprehensively validated. Sweat patches were mixed with 6 mL acetate buffer at pH 4.5, and supernatant extracted with Strata-XC-cartridges. Reverse-phase separation was achieved with a gradient mobile phase of 0.1% formic acid and acetonitrile in 15 min. Quantification was achieved by multiple reaction monitoring of two transitions per compound. The assay was a linear 1–1,000 ng/patch, except EME 5–1,000 ng/patch. Intra-, inter-day and total imprecision were <10.1%CV, analytical recovery 87.2–107.7%, extraction efficiency 35.3– 160.9%, and process efficiency 25.5–91.7%. Ion suppression was detected for EME (−63.3%) and EDDP (−60.4%), and enhancement for NBUP (42.6%). Deuterated internal standards compensated for these effects. No carryover was detected, and all analytes were stable for 24 h at 22 °C, 72 h at 4 °C, and after three freeze/thaw cycles. The method was applied to weekly sweat patches from an opioid-dependent BUP-maintained pregnant woman; 75.0% of sweat patches were positive for BUP, 93.8% for cocaine, 37.5% for opiates, 6.3% for methadone and all for tobacco biomarkers. This method permits a fast and simultaneous quantification of 14 drugs and metabolites in sweat patches, with good selectivity and sensitivity. PMID:21125263

  8. Coexisting addiction and pain in people receiving methadone for addiction.

    PubMed

    St Marie, Barbara

    2014-04-01

    The aim of this qualitative study was to examine the narratives of people who experience chronic pain (lasting 6 months or more) and were receiving methadone for the treatment of their opiate addiction through a major methadone clinic. This paper featured the pathway of how the participants developed chronic pain and addiction, and their beliefs of how prescription opioids would impact their addiction in the future. Thirty-four participants who experienced chronic pain and received methadone for treatment of opiate addiction were willing to tell the story of their experiences. The findings in three areas are presented: (a) whether participants experienced addiction first or pain first and how their exposures to addictive substances influenced their experiences, (b) the significance of recreational drug use and patterns of abuse behaviors leading to chronic pain, and (c) participants' experiences and beliefs about the potential for abuse of prescription opioid used for treatment of pain.

  9. Assessment of Cognitive Functions in Methadone Maintenance Patients

    PubMed Central

    Mazhari, Shahrzad; Keshvari, Zeinab; Sabahi, Abdolreza; Mottaghian, Shirin

    2015-01-01

    Background Methadone maintenance has received little scientific attention regarding neurocognitive effects. This study is aimed to assess the neuropsychological performance of methadone maintenance patients (MMP) compared to those healthy controls. Methods Thirty-five MMP and 35 healthy controls, matched for age, gender, education and employment status, examined on a battery of tests aimed at assessing verbal fluency, executive functions, verbal memory, and working memory, using controlled oral word association test (COWAT), trial making test (TMT) Part A and B, Rey auditory verbal learning test (RAVLT), and backward digit span. Findings MMP performed significantly poorly than controls in cognitive domains of verbal fluency, executive function, and verbal memory. MMP did not exhibit impairment in working memory, and TMT Part A compared to controls. Conclusion These results suggest that methadone consumption induces significant cognitive impairment that could compromise drug-treatment outcomes in MMP. PMID:26885347

  10. Effectiveness of Relapse Prevention Cognitive-Behavioral Model in Opioid-Dependent Patients Participating in the Methadone Maintenance Treatment in Iran

    PubMed Central

    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

  11. Dynorphin A-(1-13)-morphine interactions: quantitative and qualitative EEG properties differ in morphine-naive vs. morphine-tolerant rats.

    PubMed

    Meng, Y; Young, G A

    1994-01-01

    The effects of dynorphin A-(1-13) on cumulative IV morphine-induced EEG and EEG power spectra were studied in naive and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling ICV and IV cannulae. In naive rats, dynorphin A-(1-13) quantitatively decreased cumulative IV morphine-induced EEG spectral power as well as qualitatively shifting the relative distribution of spectral power to predominantly faster frequencies. In morphine-tolerant rats, the quantitative and qualitative EEG properties were identical to those in dynorphin A-(1-13) pretreated morphine-naive rats. Thus, dynorphin A-(1-13) pretreatment apparently produced instantaneous acute morphine tolerance. Furthermore, in morphine-tolerant rats, dynorphin A-(1-13) pretreatment quantitatively increased morphine-induced EEG power without qualitatively changing the relative distribution of EEG spectral power. This latter effect may be due to a summation of increased endogenous levels of dynorphin A-(1-13) associated with the development of morphine tolerance and the experimentally administered dynorphin A-(1-13). These results indicate that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. That is, quantitative changes may reflect the number of receptors that are activated, while qualitative changes may reflect the nature of the receptor-effector coupling.

  12. A possible link between sensation-seeking status and positive subjective effects of oxycodone in healthy volunteers

    PubMed Central

    Zacny, James P.

    2010-01-01

    Sensation seeking is a personality trait that is linked to use and abuse of drugs. Laboratory studies have established that high sensation seekers, as measured by different instruments, are more likely to report abuse liability-related subjective effects from drugs such as nicotine, alcohol, and d-amphetamine than low sensation seekers. One class of drugs that has not been studied to date in this fashion is opioids. Accordingly, a retrospective analysis encompassing five studies that examined oxycodone effects, including its abuse liability-related effects, was conducted in subjects categorized as high or low sensation seekers. In addition, because there appear to be sex differences in how males and females respond to opioids, this factor was taken into account in the analysis. Seventy one subjects who scored on the lower end (15 and 19 low sensation seeking males and females, respectively) or the higher end (23 and 14 high sensation seeking males and females) of the Disinhibition subscale of the Sensation Seeking Scale-Form V were studied for their responses to 0, 10, and 20 mg of oral oxycodone. Ratings of “pleasant bodily sensations” were significantly higher after oxycodone administration than placebo only in male and female high sensation seekers. Ratings of “take again,” “drug liking,” “carefree,” and “elated (very happy)” also tended to differentiate high from low sensation seekers although Group × Dose interactions were only marginally significant with the latter three ratings. Male and female low sensation seekers and female high sensation seekers reported dysphoric effects (e.g., ratings of nauseated) particularly after administration of the 20-mg oxycodone dose. The results of this analysis provide suggestive evidence that high sensation seekers are more likely to experience greater positive subjective effects from oxycodone than low sensation seekers, but likelihood of experiencing negative effects is more complex (involving both

  13. Efficacy and tolerability of oral oxycodone and oxycodone/naloxone combination in opioid-naïve cancer patients: a propensity analysis

    PubMed Central

    Lazzari, Marzia; Greco, Maria Teresa; Marcassa, Claudio; Finocchi, Simona; Caldarulo, Clarissa; Corli, Oscar

    2015-01-01

    Background World Health Organization step III opioids are required to relieve moderate-to-severe cancer pain; constipation is one of the most frequent opioid-induced side effects. A fixed combination, prolonged-release oxycodone/naloxone (OXN), was developed with the aim of reducing opioid-related gastrointestinal side effects. The objective of this study was to compare the efficacy and safety of prolonged-release oxycodone (OXY) alone to OXN in opioid-naïve cancer patients with moderate-to-severe pain. Methods Propensity analysis was utilized in this observational study, which evaluated the efficacy, safety, and quality of life. Results Out of the 210 patients recruited, 146 were matched using propensity scores and included in the comparative analysis. In both groups, pain intensity decreased by ≈3 points after 60 days, indicating comparable analgesic efficacy. Responder rates were similar between groups. Analgesia was achieved and maintained with similarly low and stable dosages over time (12.0–20.4 mg/d for OXY and 11.5–22.0 mg/d for OXN). Bowel Function Index (BFI) and laxative use per week improved from baseline at 30 days and 60 days in OXN recipients (−16, P<0.0001 and −3.5, P=0.02, respectively); BFI worsened in the OXY group. The overall incidence of drug-related adverse events was 28.9% in the OXY group and 8.2% in the OXN group (P<0.01); nausea and vomiting were two to five times less frequent with OXN. Quality of life improved to a significantly greater extent in patients receiving OXN compared to OXY (increase in Short Form-36 physical component score of 7.1 points vs 3.2 points, respectively; P<0.001). Conclusion In patients with chronic cancer pain, OXN provided analgesic effectiveness that is similar to OXY, with early and sustained benefits in tolerability. The relationship between responsiveness to OXN and clinical characteristics is currently being investigated. PMID:26586937

  14. Tianeptine reduces morphine antinociceptive tolerance and physical dependence.

    PubMed

    Chu, Chin-Chen; Shieh, Ja-Ping; Shui, Hao-Ai; Chen, Jen-Yin; Hsing, Chung-Hsi; Tzeng, Jann-Inn; Wang, Jhi-Joung; Ho, Shung-Tai

    2010-09-01

    Long-term use of morphine can cause neuronal dystrophic changes in specific areas of the brain. These changes may underlie the mechanism for developing morphine antinociceptive tolerance and physical dependence. We evaluated the effect of tianeptine, an antidepressant with prominent neuroprotective and neuroplastic properties, on the development of morphine antinociceptive tolerance and physical dependence. Male C57BL/6 mice were rendered tolerant to or dependent on morphine by subcutaneously injecting them with morphine (10 mg/kg) and intraperitoneally with saline or tianeptine (1, 3, or 5 mg/kg) twice daily for 6 days. The mice were given a daily tail-flick test 1 h after the first morphine injection to evaluate the development of their tolerance to morphine antinociception. To evaluate their physical dependence on morphine, 3 h after the final morphine injection on day 6, naloxone-HCl-precipitated (2 mg/kg, intraperitoneally) withdrawal symptoms were counted for 30 min, and body weight was checked 1 h after the naloxone injection. Tianeptine per se produced no antinociception, neither did it modify the antinociception produced by morphine, nor did it evoke the behavioral responses different from those in the saline controls. The combination of tianeptine with morphine significantly reduced the development of morphine antinociceptive tolerance and suppressed the incidence of naloxone-precipitated withdrawal symptoms. We conclude that tianeptine is an effective inhibitor of morphine-induced antinociceptive tolerance and physical dependence in mice. Our results would imply that comedication with tianeptine and morphine might benefit those who need long-term morphine treatment.

  15. Quantitation of methadone enantiomers in humans using stable isotope-labeled (2H3)-, (2H5)-, and (2H8)Methadone

    SciTech Connect

    Nakamura, K.; Hachey, D.L.; Kreek, M.J.; Irving, C.S.; Klein, P.D.

    1982-01-01

    A new technique for simultaneous stereoselective kinetic studies of methadone enantiomers was developed using three deuterium-labeled forms of methadone and GLC-chemical-ionization mass spectrometry. A racemic mixture (1:1) of (R)-(-)-(2H5)methadone (l-form) and (S)-(R)-(2H3)methadone (d-form) was administered orally in place of a single daily dose of unlabeled (+/-)-(2H0)methadone in long-term maintenance patients. Racemic (+/-)-(2H8)methadone was used as an internal standard for the simultaneous quantitation of (2H0)-, (2H3)-, and (2H5)methadone in plasma and urine. A newly developed extraction procedure, using a short, disposable C18 reversed-phase cartridge and improved chemical-ionization procedures employing ammonia gas, resulted in significant reduction of the background impurities contributing to the ions used for isotopic abundance measurements. These improvements enabled the measurement of labeled plasma methadone levels for 120 hr following a single dose. This methodology was applied to the study of methadone kinetics in two patients; in both patients, the analgesically active l-enantiomer of the drug had a longer plasma elimination half-life and a smaller area under the plasma disappearance curve than did the inactive d-form.

  16. METODO, a prospective observational study to assess the efficacy and tolerability of methadone in heroin-addicted patients undergoing a methadone maintenance treatment: preliminary results at baseline evaluation.

    PubMed

    D'Egidio, Pietro Fausto; Bignamini, Emanuele; De Vivo, Enrico; Leonardi, Claudio; Pieri, Maria Chiara; González-Saiz, Francisco; Lucchini, Alfio

    2013-12-01

    METODO (methadone efficacy therapy optimization dosage on-going) is a prospective observational study to assess the efficacy and tolerability of methadone in 500 heroin-addicted patients taking a methadone maintenance treatment, enrolled through 2010 to 2011 in five Italian sites, observed over 2 years. The Opiate Dosage Adequacy Scale has been used for the evaluation of the "adequacy" of the methadone dosage and to stratify patients in adequate and not adequate groups. The treatment efficacy has been evaluated in correlation to the dosage adequacy during the visits. Moreover, patients have been evaluated according to the retention rate and duration of retention in treatment and a series of questionnaires.

  17. Ethnic and genetic factors in methadone pharmacokinetics: A population pharmacokinetic study☆

    PubMed Central

    Bart, Gavin; Lenz, Scott; Straka, Robert J.; Brundage, Richard C.

    2014-01-01

    Background Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. Methods Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of racmethadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. Results In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G > T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G > T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone. Conclusion This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. PMID:25456329

  18. Morphine reduces social cohesion in rats.

    PubMed

    Panksepp, J; Najam, N; Soares, F

    1979-08-01

    The effect of low (1 mg/kg) doses of morphine on maintenance of physical proximity were evaluated in paired rats observed in a 4 square foot test arena. Morphine reliably reduced proximity maintenance time, and this was apparently not due to sedation, since the effect was unmodified by doses of amphetamine which substantially increased motor activity. The effects of naloxone were inconsistent on this measure of social motivation. In general, the results are consistent with the theoretical proposition that a brain neurochemical change which might lead to social attraction is the activation of endogenous opioid systems. When opiate activity is exogenously sustained, animals exhibit a subnormal tendency to be gregarious.

  19. Synthetic substances with morphine-like effect

    PubMed Central

    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

  20. A randomised controlled trial of morphine versus phenobarbitone for neonatal abstinence syndrome

    PubMed Central

    Jackson, L; Ting, A; Mckay, S; Galea, P; Skeoch, C

    2004-01-01

    Background: The incidence of neonatal abstinence syndrome (NAS) has increased 10-fold over the last decade in Glasgow. In the Princess Royal Maternity Hospital, it now accounts for 17% of special care baby unit (SCBU) admissions. Objective: To compare opiate replacement therapy (morphine sulphate) with the present standard treatment (phenobarbitone) for management of NAS. The primary study end point was duration of pharmaceutical treatment. Secondary end points were the requirement for additional drugs and the requirement for SCBU admission. Design: Double blind, randomised controlled clinical trial. Methods: Differential diagnoses were excluded, and two consecutive Lipsitz scores > 4 defined NAS requiring treatment. Infants were randomised to receive morphine sulphate or phenobarbitone. Treatments were identical in appearance, odour, and volume. Increments, decrements, and discontinuation of treatments were protocol driven. Results: Seventy five infants participated. All mothers received opiate replacement therapy (methadone) during pregnancy and most used other drugs (n  =  62, 83%). No significant difference in maternal drug use patterns was observed between treatment groups. Median treatment duration was four days shorter with opiate replacement (8 v 12 days, Mann-Whitney U test, p  =  0.02). Phenobarbitone treated infants tended to require second line treatment (47% v 35%, χ2 test, p  =  0.11) and SCBU admission (62% v 30%, χ2 test, p = 0.04) more often. Conclusions: Opiate replacement therapy appears to be superior for management of symptomatic NAS when maternal opiate use is prevalent. The shorter treatment duration and lower requirement for higher intensity nursing may have significant cost implications. Tailoring NAS treatment to local maternal drug use may result in similar benefits. PMID:15210660

  1. Endogenous morphine-like compound immunoreactivity increases in parkinsonism.

    PubMed

    Charron, Giselle; Doudnikoff, Evelyne; Laux, Alexis; Berthet, Amandine; Porras, Gregory; Canron, Marie-Hélène; Barroso-Chinea, Pedro; Li, Qin; Qin, Chuan; Nosten-Bertrand, Marika; Giros, Bruno; Delalande, François; Van Dorsselaer, Alain; Vital, Anne; Goumon, Yannick; Bezard, Erwan

    2011-08-01

    Morphine is endogenously synthesized in the central nervous system and endogenous dopamine is thought to be necessary for endogenous morphine formation. As Parkinson's disease results from the loss of dopamine and is associated with central pain, we considered how endogenous morphine is regulated in the untreated and l-DOPA-treated parkinsonian brain. However, as the cellular origin and overall distribution of endogenous morphine remains obscure in the pathological adult brain, we first characterized the distribution of endogenous morphine-like compound immunoreactive cells in the rat striatum. We then studied changes in the endogenous morphine-like compound immunoreactivity of medium spiny neurons in normal, Parkinson's disease-like and l-DOPA-treated Parkinson's disease-like conditions in experimental (rat and monkey) and human Parkinson's disease. Our results reveal an unexpected dramatic upregulation of neuronal endogenous morphine-like compound immunoreactivity and levels in experimental and human Parkinson's disease, only partially normalized by l-DOPA treatment. Our data suggest that endogenous morphine formation is more complex than originally proposed and that the parkinsonian brain experiences a dramatic upregulation of endogenous morphine immunoreactivity. The functional consequences of such endogenous morphine upregulation are as yet unknown, but based upon the current knowledge of morphine signalling, we hypothesize that it is involved in fatigue, depression and pain symptoms experienced by patients with Parkinson's disease.

  2. Long-term effects of methadone maintenance treatment with different psychosocial intervention models.

    PubMed

    Wang, Lirong; Wei, Xiaoli; Wang, Xueliang; Li, Jinsong; Li, Hengxin; Jia, Wei

    2014-01-01

    This study evaluated the long-term effects of different psychosocial intervention models in methadone maintenance treatment (MMT) in Xi'an China. Patients from five MMT clinics were divided into three groups receiving MMT only, MMT with counseling psychology (CP) or MMT with contingency management (CM). A five-year follow-up was carried out with daily records of medication, monthly random urine morphine tests, and tests for anti-HIV and anti-HCV every six months. Drug use behavior was recorded six months after initial recruitment using a survey. Adjusted RRs and their 95% confidence intervals (CIs) were estimated using an unconditional logistic regression model or a Cox proportional hazard model. A total of 2662 patients were recruited with 797 in MMT, 985 in MMT with CP, and 880 in MMT with CM. Following six months of treatment, the injection rates of MMT with CP and MMT with CM groups were significantly lower than that of MMT (5.1% and 6.9% vs. 16.3%, x²  =  47.093 and 29.908, respectively; P<0.05). HIV incidences for MMT, MMT with CP and MMT with CM at the five year follow-up were 20.09, 0.00 and 10.02 per ten thousand person-years, respectively. HCV incidences were 18.35, 4.42 and 6.61 per hundred person-years, respectively, demonstrating that CP and CM were protective factors for HCV incidence (RR  =  0.209 and 0.414, with range of 0.146-0.300 and 0.298-0.574, respectively). MMT supplemented with CP or CM can reduce heroin use and related risk behaviors, thereby reducing the incidence of HIV and HCV. PMID:24498406

  3. Prenatal buprenorphine versus methadone exposure and neonatal outcomes: systematic review and meta-analysis.

    PubMed

    Brogly, Susan B; Saia, Kelley A; Walley, Alexander Y; Du, Haomo M; Sebastiani, Paola

    2014-10-01

    Increasing rates of maternal opioid use during pregnancy and neonatal withdrawal, termed neonatal abstinence syndrome (NAS), are public health concerns. Prenatal buprenorphine maintenance treatment (BMT) versus methadone maintenance treatment (MMT) may improve neonatal outcomes, but associations vary. To summarize evidence, we used a random-effects meta-analysis model and estimated summary measures of BMT versus MMT on several outcomes. Sensitivity analyses evaluated confounding, publication bias, and heterogeneity. Subjects were 515 neonates whose mothers received BMT and 855 neonates whose mothers received MMT and who were born from 1996 to 2012 and who were included in 12 studies. The unadjusted NAS treatment risk was lower (risk ratio=0.90, 95% confidence interval (CI): 0.81, 0.98) and mean length of hospital stay shorter (-7.23 days, 95% CI: -10.64, -3.83) in BMT-exposed versus MMT-exposed neonates. In treated neonates, NAS treatment duration was shorter (-8.46 days, 95% CI: -14.48, -2.44) and morphine dose lower (-3.60 mg, 95% CI: -7.26, 0.07) in those exposed to BMT. BMT-exposed neonates had higher mean gestational age and greater weight, length, and head circumference at birth. Fewer women treated with BMT used illicit opioids near delivery (risk ratio=0.44, 95% CI: 0.28, 0.70). Simulations suggested that confounding by indication could account for some of the observed differences. Prenatal BMT versus MMT may improve neonatal outcomes, but bias may contribute to this protective association. Further evidence is needed to guide treatment choices.

  4. Optical properties of aqueous morphine solutions

    NASA Astrophysics Data System (ADS)

    Kuznetsov, Pavel E.; Gracheva, Anna A.; Zlobin, Vladimir A.; Nazarov, Georgy V.; Kuznetsova, Nina B.; Rogacheva, Svetlana M.

    2003-10-01

    We have studied morphine action on mobility and structure of water by means of fluorescent investigations and light scattering analysis. Wave-like concentration dependences have been plotted in the both cases. Theoretical description of the discovered effect has been made based on the formalism of N.N.Bogolubov.

  5. Methadone during pregnancy: the search for a valid animal model.

    PubMed

    Hutchings, D E; Zmitrovich, A; Church, S; Malowany, D

    1993-01-01

    It has long been known that maternal addiction to opiates during pregnancy produces passive addiction in the newborn. When the synthetic opiate, methadone, became widely used for the treatment of heroin addiction, attention was focused on its possible reproductive and developmental toxicity. The clinical data clearly indicate that prenatal exposure to methadone produces a neonatal abstinence syndrome and that the symptoms, characterized by generalized CNS arousal, persist for as long as 4-6 month after birth. Long-term neurobehavioral follow-up studies to pre-school age have not found any obvious cognitive impairments or deficits in IQ. Some of the children, however, may be at risk for developing problems of fine motor coordination and attention deficit disorder that are likely to lead to poor school performance. These effects probably have complex origins and include primary drugs effects, postnatal/environmental interactions and genetic susceptibilities. Regardless of their interpretation, however, it is important to emphasize that from a risk/benefit point of view, most workers would agree that methadone maintenance poses far fewer hazards, both to the mother and her offspring, than continued abuse of heroin with its associated medical complications, psychosocial turmoil, but most importantly, risk of HIV infection. Because of their pharmacological relevance to the issue of human kinetics, it is hoped that the more recent animal studies of prenatal methadone exposure using the osmotic mini-pump will shed more light on the problem of developmental toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Physician Peer Assessments for Compliance with Methadone Maintenance Treatment Guidelines

    ERIC Educational Resources Information Center

    Strike, Carol; Wenghofer, Elizabeth; Gnam, William; Hillier, Wade; Veldhuizen, Scott; Millson, Margaret

    2007-01-01

    Introduction: Medical associations and licensing bodies face pressure to implement quality assurance programs, but evidence-based models are lacking. To improve the quality of methadone maintenance treatment (MMT), the College of Physicians and Surgeons of Ontario, Canada, conducts an innovative quality assurance program on the basis of peer…

  7. Changing Needle Practices in Community Outreach and Methadone Treatment.

    ERIC Educational Resources Information Center

    Wechsberg, Wendee M.; And Others

    1994-01-01

    This pretest/posttest study used two samples of injecting drug users (184 from street outreach and 103 from a methadone program) to assess drug use and human immunodeficiency virus risk practices. The improvement in risk behaviors at posttest suggests that intervention programs were agents of change. (SLD)

  8. Cost Analysis of Training and Employment Services in Methadone Treatment.

    ERIC Educational Resources Information Center

    French, Michael T.; And Others

    1994-01-01

    A cost analysis is presented for developing a training and employment (TEP) program at four methadone treatment centers in a quasi-experimental pilot study. Average annual costs for TEP per client were derived. The methodology can be used in other projects to compare standard and TEP-enhanced substance-abuse treatment. (SLD)

  9. Integrating Fieldwork into Employment Counseling for Methadone-Treatment Patients

    ERIC Educational Resources Information Center

    Blankertz, Laura; Spinelli, Michael; Magura, Stephen; Bali, Priti; Madison, Elizabeth M.; Staines, Graham L.; Horowitz, Emily; Guarino, Honoria; Grandy, Audrey; Fong, Chunki; Gomez, Augustin; Dimun, Amy; Friedman, Ellen

    2005-01-01

    An innovative employment counseling model, Customized Employment Supports, was developed for methadone-treatment patients, a population with historically low employment rates. The effectiveness of a key component of the model, "vocational fieldwork," the delivery of services in the community rather than only within the clinic, was assessed through…

  10. Counseling with Methadone Clients: A Review of Recent Research

    ERIC Educational Resources Information Center

    Powers, Robert J.; Powers, Henrietta B.

    1978-01-01

    A review of studies on counseling with methadone clients affirmed the importance of counseling services. Support was found for analytic therapy, T-group therapy, behavioral training, reality therapy, and family therapy. There was evidence of client resistance to group therapy. (Author)

  11. Attitudes of Employers toward Hiring Methadone Maintenance Patients.

    ERIC Educational Resources Information Center

    Pugliese, Anthony

    1978-01-01

    Results of this study indicate that at present employers are not ready to accept methadone maintained patients into their firms. The stigma placed on heroin addicts by employers is a very important issue when the treated patient tries to make it in the employment field. More employer education is needed. (Author)

  12. Tandem DART™ MS Methods for Methadone Analysis in Unprocessed Urine.

    PubMed

    Beck, Rachel; Carter, Patrick; Shonsey, Erin; Graves, David

    2016-03-01

    Current methods of methadone analysis in untreated urine are traditionally limited to enzyme immunoassays (EIA) while confirmation techniques require specimen processing (i.e., sample clean-up) before analyzing by gas or liquid chromatography coupled with mass spectrometry (GC-MS or LC-MS-MS). EIA and traditional confirmation techniques can be costly and, at times inefficient. As an alternative approach, we present Direct Analysis in Real Time (DART™) coupled with both time-of-flight and triple quadrupole linear ion trap (Q-TRAP™) mass spectrometers for screening and confirming methadone in untreated urine specimens. These approaches require neither expensive kits nor sample clean-up for analysis. More importantly, the total combined analysis time for both screening and confirmation methods was <5 min per sample; in contrast to the 3-5 day process required by traditional EIA, GC-MS and LC-MS-MS techniques. To examine the fundamental protocol and its applicability for routine drug screening, studies were performed that included limits of detection, precision, selectivity and specificity, sample recovery and stability and method robustness. The methods described in this report were determined to be highly specific and selective; allowing for detection of methadone at 250 ng/mL, consistent with cutoffs for current EIA techniques (300 ng/mL). The results reported here demonstrate the DART™ MS platform provides rapid and selective methadone analysis and the potential for providing savings of both time and resources compared with current analysis procedures. PMID:26590378

  13. Pharmacologic Evidence to Support Clinical Decision Making for Peripartum Methadone Treatment

    PubMed Central

    Bogen, D. L.; Perel, J. M.; Helsel, J. C.; Hanusa, B. H.; Romkes, M.; Nukui, T.; Friedman, C. R.; Wisner, K. L.

    2012-01-01

    Rationale Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. Objectives Study goals were to: 1) Characterize changes in methadone dose across childbearing, 2) Determine enantiomer-specific methadone withdrawal kinetics from steady-state during late pregnancy, 3) Assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and 4) Explore relationships between CYP2B6, CYP2C19 and CYP3A4 single nucleotide polymorphisms and maternal dose, plasma concentration and L/D. Methods Methadone dose changes and timed plasma samples were obtained for women on methadone (n=25) followed prospectively from third trimester of pregnancy to three months postpartum. Results Participants were primarily white, Medicaid insured and multiparous. All women increased their dose from first to end of second trimester (mean peak increase=23 mg/day); 71% of women increased from second trimester to delivery (mean peak increase=19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7-24.9 hours; S-methadone 8.02-18.9 hours) were about half of those reported in non-pregnant populations. In 3 women with weekly 24-hour methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. Conclusions Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery. PMID:22926004

  14. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    PubMed

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. PMID:27102159

  15. Methadone-induced Damage to White Matter Integrity in Methadone Maintenance Patients: A Longitudinal Self-control DTI Study

    PubMed Central

    Li, Wei; Li, Qiang; Wang, Yarong; Zhu, Jia; Ye, Jianjun; Yan, Xuejiao; Li, Yongbin; Chen, Jiajie; Liu, Jierong; Li, Zhe; Wang, Wei; Liu, Yijun

    2016-01-01

    Methadone maintenance treatment (MMT) can induce impairments in brain function and structure, despite its clinical effectiveness. However, the effect of chronic MMT on brain white matter (WM) is not fully known. Thirty-three MMT patients underwent diffusion tensor imaging (DTI) twice – at the start of the study (Scan1) and one year later (Scan2). Tract-based spatial statistics were used to investigate changes in fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) between the two scans. The correlations between DTI indices and methadone consumption and neuropsychological status were analysed. We found significantly decreased FA, decreased AD and increased RD in Scan2 in extensive WM regions; overlapping regions were found in the left posterior limb and the retrolenticular part of internal capsule, superior and posterior corona radiata, bilateral external capsule and the right superior longitudinal fasciculus. In addition, the change of FA in the overlapping regions was positively correlated with the accumulated dosage of methadone use, the RD value in Scan2 and non-planning impulsiveness (NPI) measured at follow-up. The results suggest that methadone has damaging effects on WM integrity. The dose-dependent pattern and characteristics of the impairment may suggest new strategies for MMT. PMID:26794650

  16. Estimated Infant Exposure to Enantiomer-Specific Methadone Levels in Breastmilk

    PubMed Central

    Perel, James M.; Helsel, Joseph C.; Hanusa, Barbara H.; Thompson, Matthew; Wisner, Katherine L.

    2011-01-01

    Abstract Background and Objectives Breastfeeding, a public health priority, improves outcomes for infants. Methadone is dispensed as a racemic mixture; R-methadone is the active enantiomer. Pharmacologic data for R-methadone in breastmilk could improve risk–benefit decision-making for treatment of lactating women. This study estimated infant exposure to R- and S-methadone via breastmilk by theoretic infant dose (TID) and relative infant dose (RID) and reported the milk-to-maternal plasma (M/P) ratio. Methods Women treated with methadone doses of 40–200 mg/day (mean, 102 mg/day) provided concomitantly collected plasma and breastmilk samples 1–6 days after delivery. Most (16 of 20) samples were taken at the time of peak maternal plasma levels; thus infant exposure estimates are for maximum possible exposure. Concentrations of R- and S-methadone were measured in maternal plasma and breastmilk; M/P ratio, TID, and RID were calculated for each enantiomer and total methadone. Results The 20 participants were 18–38 years old and publicly insured; a quarter did not complete high school, and only one was not white. R-Methadone concentration was 1.3–3.0 times that of S-methadone in all breastmilk samples. The mean (SD) R-, S-, and total methadone M/P ratios were 0.52 (0.28), 0.28 (0.15), and 0.40 (0.21), respectively. Mean (range) R-, S-, and total methadone TID were 0.02 mg/kg/day (0.004–0.099), 0.013 mg/kg/day (0.002–0.071), and 0.033 mg/kg/day (0.006–0.170), respectively. Mean (range) RID of R-, S-, and total methadone were 2.7% (0.7–10.1%), 1.6% (0.3–7.2%), and 2.1% (0.52–8.8%), respectively. Conclusions R-Methadone is found in higher concentrations than S-methadone in breastmilk. Even at high methadone doses, breastmilk methadone concentrations were relatively low and support American Academy of Pediatrics recommendations that dose should not be a factor in determining whether women on methadone breastfeed. PMID:21348770

  17. A single-dose, 3-way crossover pharmacokinetic comparison between immediate-release oxycodone hydrochloride with aversion technology (IRO-A, Oxecta), IRO-a with Niacin, and Oxycodone Hydrochloride (Roxicodone) in healthy adults under fasting conditions.

    PubMed

    Leibowitz, Mark T; Zamora, Cynthia A; Brzeczko, Albert W; Stark, Jeffrey G

    2014-01-01

    Snorting and intravenous use are common routes of administration for advanced opioid abusers. A tablet form of immediate-release oxycodone (IRO) developed using Aversion Technology combines immediate release (IR) oxycodone HCl with inactive functional excipients that are intended to discourage tampering associated with intranasal and intravenous abuse (IRO-A; Oxecta, Pfizer). The purpose of this single-dose, open-label, randomized, 3-period, 3-treatment crossover study was to evaluate the bioequivalence of IRO-A to the marketed immediate-release oxycodone HCl (IRO; Roxicodone, Xanodyne Pharmaceuticals Inc., Newport, KY). IRO-A was also compared with IRO-A with niacin, a product previously developed containing the same functional excipients plus niacin as an aversive agent to discourage oral overconsumption. Healthy adults (N = 40) aged 18-55 years received single 15-mg doses of IRO-A, IRO-A with niacin (60 mg), or IRO after fasting overnight. Naltrexone was administered to diminish opioid effects. Doses were separated by a ≥7-day washout. Plasma samples taken at designated time points were analyzed using liquid chromatography with tandem mass spectrometry. Geometric mean ratios for ln-transformed parameters for IRO-A and IRO were 92%, 104%, and 104% for Cmax, AUClast (AUC is area under the concentration-time curve), and AUCinf; 90% confidence intervals were within the accepted 80%-125% range. IRO-A was also bioequivalent to IRO-A with niacin. Adverse events were mild to moderate in intensity and typical of opioid therapy (nausea, headache, vomiting). Flushing only occurred when the subjects received the IRO-A with niacin treatment (9/37 subjects). The results demonstrated that IRO-A is bioequivalent to IRO and IRO-A with niacin. With features designed to discourage tampering associated with common forms of abuse, IRO-A may provide an alternative to conventional immediate-release oxycodone formulations.

  18. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    PubMed

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18-55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant.

  19. Investigation of structure, vibrational and NMR spectra of oxycodone and naltrexone: A combined experimental and theoretical study

    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.

  20. Incarcerated intravenous heroin users: predictors of post-release utilization of methadone maintenance treatment.

    PubMed

    Lin, Huang-Chi; Wang, Peng-Wei; Yang, Yi-Hsin; Tsai, Jih-Jin; Yen, Cheng-Fang

    2016-01-01

    Incarcerated intravenous heroin users have more problematic patterns of heroin use, but are less likely to access methadone maintenance treatment by their own initiative than heroin users in the community. The present study examined predictors for receiving methadone maintenance treatment post-release among incarcerated intravenous heroin users within a 24-month period. This cohort study recruited 315 incarcerated intravenous heroin users detained in 4 prisons in southern Taiwan and followed up within the 24-month period post-release. Cox proportional hazards regression analysis was applied to determine the predictive effects of sociodemographic and drug-use characteristics, attitude toward methadone maintenance treatment, human immunodeficiency virus serostatus, perceived family support, and depression for access to methadone maintenance treatment after release. There were 295 (93.7%) incarcerated intravenous heroin users released that entered the follow-up phase of the study. During the 24-month follow-up period, 50.8% of them received methadone maintenance treatment. After controlling for the effects of the detainment period before and after recruitment by Cox proportional hazards regression analysis, incarcerated intravenous heroin users who had positive human immunodeficiency virus serostatus (HR = 2.85, 95% CI = 1.80-4.52, p < .001) and had ever received methadone maintenance treatment before committal (HR = 1.94, 95% CI = 1.23-3.05, p < .01) were more likely to enter methadone maintenance treatment within the 24-month follow-up period. Positive human immunodeficiency virus serostatus with fully subsidized treatment and previous methadone maintenance treatment experiences predicted access of methadone maintenance treatment post-release. Strategies for getting familiar with methadone maintenance treatment during detainment, including providing methadone maintenance treatment prior to release and lowering the economic burden of receiving treatment, may

  1. Methadone toxicity fatalities: a review of medical examiner cases in a large metropolitan area.

    PubMed

    Shields, Lisa B E; Hunsaker Iii, John C; Corey, Tracey S; Ward, Michael K; Stewart, Donna

    2007-11-01

    Over the past several years, Medical Examiners in Kentucky and around the nation have observed a dramatic rise in drug intoxication deaths involving the prescription medication methadone. This documented rise in methadone-related deaths requires a better understanding of methadone's pathophysiology and the ways it contributes to significantly increase morbidity and mortality. This study reviews 176 fatalities ascribed to methadone toxicity by the Office of the Chief Medical Examiner in Kentucky between 2000 and 2004. Postmortem toxicological analysis recorded a more than 10-fold increase in methadone toxicity fatalities, rising from 6 cases in 2000 to 68 cases in 2003. Of the 176 methadone-related fatalities, methadone was the only drug detected in postmortem blood and urine toxicological analyses in 11 (6.25%) cases. The mean methadone blood concentration of all 176 cases was 0.535 mg / L (0.02-4.0). The following psychoactive medications were detected: antidepressants (39.8%), benzodiazepines (32.4%), and other opioids in addition to methadone (27.8%). Cannabinoids were detected in 44 (28.4%) cases and cocaine or metabolite in 34 (21.9%) cases. Of the 95 cases with a known history of methadone use, 46 (48.4%) involved prescription by private physician. The interpretation of blood methadone concentrations alone or combined with other psychoactive drugs requires consideration of the subject's potential chronic use of and tolerance to the drug. A thorough investigation into the practices of procurement and use/abuse of methadone is essential to arrive at the proper designation of the cause of death.

  2. Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States.

    PubMed

    Cicero, Theodore J; Ellis, Matthew S; Surratt, Hilary L; Kurtz, Steven P

    2013-12-01

    The purpose of the present study was to identify the factors that influence the selection of hydrocodone and oxycodone as primary drugs of abuse in opioid-dependent subjects (n = 3520) entering one of 160 drug treatment programs around the country. Anonymous, self-administered surveys and direct qualitative interviews were used to examine the influence of demographic characteristics, drug use patterns, and decision-related factors on primary opioid selection. Our results showed that oxycodone and hydrocodone were the drugs of choice in 75% of all patients. Oxycodone was the choice of significantly more users (44.7%) than hydrocodone (29.4%) because the quality of the high was viewed to be much better by 54% of the sample, compared to just 20% in hydrocodone users, who cited acetaminophen as a deterrent to dose escalation to get high and hence, its low euphoric rating. Hydrocodone users were generally risk-averse women, elderly people, noninjectors, and those who prefer safer modes of acquisition than dealers (ie, doctors, friends, or family members). In contrast, oxycodone was a much more attractive euphorigenic agent to risk-tolerant young, male users who prefer to inject or snort their drugs to get high and are willing to use more aggressive forms of diversion. Prevention and treatment approaches, and pain physicians, should benefit from these results because it is clear that not all drug abusers share the same characteristics, and the decision to use one drug over another is a complex one, which is largely attributable to individual differences (eg, personality, gender, age, and other factors).

  3. Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats

    PubMed Central

    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

  4. Methadone, monoamine oxidase, and depression: opioid distribution and acute effects on enzyme activity

    SciTech Connect

    Kaufmann, C.A.; Kreek, M.J.; Raghunath, J.; Arns, P.

    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 24 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.

  5. Impact of early methadone initiation in critically injured burn patients: a pilot study.

    PubMed

    Jones, G Morgan; Porter, Kyle; Coffey, Rebecca; Miller, Sidney F; Cook, Charles H; Whitmill, Melissa L; Murphy, Claire V

    2013-01-01

    Numerous studies have identified strategies to reduce mechanical ventilation duration by targeting appropriate sedation levels. However, applicability of these strategies to critically injured patients with burn injury has not been established. At our medical center, methadone is commonly used early in the care of burn patients to treat background pain and limit the development of opioid tolerance. The aim of this study is to evaluate the effect of early methadone initiation in critically injured burn patients requiring mechanical ventilation. This retrospective study compared patients who received early methadone with patients who did not while mechanically ventilated with the primary outcome of ventilator-free days in a 28-day period. Those who received methadone within 4 days of intubation and remained ventilated for 2 days after the first dose were included in the methadone group. Propensity scores were used to match up to three control patients to each methadone patient. Seventy patients (18 methadone and 52 matched control patients) were included in the final evaluation. Patients in the methadone group averaged 16.5 ventilator-free days compared with 11.5 in the control group (P = .03). There was no statistical difference in the duration of intensive care unit or hospital length of stay between groups. Our results suggest that early methadone initiation may have a significant effect on ventilator outcomes in critically injured patients with burn injury. However, further research is warranted.

  6. Metabolism and pharmacokinetics of morphine in neonates: A review

    PubMed Central

    Pacifici, Gian Maria

    2016-01-01

    Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

  7. Metabolism and pharmacokinetics of morphine in neonates: A review

    PubMed Central

    Pacifici, Gian Maria

    2016-01-01

    Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based. PMID:27626479

  8. Blockade of tolerance to morphine analgesia by cocaine.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1989-07-01

    Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system. PMID:2780065

  9. Metabolism and pharmacokinetics of morphine in neonates: A review.

    PubMed

    Pacifici, Gian Maria

    2016-08-01

    Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords "morphine metabolism neonate" and "morphine pharmacokinetics neonate". The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based. PMID:27626479

  10. Valproate attenuates the development of morphine antinociceptive tolerance.

    PubMed

    Dobashi, Tamae; Tanabe, Serabi; Jin, Hisayo; Nishino, Takashi; Aoe, Tomohiko

    2010-11-19

    Morphine is a potent opioid analgesic. Repeated administration of morphine induces tolerance, thus reducing the effectiveness of analgesic treatment. Although some adjuvant analgesics can increase morphine analgesia, the precise molecular mechanism behind their effects remains unclear. Opioids bind to the mu opioid receptor (MOR). Morphine tolerance may be derived from alterations in the intracellular signal transduction after MOR activation. Chronic morphine treatment activates glycogen synthase kinase 3β (GSK3β), whose inhibition diminishes morphine tolerance. Valproate is widely prescribed as an anticonvulsant and a mood stabilizer for bipolar disorders because it increases the amount of γ-aminobutyric acid (GABA) in the central nervous system. Although the activation of GABAergic neurons may be responsible for the chief pharmacologic effect of valproate, recent studies have shown that valproate also suppresses GSK3β activity. We examined the effect of valproate on the development of morphine antinociceptive tolerance in a mouse model of thermal injury. Mice were treated with morphine alone or with morphine and valproate twice daily for 5 days. The resulting antinociceptive effects were assessed using a hot plate test. While mice treated with morphine developed tolerance, co-administration of valproate attenuated the development of tolerance and impaired the activation of GSK3β in mice brains. Valproate alone did not show analgesic effects; nevertheless, it functioned as an adjuvant analgesic to prevent the development of morphine tolerance. These results suggest that the modulation of GSK3β activity by valproate may be useful and may play a role in the prevention of morphine tolerance. PMID:20816918

  11. Determination of Oxycodone, Noroxycodone and Oxymorphone by High-Performance Liquid Chromatography–Electrospray Ionization-Tandem Mass Spectrometry in Human Matrices: In vivo and In vitro Applications

    PubMed Central

    Fang, Wenfang B.; Lofwall, Michelle R.; Walsh, Sharon L.; Moody, David E.

    2013-01-01

    The opioid analgesic oxycodone is widely abused and increasingly associated with overdose deaths. A sensitive analytical method was developed for oxycodone and its metabolites, noroxycodone and oxymorphone, in human plasma, urine (±enzymatic hydrolysis at 50°C for 16 h) and liver microsomes (HLMs). Liquid–liquid extraction was followed by high-performance liquid chromatography–electrospray ionization-tandem mass spectrometry. The calibration range was 0.2–250 ng/mL for plasma and HLM and 10–5000 ng/mL for urine. Intra- and interrun accuracies were within 13.3% of target; precisions were within 12.8% for all matrices. Recoveries from plasma were: oxycodone, 75.6%; noroxycodone, 37.4% and oxymorphone, 18.2%. Analytes exhibited room temperature stability in plasma and urine up to 24 h, and freeze–thaw stability in plasma up to three cycles. In 24-h hydrolyzed urine from subjects administered intranasal oxycodone (30 mg/70 kg, n = 5), mean concentrations (ng/mL) and % daily doses excreted were: oxycodone, 1150, 6.53%; noroxycodone, 1330, 7.81% and oxymorphone, 3000, 17.1%. Oxycodone incubated with HLM produced more noroxycodone than oxymorphone. With a panel of recombinant human cytochrome P450s (CYPs), CYP2C18 and CYP3A4 produced the most noroxycodone, whereas CYP2D6 produced the most oxymorphone. These results demonstrate a new method suitable for both in vivo and in vitro metabolism and pharmacokinetic studies of oxycodone. PMID:23743505

  12. The effect of morphine in rat small mesenteric arteries.

    PubMed

    Ozdem, Sadi S; Batu, Ozlem; Tayfun, Fatma; Yalcin, Ozlem; Meiselman, Herbert J; Baskurt, Oguz K

    2005-06-01

    We investigated the effect of morphine in phenylephrine (PE)- or KCl-precontracted rat small mesenteric arteries. Morphine (10(-6)-10(-4) M) administration caused concentration-dependent relaxation responses in small mesenteric arteries precontracted by PE or KCl. Removal of endothelium did not significantly alter the relaxation responses to morphine. The relaxant responses to morphine were partially inhibited by pre-treatment of tissues with naloxone (NAL, 10(-5) M) for 20 min. The inhibitory effect of NAL on relaxant responses to morphine in PE- or KCl-precontracted arteries did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of endothelium-intact or endothelium-denuded arterial segments with NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or cyclooxygenase (COX) inhibitor indomethacin (10(-5) M) or histamine H(1)-receptor blocker diphenhydramine (10(-6) M), for 20 min did not inhibit the relaxation responses to morphine. Small mesenteric arterial segment contractions induced by stepwise addition of calcium to high KCl solution with no calcium were almost completely inhibited by morphine. These findings suggested that morphine-induced relaxation responses in isolated rat small mesenteric arteries were neither dependent on endothelium nor blocked by NOS or COX inhibition but they rather seem to depend on an interaction of morphine with calcium influx pathways. PMID:15939674

  13. Effect of morphine on PC12 cells with molecular radar

    NASA Astrophysics Data System (ADS)

    Shi, Chen; Yu, Xiaoli; Lu, Jiuyi; Zhang, Chunyang; Jin, Lei; Ma, Hui; Zhang, Dacheng; Chen, Die Yan

    2000-10-01

    Molecular Radar (MR) is a new method to detect biological processes in living cells at the level of molecular, it is also the newest means to get intracellular information. In this paper we study the effect of morphine on PC12 cells using MR. The results show that the effect of morphine on PC12 cells is time- and concentration-dependent. Morphine treating for short time induces the increase and fluctuation of intracellular (CA2+), while morphine treating for long time induces chromatin condensation, loss of mitochondria membrane potential apoptosis.

  14. Morphine in the treatment of acute pulmonary oedema--Why?

    PubMed

    Ellingsrud, C; Agewall, S

    2016-01-01

    Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, p<0.001). Other, smaller studies have shown a significant association between morphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.

  15. Risk Factors for Mortality and Endotracheal Intubation after Methadone Intoxication.

    PubMed

    Hassanian-Moghaddam, Hossein; Soltaninejad, Kambiz; Shadnia, Shahin; Kabir, Ali; Movahedi, Mitra; Mirafzal, Amirhossein

    2016-03-01

    This was a retrospective chart review to evaluate various risk factors associated with in-hospital mortality and intubation risk in acute methadone overdose. All patients admitted to an academic hospital in Tehran, Iran, during a 10-year period (2000-2009) constituted the study sample. Exclusion criteria were significant comorbidities and age under 18 years. Outcome variables were in-hospital mortality and being intubated during admission. A total of 802 patients were enrolled in the study. There were 15 (1.8%) deaths due to methadone overdose or its complications. The number of yearly admissions was 15 patients in 2000, 16 in 2001, 16 in 2002, 18 in 2003, 23 in 2004, 38 in 2005, 59 in 2006, 110 in 2007, 206 in 2008 and 301 in 2009. Based on logistic regression analysis, the most important independent variable predicting mortality was length of admission in toxicology ward [OR (95% CI): 1.6 (1.1-2.3)]. For the prediction of intubation, independent variables were Glasgow Coma Scale (GCS) score of 5-9 [OR (95% CI): 356.5 (9.8-12907.4)] in the emergency department (ED), miosis in the ED [356.9 (1.4-87872.5)] and respiratory rate in the ED [1.5 (1.1-2.1)]. Linear regression model for length of hospitalization showed patient age as the most important variable for prediction of this outcome. Despite a relatively low mortality rate, the increasing number of methadone-poisoned patients requires special attention to this common intoxication. Careful disposition of patients from ED to ordinary wards or intensive care units and also from higher to lower levels of care should be considered in methadone overdose. PMID:26301535

  16. Respiratory Variability during Sleep in Methadone Maintenance Treatment Patients

    PubMed Central

    Nguyen, Chinh D.; Kim, Jong Won; Grunstein, Ronald R.; Thamrin, Cindy; Wang, David

    2016-01-01

    Study Objectives: Methadone maintenance treatment (MMT) patients have a high prevalence of central sleep apnea and ataxic breathing related to damage to central respiratory rhythm control. However, the quantification of sleep apnea indices requires laborious manual scoring, and ataxic breathing pattern is subjectively judged by visual pattern recognition. This study proposes a semi-automated technique to characterize respiratory variability in MMT patients. Methods: Polysomnography, blood, and functional outcomes of sleep questionnaire (FOSQ) from 50 MMT patients and 20 healthy subjects with matched age, sex, and body mass index, were analyzed. Inter-breath intervals (IBI) were extracted from the nasal cannula pressure signal. Variability of IBI over 100 breaths was quantified by standard deviation (SD), coefficient of variation (CV), and scaling exponent (α) from detrended fluctuation analysis. The relationships between these variability measures and blood methadone concentration, central sleep apnea index (CAI), apnea-hypopnea index (AHI), and clinical outcome (FOSQ), were then examined. Results: MMT patients had significantly higher SD and CV during all sleep stages. During NREM sleep, SD and CV were correlated with blood methadone concentration (Spearman R = 0.52 and 0.56, respectively; p < 0.01). SD and CV were also correlated with CAI (R = 0.63 and 0.71, p < 0.001, respectively), and AHI (R = 0.45 and 0.58, p < 0.01, respectively). Only α showed significant correlation with FOSQ (R = −0.33, p < 0.05). Conclusions: MMT patients have a higher respiratory variability during sleep than healthy controls. Semi-automated variability measures are related to apnea indices obtained by manual scoring and may provide a new approach to quantify opioid-related sleep-disordered breathing. Citation: Nguyen CD, Kim JW, Grunstein RR, Thamrin C, Wang D. Respiratory variability during sleep in methadone maintenance treatment patients. J Clin Sleep Med 2016;12(4):607–616

  17. Factors Associated with High-Frequency Illicit Methadone Use among Rural Appalachian Drug Users

    PubMed Central

    Hall, Martin T.; Leukefeld, Carl G.; Havens, Jennifer R.

    2013-01-01

    Background In recent years there has been a sharp increase in the use of illicit methadone as well as methadone-related overdose deaths. Objective The purpose of this study is to describe factors associated low- and high-frequency methadone use in a cohort of rural Appalachian drug users. Methods Interviews assessing sociodemographics, illicit drug use and drug treatment, psychiatric disorders, health, and sociometric drug network characteristics were conducted with 503 rural drug users between 2008 and 2010. A two-level mixed effects regression model was utilized to differentiate low- (one use per month or less in the past 6 months) versus high-frequency (daily or weekly use in the past 6 months) illicit methadone users. Results The lifetime prevalence of illicit methadone use in this population was 94.7% (n=476) and slightly less than half (46.3%) were high-frequency users. In the mixed effects regression model, initiating illicit methadone use at a younger age was associated with high-frequency illicit methadone use. Whereas taking a prescribed medication for a physical problem, undergoing additional weeks of outpatient drug free treatment, daily OxyContin® use in the past month, and having fewer ties and second order connections in the drug network reduced the odds of high-frequency illicit methadone use. Conclusions Rates of illicit methadone use and high-frequency illicit methadone use among this sample of rural drug users were considerably higher than those previously reported in the literature. Health practitioners in rural areas should routinely screen for illicit opioid use, including methadone. PMID:23841864

  18. Methadone treatment, bruxism, and temporomandibular disorders among male prisoners.

    PubMed

    Enguelberg-Gabbay, Judith V; Schapir, Lior; Israeli, Yair; Hermesh, Haggai; Weizman, Abraham; Winocur, Ephraim

    2016-06-01

    There is little information on bruxism related to illicit drug use. Prolonged drug use may damage the stomatognathic system via oral motor overactivity. The aim of the present study was to compare the rates of bruxism and temporomandibular disorders (TMDs) between prisoners with and without drug-use disorders, to evaluate the association between methadone treatment and bruxism and to assess the possible relationship between bruxism and pain. The sample included 152 male prisoners, 69 of whom were drug users maintained on methadone. All prisoners were examined by an experienced dentist and completed a questionnaire on their oral habits, with the aim of detecting signs or symptoms of TMD and/or bruxism. Additional data were collected from medical files. The prevalence of sleep bruxism and awake bruxism, but not of TMDs, was significantly higher among drug-user than non-drug user prisoners (52.2% vs. 34.9% for sleep bruxism, 59.7% vs. 30.1% for awake bruxism, and 46.3% vs. 25.6% for TMDs, respectively). Participants with awake bruxism were statistically more sensitive to muscle palpation compared with participants with sleep bruxism [rating scores (mean ± SD): 0.32 ± 0.21 vs. 0.19 ± 0.28, respectively]. An association was found between sleep bruxism and awake bruxism. It seems that there is a direct or an indirect association between methadone maintenance treatment and sleep bruxism or awake bruxism in male prisoners.

  19. Methadone treatment, bruxism, and temporomandibular disorders among male prisoners.

    PubMed

    Enguelberg-Gabbay, Judith V; Schapir, Lior; Israeli, Yair; Hermesh, Haggai; Weizman, Abraham; Winocur, Ephraim

    2016-06-01

    There is little information on bruxism related to illicit drug use. Prolonged drug use may damage the stomatognathic system via oral motor overactivity. The aim of the present study was to compare the rates of bruxism and temporomandibular disorders (TMDs) between prisoners with and without drug-use disorders, to evaluate the association between methadone treatment and bruxism and to assess the possible relationship between bruxism and pain. The sample included 152 male prisoners, 69 of whom were drug users maintained on methadone. All prisoners were examined by an experienced dentist and completed a questionnaire on their oral habits, with the aim of detecting signs or symptoms of TMD and/or bruxism. Additional data were collected from medical files. The prevalence of sleep bruxism and awake bruxism, but not of TMDs, was significantly higher among drug-user than non-drug user prisoners (52.2% vs. 34.9% for sleep bruxism, 59.7% vs. 30.1% for awake bruxism, and 46.3% vs. 25.6% for TMDs, respectively). Participants with awake bruxism were statistically more sensitive to muscle palpation compared with participants with sleep bruxism [rating scores (mean ± SD): 0.32 ± 0.21 vs. 0.19 ± 0.28, respectively]. An association was found between sleep bruxism and awake bruxism. It seems that there is a direct or an indirect association between methadone maintenance treatment and sleep bruxism or awake bruxism in male prisoners. PMID:27041534

  20. The Comparison of Intrathecal Morphine and IV Morphine PCA on Pain Control, Patient Satisfaction, Morphine Consumption, and Adverse Effects in Patients Undergoing Reduction Mammoplasty

    PubMed Central

    Akdağ, Osman; Kara, İnci; Yıldıran, Gokce Unal; Tosun, Zekeriya

    2015-01-01

    Background: Following breast reduction procedures, the level of postoperative pain can be severe, and sufficient pain control influences a patient's physiological, immunological, and psychological status. Objective: The aim of this study was to examine the use of intrathecal morphine (ITM) in breast reduction surgery with patient-controlled analgesia (PCA). Methods: Sixty-two female patients who underwent breast reductions with the same technique participated in this study. The study group (ITM + PCA) included 32 patients; a single shot (0.2 mg) of ITM and intravenous morphine with PCA were administered. In the control group, morphine PCA alone was intravenously administered to 30 patients. Comparisons between the groups of cumulative morphine consumption, visual analog scale scores, and patient satisfaction scores, which were the primary outcome measures, and adverse effects, which were the secondary outcome measures, were conducted. Results: The patients in the 2 groups had similar degrees of pain and satisfaction scores. The study group had lower cumulative morphine consumption (P = .001) than the PCA-only control group; there was no statistically significant difference in adverse effects between the 2 groups. Conclusion: Intrathecal morphine may effectively control pain with lower total morphine consumption following breast reduction surgery. PMID:25987940

  1. A Comparison of Oxycodone and Alfentanil in Intravenous Patient-Controlled Analgesia with a Time-Scheduled Decremental Infusion after Laparoscopic Cholecystectomy

    PubMed Central

    Jang, Ji Su; Kim, Seong Su; Kim, Young Ki; Hwang, Byeong Mun; Kang, Seong Sik; Son, Hee Jeong

    2016-01-01

    Background. Oxycodone, a semisynthetic opioid, has been widely used for acute and chronic pain. Objectives. The aim of this study was to compare the analgesic and adverse effects of oxycodone and alfentanil on postoperative pain after laparoscopic cholecystectomy. Methods. This was a prospective, randomized, double-blind study. A total of 82 patients undergoing laparoscopic cholecystectomy were randomly assigned to receive either oxycodone or alfentanil using intravenous patient-controlled analgesia (PCA). PCA was administered as a time-scheduled decremental continuous infusion based on lean body mass for 48 hours postoperatively. Patients were assessed for pain with a visual analogue scale (VAS), the cumulative PCA dose, adverse effects, sedation level at 1, 4, 8, 16, 24, and 48 hours postoperatively, and satisfaction during the postoperative 48 hours. Results. There were no significant differences (p < 0.05) between the two groups in VAS score, cumulative PCA dose, adverse effects, sedation level at 1, 4, 8, 16, 24, and 48 hours postoperatively, and satisfaction during the postoperative 48 hours. Conclusions. Our data showed that the analgesic and adverse effects of oxycodone and alfentanil were similar. Therefore, oxycodone may be a good alternative to alfentanil for pain management using intravenous PCA after laparoscopic cholecystectomy when used at a conversion ratio of 10 : 1. This trial is registered with KCT0001962. PMID:27725791

  2. Is ethnicity associated with morphine's side effects in children? morphine pharmacokinetics, analgesic response and side effects in children having tonsillectomy

    PubMed Central

    Jimenez, Nathalia; Anderson, Gail D.; Shen, Danny D.; Nielsen, Susan Searles; Farin, Federico M.; Seidel, Kristy; Lynn, Anne M.

    2012-01-01

    Objectives/Aims To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. Background Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. Methods Prospective cohort study in L and NL children, 3–17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6-and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Non-compartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in 8 genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were done. Results We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (p=0.001). Pruritus was 4 times (p=0.006) and emesis 7 times (p=0.025) more frequent in L compared to NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. Conclusions We found statistically significant differences in occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined, explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity. PMID:22486937

  3. Monkey motor stimulation and altered social behavior during chronic methadone administration.

    PubMed

    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.

  4. Can methadone concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence syndrome?

    PubMed Central

    Kuschel, C; Austerberry, L; Cornwell, M; Couch, R; Rowley, R

    2004-01-01

    Aim: To assess the usefulness of cord and serum methadone concentrations at 2 days of age in predicting the severity of neonatal abstinence syndrome (NAS) in infants whose mothers received methadone during pregnancy. Methods: After informed consent, infants were enrolled if they were delivered at 35 weeks gestation or greater. Relevant information was collected from maternal notes. A sample of cord blood was taken at delivery, with a follow up sample at 48 hours of age. The samples were analysed in batches, and the results were unavailable to the attending clinical staff. Infants were treated for NAS on clinical grounds according to a standardised scoring system. Results: Twenty five of 36 eligible infants over the 21 month period of the study were enrolled. Of these, 12 required treatment for NAS. Maternal methadone dose did not predict the need for treatment. However, infants who required treatment had significantly lower methadone concentrations in cord blood than the group who did not receive treatment (31 v 88 ng/ml respectively; p  =  0.029). Paired blood samples for methadone concentrations were available for 17 infants. All but one of the 12 infants who required treatment had undetectable concentrations of methadone in the postnatal sample, whereas the median postnatal methadone concentration in untreated infants was 23 ng/ml (p  =  0.002). Conclusions: Methadone concentrations taken from cord blood may identify infants at greater risk of neonatal withdrawal and therefore requiring treatment. PMID:15321955

  5. A 12-month controlled trial of methadone medical maintenance integrated into an adaptive treatment model.

    PubMed

    King, Van L; Kidorf, Michael S; Stoller, Kenneth B; Schwartz, Robert; Kolodner, Kenneth; Brooner, Robert K

    2006-12-01

    Methadone medical maintenance (MMM) reduces the reporting schedule for stable and well-functioning methadone maintenance patients to once a month, with counseling provided by medical staff. We report on the 12-month outcomes of 92 highly stable methadone maintenance patients randomly assigned to one of three study conditions: routine care, MMM at the methadone maintenance program, and MMM at a physician's office. Methadone medical maintenance patients received a 28-day supply of methadone, whereas routine care patients received five or six take-home methadone doses each week. All patients performed a medication recall once a month and submitted two urine samples each month. An adaptive stepped-care system of treatment intensification was used for patients who failed recall or who had drug-positive urine specimens. Seventy-seven patients completed the 12-month study period. Dropout was caused primarily by problems with handling methadone and disliking the recall frequency. There were low rates of drug use or failed medication recall. Treatment satisfaction was high in all groups, but the MMM patients initiated more new employment or family/social activities than did routine care patients over the study period. The stepped-care approach was well tolerated and matched patients to an appropriate step of service within a continuum of treatment intensity. PMID:17084792

  6. The glycosylation of AGP and its associations with the binding to methadone.

    PubMed

    Behan, Jennifer L; Cruickshank, Yvonne E; Matthews-Smith, Gerri; Bruce, Malcolm; Smith, Kevin D

    2013-01-01

    Methadone remains the most common form of pharmacological therapy for opioid dependence; however, there is a lack of explanation for the reports of its relatively low success rate in achieving complete abstinence. One hypothesis is that in vivo binding of methadone to the plasma glycoprotein alpha-1-acid glycoprotein (AGP), to a degree dependent on the molecular structure, may render the drug inactive. This study sought to determine whether alterations present in the glycosylation pattern of AGP in patients undergoing various stages of methadone therapy (titration < two weeks, harm reduction < one year, long-term > one and a half years) could affect the affinity of the glycoprotein to bind methadone. The composition of AGP glycosylation was determined using high pH anion exchange chromatography (HPAEC) and intrinsic fluorescence analysed to determine the extent of binding to methadone. The monosaccharides galactose and N-acetyl-glucosamine were elevated in all methadone treatment groups indicating alterations in AGP glycosylation. AGP from all patients receiving methadone therapy exhibited a greater degree of binding than the normal population. This suggests that analysing the glycosylation of AGP in patients receiving methadone may aid in determining whether the therapy is likely to be effective.

  7. 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…

  8. The Costs of Pursuing Accreditation for Methadone Treatment Sites: Results from a National Study

    ERIC Educational Resources Information Center

    Zarkin, Gary A.; Dunlap, Laura J.; Homsi, Ghada

    2006-01-01

    The use of accreditation has been widespread among medical care providers, but accreditation is relatively new to the drug abuse treatment field. This study presents estimates of the costs of pursuing accreditation for methadone treatment sites. Data are from 102 methadone treatment sites that underwent accreditation as part of the Center for…

  9. Methadone as an analgesic: a review of the risks and benefits.

    PubMed

    Terpening, Chris M; Johnson, W Michael

    2007-01-01

    While methadone has been available for over 50 years, its use in opiate dependence has overshadowed its use as an analgesic. Within the last 10-15 years, though, methadone has been increasingly used to manage neuoropathic pain and cancer pain, but its use is causing an alarming number of deaths in the U.S. Last June, The Charleston Gazette ran a series titled "The Killer Cure" by Scott Finn and Tara Tuckwiller that found that the number of Americans whose deaths were caused by methadone rose from 790 in 1999 to 2,992 in 2003. The series also reported other statistics from the National Center for Health Statistics that revealed that West Virginia ranked first per capita in methadone overdose deaths, and that methadone was more likely involved in overdose deaths than any other prescription drug. Methadone has several unique properties that can be beneficial in the treatment of neuropathic pain and cancer pain unresponsive to other opioids, but some of these properties make it very dangerous and difficult to prescribe properly. As a result of these factors, methadone should not be the first-choice drug for pain and it should not be used in opioid-naive patients. The goal of this article is to provide a review of the properties and protocols for safe prescribing of methadone to help physicians recognize situations where this drug offers the greatest advantage as an analgesic. PMID:17432310

  10. Evaluation of Drug Abuse Treatment: A Repeated Measures Design Assessing Methadone Maintenance.

    ERIC Educational Resources Information Center

    Hser, Yih-Ing; And Others

    1988-01-01

    A repeated measures design was used to evaluate methadone maintenance (MM) treatment effects for 720 heroin addicts who entered MM in Southern California in 1971-1978. Compared to pretreatment measures, results show significant improvement for methadone users. Level of improvement was affected by sex, ethnicity, and treatment duration. (TJH)

  11. Contingent Take-Home Incentive: Effects on Drug Use of Methadone Maintenance Patients.

    ERIC Educational Resources Information Center

    Stitzer, Maxine L.; And Others

    1992-01-01

    Examined contingent methadone take-home privileges for effectiveness in reducing supplemental drug use of methadone maintenance patients. Assigned 53 new intakes to begin receiving take-home privileges after 2 consecutive weeks of drug-free urines or to noncontingent procedure in which take-homes were delivered independently of urine results.…

  12. Developing Training and Employment Programs to Meet the Needs of Methadone Treatment Clients.

    ERIC Educational Resources Information Center

    Dennis, Michael L.; And Others

    1993-01-01

    Research on vocational services for methadone clients is reviewed, and preliminary results of an evaluation of a training and employment program for 249 methadone treatment clients in 3 community-based programs are presented. Results suggest the usefulness of vocational services in increasing training access and use. (SLD)

  13. Dyads at Risk: Methadone-Maintained Women and Their Four-Month-Old Infants.

    ERIC Educational Resources Information Center

    Jeremy, Rita Jeruchimowicz; Bernstein, Victor J.

    1984-01-01

    Compares 17 methadone-exposed and 23 control four-month-old infants in interactions with their mothers. Results indicate that methadone is only one of several risk factors affecting interaction. Mothers rated poor in communication have poor psychosocial and psychological resources, and infants rated poor in communication showed problematic motor…

  14. Addict Descriptions of Therapeutic Community, Multimodality, and Methadone Maintenance Treatment Clients and Staff.

    ERIC Educational Resources Information Center

    Stuker, Patricia B.; And Others

    1978-01-01

    Compared the Adjective Check List descriptions of addicts in treatment toward methadone maintenance, multimodality, and therapeutic community clients and program staff. Results indicate client pessimism regarding methadone maintenance. Results suggest addict opinions represent a valuable source for evaluating treatment approaches and identifying…

  15. 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…

  16. Morphine as a Potential Oxidative Stress-Causing Agent

    PubMed Central

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-01-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress. PMID:24376392

  17. Continuous morphine produces more tolerance than intermittent or acute treatment.

    PubMed

    Dighe, Shveta V; Madia, Priyanka A; Sirohi, Sunil; Yoburn, Byron C

    2009-05-01

    Dosing protocol and analgesic efficacy have been proposed to be important determinants of the magnitude of opioid tolerance. The present study examined the effect of acute, intermittent and continuous treatment with the low analgesic efficacy agonist morphine on analgesic tolerance. Mice were implanted s.c. with a 25 mg morphine pellet for 1-7 days. Other mice were implanted s.c. with two 25 mg, or one 75 mg morphine pellet for 7 days. The release of morphine from subcutaneous implanted pellets was quantitated using a spectrophotometric assay. In other studies, mice were injected with morphine once (18.5-185 mg/kg/day; approximately 10-100 times ED(50) for morphine analgesia) or once/day for 7 days. Controls were implanted with a placebo pellet or injected with saline. Analysis of drug release from a 25 mg pellet indicated that release was greatest during the first 24 h, declined and then remained relatively constant. The amount of morphine released over 7 days by a 75 mg pellet (23.9 mg) was more than that of a single 25 mg pellet (15.4 mg) but less than two 25 mg pellets (30.8 mg). Following treatment, morphine cumulative dose-response studies were conducted (tail flick). Continuous treatment with morphine using pellet implantation produced a dose-dependent shift in the morphine ED(50) by 3.3, 5.8 and 8.5 fold for one 25 mg pellet, one 75 mg pellet and two 25 mg pellets, respectively. Acute and intermittent morphine administration produced substantially less analgesic tolerance than continuous release of morphine by implant pellets. The maximum shift in the ED(50) was 1.6 for acute treatment and 2.7 for 7 day intermittent treatment; despite a larger total daily dose. The present results indicate that continuous treatment with morphine results in greater analgesic tolerance than acute or intermittent morphine treatment even at comparable daily doses. These results are consistent with the suggestion that intermittent dosing has reduced risk of producing opioid

  18. Non-Addictive Painkiller Shows Promise in Animal Trials

    MedlinePlus

    ... The experimental medication "has the potential to replace morphine as the gold standard for treating severe pain," ... such as Percocet (acetaminophen/oxycodone), OxyContin (oxycodone) and morphine, but minus the negative effects, doctors say. The ...

  19. Methadone maintenance in the treatment of opioid dependence. A current perspective.

    PubMed

    Zweben, J E; Payte, J T

    1990-05-01

    We describe the historical underpinnings of negative attitudes towards methadone and how these affect medical decisions. Current developments have increased the understanding of the origins of opioid addiction, such as how receptor system dysfunction may affect the ability to remain abstinent once out of treatment. Specialized topics include the pregnant addict, the role of methadone maintenance in limiting the spread of the acquired immunodeficiency syndrome, and patients with a dual diagnosis. We also describe issues that arise when methadone is used in conjunction with prescribed or abused drugs, noting pharmacologic alternatives and adjuncts to methadone treatment. Finally, we comment on treatment issues such as methadone patients in 12-step programs and the growing legitimacy of this treatment method.

  20. Self-intoxication with morphine obtained from an infusion pump.

    PubMed

    Gock, S B; Wong, S H; Stormo, K A; Jentzen, J M

    1999-01-01

    A 36-year-old Caucasian male was found unresponsive by his wife. He had white foam around his mouth and was pronounced dead shortly thereafter. He had a history of back pain and was treated with intrathecal morphine because of his previous addiction to oral opiate medications. Because of crimping of the pump catheter, it was replaced 4 days before his death. Toxicological findings included urine screen positive for amitriptyline, nortriptyline, opiates, hydrocodone metabolites, ibuprofen, acetaminophen, caffeine, nicotine, and metabolite. Drug concentrations were as follows: blood, 0.260 mg/L amitriptyline, 0.160 mg/L nortriptyline, 0.460 mg/L unconjugated morphine, and 0.624 mg/L total morphine; vitreous humor, 0.034 mg/L unconjugated morphine and 0.080 mg/L total morphine; and cerebrospinal fluid, 0.099 mg/L unconjugated morphine and 0.095 mg/L total morphine. Shortly after death, the volume of the residual pump reservoir was only 8 mL instead of the expected 17 mL. Testing by the FDA showed that the pump was functional. The residual content of the pump accounted for only 230 mg instead of the expected 488 mg. The high blood-morphine concentrations did not correlate with the intrathecal infusion dose. The symptoms were consistent with opiate overdose, possibly by injection of morphine withdrawn from the pump reservoir. The cause of death was determined to be fatal morphine self-intoxication, and the manner of death was accidental. This case is intended to alert regulatory agencies, pain management health professionals, pathologists, and toxicologists to the abuse potential of one of the newer analgesic-delivery systems. PMID:10192419

  1. Dopamine-dependent responses to morphine depend on glucocorticoid receptors

    PubMed Central

    Marinelli, Michela; Aouizerate, Bruno; Barrot, Michel; Le Moal, Michel; Piazza, Pier Vincenzo

    1998-01-01

    Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 μg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction. PMID:9636221

  2. Buprenorphine-based regimens and methadone for the medical management of opioid dependence: selecting the appropriate drug for treatment.

    PubMed

    Maremmani, Icro; Gerra, Gilberto

    2010-01-01

    Maintenance therapy with methadone or buprenorphine-based regimens reduces opioid dependence and associated harms. The perception that methadone is more effective than buprenorphine for maintenance treatment has been based on low buprenorphine doses and excessively slow induction regimens used in early buprenorphine trials. Subsequent studies show that the efficacy of buprenorphine sublingual tablet (Subutex®) or buprenorphine/naloxone sublingual tablet (Suboxone®) is equivalent to that of methadone when sufficient buprenorphine doses, rapid induction, and flexible dosing are used. Although methadone remains an essential maintenance therapy option, buprenorphine-based regimens increase access to care and provide safer, more appropriate treatment than methadone for some patients. PMID:20958853

  3. Potentiation of morphine analgesia by caffeine.

    PubMed Central

    Misra, A. L.; Pontani, R. B.; Vadlamani, N. L.

    1985-01-01

    Significant potentiation of morphine (5 mg kg-1 s.c. or 1 mg kg-1 i.v.) analgesia (tail-withdrawal reflex at 55 degrees C) was observed in caffeine-treated (100 mg kg-1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg-1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation. PMID:4005485

  4. Potentiation of morphine analgesia by caffeine.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1985-04-01

    Significant potentiation of morphine (5 mg kg-1 s.c. or 1 mg kg-1 i.v.) analgesia (tail-withdrawal reflex at 55 degrees C) was observed in caffeine-treated (100 mg kg-1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg-1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation. PMID:4005485

  5. A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee.

    PubMed

    Spierings, Egilius L H; Fidelholtz, James; Wolfram, Gernot; Smith, Michael D; Brown, Mark T; West, Christine R

    2013-09-01

    Tanezumab is a humanized monoclonal antinerve growth factor antibody in development for treatment of chronic pain. In a phase III, placebo- and active-controlled study, we investigated the efficacy and safety of tanezumab for osteoarthritis (OA) hip or knee pain. Patients (N=610) received up to 2 doses of intravenous tanezumab (5 or 10mg in 8-week intervals), controlled-release oral oxycodone (10 to 40 mg every 12 hours), or placebo. The primary endpoint was mean change from baseline to week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain score for tanezumab versus placebo and oxycodone. Secondary endpoints included change from baseline in WOMAC Physical Function and Stiffness scores, Patient's Global Assessment (PGA) of OA, and patient response, defined as ≥ 30%, ≥ 50%, ≥ 70%, and ≥ 90% improvement from baseline in WOMAC Pain score. Tolerability and safety also were assessed. Both tanezumab groups demonstrated significant improvements in WOMAC Pain score versus placebo (P<.001) and oxycodone (P ≤.018). Tanezumab also provided significant improvements versus placebo and oxycodone for WOMAC Physical Function and Stiffness scores and PGA of OA (P ≤.002 for all) at week 8. For all analyses, oxycodone did not differ from placebo. Adverse event frequency was higher with oxycodone (63.3%) than tanezumab (40.7% to 44.7%) or placebo (35.5%); serious adverse event frequency was similar among treatments. The adverse event profile for tanezumab was similar to previous tanezumab studies. Results indicate that tanezumab is efficacious in the treatment of OA pain; no new safety signals were identified.

  6. Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

    PubMed

    Setnik, Beatrice; Bramson, Candace; Bass, Almasa; Levy-Cooperman, Naama; Malhotra, Bimal; Matschke, Kyle; Sommerville, Kenneth W; Wolfram, Gernot; Geoffroy, Pierre

    2015-12-01

    ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2  h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2  h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2  h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

  7. Postoperative morphine requirements, nausea and vomiting following anaesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques.

    PubMed

    Mather, S J; Peutrell, J M

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be as effective as opioid analgesia following tonsillectomy in children. Opioids are still frequently used but tonsillectomy is associated with a high incidence of vomiting. This study has attempted to assess postoperative analgesic consumption and nausea and vomiting after general anaesthesia for tonsillectomy using either paracetamol premedication, paracetamol plus a NSAID or intravenous morphine to provide postoperative analgesia. Some children required a rescue dose of morphine in the recovery room, including some who had received intravenous morphine at induction. Least supplementary morphine was required by those who had received paracetamol plus ketorolac. Postoperative nausea and vomiting was significantly less in the two groups which were not given intraoperative morphine. The number of vomiting incidents was also much less. We conclude that the preoperative administration of paracetamol alone provides satisfactory analgesia in many children but that supplementary analgesia is still required for some.

  8. Postoperative morphine requirements, nausea and vomiting following anaesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques.

    PubMed

    Mather, S J; Peutrell, J M

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be as effective as opioid analgesia following tonsillectomy in children. Opioids are still frequently used but tonsillectomy is associated with a high incidence of vomiting. This study has attempted to assess postoperative analgesic consumption and nausea and vomiting after general anaesthesia for tonsillectomy using either paracetamol premedication, paracetamol plus a NSAID or intravenous morphine to provide postoperative analgesia. Some children required a rescue dose of morphine in the recovery room, including some who had received intravenous morphine at induction. Least supplementary morphine was required by those who had received paracetamol plus ketorolac. Postoperative nausea and vomiting was significantly less in the two groups which were not given intraoperative morphine. The number of vomiting incidents was also much less. We conclude that the preoperative administration of paracetamol alone provides satisfactory analgesia in many children but that supplementary analgesia is still required for some. PMID:7489439

  9. Treatment of Failed Back Surgery Syndrome in a Forty-Three-Year-Old Man With High-Dose Oxycodone/Naloxone

    PubMed Central

    Bujedo, Borja Mugabure

    2015-01-01

    Introduction: Failed back surgery syndrome (FBSS) is an increasing cause of chronic pain in most countries. This poses high costs to both patients and National Health Organizations. Case Presentation: In this report, multimodal pain management based on daily high-dose oxycodone/naloxone (OXN 180/90 mg) led to reduced patient's pain score and improved quality of life. Conclusions: Oxycodone/naloxone can be a good alternative for the management of FBSS when other interventional or pharmacologic strategies have failed. In this case report, higher doses than those recommended as a maximum daily ceiling (80/40 mg) were safely used in one selected patient with noncancer severe pain. PMID:25893186

  10. Modeling the Frequency and Costs Associated with Postsurgical Gastrointestinal Adverse Events for Tapentadol IR versus Oxycodone IR

    PubMed Central

    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

  11. Barriers to Telephone Quitline Use Among Methadone-Maintained Smokers

    PubMed Central

    Griffin, Judith L.; Segal, Kate S.

    2015-01-01

    Introduction: Drug users have high rates of tobacco use and tobacco-related disease. Telephone quitlines promote smoking cessation, but their reach among drug users is unknown. We thus aimed to assess utilization of and barriers to telephone quitlines among methadone-maintained smokers. Methods: Subjects were opioid-dependent smokers in Bronx, New York, methadone treatment programs who were enrolled in a clinical trial of varenicline. All subjects were offered referral to a free, proactive quitline. We examined quitline records, surveyed barriers to quitline use, and queried reasons for declining referral. Results: Of the 112 subjects enrolled, 47% were male, 54% were Hispanic, and 28% were Black. All subjects were offered referral, and 25 (22% of study participants) utilized the quitline. Quitline utilizers (vs. nonutilizers) were significantly more likely to have landline phone service (72 vs. 42%, p = .01), interest in quitline participation (92 vs. 62%, p < .01), and willingness to receive calls (96 vs. 76%, p = .02). Nonutilizers were significantly more likely to report cell phone service lapse (38 vs. 14%, p = .04), and difficulty charging cell phones (19 vs. 0%, p = .02). Reasons for quitline refusal included: (a) skepticism of quitline efficacy; (b) aversion to telephone communication; (c) competing life demands (e.g., drug treatment, shelter); and (d) problems with cell phone service or minutes. Conclusions: Despite several limitations to quitline access among methadone-maintained smokers, routine quitline referral was associated with 22% utilization. To expand provision of smoking cessation treatment to opioid-dependent smokers, interventions to promote routine quitline referral in substance abuse treatment programs warrant investigation. PMID:26180217

  12. Effect of Bacopasides on acquisition and expression of morphine tolerance.

    PubMed

    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.

  13. Morphine tolerance offers protection from radiogenic performance deficits

    SciTech Connect

    Mickley, G.A.; Stevens, K.E.; Burrows, J.M.; White, G.A.; Gibbs, G.L.

    1983-02-01

    When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad /sup 60/Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation.

  14. Changes in morphine reward in a model of neuropathic pain.

    PubMed

    Cahill, Catherine M; Xue, Lihua; Grenier, Patrick; Magnussen, Claire; Lecour, Samantha; Olmstead, Mary C

    2013-06-01

    In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states.

  15. Buprenorphine and methadone for opioid addiction during pregnancy.

    PubMed

    Mozurkewich, Ellen L; Rayburn, William F

    2014-06-01

    Buprenorphine and methadone are opioid-receptor agonists used as opioid substitution therapy during pregnancy to limit exposure of the fetus to cycles of opioid withdrawal and reduce the risk of infectious comorbidities of illicit opioid use. As part of a comprehensive care plan, such therapy may result in improved access to prenatal care, reduced illicit drug use, reduced exposure to infections associated with intravenous drug use, and improved maternal nutrition and infant birth weight. This article describes differences in patient selection between the two drugs, their relative safety during pregnancy, and changes in daily doses as a guide for prescribing clinicians.

  16. Morphine dependence and withdrawal induced changes in cholinergic signaling

    PubMed Central

    Neugebauer, Nichole M.; Einstein, Emily B.; Lopez, Maria B.; McClure-Begley, Tristan D.; Mineur, Yann S.; Picciotto, Marina R.

    2013-01-01

    Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]-epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of β4-containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4 mg/kg) and lobeline (3 mg/kg) decreased jumping behavior while mecamylamine (1 mg/kg) had no effect. Knock-down of β4 subunit-containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. PMID:23651795

  17. Effectiveness of Methadone Maintenance Therapy and Improvement in Quality of Life Following a Decade of Implementation.

    PubMed

    Teoh Bing Fei, Joni; Yee, Anne; Habil, Mohamad Hussain Bin; Danaee, Mahmoud

    2016-10-01

    Methadone maintenance therapy has been found to be an effective harm reduction treatment for opioid use disorder. However evidence of its benefits over a longer duration of treatment is limited as most studies focus on its short term benefits. As methadone maintenance therapy reaches a decade since its implementation in Malaysia, this study sought to examine the effectiveness of methadone treatment, change in quality of life among patients since entry to methadone treatment, as well as factors predicting the magnitude of change in quality of life. This study found that methadone maintenance therapy was effective in reducing heroin use, injecting practices and crime, and in improving in social functioning and physical symptoms, but not in reducing sex-related HIV risk-taking behavior. Though patients had a significantly better quality of life at follow-up than at entry to methadone maintenance therapy, the improvement in quality of life was not significantly greater as the duration of treatment increased. Age above 50 years old, human immunodeficiency virus (HIV) positive status and physical symptoms predicted a poorer improvement in quality of life between baseline and follow-up. On the other hand, patients with hepatitis B showed a greater improvement in quality of life in the social relationships domain compared to patients without hepatitis B. In conclusion, methadone maintenance therapy is an effective treatment for opioid use disorder and improves quality of life but its benefits in further improving quality of life beyond a decade of treatment need further evaluation. PMID:27568510

  18. A Retrospective Evaluation of Inpatient Transfer from High-Dose Methadone to Buprenorphine Substitution Therapy.

    PubMed

    Oretti, Rossana

    2015-10-01

    The product license of buprenorphine/naloxone for opioid substitution therapy indicates reducing methadone concentrations to 30 mg or less per day for a minimum of 1 week before transferring patients to buprenorphine and no sooner than 24 hours after the last methadone dose, because of the risk of precipitated withdrawal and a corresponding high risk of relapse to opioid use. There are few studies describing high-dose methadone transfers. This retrospective case review assessed the feasibility of transferring patients on methadone doses above 30 mg/day to buprenorphine or buprenorphine/naloxone in the inpatient setting. Six of seven patients on 60-120 mg/day of methadone successfully completed the transfer, and four cases tested negative for opiates at long-term follow-up (6-15 months). This suggests that methadone transfer to buprenorphine can be performed rapidly without the need to taper methadone doses in patients indicated for a therapeutic switch. This small study is hypothesis-generating; larger, well-designed trials are needed to define a protocol that can be used routinely to improve and widen transfers to buprenorphine when indicated.

  19. Effectiveness of Methadone Maintenance Therapy and Improvement in Quality of Life Following a Decade of Implementation.

    PubMed

    Teoh Bing Fei, Joni; Yee, Anne; Habil, Mohamad Hussain Bin; Danaee, Mahmoud

    2016-10-01

    Methadone maintenance therapy has been found to be an effective harm reduction treatment for opioid use disorder. However evidence of its benefits over a longer duration of treatment is limited as most studies focus on its short term benefits. As methadone maintenance therapy reaches a decade since its implementation in Malaysia, this study sought to examine the effectiveness of methadone treatment, change in quality of life among patients since entry to methadone treatment, as well as factors predicting the magnitude of change in quality of life. This study found that methadone maintenance therapy was effective in reducing heroin use, injecting practices and crime, and in improving in social functioning and physical symptoms, but not in reducing sex-related HIV risk-taking behavior. Though patients had a significantly better quality of life at follow-up than at entry to methadone maintenance therapy, the improvement in quality of life was not significantly greater as the duration of treatment increased. Age above 50 years old, human immunodeficiency virus (HIV) positive status and physical symptoms predicted a poorer improvement in quality of life between baseline and follow-up. On the other hand, patients with hepatitis B showed a greater improvement in quality of life in the social relationships domain compared to patients without hepatitis B. In conclusion, methadone maintenance therapy is an effective treatment for opioid use disorder and improves quality of life but its benefits in further improving quality of life beyond a decade of treatment need further evaluation.

  20. Nurse case management program of chronic pain patients treated with methadone.

    PubMed

    Lamb, Louise; Pereira, John Xavier; Shir, Yoram

    2007-09-01

    Methadone treatment in chronic pain patients is still limited owing to misconceptions about addiction, safety, and its unique pharmacokinetic and pharmacodynamic properties. Nevertheless, patients with chronic noncancer pain are frequently treated with methadone at our Pain Centre either as the first opioid of choice, for specific pain conditions, or as a second-line opioid in patients developing tolerance or intractable side effects with other opioids. The aim of this study was to examine whether a nurse case management program of chronic pain patients treated with methadone is feasible and safe in trying to improve patients' care in an ambulatory setting. This program consisted of three phases: initial primary education session, telephone follow-up during methadone titration, and a subsequent maintenance period. The nurse case manager functioned autonomously and when required reported to and consulted the physician. The study included 75 subjects and was done over a nine-month period by completing follow-up questionnaires for every call. Of a total of 194 recorded calls, 41% were unscheduled. Forty-four percent of phone calls resulted in a methadone increase and 11% led to a decrease or cessation of methadone. No patients developed serious morbidity or mortality. Fifty-seven percent of patients were either satisfied or very satisfied with their treatment. A nurse-led case management program of methadone in chronic pain patients can improve patient care in an ambulatory setting. PMID:17723930

  1. The effects of methadone treatment on the reactivity of the nonstress test.

    PubMed

    Archie, C L; Lee, M I; Sokol, R J; Norman, G

    1989-08-01

    The effect of methadone treatment on the nonstress test (NST) was studied. Thirty narcotic-addicted gravidas on methadone maintenance underwent NSTs, performed and interpreted in a standard manner, before and 1 hour after taking the usual methadone dose. Urines were screened for commonly abused substances on the day of testing. Mean gestation when tested was 34 weeks and mean methadone dose was 26 mg/day. All urines were positive for methadone, six for cocaine, two for opiates, and one for amphetamines. The reactivity of the NSTs performed 1 hour after methadone ingestion was decreased significantly compared with that of tests performed before medication (P less than .04). Decreases in the frequencies of fetal movements and fetal heart rate accelerations were significant (P less than .001 and P less than .01, respectively). These results suggest that methadone treatment altered the morphology of the NST, which may limit the reliability of this test for determining fetal well-being in these high-risk gravidas if time of medication is not taken into consideration.

  2. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

    SciTech Connect

    Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.; Sotoudeh, M.; Ghazi-Khansari, M.

    2008-10-01

    Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.

  3. Recent Advances in the Synthesis of Morphine and Related Alkaloids

    NASA Astrophysics Data System (ADS)

    Chida, Noritaka

    Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

  4. 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.

  5. Effects of morphine and naloxone on feline colonic transit

    SciTech Connect

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred.

  6. Cholescintigraphy in acute cholecystitis: use of intravenous morphine

    SciTech Connect

    Choy, D.; Shi, E.C.; McLean, R.G.; Hoschl, R.; Murray, I.P.C.; Ham, J.M.

    1984-04-01

    Conventional cholescintigraphy (60 patients) and a modified protocol (59 patients) were compared in 74 females and 45 males with acute cholecystitis. In the modified protocol, intravenous morphine was administered whenever the gallbladder was not seen 40 minutes after injection of Tc-99m-pyroxylidene-glutamate. Accuracy was 98% with morphine, compared with 88% for the conventional protocol; specificity improved from 83% to 100% with no loss of sensitivity. Low doses of morphine are well tolerated and can result in a highly accurate diagnosis of acute cholecystitis without the need for delayed imaging.

  7. Rates of Fetal Polydrug Exposures in Methadone-Maintained Pregnancies from a High-Risk Population

    PubMed Central

    Delano, Kaitlyn; Gareri, Joey; Koren, Gideon

    2013-01-01

    Methadone maintenance treatment (MMT) is the standard of care during pregnancy for opioid-dependency, showing efficacy in improving prenatal care and reducing risk of relapse. By design, however, MMT is only intended to prevent withdrawal thus facilitating cognitive behavioural interventions. In order to maximize the benefits of MMT, it is essential that methadone is both properly prescribed and that additional addiction treatment is concurrently administered. This study aims to determine the effectiveness of MMT engagement in high-risk pregnant women in reducing polydrug use by objective laboratory examination of neonatal meconium. Patients and Methods Over a 29-month period, the Motherisk Laboratory at the Hospital for Sick Children in Toronto analyzed meconium samples as per request by social services and hospitals for drugs of abuse. Results Of the 904 meconium samples received, 273 were tested for methadone with 164 positive and 109 negative for methadone. Almost half of the methadone positive samples (46.34%) were also positive for at least one other opioid compound, which did not differ statistically from the methadone-negative control samples (46.79%; Chi square test, p=0.94). No differences were found between the methadone positive and negative groups in rates of concurrent amphetamines, cocaine, cannabis, and alcohol use indicating a similar risk of polydrug use between pregnant women taking or not taking methadone in this population. Discussion The high rates of additional opioid and other drug use in the MMT group, suggest that MMT is failing this population of patients. It is possible that methadone doses during pregnancy are not appropriately adjusted for changes in pharmacokinetic parameters (e.g. blood volume, renal function) during the second and third trimesters. This may result in sub-therapeutic dosing creating withdrawal symptoms leading to additional substance use. Alternatively, these results may be demonstrating a substantial lack in

  8. Pain management by a new series of dual inhibitors of enkephalin degrading enzymes: long lasting antinociceptive properties and potentiation by CCK2 antagonist or methadone.

    PubMed

    Le Guen, Stéphanie; Mas Nieto, Magdalena; Canestrelli, Corinne; Chen, Huixiong; Fournié-Zaluski, Marie-Claude; Cupo, Annie; Maldonado, Rafaël; Roques, Bernard P; Noble, Florence

    2003-07-01

    The discovery that the endogenous morphine-like peptides named enkephalins are inactivated by two metallopeptidases, neutral endopeptidase and aminopeptidase N, which can be blocked by dual inhibitors, represents a promising way to develop 'physiological' analgesics devoid of the side effects of morphine. A new series of dual aminophosphinic inhibitors of the two enkephalin-catabolizing enzymes has been recently designed. In this study, one of these inhibitors, RB3007, was tested in various assays commonly used to select analgesics (mouse hot-plate test, rat tail-flick test, writhing and formalin tests in mice, and paw pressure test in rats), and the extracellular levels of the endogenous enkephalins in the ventrolateral periaqueductal grey have been measured by microdialysis after systemic administration of RB3007. In the mouse hot-plate test, the dual inhibitor induced long-lasting (2 h) antinociceptive effects with a maximum of 35% analgesia 60 min after i.v. or i.p. administration. These antinociceptive responses were antagonized by prior injection of naloxone (0.1 mg/kg, s.c.). Similar long lasting effects were observed in the other animal models used. Very interestingly, injection of RB3007 (50 mg/kg, i.p.) significantly increased (82%) the extracellular levels of Met-enkephalin with a peak 60 min after i.p. injection. This increase parallels the antinociceptive responses observed. In addition, strong facilitatory effects of subanalgesic doses of the CCK(2) receptor antagonist, PD-134,308 or the synthetic opioid agonist, methadone on RB3007-induced antinociceptive responses were observed. These findings may constitute promising data for future development of a new class of analgesics that could be of major interest in a number of severe and persistent pain syndromes.

  9. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant mu-opioid receptor.

    PubMed

    He, Li; Kim, Joseph A; Whistler, Jennifer L

    2009-12-01

    Growing evidence shows that trafficking of the mu-opioid receptor (MOR) is a critical process in functional recovery from desensitization following activation and plays important roles in morphine tolerance and dependence largely because of the failure of morphine to promote such trafficking. However, morphine tolerance and dependence are believed to be mediated by multiple mechanisms, including well-documented biochemical changes in cAMP activity, N-methyl-D-aspartate receptors (NMDARs), glucocorticoid receptors (GRs), and c-fos. Here, we assess the consequences of promoting morphine-induced endocytosis on these biochemical changes utilizing a knock-in mouse model, RMOR, in which MORs undergo morphine-induced endocytosis. Chronic morphine treatment of wild-type (WT) mice promoted superactivation of adenylyl cyclase, alterations in NMDARs, and up-regulation of GR and c-fos in distinct brain regions. Notably, none of these biochemical changes occurred in the RMOR-knock-in mice. Together, these data demonstrate that morphine tolerance and dependence are mediated by multiple biochemical mechanisms and that MOR endocytosis plays a critical role in each of these mechanisms.

  10. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain.

    PubMed

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup; Drewes, Asbjørn Mohr; Christrup, Lona Louring; Kreilgaard, Mads

    2015-07-10

    Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.

  11. A Pilot Study of the Nutritional Status of Opiate Abusing Pregnant Women on Methadone Maintenance Therapy

    PubMed Central

    Tomedi, Laura E.; Bogen, Debra; Hanusa, Barbara H.; Wisner, Katherine L.; Bodnar, Lisa M.

    2011-01-01

    Pregnant women in methadone maintenance therapy may have poor nutrition during pregnancy. In 2006–2008, methadone treated pregnant women (n = 22) were recruited at an urban academic medical center and compared with non-drug using pregnant women (n = 119) at 20–35 weeks gestation. We measured adiposity using pre-pregnancy body mass index (BMI), dietary intake using a food frequency questionnaire, and micronutrient and essential fatty acid status using biomarkers. Methadone treated women had lower BMI, consumed more calories, had lower serum carotenoid concentrations and higher plasma homocysteine concentrations than controls. The study’s limitations and implications for future research are discussed. PMID:22217127

  12. Long-Term Methadone Intake and Genotoxicity in Addicted Patients

    PubMed Central

    Rezaei, Mohsen; Khodaei, Forouzan; Sayah Bargard, Mehdi; Abasinia, Mahsa

    2015-01-01

    Background: It is well known that contact with some physical, chemical or biological compounds can increase the incidence of mutation. Among these compounds, are pharmaceuticals that meet long duration of use and potentially could be misused and taken more than the ordered dosage. Objectives: The aim of this study was to evaluate mutagenic effect of methadone in addicted patients referred to Imam Khomeini Hospital in Ahvaz by single cell gel electrophoresis technic or comet assay. Patients and Methods: In this study, 90 subjects were divided into dichromate treated group, no treated healthy volunteers group and test group. Each group included 30 subjects. Screening was performed according to questionnaire and qualified subjects were entered the study. Blood samples were collected and lymphocytes were isolated, mixed with low melting point agarose for slide preparation according to standard method. Slides were analyzed using fluorescence microscope and comet patterns were assessed. Results: The mutagenicity index in addicted group was robustly higher than healthy volunteers. Fortunately, this significant difference was lower than positive control. Conclusions: Genome instability in addicted patients was demonstrated in this study. Controversially, considering incoherent results of previous studies and our data, more studies in longer duration of methadone use are needed to elucidate the consequence. PMID:25866713

  13. Correlates of alcohol use among methadone-maintained adults.

    PubMed

    Nyamathi, Adeline; Cohen, Allan; Marfisee, Mary; Shoptaw, Steven; Greengold, Barbara; de Castro, Viviane; George, Daniel; Leake, Barbara

    2009-04-01

    This prospective study (n=190) examined correlates of alcohol use from baseline data of a longitudinal trial conducted among moderate and heavy alcohol users receiving methadone maintenance therapy (MMT). The sample included MMT clients who were 18-55 years of age, and were receiving MMT from five large methadone maintenance clinics in the Los Angeles area. Half of the sample was heavy drinkers and nearly half (46%) reported heroin use. Using a structured questionnaire, correlates of heavy alcohol use included White and Hispanic ethnicity, and fair or poor physical health combined with older age (> or =50 years). We also found that MMT clients who were younger than 50 years, regardless of health status, were more likely to be heavy drinkers. Compared with moderate alcohol consumers, a greater number of heavy alcohol users also experienced recent victimization. To optimize MMT, alcohol screening should be part of routine assessment and alcohol treatment should be made available within MMT programs. Moreover, special consideration should be provided to the most vulnerable clients, such as the younger user, those with a long-term and current history of heavy drug use, and those victimized and reporting fair or poor health. In addition, promoting attention to general physical and mental health problems within MMT programs may be beneficial in enhancing health outcomes of this population.

  14. Intimate partner violence among individuals in methadone maintenance treatment

    PubMed Central

    de Dios, Marcel A.; Anderson, Bradley J.; Caviness, Celeste M.; Stein, Michael

    2013-01-01

    Background Intimate partner violence (IPV) is a highly prevalent and concerning problem among methadone maintenance populations, and previous studies have shown a relationship between a history of IPV and increased substance use and affective disturbances. Methods The current study examined 1) the association between recent IPV victimization and alcohol and cocaine use and 2) the relationship between recent IPV victimization and depression in a sample of smokers (n=203) in methadone maintenance treatment (MMT). Participants in this study completed a battery of assessments that included standard questionnaires of trauma, alcohol and substance use, and depression. Parallel logistic and linear regression models were used to estimate the adjusted association of IPV victimization and depressive symptoms and evaluate the adjusted association of victimization with recent substance use. Results Participants recently victimized by partners were shown to have significantly higher mean CES-D scores (b = 0.54, 95%CI 0.07; 1.02, p < .05) and were found to have a 6 times greater likelihood of cocaine use (OR = 6.65, 95%CI 1.61; 27.46, p < .01) after controlling for age, gender, education, opiate use and ethnicity. Conclusions These findings support the notion that IPV victimization can potentially increase depression and other substance use among MMT patients, which can have a deleterious impact on treatment. PMID:24821357

  15. [Controlled release oxycodone--a new option in the treatment of severe and very severe pain. Review of studies on neuropathic, physical activity-related and postoperative pain].

    PubMed

    Stiehl, M

    2004-08-01

    Opioids are used not only in the treatment of cancer pain, but also pain of non-malignant genesis. In recent years, the efficacy of controlled release (CR) oxycodone in the treatment of the above-mentioned types of pain has been investigated in a number of clinical studies. The present article reviews the clinical studies that have been already published. Thanks to its outstanding pharmacological and pharmacodynamic properties, CR oxycodone is fast acting and brings about long lasting pain relief, coupled with benefits for physical and mental activities. This results in a significant quality-of-life improvement. Oral therapy with CR oxycodone is safe and can be precisely controlled. Since there are no clinical relevant metabolites, there is no danger of accumulation in patients with renal infarction due to these metabolites. Side effects are those typical for opioids, and are readily manageable. CR oxycodone is a good alternative in the treatment of non-cancer pain and can be recommended as first-line treatment for the above-mentioned indications. PMID:16739361

  16. Morphine withdrawal, treatments 1900-30.

    PubMed

    Malcolm, M T

    1999-03-01

    The treatments used between 1900 and 1930 for morphine withdrawal are discussed. The accounts are mainly taken from contemporary textbooks which contain fascinating descriptions of their authors' preferred methods and criticisms of regimes given by other therapists. Delirium, produced by atropine or similar substances, is advocated to cover withdrawal symptoms. The present paper draws parallels with current issues, e.g. withdrawal of opiate under cover of general anaesthesia, follow-up studies and cost-benefit analyses. The particular problems of addicted doctors in 1900-1930 are addressed as are the comparisons then made with non-medically qualified addicts. It is important we keep in mind past mistakes and over-valued ideas so as to reduce any similarly misplaced optimism in our current treatment options. PMID:11623818

  17. Spinal morphine anesthesia and urinary retention.

    PubMed

    Mahan, K T; Wang, J

    1993-11-01

    Spinal anesthetic is a common form of surgical anesthetic used in foot and ankle surgery. Spinal morphine anesthetic is less common, but has the advantage of providing postoperative analgesia for 12 to 24 hr. A number of complications can occur with spinal anesthesia, including urinary retention that may be a source of severe and often prolonged discomfort and pain for the patient. Management of this problem may require repeated bladder catheterization, which may lead to urinary tract infections or impairment of urethrovesicular function. This study reviews the incidence of urinary retention in 80 patients (40 after general anesthesia and 40 after spinal anesthesia) who underwent foot and ankle surgery at Saint Joseph's Hospital, Philadelphia, PA. Twenty-five percent of the patients who had spinal anesthesia experienced urinary retention, while only 7 1/2% of the group who had general anesthesia had this complication. Predisposing factors, treatment regimen, and recommendations for the prevention and management of urinary retention are presented.

  18. Reduced nocturnal morphine analgesia in mice following a geomagnetic disturbance.

    PubMed

    Ossenkopp, K P; Kavaliers, M; Hirst, M

    1983-10-10

    Latency to respond to an aversive thermal stimulus and the degree of analgesia induced by morphine were examined in mice injected with either isotonic saline or morphine sulfate (10 mg/kg) during midscotophase of a 12:12 h LD cycle. When mean response latencies were compared to the degree of geomagnetic disturbance (Ap index) present on test days, it was found that during the geomagnetic storm on December 17th, 1982, a significant reduction (P less than 0.01) in response latency was evident in both saline- and morphine-treated mice. The reduction in response latencies was greater, and lasted longer in the morphine-treated animals. It is suggested that the pineal gland may mediate this biomagnetic effect. PMID:6646507

  19. Increased brain uptake of morphine in the presence of the antihistamine tripelennamine.

    PubMed

    Vadlamani, N L; Pontani, R B; Misra, A L

    1984-01-01

    Disposition of [6 3H (N)]morphine in plasma, brain and liver of rats was studied 15 min after intravenous injection of either a 2 mg kg-1 dose of morphine or a combination of the same dose of morphine with a 6 mg kg-1 dose of tripelennamine. The concentrations of morphine in brain and the brain to plasma morphine ratios in animals receiving the combination of drugs concurrently were significantly higher than those in the control morphine group. No significant differences were seen in the morphine or morphine metabolite concentrations in plasma and liver or liver to plasma morphine concentration ratios in the 2 groups. Data suggest that pharmacokinetic factors play a role in the potentiation of opiate effects by antihistamine on concurrent i.v. administration of the two drugs. PMID:6141270

  20. Expression of spinal cord GABA transporter 1 in morphine-tolerant male Wistar rats.

    PubMed

    Shokoofeh, Siroosi; Homa, Manaheji; Leila, Dargahi; Samira, Daniali

    2015-11-15

    Chronic morphine exposure produces morphine tolerance. One of the mechanisms of morphine tolerance involves γ-aminobutric acid (GABA), whose level is regulated by GABA transporter 1 (GAT-1). The aim of this study was to investigate the expression of GAT-1 in the spinal cord during morphine treatment. Morphine was administrated to rats via drinking water for 21 days. On day 21, a single dose of morphine (10mg/kg) was injected, followed by the administration of 5% formalin after 30 min. Expression of GAT-1 in the lumbar spinal cord during morphine treatment was analyzed by Western blotting and immunohistochemistry assay. In another set of experiments, a morphine-tolerant group was treated with a GAT-1 inhibitor, ethyl nipecotate (60 mg/kg), 5 min prior to the formalin test. To assess a possible analgesic effect of the GAT-1 inhibitor, a non-tolerant group was injected only with ethyl nipecotate 5 min prior to the formalin test. Our results indicated that a chronic consumption of morphine led to morphine tolerance. Morphine tolerance was also concomitant with GAT-1 up-regulation in the lumbar spinal cord. The GAT-1 inhibitor ethyl nipecotate improved the antinociceptive effect of morphine in the morphine-tolerant group. Ethyl nipecotate also had an antinociceptive effect on the non-tolerant group. Thus, our data suggest that GAT-1 overexpression in the spinal cord plays an important role in morphine tolerance.

  1. A Comparison of Morphine Delivery in Neonatal Opioid Withdrawal

    PubMed Central

    Chisamore, Brian; Labana, Safaa; Blitz, Sandra; Ordean, Alice

    2016-01-01

    Current estimates of the prevalence of opioid withdrawal in newborns from the 2012 Better Outcomes Registry and Network Ontario reveal that more than 4 births per 1000 display recognizable symptoms of neonatal abstinence syndrome (NAS). With a growing consensus surrounding aspects of newborn opioid withdrawal care, clinicians might agree that all infants exposed to maternal opioids require supportive observation and care to ensure appropriate adaptation and growth in the newborn period and, likewise, that there exists a smaller percentage of newborns who require additional pharmacotherapy. However, due to the dearth of comparative studies of NAS tools, there remains a lack of evidence to support the use of a specific NAS method of scoring or treatment. Two types of NAS treatment protocols currently in use include a symptom-only versus weight-based protocols. Our Neonatal Intensive Care Unit (NICU) has used both models. A formal structured NAS tool and weight-based morphine delivery system began in our NICU in 1999. We audited all newborns with known exposure to maternal opioids in our NICU from the years 2000 to 2014. The Finnegan scoring tool was used throughout all years of the chart audit. Modifications made to the Finnegan scoring tool from the MOTHER study were adapted for use in our NICU at the same time as adopting the Johns Hopkins model of symptom-only based morphine delivery in 2006. The objective of this comparative study using a retrospective chart audit is to compare length of stay (LOS) and total accumulative morphine dose across these two morphine delivery protocols. Our audit revealed that there were a significantly higher proportion of newborns in the symptom-only model that received morphine and, perhaps accordingly, also had a significantly higher LOS compared to those in the weight-based model. Comparing only those infants who did receive morphine, the comparative total accumulative dose of morphine and LOS were not significantly different

  2. A Comparison of Morphine Delivery in Neonatal Opioid Withdrawal

    PubMed Central

    Chisamore, Brian; Labana, Safaa; Blitz, Sandra; Ordean, Alice

    2016-01-01

    Current estimates of the prevalence of opioid withdrawal in newborns from the 2012 Better Outcomes Registry and Network Ontario reveal that more than 4 births per 1000 display recognizable symptoms of neonatal abstinence syndrome (NAS). With a growing consensus surrounding aspects of newborn opioid withdrawal care, clinicians might agree that all infants exposed to maternal opioids require supportive observation and care to ensure appropriate adaptation and growth in the newborn period and, likewise, that there exists a smaller percentage of newborns who require additional pharmacotherapy. However, due to the dearth of comparative studies of NAS tools, there remains a lack of evidence to support the use of a specific NAS method of scoring or treatment. Two types of NAS treatment protocols currently in use include a symptom-only versus weight-based protocols. Our Neonatal Intensive Care Unit (NICU) has used both models. A formal structured NAS tool and weight-based morphine delivery system began in our NICU in 1999. We audited all newborns with known exposure to maternal opioids in our NICU from the years 2000 to 2014. The Finnegan scoring tool was used throughout all years of the chart audit. Modifications made to the Finnegan scoring tool from the MOTHER study were adapted for use in our NICU at the same time as adopting the Johns Hopkins model of symptom-only based morphine delivery in 2006. The objective of this comparative study using a retrospective chart audit is to compare length of stay (LOS) and total accumulative morphine dose across these two morphine delivery protocols. Our audit revealed that there were a significantly higher proportion of newborns in the symptom-only model that received morphine and, perhaps accordingly, also had a significantly higher LOS compared to those in the weight-based model. Comparing only those infants who did receive morphine, the comparative total accumulative dose of morphine and LOS were not significantly different

  3. Urinary excretion of morphine and biosynthetic precursors in mice

    PubMed Central

    Grobe, Nadja; Lamshöft, Marc; Orth, Robert G.; Dräger, Birgit; Kutchan, Toni M.; Zenk, Meinhart H.; Spiteller, Michael

    2010-01-01

    It has been firmly established that humans excrete a small but steady amount of the isoquinoline alkaloid morphine in their urine. It is unclear whether it is of dietary or endogenous origin. There is no doubt that a simple isoquinoline alkaloid, tetrahydropapaveroline (THP), is found in human and rodent brain as well as in human urine. This suggests a potential biogenetic relationship between both alkaloids. Unlabeled THP or [1,3,4-D3]-THP was injected intraperitoneally into mice and the urine was analyzed. This potential precursor was extensively metabolized (96%). Among the metabolites found was the phenol-coupled product salutaridine, the known morphine precursor in the opium poppy plant. Synthetic [7D]-salutaridinol, the biosynthetic reduction product of salutaridine, injected intraperitoneally into live animals led to the formation of [7D]-thebaine, which was excreted in urine. [N-CD3]-thebaine was also administered and yielded [N-CD3]-morphine and the congeners [N-CD3]-codeine and [N-CD3]-oripavine in urine. These results show for the first time that live animals have the biosynthetic capability to convert a normal constituent of rodents, THP, to morphine. Morphine and its precursors are normally not found in tissues or organs, presumably due to metabolic breakdown. Hence, only that portion of the isoquinoline alkaloids excreted in urine unmetabolized can be detected. Analysis of urine by high resolution-mass spectrometry proved to be a powerful method for tracking endogenous morphine and its biosynthetic precursors. PMID:20421505

  4. Urinary excretion of morphine and biosynthetic precursors in mice.

    PubMed

    Grobe, Nadja; Lamshöft, Marc; Orth, Robert G; Dräger, Birgit; Kutchan, Toni M; Zenk, Meinhart H; Spiteller, Michael

    2010-05-01

    It has been firmly established that humans excrete a small but steady amount of the isoquinoline alkaloid morphine in their urine. It is unclear whether it is of dietary or endogenous origin. There is no doubt that a simple isoquinoline alkaloid, tetrahydropapaveroline (THP), is found in human and rodent brain as well as in human urine. This suggests a potential biogenetic relationship between both alkaloids. Unlabeled THP or [1,3,4-D(3)]-THP was injected intraperitoneally into mice and the urine was analyzed. This potential precursor was extensively metabolized (96%). Among the metabolites found was the phenol-coupled product salutaridine, the known morphine precursor in the opium poppy plant. Synthetic [7D]-salutaridinol, the biosynthetic reduction product of salutaridine, injected intraperitoneally into live animals led to the formation of [7D]-thebaine, which was excreted in urine. [N-CD(3)]-thebaine was also administered and yielded [N-CD(3)]-morphine and the congeners [N-CD(3)]-codeine and [N-CD(3)]-oripavine in urine. These results show for the first time that live animals have the biosynthetic capability to convert a normal constituent of rodents, THP, to morphine. Morphine and its precursors are normally not found in tissues or organs, presumably due to metabolic breakdown. Hence, only that portion of the isoquinoline alkaloids excreted in urine unmetabolized can be detected. Analysis of urine by high resolution-mass spectrometry proved to be a powerful method for tracking endogenous morphine and its biosynthetic precursors.

  5. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

    PubMed

    Khor, Beng-Siang; Jamil, Mohd Fadzly Amar; Adenan, Mohamad Ilham; Shu-Chien, Alexander Chong

    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

  6. Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish

    PubMed Central

    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

  7. Comparative evaluation of morphine, pentazocine and ciramadol in postaddicts.

    PubMed

    Preston, K L; Bigelow, G E; Liebson, I A

    1987-03-01

    The subjective, physiological and behavioral effects of morphine, pentazocine and ciramadol, an opioid agonist/antagonist, were studied in adult male nondependent opioid abusers living on a clinical research ward. Fifteen subjects were assigned randomly to one of three groups. Each group received, by i.m. injection, placebo and three doses of one active drug, twice in randomized block order under double-blind conditions in 4.5-hr experimental sessions. Physiological measures did not differentiate between the three drugs. All three drugs decreased respiratory rate and pupil diameter and increased blood pressure. However, morphine, ciramadol and pentazocine produced different profiles on the subjective effect measures. All three drugs increased "liking," "good effects," "any effects" and "high" subjective effect scales. Pentazocine increased subjective "bad effects" scale scores and scales measuring dysphoria and sedation. Observers reported significant behavioral changes after administration of morphine and pentazocine, but not after ciramadol. Overall, the effects of morphine (7.5, 15 and 30 mg) and pentazocine (22.5, 45 and 90 mg) were dose-related. Although pentazocine produced increases in scales that indicated negative subjective effects, it also produced significant changes in most self-report measures that were increased by morphine, including liking and good effects scales. The effects of ciramadol were not dose-related, with all three doses (30, 60 and 120 mg) producing effects approximately equivalent to morphine 15 mg. Thus, ciramadol exhibited a ceiling effect typical of the opioid agonist/antagonist.

  8. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

    PubMed

    Khor, Beng-Siang; Jamil, Mohd Fadzly Amar; Adenan, Mohamad Ilham; Shu-Chien, Alexander Chong

    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.

  9. Protective effect of crocin on liver toxicity induced by morphine.

    PubMed

    Salahshoor, Mohammad Reza; Khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  10. Protective effect of crocin on liver toxicity induced by morphine

    PubMed Central

    Salahshoor, Mohammad Reza; khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  11. Treadmill running reverses retention deficit induced by morphine.

    PubMed

    Alaei, Hojjatallah; Borjeian, Lila; Azizi, Mohammad; Orian, Shahrbanoo; Pourshanazari, Aliasghar; Hanninen, Osmo

    2006-04-24

    Human and animal studies have suggested that exercise has benefits overall health and cognitive function. The aim of this study was to investigate the effect of treadmill running on passive avoidance learning and memory deficit in morphine-treated rats. The passive avoidance learning was measured in different time intervals (1, 2 and 24 h as well as 1 week and 1 month). Four groups of rats were included as follows: control, morphine-treated, exercised-saline and exercised-morphine-treated group. The electrical foot shock and treadmill training (2 h at a speed of 5 m/min for 10 days) were applied for all the groups. The data obtained was analyzed using unpaired Students t-test and ANOVA test with group as the independent variable, and performance in each session (avoidances and crossings) as the dependent variables. The results show that the total time staying in dark box was decreased in exercised-saline and exercised-morphine-treated rats by treadmill running (P<0.05). The avoidance learning was significantly reduced in morphine-treated group as indicated by the increased total time of staying in the dark box compared with the control group (P<0.05). We could conclude that exercise increased the delay time of entry to the dark electrical foot shock box, suggesting that morphine impaired the short-term memory and learning and this was reversed by the treadmill running.

  12. Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

    PubMed

    Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

    2014-09-01

    We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance

  13. Sex effects in cocaine using methadone patients randomized to contingency management interventions

    PubMed Central

    Burch, Ashley E.; Rash, Carla J.; Petry, Nancy M.

    2015-01-01

    Contingency management (CM) is an effective treatment for promoting cocaine abstinence in patients receiving methadone maintenance. However, few studies have examined the effect of sex on treatment outcomes in this population. This study evaluated the impact of sex on longest duration of abstinence (LDA) and percent negative urine samples in 323 cocaine-using methadone patients from four randomized clinical trials comparing CM to standard methadone care. Overall, women had better treatment outcomes compared to men, demonstrated by an increase in both LDA and percentages of negative samples. Patients receiving CM also had significantly higher LDA and percentages of negative samples compared to patients receiving standard care, but sex by treatment condition effects were not significant. These data suggest that cocaine using methadone patients who are women have better substance use outcomes than men in interventions that regularly monitor cocaine use, and CM is equally efficacious regardless of sex. PMID:26237326

  14. QT Interval Screening in Methadone Maintenance Treatment: Report of a SAMHSA Expert Panel

    PubMed Central

    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

  15. Methadone block of K+ current in squid giant fiber lobe neurons.

    PubMed

    Horrigan, F T; Gilly, W F

    1996-02-01

    Voltage-dependent ionic currents were recorded from squid giant fiber lobe neurons using the whole-cell patch-clamp technique. When applied to the bathing solution, methadone was found to block IK, I Na and I Ca. Both I Na and I Ca were reduced without apparent change in kinetics and exhibited IC(50)'s of 50-100 and 250-500 mu M, respectively, at +10 mV. In contrast, IK was reduced in a time-dependent manner that is well fit by a simple model of open channel block (K(D)= 32+/- or 2 mu M, +60 mV, 10 degrees Celsius). The mechanism of I(K) block was examined in detail and involves a direct action of methadone, a tertiary amine, on K channels rather than an opioid receptor-mediated pathway. The kinetics of I(K) block resemble those reported for internally applied long chain quaternary ammonium (QA) compounds; and recovery from I(K) block is QA-like in its slow time course and strong dependence on holding potential. A quaternary derivative of methadone (N-methyl-methadone) only reproduced the effects of methadone on I(K) when included in the pipette solution; this compound was without effect when applied externally. I(K) block thus appears to involve diffusion of methadone into the cytoplasm and occlusion of the open K channel at the internal QA blocking site by the protonated form of the drug. This proposed mode of action is supported by the pH and voltage dependence of block as well as by the observation that high external K+ speeds the rate of drug dissociation. In addition, the effect of methadone on I(K) evoked during prolonged (300 ms) depolarizations suggests that methadone block may interfere with endogenous K+ channel inactivation. The effects of temperature, methadone stereoisomers, and the methadone-like drugs propoxyphene and nor-propoxyphene on IK block were examined. Methadone was also found to block I(K) in GH3 cells and in chick myoblasts.

  16. Methadone block of K+ current in squid giant fiber lobe neurons

    PubMed Central

    1996-01-01

    Voltage-dependent ionic currents were recorded from squid giant fiber lobe neurons using the whole-cell patch-clamp technique. When applied to the bathing solution, methadone was found to block IK, I Na and I Ca. Both I Na and I Ca were reduced without apparent change in kinetics and exhibited IC(50)'s of 50-100 and 250-500 mu M, respectively, at +10 mV. In contrast, IK was reduced in a time-dependent manner that is well fit by a simple model of open channel block (K(D)= 32+/- or 2 mu M, +60 mV, 10 degrees Celsius). The mechanism of I(K) block was examined in detail and involves a direct action of methadone, a tertiary amine, on K channels rather than an opioid receptor-mediated pathway. The kinetics of I(K) block resemble those reported for internally applied long chain quaternary ammonium (QA) compounds; and recovery from I(K) block is QA-like in its slow time course and strong dependence on holding potential. A quaternary derivative of methadone (N-methyl- methadone) only reproduced the effects of methadone on I(K) when included in the pipette solution; this compound was without effect when applied externally. I(K) block thus appears to involve diffusion of methadone into the cytoplasm and occlusion of the open K channel at the internal QA blocking site by the protonated form of the drug. This proposed mode of action is supported by the pH and voltage dependence of block as well as by the observation that high external K+ speeds the rate of drug dissociation. In addition, the effect of methadone on I(K) evoked during prolonged (300 ms) depolarizations suggests that methadone block may interfere with endogenous K+ channel inactivation. The effects of temperature, methadone stereoisomers, and the methadone- like drugs propoxyphene and nor-propoxyphene on IK block were examined. Methadone was also found to block I(K) in GH3 cells and in chick myoblasts. PMID:8833344

  17. Rapid determination of methadone and its major metabolite in biological fluids by gas-liquid chromatography with thermionic detection for maintenance treatment of opiate addicts.

    PubMed

    Chikhi-Chorfi, N; Pham-Huy, C; Galons, H; Manuel, N; Lowenstein, W; Warnet, J M; Claude, J R

    1998-11-01

    A rapid gas-liquid chromatographic assay is developed for the quantification of methadone (Mtd) and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in biological fluids of opiate addicts. After alkaline extraction from samples with lidocaine hydrochloride as internal standard, Mtd and EDDP are separated on SP-2250 column at 220 degrees C and detected with a thermionic detector. The chromatographic time is about 6 min. The relative standard deviations (R.S.D.) of Mtd and EDDP standards are between 1.5 and 5.5%. Most drugs of abuse (morphine, codeine, narcotine, cocaine, benzoylecgonine, cocaethylene, dextropropoxyphene etc) are shown not to interfere with this technique. The method has been applied to study the levels of Mtd and EDDP metabolite in serum, saliva and urine of patients under maintenance treatment for opiate dependence. EDDP levels were found higher than those of Mtd in urine samples from four treated patients, but lower in serum and undetectable in saliva. However, Mtd concentrations were higher in saliva than in serum.

  18. Highly selective electrode for potentiometric analysis of methadone in biological fluids and pharmaceutical formulations.

    PubMed

    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. PMID:27040192

  19. A Study of Methadone-Poisoned Children Referred to Hamadan’s Besat Hospital/Iran

    PubMed Central

    BAZMAMOUN, Hassan; FAYYAZi, Afshin; KHAJEH, Ali; SABZEHEI, Mohammad Kazem; KHEZRIAN, Fuzieh

    2014-01-01

    Objective Increasing use of methadone in withdrawal programs has increased methadone poisoning in children. This research aimed to study the causes of incidence of poisoning in children and its side-effects. Materials & Methods In this research, The hospital records of all methadone-poisoned children referred to Hamadan’s Be’sat Hospital from June 2007 to March 2013, were studied. Children with a definite history of methadone use or proven existence of methadone in their urine, were studied. Results During 5 years, 62 children with the mean age of 53.24±29.50 months were hospitalized due to methadone use. There was a significant relationship between delayed referral to hospital and increased bradypnea. According to their history, 25.8% and 58.1% of the children had been poisoned by methadone tablet and syrup, respectively. The most common initial complaint expressed by parents, was decreased consciousness (85.5%). During the initial examination, decreased consciousness, meiosis, and respiratory depression were observed in 91.9%, 82.3%, and 69.4% of the cases, respectively. Nine patients required mechanical ventilation. There was a significant relationship between the need for mechanical ventilation and seizure with initial symptom of emesis. There were two cases of death (3.2%), both of which were secondary to prolonged hypoxia and brain death. There was a significant relationship between poor patient prognosis (death) and presence of cyanosis in early symptoms, seizure, hypotension, duration of decreased consciousness, and duration of mechanical ventilation. Conclusion This research indicated that the occurrence of seizure, hypotension, and cyanosis in the early stages of poisoning is associated with an increased risk of side effects and death and are serious warning signs. Early diagnosis and intervention can improve outcomes of methadone-poisoned children. PMID:24949049

  20. Trans-stilbene oxide administration increased hepatic glucuronidation of morphine but decreased biliary excretion of morphine glucuronide in rats

    SciTech Connect

    Fuhrman-Lane, C.; Fujimoto, J.M.

    1982-09-01

    The effect of the inducing agent trans-stilbene oxide (TSO) on the metabolism and biliary excretion of (/sup 14/C)morphine was studied in the isolated in situ perfused rat liver. After administration of morphine by intraportal injection or by the segmented retrograde intrabiliary injection technique, the TSO-treated group showed a marked decrease in the biliary recovery of morphine as its glucuronide conjugate (morphine-3-glucuronide (MG)). However, recovery of MG in the venous outflow of the single pass perfusate was greatly increased. These findings suggested that TSO treatment enhanced the formation of MG from morphine and changed the primary route of hepatic elimination of MG. TSO treatment also decreased the excretion of morphine (as MG) in the bile of anesthetized renal-ligated rats. This decreased biliary function required several days to develop and appeared closely associated with the inductive effect of TSO. After i.v. administration of (/sup 14/C)MG itself, biliary recovery was also markedly decreased in TSO-treated rats. It is postulated that the effect of the TSO treatment led to either a decrease in canalicular transport of MG into bile or an increase in the efficiency of transfer of MG to the blood at the sinusoidal side of the hepatocyte. Regardless of the mechanism, the results indicate the need to study compartmentalization of drug transport and metabolism functions.

  1. Combined morphine-bupivacaine caudals for reconstructive penile surgery in children: systemic absorption of morphine and postoperative analgesia.

    PubMed

    Wolf, A R; Hughes, D; Hobbs, A J; Prys-Roberts, C

    1991-02-01

    We wished to determine if the addition of a small dose of morphine (0.05 mg.kg-1) to a caudal solution of 0.25% bupivacaine could extend the duration of analgesia after major reconstructive penile surgery and also to measure the systemic absorption of morphine after caudal injection. Thirty children undergoing reconstructive penile surgery received a caudal injection of 0.25% bupivacaine 0.75 ml.kg-1 with or without morphine 0.05 mg.kg-1. All patients awoke pain-free, but eight of the fifteen patients receiving bupivacaine alone required supplementary injections of opioid postoperatively, whereas none of the patients receiving the bupivacaine-morphine mixture required additional opioids. The incidence of side-effects was similar for the two groups. Morphine was absorbed rapidly after caudal injection to reach a peak plasma level of 21.2 (+/- 4.8) ng.ml-1 at ten minutes and then fell to 10.1 (+/- 3.8) ng.ml-1 at one hour and 4.1 (+/- 2.6) ng.ml-1 at three hours. These levels are low compared with plasma levels associated with systemic analgesia. We conclude that the extended duration of analgesia from morphine 0.05 mg/kg given caudally is due at least in part to specific spinal analgesia. PMID:2012289

  2. Correlates of illicit methadone use in New York City: A cross-sectional study

    PubMed Central

    Ompad, Danielle C; Fuller, Crystal M; Chan, Christina A; Frye, Victoria; Vlahov, David; Galea, Sandro

    2008-01-01

    Background Despite growing concern about illicit methadone use in the US and other countries, there is little data about the prevalence and correlates of methadone use in large urban areas. We assessed the prevalence and examined correlates of lifetime and recent illicit methadone use in New York City (NYC). Methods 1,415 heroin, crack, and cocaine users aged 15–40 years were recruited in NYC between 2000 and 2004 to complete interviewer-administered questionnaires. Results In multivariable logistic regression, non-injection drug users who used illicit methadone were more likely to be heroin dependent, less than daily methamphetamine users and to have a heroin using sex partner in the last two months. Injection drug users who used illicit methadone were more likely to use heroin daily, share injection paraphernalia and less likely to have been in a detoxification program and to have not used marijuana in the last six months. Conclusion The results overall suggest that illicit (or street) methadone use is likely not a primary drug of choice, but is instead more common in concert with other illicit drug use. PMID:18957116

  3. Laeve-[1-3H]Methadone disposition in tolerant dogs.

    PubMed

    Misra, A L; Bloch, R; Vadlamani, N L; Mulé, S J

    1975-04-01

    1. Following a subcutaneous dose (4mg/kg) of [3H]methadone, peak levels of drug occurred in plasma, tissues and selected areas of the central nervous system (CNS) 2h after injection in both non-tolerant and tolerant dogs. Highest concentrations of methadone were attained in bile and lung compared to other tissues. 2. Levels of methadone in plasma, tissue and CNS of tolerant and non-tolerant animals were not markedly different up to 8h after injection, but a much faster rate of egression of free drug (lower t1/2) was observed subsequently in tolerant dogs. 3. Peak levels of methadone in various areas of the CNS ranged between 2-7 (spinal cord) to 3-6 (thalamus) mug/g in non-tolerant and 3-0 -rebellum) to 4-1 (thalamus) mug/g in tolerant dogs 2h after injection. No marked accumulation of methadone occurred in selected areas of the CNS in spite of the persistence of drug in these areas. 4. The plasma protein electrophoretic profiles did not differ between control, non-tolerant and tolerant dogs. 5. Similar qualitative patterns of metabolites were observed in non-tolerant and tolerant dogs and the development of tolerance did not appear to modify the metabolic pathways of methadone. PMID:1154803

  4. Effects of regulation on methadone and buprenorphine provision in the wake of Hurricane Sandy.

    PubMed

    McClure, Bridget; Mendoza, Sonia; Duncan, Laura; Rotrosen, John; Hansen, Helena

    2014-10-01

    Hurricane Sandy led to the closing of many major New York City public hospitals including their substance abuse clinics and methadone programs, and the displacement or relocation of thousands of opioid-dependent patients from treatment. The disaster provided a natural experiment that revealed the relative strengths and weaknesses of methadone treatment in comparison to physician office-based buprenorphine treatment for opioid dependence, two modalities of opioid maintenance with markedly different regulatory requirements and institutional procedures. To assess these two modalities of treatment under emergency conditions, semi-structured interviews about barriers to and facilitators of continuity of care for methadone and buprenorphine patients were conducted with 50 providers of opioid maintenance treatment. Major findings included that methadone programs presented more regulatory barriers for providers, difficulty with dose verification due to impaired communication, and an over reliance on emergency room dosing leading to unsafe or suboptimal dosing. Buprenorphine treatment presented fewer regulatory barriers, but buprenorphine providers had little to no cross-coverage options compared to methadone providers, who could refer to alternate methadone programs. The findings point to the need for well-defined emergency procedures with flexibility around regulations, the need for a central registry with patient dose information, as well as stronger professional networks and cross-coverage procedures. These interventions would improve day-to-day services for opioid-maintained patients as well as services under emergency conditions.

  5. The relative risk of fatal poisoning by methadone or buprenorphine within the wider population of England and Wales

    PubMed Central

    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

  6. Factor analytic study of the personality of female methadone outpatients.

    PubMed

    Duthie, R B

    1980-10-01

    Several researchers have examined the personality of chemical abusers by employing a multivariate clustering strategy. All of these studies focused on hospitalized inpatient addicts. Only one included females in the study. The purpose of this study is to examine the transposed data factor analytically derived profiles of female methadone maintained outpatients. All clients were given the Mini-Mult short form version of the Minnesota Multiphasic Personality Inventory. Seventy profiles were randomly selected from 130 female profiles. Program Factor of the Analyses of Behavioral Sciences Data program series was employed in statistically processing this data. Descriptions of the five factors are provided. Most of the profile types seem to fall into the normal or personality disordered categories. Forth-two percent of the profiles were normal, 24% were Personality Disorders, 6% were Neurotic, and 28% were unclassified using five factors.

  7. Forced withdrawal from methadone maintenance therapy in criminal justice settings: a critical treatment barrier in the United States.

    PubMed

    Fu, Jeannia J; Zaller, Nickolas D; Yokell, Michael A; Bazazi, Alexander R; Rich, Josiah D

    2013-01-01

    The World Health Organization classifies methadone as an essential medicine, yet methadone maintenance therapy remains widely unavailable in criminal justice settings throughout the United States. Methadone maintenance therapy is often terminated at the time of incarceration, with inmates forced to withdraw from this evidence-based therapy. We assessed whether these forced withdrawal policies deter opioid-dependent individuals in the community from engaging methadone maintenance therapy in two states that routinely force inmates to withdraw from methadone (N = 205). Nearly half of all participants reported that concern regarding forced methadone withdrawal during incarceration deterred them engaging methadone maintenance therapy in the community. Participants in the state where more severe methadone withdrawal procedures are used during incarceration were more likely to report concern regarding forced withdrawal as a treatment deterrent. Methadone withdrawal policies in the criminal justice system may be a broader treatment deterrent for opioid-dependent individuals than previously realized. Redressing this treatment barrier is both a health and human rights imperative. PMID:23433809

  8. Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

    PubMed Central

    Fonseca, Francina; de la Torre, Rafael; Díaz, Laura; Pastor, Antonio; Cuyàs, Elisabet; Pizarro, Nieves; Khymenets, Olha; Farré, Magí; Torrens, Marta

    2011-01-01

    Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements. PMID:21589866

  9. Morphine Self-Administration following Spinal Cord Injury

    PubMed Central

    Malik, Jamal S.; Aceves, Miriam; Hook, Michelle A.

    2014-01-01

    Abstract Neuropathic pain develops in up to two-thirds of people following spinal cord injury (SCI). Opioids are among the most effective treatments for this pain and are commonly prescribed. There is concern surrounding the use of these analgesics, however, because use is often associated with the development of addiction. Previous data suggests that this concern may not be relevant in the presence of neuropathic pain. Yet, despite the common prescription of opioids for the treatment of SCI-related pain, there has been only one previous study examining the addictive potential of morphine following spinal injury. To address this, the present study used a self-administration paradigm to examine the addictive potential of morphine in a rodent model of SCI. Animals were placed into self-administration chambers 24 h, 14 d, or 35 d following a moderate spinal contusion injury. They were placed into the chambers for seven 12-hour sessions with access to 1.5 mg morphine/lever depression (up to 30 mg/d). In the acute phase of SCI, contused animals self-administered significantly less morphine than their sham counterparts, as previously shown. However, contused animals showing signs of neuropathic pain did not self-administer less morphine than their sham counterparts when administration began 14 or 35 d after injury. Instead, these animals administered nearly the full amount of morphine available each session. This amount of morphine did not affect recovery of locomotor function but did cause significant weight loss. We suggest caution is warranted when prescribing opioids for the treatment of neuropathic pain resulting from SCI, as the addictive potential is not reduced in this model. PMID:24827476

  10. Purification and characterization of guinea pig liver morphine 6-dehydrogenase.

    PubMed

    Yamano, S; Kageura, E; Ishida, T; Toki, S

    1985-05-10

    Morphine 6-dehydrogenase, which catalyzes the dehydrogenation of morphine to morphinone, has been purified about 440-fold from the soluble fraction of guinea pig liver with a yield of 38%. The purified enzyme was a homogeneous protein on polyacrylamide gel disc electrophoresis and isoelectric focusing. The molecular weight and isoelectric point of the enzyme were 29,000 and 7.6, respectively. The enzyme utilizes both NAD and NADP as a cofactor, and the Km values were 0.12 mM for NAD and 0.42 mM for NADP. The Vmax values for morphine were 588 milliunits/mg of protein (with NAD) and 1600 milliunits/mg of protein (with NADP). The Km values for morphine were 0.12 mM (with NAD) and 0.49 mM (with NADP). The enzyme also exhibited activity for morphine-related compounds: nalorphine, normorphine, codeine, and ethylmorphine; however, 7,8-saturated congeners such as dihydromorphine and dihydrocodeine were poor substrates. The enzyme was inactivated by removal of 2-mercaptoethanol from the enzyme solution. The inactivated enzyme was rapidly recovered by the addition of 2-mercaptoethanol. Phenylarsine oxide and CdCl2 (dithiol modifiers) inhibited competitively toward cofactor binding and noncompetitively toward morphine binding. These results suggest that the enzyme possesses the essential thiol groups, probably vicinal dithiol, at or near the cofactor-binding site. Using the partially purified enzyme, 8-(2-hydroxyethylthio)dihydromorphinone was isolated as the product and identified by UV, mass, and NMR spectra. It was confirmed that morphinone proposed as the dehydrogenation product was nonenzymatically and covalently bound to 2-mercaptoethanol. Accordingly, the isolated morphinone-2-mercaptoethanol conjugate must be formed by two steps: enzymatic production of morphinone from morphine and then nonenzymatic binding of 2-mercaptoethanol to morphinone. PMID:2580834

  11. Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics

    PubMed Central

    Vaidya, Naveen K.; Ribeiro, Ruy M.; Perelson, Alan S.; Kumar, Anil

    2016-01-01

    Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses. Based on the small sample size Akaike information criterion, these models were inferior to the new model based on changes in co-receptor expression. The model with morphine affecting co-receptor expression agrees well with the experimental data from simian immunodeficiency virus infections in morphine-addicted macaques. Our results show that morphine promotes a target cell subpopulation switch from a lower level of susceptibility to a state that is about 2-orders of magnitude higher in susceptibility to SIV infection. As a result, the proportion of target cells with higher susceptibility remains extremely high in morphine conditioning. Such a morphine-induced population switch not only has adverse effects on the replication rate, but also results in a higher steady state viral load and larger CD4 count drops. Moreover, morphine conditioning may pose extra obstacles to controlling viral load during antiretroviral therapy, such as pre-exposure prophylaxis and post infection treatments. This study provides, for the first time, a viral dynamics model, viral dynamics parameters, and related analytical and simulation results for SIV dynamics under drugs of abuse. PMID:27668463

  12. High-throughput simultaneous analysis of buprenorphine, methadone, cocaine, opiates, nicotine, and metabolites in oral fluid by liquid chromatography tandem mass spectrometry

    PubMed Central

    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

  13. High-throughput simultaneous analysis of buprenorphine, methadone, cocaine, opiates, nicotine, and metabolites in oral fluid by liquid chromatography tandem mass spectrometry.

    PubMed

    Concheiro, Marta; Gray, Teresa R; Shakleya, Diaa M; Huestis, Marilyn A

    2010-09-01

    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

  14. Involvement of histaminergic system in the discriminative stimulus effects of morphine.

    PubMed

    Mori, Tomohisa; Narita, Minoru; Onodera, Kenji; Suzuki, Tsutomu

    2004-05-01

    The interactions between morphine and the histaminergic system are not yet fully clarified. More especially, the involvement of the histaminergic system in the discriminative stimulus effects of morphine has not been determined. Therefore, the effects of histamine-related compounds on the discriminative stimulus effects of morphine were examined in rats. Combination tests using histamine-related compounds with morphine were initiated in rats trained to discriminate between 3.0 mg/kg morphine and saline. Zolantidine (central histamine H2-receptor antagonist), but not pyrilamine (central histamine H1-receptor antagonist) or ranitidine (peripheral histamine H2-receptor antagonist), significantly attenuated the discriminative stimulus effects of morphine. The histamine precursor L-histidine significantly potentiated the discriminative stimulus effects of morphine. These results suggest that the discriminative stimulus effects of morphine are, at least in part, mediated through the central activation of histamine H2-receptors in rats.

  15. Methadone induction in primary care (ANRS-Methaville): a phase III randomized intervention trial

    PubMed Central

    2012-01-01

    Background In France, the rapid scale-up of buprenorphine, an opioid maintenance treatment (OMT), in primary care for drug users has led to an impressive reduction in HIV prevalence among injecting drug users (IDU) but has had no major effect on Hepatitis C incidence. To date, patients willing to start methadone can only do so in a methadone clinic (a medical centre for drug and alcohol dependence (CSAPA) or a hospital setting) and are referred to primary care physicians after dose stabilization. This study aims to assess the effectiveness of methadone in patients who initiated treatment in primary care compared with those who initiated it in a CSAPA, by measuring abstinence from street opioid use after one year of treatment. Methods/Design The ANRS-Methaville study is a randomized multicenter non-inferiority control trial comparing methadone induction (lasting approximately 2 weeks) in primary care and in CSAPA. The model of care chosen for methadone induction in primary care was based on study-specific pre-training of all physicians, exclusion criteria and daily supervision of methadone during the initiation phase. Between January 2009 and January 2011, 10 sites each having one CSAPA and several primary care physicians, were identified to recruit patients to be randomized into two groups, one starting methadone in primary care (n = 147), the other in CSAPA (n = 48). The primary outcome of the study is the proportion of participants abstinent from street opioids after 1 year of treatment i.e. non-inferiority of primary care model in terms of the proportion of patients not using street opioids compared with the proportion observed in those starting methadone in a CSAPA. Discussion The ANRS-Methaville study is the first in France to use an interventional trial to improve access to OMT for drug users. Once the non-inferiority results become available, the Ministry of Health and agency for the safety of health products may change the the New Drug Application

  16. Sexual Dysfunction in Men Receiving Methadone Maintenance Treatment: Clinical History and Psychobiological Correlates.

    PubMed

    Gerra, Gilberto; Manfredini, Matteo; Somaini, Lorenzo; Maremmani, Icro; Leonardi, Claudio; Donnini, Claudia

    2016-01-01

    A variety of studies evidenced a relationship between drug use disorders and sexual dysfunction. In particular, heroin and opioid agonist medications to treat heroin dependence have been found to be associated with erectile dysfunction and reduced libido. Controversial findings also indicate the possibility of factors other than the pharmacological effects of opioid drugs concurring to sexual dysfunction. With the present study, we investigated the link between sexual dysfunction and long-term exposure to opioid receptor stimulation (heroin dependence, methadone maintenance treatment, methadone dosage), the potentially related hormonal changes reflecting hypothalamus-pituitary-gonadal axis function and prolactin (PRL) pituitary release, the role of adverse childhood experiences in the clinical history and the concomitant symptoms of comorbid mental health disorders in contributing to sexual problems. Forty male patients participating in a long-term methadone treatment program were included in the present study and compared with 40 healthy control subjects who never used drugs nor abused alcohol. All patients and controls were submitted to the Arizona Sexual Experiences Scale (ASEX), Child Experiences of Care and Abuse-Questionnaire (CECA-Q) and the Symptom Check List-90 Scale. A blood sample for testosterone and PRL assays was collected. Methadone dosages were recorded among heroin-dependent patients on maintenance treatment. Methadone patients scored significantly higher than controls on the 5-item rating ASEX scale, on CECA-Q and on Symptoms Check List 90 (SCL 90) scale. Testosterone plasma levels were significantly lower and PRL levels significantly higher in methadone patients with respect to the healthy control group. ASEX scores reflecting sexual dysfunction were directly and significantly correlated with CECA-Q neglect scores and SCL 90 psychiatric symptoms total score. The linear regression model, when applied only to addicted patients, showed that

  17. The use of liquid chromatography/mass spectrometry for quantitative analysis of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue.

    PubMed

    Boström, Emma; Jansson, Britt; Hammarlund-Udenaes, Margareta; Simonsson, Ulrika S H

    2004-01-01

    Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

  18. Extended-release morphine sulfate in treatment of severe acute and chronic pain

    PubMed Central

    Balch, Robert J; Trescot, Andrea

    2010-01-01

    Morphine is the archetypal opioid analgesic. Because it is a short-acting opioid, its use has been limited to the management of acute pain. The development of extended-release formulations have resulted in the increased utilization of morphine in chronic pain conditions. This review documents the history of morphine use in pain treatment, and describes the metabolism, pharmacodynamics, formulations, and efficacy of the currently available extended-release morphine medications. PMID:21197323

  19. The Effect of Acute and Chronic Morphine on Some Blood Biochemical Parameters in an Inflammatory Condition in Gonadectomized Male Rats

    PubMed Central

    Chahkandi, Mohadeseh; Askari, Nayerreh; Asadikaram, Gholamreza

    2015-01-01

    Background Opiates affect blood factors as well as pain and inflammation in a gender-dependent manner. The aim of the present study was to evaluate the effects of morphine on serum glucose, cholesterol, triglycerides, and urea in gonadectomized and inflammation conditions. Methods Animals were divided as follows: control group, carrageenan and chronic morphine recipients, acute morphine recipients, chronic morphine recipients, carrageenan recipients, acute morphine and carrageenan recipients, gonadectomized group, gonadectomized recipients of carrageenan, gonadectomized recipients of morphine, gonadectomized recipients of chronic morphine, gonadectomized recipients of carrageenan and chronic morphine, gonadectomized recipients of acute morphine and carrageenan. Findings Our results have shown that acute and chronic morphine elevates blood glucose level in the acute and chronic morphine group. Cholesterol level has shown to be increasing in the morphine and carrageenan recipient group compared with a group which merely received morphine. Triglyceride has shown to be decreasing in acute and chronic morphine recipient group compared with control group. A significant increase in serum urea was observed in acute and chronic morphine recipients compared with the carrageenan recipient group. Conclusion Morphine alters the serum glucose, cholesterol, triglyceride, and urea in the normal and inflammatory conditions differently, hence, this finding should be considered in the patients who use morphine as a relief of pain, especially in an inflammatory condition. PMID:26885349

  20. Fangchinoline inhibited the antinociceptive effect of morphine in mice.

    PubMed

    Fang, L H; Zhang, Y H; Ku, B S

    2005-03-01

    Fangchinoline (FAN), a non-specific calcium antagonist, is a major alkaloidal component of the creeper Stephania tetrandra S. Moore (or fenfangji). It has been shown to possess antagonistic activity on morphine-induced antinociception in mice. This study was undertaken to assess the antagonistic mechanism. The results demonstrated that FAN (IP) attenuated morphine (SC)-induced antinociception in a dose-dependent manner with significant effect at doses of 30 and 60mg/kg body wt. (IP) in the tail-flick test but not the tail-pinch tests, carried out in mice. This antagonism was abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan (5-HTP, IP), but not by pretreatment with a noradrenaline precursor, L-dihydroxyphenylalanine (L-DOPA, IP) in the tail-flick test. On the other hand, the development of morphine-induced analgesic tolerance was not prevented by FAN. These results suggest that the serotonergic pathway may be involved in the antagonism of morphine-induced antinociception by FAN and, in agreement with other reports, also indicates the possible dissociation of the morphine analgesic effect from its tolerance-development mechanism. PMID:15830839

  1. Narp regulates long-term aversive effects of morphine withdrawal

    PubMed Central

    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

  2. Effect of morphine on sympathetic nerve activity in humans

    NASA Technical Reports Server (NTRS)

    Carter, Jason R.; Sauder, Charity L.; Ray, Chester A.

    2002-01-01

    There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 +/- 2 to 22 +/- 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 +/- 2 to 91 +/- 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 +/- 4 to 59 +/- 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug x exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.

  3. Effect of linalool on morphine tolerance and dependence in mice.

    PubMed

    Hosseinzadeh, Hossein; Imenshahidi, Mohsen; Hosseini, Mohammadreza; Razavi, Bibi Marjan

    2012-09-01

    Linalool, a terpene alcohol, has been shown to interact with the opioid system and N-methyl-D-aspartate (NMDA) receptor. Therefore, the effect of linalool on morphine dependence and tolerance was studied. Dependence and tolerance were induced in mice using subcutaneous morphine injections, three times a day (50, 50 and 75 mg/kg /day) for 3 days. To evaluate the effect of agents on the induction of morphine dependence and tolerance, linalool (50, 75 and 100 mg/kg), clonidine (positive control), alpha-2 receptor agonist, (0.1 mg/kg), memantine, NMDA receptor antagonist (positive control), (30 mg/kg) and saline were injected intraperitoneally three times a day for 3 days. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The effect of linalool and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). The tolerance was evaluated by the tail-flick test. The results showed that linalool in the induction and expression phase increased the nociception threshold. Linalool (48% and 95.6% at doses 75 and 100 mg/kg, respectively), clonidine and memantine reduced the severity of withdrawal signs in the induction and expression phases. This study indicated that linalool has a significant effect on morphine tolerance and dependence. This effect may be mediated partially through the inhibition of NMDA receptors.

  4. The effect of morphine on fear extinction in rats.

    PubMed

    Morris, M D; Gebhart, G F

    1978-05-31

    Rats were trained on an appetitive discretetrial discriminated-punishment task in which they learned to suppress responding when an intense flashing light predicting punishment was present and to respond rapidly on trials when the flashing light was absent. Once animals were performing discriminatively, 0.75, 3.0, or 6.0 mg/kg of morphine (base) was administered and a fear extinction session consisting of 60 nonshocked presentations of the flashing light was given. Two saline control groups, one that received fear extinction and one that did not, were also included in the experiment. On the day following fear extinction, all rats were tested in the undrugged state on the discriminated punishment problem, but without shock. The rats receiving 3.0 and 6.0 mg/kg of morphine before the fear extinction session were suppressed by the flashing light more than the saline extinction group or the 0.75 mg/kg morphine treatment group. Moreover, the two higher dose morphine groups were suppressed as readily as the saline group that received no fear extinction. These results are attributed to the antiemotionality effects of morphine. PMID:97707

  5. Variables associated with perceived sleep disorders in methadone maintenance treatment (MMT) patients.

    PubMed

    Peles, Einat; Schreiber, Shaul; Adelson, Miriam

    2006-04-28

    To characterize sleep disorders in methadone maintenance treatment (MMT) patients, we evaluated sleep quality of 101 non-selective patients from our MMT clinic in Israel between July, 2003 and July, 2004 by using the self-report questionnaire Pittsburgh Sleep Quality Index (PSQI). Patients' urine tests were analyzed for methadone metabolite, opiates, benzodiazepine, cocaine, cannabis and amphetamines. Their urine results for drug abuse throughout the months prior to filling in the questionnaire and their maintenance methadone doses were recorded. Drug abuse was defined by at least one positive urine test. Methadone serum levels were available in 55 patients, assessed by Gas Chromatography Mass Spectroscopy. The patients' self-reported chronic pain questionnaires and their diagnosed psychiatric disorders were analyzed. Out of the 101 study patients, 78.2% were male, 52.5% had psychiatric disorders, 46.5% reported having chronic pain and 46.5% had positive urine for benzodiazepine. The mean daily methadone dose was 157+/-52.9 mg. The mean PSQI score was 9+/-4.8 (75.2% had scores >5 indicating "poor sleepers"). PSQI scores were higher in patients with positive urine for benzodiazepine, chronic pain and psychiatric disorders and they correlated with years of opiate abuse before admission to MMT, and with the methadone dose (r=0.48, p<0.0005). The latter two also correlated with each other. The PSQI was not correlated with duration in MMT, gender, age, abuse of opiates, cannabis or cocaine. We concluded that sleep disorders should be evaluated and treated among MMT patients, particularly in those with psychiatric disorders, benzodiazepine abuse, chronic pain and high methadone dose. PMID:16154297

  6. Harpagophytum procumbens extract potentiates morphine antinociception in neuropathic rats.

    PubMed

    Parenti, Carmela; Aricò, Giuseppina; Pennisi, Marzio; Venditti, Alessandro; Scoto, Giovanna M

    2016-06-01

    The association of opioids and non-steroidal anti-inflammatory drugs, to enhance pain relief and reduce the development of side effects, has been demonstrated. Given many reports concerning the antinociceptive and anti-inflammatory effects of Harpagophytum procumbens extracts, the aim of our study was to investigate the advantage of a co-administration of a subanalgesic dose of morphine preceded by a low dose of H. procumbens to verify this therapeutically useful association in a neuropathic pain model. Time course, registered with the association of the natural extract, at a dose that does not induce an antinociceptive effect, followed by a subanalgesic dose of morphine showed a well-defined antiallodynic and antihyperalgesic effect, suggesting a synergism as a result of the two-drug association. H. procumbens cooperates synergistically with morphine in resolving hyperalgesia and allodynia, two typical symptoms of neuropathic pain. The results support the strategy of using an adjuvant drug to improve opioid analgesic efficacy. PMID:26189616

  7. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    SciTech Connect

    Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  8. Potentiation of morphine analgesia by subanesthetic doses of pentobarbital.

    PubMed

    Pontani, R B; Vadlamani, N L; Misra, A L

    1985-03-01

    Pentobarbital pretreatment reportedly either inhibits, enhances or has no effect on morphine analgesia. The effect of subanesthetic doses of sodium pentobarbital (8-12 mg kg-1, SC) delivered via a delivery system on analgesia of morphine (5 mg kg-1, SC or 1 mg kg-1, IV) acutely administered 45 min after the sodium pentobarbital pellet implantation was assessed using the warm water (55 degrees C)-induced tail-withdrawal reflex in male Wistar rats. Significant potentiation of morphine analgesia was observed in sodium pentobarbital as compared to the placebo-pelleted animals. Pharmacokinetic or dispositional factors were not involved in this potentiation, which was possibly due to the activation of the descending inhibitory control pathways of nociceptive spinal tail-withdrawal reflex by a combined interaction of two drugs at spinal and supraspinal sites of action, that mediate opiate antinociception. PMID:3991755

  9. Effects of morphine on glucose homeostasis in the conscious dog.

    PubMed Central

    Radosevich, P M; Williams, P E; Lacy, D B; McRae, J R; Steiner, K E; Cherrington, A D; Lacy, W W; Abumrad, N N

    1984-01-01

    This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma

  10. Combination of morphine with nortriptyline for neuropathic pain.

    PubMed

    Gilron, Ian; Tu, Dongsheng; Holden, Ronald R; Jackson, Alan C; DuMerton-Shore, Deborah

    2015-08-01

    First-line neuropathic pain drugs, including tricyclic antidepressants, are not always effective, and opioids have been recommended as second line. This trial evaluates a nortriptyline-morphine combination, compared with each monotherapy. In this randomized, double-blind crossover trial, patients with neuropathic pain were enrolled at 1 site between January 25, 2010, and May 22, 2014, and randomized in a 1:1:1 ratio using a balanced Latin square design to receive oral nortriptyline, morphine, and their combination. During each of three 6-week periods, doses were titrated toward maximal tolerated dose (MTD). The primary outcome was average daily pain at MTD, and secondary outcomes included other pain, mood and quality of life measures, and adverse effects. Sixty-two patients were screened, 52 enrolled, and 39 completed at least 2 treatment periods. Average daily pain (0-10) at baseline was 5.3 and at MTD was 2.6 for combination vs 3.1 for nortriptyline (P = 0.046) and 3.4 for morphine (P = 0.002). Brief Pain Inventory scores for average and present pain were also significantly lower for combination vs each monotherapy. Combination treatment resulted in moderate-severe constipation in 43% vs 46% with morphine (P = 0.82) and 5% with nortriptyline (P < 0.0001). Combination treatment resulted in moderate-severe dry mouth in 58% vs 49% with nortriptyline (P = 0.84) and 13% with morphine (P < 0.0001). This trial suggests superior efficacy of a nortriptyline-morphine combination over either monotherapy with constipation, dry mouth, and somnolence as the most frequent adverse effects.

  11. Morphine Increases Acetylcholine Release in the Trigeminal Nuclear Complex

    PubMed Central

    Zhu, Zhenghong; Bowman, Heather R.; Baghdoyan, Helen A.; Lydic, Ralph

    2008-01-01

    Study Objectives: The trigeminal nuclear complex (V) contains cholinergic neurons and includes the principal sensory trigeminal nucleus (PSTN) which receives sensory input from the face and jaw, and the trigeminal motor nucleus (MoV) which innervates the muscles of mastication. Pain associated with pathologies of V is often managed with opioids but no studies have characterized the effect of opioids on acetylcholine (ACh) release in PSTN and MoV. Opioids can increase or decrease ACh release in brainstem nuclei. Therefore, the present experiments tested the 2-tailed hypothesis that microdialysis delivery of opioids to the PSTN and MoV significantly alters ACh release. Design: Using a within-subjects design and isoflurane-anesthetized Wistar rats (n = 53), ACh release in PSTN during microdialysis with Ringer's solution (control) was compared to ACh release during dialysis delivery of the sodium channel blocker tetrodotoxin, muscarinic agonist bethanechol, opioid agonist morphine, mu opioid agonist DAMGO, antagonists for mu (naloxone) and kappa (nor-binaltorphimine; nor-BNI) opioid receptors, and GABAA antagonist bicuculline. Measurements and Results: Tetrodotoxin decreased ACh, confirming action potential-dependent ACh release. Bethanechol and morphine caused a concentration-dependent increase in PSTN ACh release. The morphine-induced increase in ACh release was blocked by nor-BNI but not by naloxone. Bicuculline delivered to the PSTN also increased ACh release. ACh release in the MoV was increased by morphine, and this increase was not blocked by naloxone or nor-BNI. Conclusions: These data comprise the first direct measures of ACh release in PSTN and MoV and suggest synaptic disinhibition as one possible mechanism by which morphine increases ACh release in the trigeminal nuclei. Citation: Zhu Z; Bowman HR; Baghdoyan HA; Lydic R. Morphine increases acetylcholine release in the trigeminal nuclear complex. SLEEP 2008;31(12):1629–1637. PMID:19090318

  12. Interaction of prenatal stress and morphine alters prolactin and seizure in rat pups.

    PubMed

    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.

  13. Gas-liquid chromatographic determination of morphine, heroin, and cocaine.

    PubMed

    Prager, M J; Harrington, S M; Governo, T F

    1979-03-01

    Morphine, heroin, and cocaine are quantitatively determined with the same gas-liquid chromatographic system. The compounds are separated on a 6 ft X 2 mm id glass column packed with a 1:1 mixture of 5% SE-30 on 80--100 mesh Chromosorb W and 3% OV-17 on 80--100 mesh Varaport 30. The column is temperature-programmed. Flame ionization detector responses are measured with a computer-based data system. Heroin and cocaine are chromatographed directly; morphine is derivatized first. The procedure was evaluated with previously analyzed commercial and forensic samples. Accuracy and precision were 5 and 3%, respectively. PMID:447602

  14. Methadone diversion as a protective strategy: the harm reduction potential of 'generous constraints'.

    PubMed

    Harris, Magdalena; Rhodes, Tim

    2013-11-01

    Methadone maintenance treatment is evidenced as a successful harm reduction initiative in regard to the prevention of blood borne viruses and other injecting related harms. This is attributable to reductions in heroin use and injecting equipment sharing incidents, yet the means by which these are achieved are rarely elaborated. Methadone diversion is predominantly presented in a negative light; associated with overdose and other harms. In our qualitative London-based study with 37 people who inject drugs, 35 on substitution therapies, we found that methadone self regulation and diversion played a prominent role in helping participants to manage their drug use, prevent withdrawal, cement social relationships, and inadvertently protect against hepatitis C transmission. The ability of participants to enact these 'indigenous harm reduction strategies' was constrained to various degrees by their treatment dosing protocols. In this article we explore the strategies participants enacted with methadone, the role of 'generous constraints' in this enactment and the associated production and reduction of risk. In order to reengage people who inject drugs with harm reduction interventions, it is necessary for initiatives to take stock of the indigenous strategies that individuals are already utilising and - in the case of methadone self regulation - support them by the implementation of more generous constraints.

  15. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone.

    PubMed Central

    Wu, D; Otton, S V; Sproule, B A; Busto, U; Inaba, T; Kalow, W; Sellers, E M

    1993-01-01

    1. In microsomes prepared from three human livers, methadone competitively inhibited the O-demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty-two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O-demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme. PMID:8448065

  16. Fluctuating QTc interval in an asymptomatic patient treated with methadone for chronic pain.

    PubMed

    Ower, Katherine; Morley-Forster, Patricia; Moulin, Dwight

    2005-01-01

    Prolongation of the QT interval associated with ventricular arrhythmias has been the most common cause of the restriction or withdrawal of drugs from the market in the past 10 years. Methadone, a synthetic opioid that is increasingly used for the management of chronic pain, has recently been implicated in the development of the prolonged QT syndrome. We present a case report of a patient who developed a prolonged QT while being treated with oral methadone for a chronic pain syndrome. Of particular interest in this patient is the fluctuation of the QT interval at a stable dose of methadone, suggesting that a single normal electrocardiogram (ECG) does not guarantee that the patient is not at risk of ventricular arrhythmias. After reviewing the current literature, we suggest that there is no dose of methadone that may be considered to be completely safe. Other risk factors for prolonged QT interval such as underlying cardiac abnormalities, electrolyte disturbances, and concurrent medications should be sought, and all patients should be monitored with serial ECGs even when methadone doses remain stable.

  17. Neonatal outcomes following in utero exposure to buprenorphine/naloxone or methadone

    PubMed Central

    Gawronski, Kristen M; Prasad, Mona R; Backes, Carl R; Lehman, K Joy; Gardner, Debra K

    2014-01-01

    Objectives: To study neonatal outcomes following buprenorphine/naloxone and methadone exposure during pregnancy. Methods: This study is a retrospective review of clinical and demographic information of 58 infants whose mothers were treated with buprenorphine/naloxone and 92 infants whose mothers were treated with methadone for opioid dependence during pregnancy. Results: Gestational age, birth weight, prematurity, admission to neonatal intensive care unit, and length of stay were similar between both groups of infants. Neonatal abstinence syndrome occurred less frequently among infants of mothers treated with buprenorphine/naloxone than those treated with methadone (64% and 80%, respectively, p = 0.03). All infants with neonatal abstinence syndrome were treated postnatally with methadone. There was a trend toward shorter duration of treatment and lower cumulative dosages of methadone among the buprenorphine/naloxone–exposed infants. Conclusions: No apparent significant adverse neonatal outcomes were detected following treatment with either maintenance medication; however, further prospective research is necessary to examine the safety and efficacy of buprenorphine/naloxone in pregnancy and its effects on the neonate. PMID:26770721

  18. Uses of diverted methadone and buprenorphine by opioid-addicted individuals in Baltimore, Maryland

    PubMed Central

    Mitchell, Shannon Gwin; Kelly, Sharon M.; Brown, Barry S.; Reisinger, Heather Schacht; Peterson, James A.; Ruhf, Adrienne; Agar, Michael H.; O'Grady, Kevin E.; Schwartz, Robert P.

    2009-01-01

    This study examined the uses of diverted methadone and buprenorphine among opiate-addicted individuals recruited from new admissions to methadone programs and from out-of-treatment individuals recruited from the streets. Self-report data regarding diversion were obtained from surveys and semi-structured qualitative interviews. Approximately 16% (n=84) of the total sample (N=515) reported using diverted (street) methadone 2–3 times per week for six months or more, and for an average of 7.8 days (SD=10.3) within the past month. The group reporting lifetime use of diverted methadone as compared to the group that did not report such use was less likely to use heroin and cocaine in the 30 days prior to admission (ps < .01) and had lower ASI Drug Composite scores (p < .05). Participants in our qualitative sub-sample (n=22) indicated that street methadone was more widely used than street buprenorphine and that both drugs were largely used as self-medication for detoxification and withdrawal symptoms. Participants reported using low dosages and no injection of either medication was reported. PMID:19874152

  19. Post-thoracotomy pain relief: combined use of cryoprobe and morphine infusion techniques.

    PubMed Central

    Orr, I. A.; Keenan, D. J.; Dundee, J. W.; Patterson, C. C.; Greenfield, A. A.

    1983-01-01

    In a reported study we found that freezing of the intercostal nerves under direct vision at thoracotomy provided better postoperative analgesia than im morphine on demand. Infusions of morphine were also more effective than when used by the intramuscular route. The benefit on the eighth postoperative day was greatest following the use of the cryoprobe. Further studies were carried out to evaluate the benefit of combining 'cryoprobe' analgesia with infusions of morphine. The combined use of morphine infusion and a cryoprobe did not produce greater postoperative pain relief than the use of the cryoprobe alone with im morphine on demand. PMID:6638849

  20. Chronic SIV and morphine treatment increases heat shock protein 5 expression at the synapse.

    PubMed

    Pendyala, Gurudutt; Periyasamy, Palsamy; Callen, Shannon; Fox, Howard S; Lisco, Steven J; Buch, Shilpa J

    2015-10-01

    The abuse of opiates such as morphine in synergy with HIV infection accelerates neurocognitive impairments and neuropathology in the CNS of HIV-infected subjects, collectively referred to as HAND. To identify potential pathogenic markers associated with HIV and morphine in perturbing the synaptic architecture, we performed quantitative mass spectrometry proteomics on purified synaptosomes isolated from the caudate of two groups of rhesus macaques chronically infected with SIV differing by one regimen-morphine treatment. The upregulation of heat shock 70-kDa protein 5 in the SIV + morphine group points to increased cellular stress during SIV/morphine interaction thus leading to CNS dysfunction.

  1. The Potential Role of an Extended-Release, Abuse-Deterrent Oxycodone/Acetaminophen Fixed-Dose Combination Product for the Treatment of Acute Pain.

    PubMed

    Pergolizzi, Joseph V; Taylor, Robert; Raffa, Robert B

    2015-06-01

    Acute pain, prevalent as part of postoperative and traumatic pain, is often sub-optimally or inadequately treated. Fixed-dose combination analgesic products that combine a reduced amount of opioid with a nonopioid analgesic such as acetaminophen (paracetamol) in a single tablet offer potential pharmacodynamic and/or pharmacokinetic benefits, and may also result in an opioid-sparing effect. A new analgesic product (XARTEMIS™ XR, Mallinckrodt Brand Pharmaceuticals, Dublin, Ireland) combines oxycodone (7.5 mg) with acetaminophen (325 mg) in an immediate-release/extended-release (ER) formulation that is indicated for the treatment of acute pain. The ER formulation of this product provides stable serum drug concentrations that in this case lasts 12 h. Oxycodone/acetaminophen is a drug combination that offers safe and effective pain relief in a variety of acute pain syndromes such as postoperative pain. The combination formulation allows a smaller amount of oxycodone per tablet and the biphasic-layered matrix of the pill for ER may present obstacles to potential abusers. No opioid is totally abuse resistant, but the lower opioid content and tamper-resistant formulation of this product might discourage abuse. Clinicians must still be mindful of the acetaminophen part of this product in the patient's overall daily intake (in light of acetaminophen hepatotoxicity). The new product appears to provide an important new choice in the armamentarium against acute pain.

  2. Effects of opioids in morphine-treated pigeons trained to discriminate among morphine, the low-efficacy agonist nalbuphine, and saline.

    PubMed

    Walker, Ellen A; Picker, Mitchell J; Granger, Arthur; Dykstra, Linda A

    2004-07-01

    In opioid-dependent subjects, the low-efficacy mu agonist nalbuphine generally precipitates withdrawal or withdrawal-like stimulus effects. To provide a more complete characterization of the discriminative stimulus effects of nalbuphine in opioid-treated subjects, seven White Carneux pigeons were treated daily with 10 mg/kg morphine i.m. and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine, and saline by responding on one of three different keys. When tested, morphine produced morphine-key responding and nalbuphine produced nalbuphine-key responding. Replacing the daily morphine injection with saline produced nalbuphine-key responding, and this effect was reversed by the administration of morphine. In substitution tests with other compounds, the antagonists naltrexone (i.m.) and CTAP (D-Phe-Cys-Tyr-D-Tryp-Lys-Thr-Pen-Thr-NH2) (i.c.v.) produced nalbuphine-key responding. High-efficacy agonists fentanyl and etorphine produced morphine-key responding. The intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol produced a pattern of morphine-, saline-, and/or nalbuphine-key responding that differed across individual pigeons. The lower efficacy agonists nalorphine and levallorphan produced predominantly nalbuphine-key responding. The kappa agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy micro agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment.

  3. Morphine with adjuvant ketamine versus higher dose of morphine alone for acute pain: a meta-analysis

    PubMed Central

    Ding, Xibing; Jin, Shuqing; Niu, Xiaoyin; Wang, Tingting; Zhao, Xiang; Ren, Hao; Tong, Yao; Li, Quan

    2014-01-01

    Purpose: Ketamine is currently the N-methyl-D-aspartate receptor channel blocker in clinical use. Morphine in pain management is usually limited by adverse effect such as nausea and vomiting. Adjuvant treatment with ketamine may be value in giving better analgesia with fewer adverse effects. The purpose of this meta-analysis was to evaluate the differences when patients received morphine with adjuvant ketamine (MK) compared with higher dose of morphine (MO) for acute pain. Methods: The PubMed, EMBASE and the Cochrane Library databases were searched (Last search performed on July 1, 2014) by two reviewers independently. Data were extracted independently by the same two individuals who searched the studies. Results: A total of 7 trials involving 492 patients were included in the current analysis. We found pain scores were lower in the MK group compared to the MO group [MD 2.19, 95% CI (1.24, 3.13) P<0.00001]. And more patients in the MO required diclofenac [OR 1.97, 95% CI (1.06, 3.67) P=0.03]. Furthermore, morphine plus ketamine can reduced post-operative nausea and vomiting (PONV) [OR 3.71, 95% CI (2.37, 5.80) P<0.00001]. Importantly, the wakefulness scores for the MK group were consistently and significantly better than those for the MO group [MD -1.53, 95% CI (-2.67, -0.40) P=0.008]. Conclusion: The use of ketamine plus 1/4~2/3 the dose of morphine is better than higher dose of morphine alone in reducing pain scores, and rescuing analgesic requirement. It also improved PONV and wakefulness. PMID:25356103

  4. Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines.

    PubMed

    Mashayekhi, S O; Sattari, M R; Routledge, P A

    2010-07-01

    Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P-glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK-PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters. PMID:21589798

  5. Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines

    PubMed Central

    Mashayekhi, S.O.; Sattari, M.R.; Routledge, P.A.

    2010-01-01

    Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P-glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK-PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters. PMID:21589798

  6. Pharmacokinetics of morphine and its metabolites in freshwater rainbow trout (Oncorhynchus mykiss).

    PubMed

    Newby, N C; Robinson, J W; Vachon, P; Beaudry, F; Stevens, E D

    2008-04-01

    In this study, we injected morphine sulfate IP into rainbow trout and measured the concentration of morphine and all potential metabolites in plasma using LC-MS/MS at a series of times after the injection. The pharmacokinetics of morphine were similar to those previously reported for seawater-acclimated rainbow trout, i.e. they were about one order of magnitude slower than in similarly sized mammals. The only metabolite of morphine present in the plasma was morphine-3-beta-D-glucuronide (M3G); morphine-6-beta-D-glucuronide (M6G) was not detected. M3G gradually increased after the morphine injection, peaked about 2 days later, then gradually decreased. In mammals, M3G plasma levels exceed morphine levels extremely rapidly, i.e. in less than an hour, regardless of dose, route of administration, or species. In trout, it took 2 days for M3G levels to exceed morphine levels. This is the first study of the metabolites of morphine in any ectotherm. We conclude that trout can metabolize morphine, but at a rate much slower than in mammals.

  7. Morphine/Codeine Ratio, a Key in Investigating a Case of Doping

    PubMed Central

    Seif-Barghi, Tohid; Moghadam, Navid; Kobarfard, Farzad

    2015-01-01

    Introduction: Consumption of codeine can lead to positive urine test for morphine in athletes. Morphine is classified as a prohibited doping drug while Codeine is not. Morphine/codeine ratio is used in forensic medicine to distinguish the consumption of codeine from abuse of morphine and other narcotics. Case Presentation: We present an athlete with positive urine test for morphine with a history of consumption of codeine. The disciplinary committee came to conclusion that the athlete had not consumed morphine and did not violate doping code based on morphine/codeine ratio. Conclusions: Analysis of codeine to morphine metabolism rate is needed when we are using morphine/codeine ratio to rule out abuse of narcotics. WADA should consider analysis for the CYP2D6 alleles (main metabolizer of codeine) in case of including morphine/codeine ratio in future prohibited list. The possibility of ultra-rapid CYP2D6 cannot be ruled out in certain results of morphine/codeine near the cut point. PMID:26715976

  8. Morphine causes persistent induction of nitrated neurofilaments in cortex and subcortex even during abstinence.

    PubMed

    Pal, A; Das, S

    2015-04-16

    Morphine has a profound role in neurofilament (NF) expression. However, there are very few studies on the fate of NFs during morphine abstinence coinciding with periods of relapse. Mice were treated chronically with morphine to render them tolerant to and dependent on morphine and sacrificed thereafter while another group, treated similarly, was left for 2 months without morphine. A long-lasting alteration in the stoichiometric ratio of the three NFs was observed under both conditions in both the cortex and subcortex. Morphine abstinence caused significant alterations in the phosphorylated and nitrated forms of the three NF subunits. Nitrated neurofilament light polypeptide chain (NFL) was significantly increased during chronic morphine treatment which persisted even after 2 months of morphine withdrawal. Mass spectrometric analysis following two-dimensional gel electrophoresis (2DE)-gel electrophoresis of cytoskeleton fractions of both cortex and subcortex regions identified enzymes associated with energy metabolism, cytoskeleton-associated proteins as well as NFs which showed sustained regulation even after abstinence of morphine for 2 months. It is suggestive that alteration in the levels of some of these proteins may be instrumental in the increased nitration of NFL during morphine exposure. Such gross alteration in NF dynamics is indicative of a concerted biological process of neuroadaptation during morphine abstinence.

  9. Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer

    PubMed Central

    Zhang, Wei; Guan, Zhong; Zhao, Hai-Dong; Li, Jing-Lin; Wang, Kai-Li; Li, Ting-Ting; Zhang, Yan; Zheng, Fei-Meng; Xu, Fan; Han, Qian-Ni; Gao, Peng; Wen, Qing-Ping; Liu, Quentin

    2015-01-01

    Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44+/CD24−/low population in BT549 cells. Consistently, morphine activates Wnt/β-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine. PMID:25686831

  10. Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy.

    PubMed

    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. PMID:24973610

  11. Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy.

    PubMed

    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.

  12. Poor Man's Methadone: A Case Report of Loperamide Toxicity.

    PubMed

    Dierksen, Jennifer; Gonsoulin, Morna; Walterscheid, Jeffrey P

    2015-12-01

    Loperamide, a common over-the-counter antidiarrheal drug and opioid derivative, is formulated to act upon intestinal opioid receptors. However, at high doses, loperamide crosses the blood-brain barrier and reaches central opioid receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report the case of a young man found dead in his residence with a known history of drug abuse. At autopsy, the only significant findings were a distended bladder and bloody oral purge. Drug screening found nontoxic levels of alprazolam, fluoxetine, and marijuana metabolites. Liquid chromatography time-of-flight mass spectrometry found an unusual set of split isotope peaks consistent with chlorine. On the basis of autopsy and toxicological findings, loperamide toxicity was suspected because of its opioid properties and molecular formula containing chlorine. A sample of loperamide was analyzed by liquid chromatography time-of-flight mass spectrometry, resulting in a matching mass and retention time to the decedent's sample. Subsequently, quantitative testing detected 63 ng/mL of loperamide or more than 6 times of therapeutic peak concentration. Cause of death was determined as "toxic effects of loperamide with fluoxetine and alprazolam." Because of its opioid effects and easy accessibility, loperamide is known as "poor man's methadone" and may go undetected at medical and forensic drug screening. PMID:26355852

  13. Treatment effectiveness for legally coerced versus voluntary methadone maintenance clients.

    PubMed

    Brecht, M L; Anglin, M D; Wang, J C

    1993-01-01

    Analyses examined whether addicts reporting themselves coerced into drug abuse treatment by actions of the criminal justice system differed from voluntary admissions in their response to treatment, and whether such responsiveness varied across gender or ethnicity. Six hundred eighteen methadone maintenance clients admitted to programs in six southern California counties were categorized into high, moderate, and low legal coercion levels. Multivariate analysis of variance procedures for repeated measures (before, during, and after initial treatment episode) were used to test relevant hypotheses. Dependent variables included criminal justice system contact, criminal activities, drug and alcohol involvement, and measures of social functioning. Few differences within any measured domain were found among the three groups. All groups were similar in showing substantial improvement in levels of narcotics use, criminal activities, and most other behaviors during treatment with some regression in these behaviors posttreatment. Results support legal coercion as a valid motivation for treatment entry; those coerced into treatment respond in ways similar to voluntary admissions regardless of gender or ethnicity. PMID:8438834

  14. Poor Man's Methadone: A Case Report of Loperamide Toxicity.

    PubMed

    Dierksen, Jennifer; Gonsoulin, Morna; Walterscheid, Jeffrey P

    2015-12-01

    Loperamide, a common over-the-counter antidiarrheal drug and opioid derivative, is formulated to act upon intestinal opioid receptors. However, at high doses, loperamide crosses the blood-brain barrier and reaches central opioid receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report the case of a young man found dead in his residence with a known history of drug abuse. At autopsy, the only significant findings were a distended bladder and bloody oral purge. Drug screening found nontoxic levels of alprazolam, fluoxetine, and marijuana metabolites. Liquid chromatography time-of-flight mass spectrometry found an unusual set of split isotope peaks consistent with chlorine. On the basis of autopsy and toxicological findings, loperamide toxicity was suspected because of its opioid properties and molecular formula containing chlorine. A sample of loperamide was analyzed by liquid chromatography time-of-flight mass spectrometry, resulting in a matching mass and retention time to the decedent's sample. Subsequently, quantitative testing detected 63 ng/mL of loperamide or more than 6 times of therapeutic peak concentration. Cause of death was determined as "toxic effects of loperamide with fluoxetine and alprazolam." Because of its opioid effects and easy accessibility, loperamide is known as "poor man's methadone" and may go undetected at medical and forensic drug screening.

  15. The trajectory of methadone maintenance treatment in Nepal.

    PubMed

    Ambekar, Atul; Rao, Ravindra; Pun, Anan; Kumar, Suresh; Kishore, Kunal

    2013-11-01

    There are about 28,500 people who inject drugs (PWID) in Nepal and HIV prevalence among this group is high. Nepal introduced harm reduction services for PWID much earlier than other countries in South Asia. Methadone maintenance treatment (MMT) was first introduced in Nepal in 1994. This initial small scale MMT programme was closed in 2002 but reopened in 2007 as an emergency HIV prevention response. It has since been scaled up to include three MMT clinics and continuation of MMT is supported by the Ministry of Home Affairs (MOHA; the nodal ministry for drug supply reduction activities) and has been endorsed in the recent National Narcotics policy. Pressure from drug user groups has also helped its reintroduction. Interestingly, these developments have taken place during a period of political instability in Nepal, with the help of strong advocacy from multiple stakeholders. The MMT programme has also had to face resistance from those who were running drug treatment centres. Despite overcoming such troubles, the MMT programme faces a number of challenges. Coverage of MMT is low and high-risk injecting and sexual behaviour among PWID continues. The finance for MMT is largely from external donors and these donations have become scarce with the current global economic problems. With a multitude of developmental challenges for Nepal, the position of MMT in the national priority list is uncertain. Ownership of the programme by government, a cost-effective national MMT scale up plan and rigorous monitoring of its implementation is needed.

  16. Patient outcomes after initiation of Sabbath closure of a methadone maintenance clinic in Israel.

    PubMed

    Gelkopf, M; Bleich, A; Hayward, R; Adelson, M

    1998-11-01

    The study examined whether closing of a methadone maintenance clinic in Israel on the Sabbath was associated with adverse patient outcomes. One take-home dose of methadone was given to all patients for that day regardless of whether they had earned take-home privileges. No difference was found in dropout rates for the six-month periods before and after Saturday closure was initiated. Results of random, twice-weekly urinalyses for all patients did not indicate increased use of heroin. The findings suggest that closure of a methadone clinic at least one day a week does not jeopardize patient outcome. Cutting hours of operation would reduce workload and enable clinics to function more economically.

  17. Indicators of buprenorphine and methadone use and abuse: what do we know?

    PubMed

    Maxwell, Jane Carlisle; McCance-Katz, Elinore F

    2010-01-01

    Abuse of prescription opioids is a growing problem. The number of methadone pain pills distributed now exceeds liquid methadone used in opioid treatment, and the increases in buprenorphine indicators provide evidence of the need to monitor and intervene to decrease the abuse of this drug. The need for additional and improved data to track trends is discussed, along with findings as to the characteristics of the users and combinations of drugs. Data on toxicities related to methadone or buprenorphine, particularly in combination with other prescribed drugs, are presented and clinical implications and considerations are offered. These findings underscore the need for physicians to be aware of potential toxicities and to educate their patients regarding these issues. PMID:20132124

  18. Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon.

    PubMed

    Alijanpour, S; Tirgar, F; Zarrindast, M-R

    2016-01-15

    The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day×3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB-334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine-induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization.

  19. Methadone and buprenorphine for the management of opioid dependence in pregnancy.

    PubMed

    Jones, Hendrée E; Finnegan, Loretta P; Kaltenbach, Karol

    2012-04-16

    This article provides an overview and discussion of the collective maternal, fetal and neonatal outcome research on women maintained on methadone or buprenorphine during pregnancy. Its focus is on an assessment of the comparative effectiveness of methadone and buprenorphine pharmacotherapy, with particular attention given to recent findings from the literature. Recommendations for clinical practice are outlined, and directions for future research are presented. Findings from comparative studies of methadone and buprenorphine underscore the efficacy of both medications in preventing relapse to illicit opioid use in the treatment of opioid-dependent pregnant patients, as well as the simplicity of induction onto methadone and patient retention while receiving such therapy. Fetal monitoring suggests that buprenorphine results in less fetal cardiac and movement suppression than does methadone. The clinical implications of these findings need future exploration. For the neonate, evidence from studies using a wide range of designs, including retrospective chart reviews, prospective observational studies, and randomized clinical trials, show consistent results, with prenatal exposure to buprenorphine resulting in less severe neonatal abstinence syndrome relative to methadone. Any medication given to pregnant women should be prescribed only after considering the risk : benefit ratio for the maternal-fetal dyad. Medication choices for each opioid-dependent patient during pregnancy need to be made on a patient-by-patient basis, taking into consideration the patient's opioid dependence history, previous and current treatment experiences, medical circumstances and treatment preferences. Moreover, for a full remission of opioid addiction to be sustainable, both post-partum and across the lifespan, treatment providers must not rely solely on medication to treat their patients but should also utilize women-specific comprehensive treatment models that address the underlying

  20. Methadone and Buprenorphine Prescribing and Referral Practices in US Prison Systems: Results from a Nationwide Survey

    PubMed Central

    Nunn, Amy; Zaller, Nickolas; Dickman, Samuel; Trimbur, Catherine; Nijhawan, Ank; Rich, Josiah D.

    2009-01-01

    Background More than 50% of incarcerated individuals have a history of substance use, and over 200,000 individuals with heroin addiction pass through American correctional facilities annually. Opiate replacement therapy (ORT) with methadone or buprenorphine is an effective treatment for opiate dependence and can reduce drug-related disease and recidivism for inmates. Provision of ORT is nevertheless a frequently neglected intervention in the correctional setting. Objective and Methods We surveyed the 50 state; Washington, District of Columbia (DC); and Federal Department of Corrections' medical directors or their equivalents about their facilities' ORT prescribing policies and referral programs for inmates leaving prison. Results We received responses from 51 of 52 prison systems nationwide. Twenty-eight prison systems (55%) offer methadone to inmates in some situations. Methadone use varies widely across states: over 50% of correctional facilities that offer methadone do so exclusively for pregnant women or for chronic pain management. Seven states' prison systems (14%) offer buprenorphine to some inmates. The most common reason cited for not offering ORT was that facilities “prefer drug-free detoxification over providing methadone or buprenorphine.” Twenty-three states' prison systems (45%) provide referrals for some inmates to methadone maintenance programs after release, which increased from 8% in 2003; 15 states' prison systems (29%) provide some referrals to community buprenorphine providers. Conclusion Despite demonstrated social, medical, and economic benefits of providing ORT to inmates during incarceration and linkage to ORT upon release, many prison systems nationwide still do not offer pharmacological treatment for opiate addiction or referrals for ORT upon release. PMID:19625142

  1. Temperament and Character Dimensions: Correlates of Impulsivity in Morphine Addicts

    PubMed Central

    Abassi, Moslem; Abolghasemi, Abbas

    2015-01-01

    Background: Given the role of temperament and character dimensions on impulsivity in addicts, the purpose of this study was to temperament and character dimensions: correlates of impulsivity in morphine addicts. Objectives: The aim of this study was to determine and verify the association of temperament and character dimensions with impulsivity in morphine addicts. Patients and Methods: The research method was descriptive and correlational. The study sample consisted of 120 morphine addicts referred to drug addiction treatment centers in Ardabil city in 2013. The participants were selected through convenience sampling method from 5 centers. We used impulsivity scale as well as temperament and character inventory to collect data. Results: The results showed that significant relationship existed between impulsivity and characteristics such as novelty seeking, harm avoidance, reward dependence, persistence, self-directedness, and cooperativeness, while no significant relationship between impulsivity and self-transcendence was observed. The results of the multiple regression analysis showed that 47% of the impulsivity variance was explained by temperament and character dimensions. Conclusions: These findings suggest that temperament and character dimensions are associated with impulsivity. The findings also have important implications for prevention, pathology, and treatment in the morphine addicts. PMID:26870706

  2. Mighty Morphin Power Ranger Play: Research and Reality.

    ERIC Educational Resources Information Center

    Crosser, Sandra

    1995-01-01

    Explores the question of whether or not Mighty Morphin Power Rangers-type aggressive play is developmentally appropriate for the early childhood classroom. Compares results from research in child development to the reality of television programming, highlighting the relationship between television violence and children's aggressive behavior. (AA)

  3. Morphine attenuates cholinergic nerve activity in human isolated colonic muscle.

    PubMed Central

    Burleigh, D. E.; Trout, S. J.

    1986-01-01

    The action of morphine on cholinergic nerves in human sigmoid taenia coli muscle strips (taenia) was investigated using a radiolabelling technique. Basal release of tritiated material from taenia was increased by electrical field stimulation (EFS). This increase was tetrodotoxin (3.14 microM)-sensitive and calcium-dependent. Analysis of basal and stimulated release of tritiated material indicated that evoked release (i.e. stimulated minus basal) is almost entirely due to an increase in [3H]-acetylcholine ([3H]-ACh) output. Evoked release of [3H]-ACh was dependent on the current strength and could be greatly reduced by exposing taenia to hemicholinium (34.8, 87.0 microM) before and during incubation with [3H]-choline (4 microCi ml-1, 15 Ci mmol-1). Spontaneous activity, muscle tone and the motor response of taenia to EFS were unaffected by morphine. Evoked, but not basal, release of tritiated material was inhibited by morphine (1.32-13.20 microM) in a concentration-dependent manner. The inhibition of release was frequency-dependent and naloxone (0.28 microM)-sensitive. The possible relationship between the effects of morphine on cholinergic nerves in taenia muscle and its actions in vivo are discussed. PMID:2873856

  4. Chronic exposure to cadmium attenuates behavioral sensitization to morphine.

    PubMed

    Nation, J R; Miller, D K; Livermore, C L

    1997-06-01

    The purpose of this investigation was to assess the impact of dietary cadmium on morphine-induced changes in locomotor activity. Adult male rats were exposed ad libitum to an adulterated food supply containing 100 ppm added cadmium chloride, or an identical diet containing no added cadmium, for 45 days prior to testing for the locomotor activating effects of successive daily morphine administration (0, 5, 10, or 20 mg/kg per session) on locomotor activity. On day 1 of testing, increasing doses of morphine produced a dose-related suppression of activity, and this sedative effect was greater in control than in cadmium-exposed animals. Repeated morphine administration resulted in tolerance to the sedative effects of the drug, and a systematic elevation of locomotor activity over the 14-day testing period was observed, with the augmentation (sensitization) effect more pronounced in control than cadmium-exposed animals. There was no indication that conditioning (context) events played a role in the effects observed here.

  5. Use of morphine in cholescintigraphy for obstructive cholecystitis

    SciTech Connect

    Kim, E.E.; Nguyen, M.; Pjura, G.; Pollack, M.; Gobuty, A.

    1985-05-01

    Non-visualization of the gallbladder (GB) during the first hour of cholescintigraphy is observed in cystic duct obstruction (e.g. in acute cholecystitis) but may also occur in chronic cholecystitis, hepatocellular disease, alcoholism and prolonged total parenteral nutrition. Low dose morphine is shown to improve the specificity of the diagnosis of acute cholecystitis (from 85% to 100%) with no loss in sensitivity (98%) at a small cost in terms of additional study time. The authors reviewed 27 selected cholescintigraphic examinations augmented by intravenous (IV) morphine (0.04 mg/Kg). Of the 16 cases with persistent nonvisualization of the GB, ultrasound revealed gallstones in 5 cases, sludge in 4, acalculous cholecystitis in 3, one distended GB, one contracted GB and 2 normal GB's. Of the 4 patients taken to surgery, one with gallstones and one with acalculous cholecystitis were confirmed to have acute cholecystitis while another with gallstones had chronic cholecystitis and the final patient, who was sonographically normal, presented a single common duct stone. The authors conclude that the use of IV morphine is an effective adjunct to cholescintigraphy in the evaluation of gallbladder disease, especially when visualization post morphine rules out acute cholecystitis.

  6. Morphine-augmented cholescintigraphy in the diagnosis of acute cholecystitis

    SciTech Connect

    Kim, E.E.; Pjura, G.; Lowry, P.; Nguyen, M.; Pollack, M.

    1986-12-01

    Cholescintigraphy is a sensitive procedure for diagnosing or excluding acute cholecystitis. However, when rapid diagnosis is critical, the requirement for delayed images (4 hr or more after injection) to minimize the false-positive rate diminishes its utility. We prospectively evaluated 40 cholescintigraphic examinations that did not visualize the gallbladder 1 hr after injection of 99mTc diisopropyliminodiacetic acid. These examinations were then augmented by administration of IV morphine, followed by an additional 30 min of imaging. After the morphine, 18 of these examinations demonstrated visualization of the gallbladder; none subsequently required surgical exploration. Of the remaining 22, who demonstrated persistent nonvisualization of the gallbladder post-morphine, 11 were explored surgically and found to be abnormal. The 11 others were treated medically. Low-dose morphine administered when the gallbladder fails to visualize after 1 hr is a useful adjunct to conventional cholescintigraphy because it reduces the time required to obtain a diagnostic result and decreases the number of false-positive results.

  7. Exposure of consumers to morphine from poppy seeds in Hungary.

    PubMed

    Zentai, A; Sali, J; Szeitzné-Szabó, M; Szabó, I J; Ambrus, Á

    2012-01-01

    Poppy seed-containing foods are popular dishes in Hungary and some other Central European countries. The alkaloids of poppy are used in the production of medicines. Poppy seeds used as food may also contain considerable amounts of alkaloids, which raises the question of food safety. Morphine, codeine, thebaine and noscapine concentrations of poppy seed samples from the period 2001-2010 and consumption data from two Hungarian surveys, carried out in 2003 and 2009, were evaluated. Exposure calculations were made for morphine intake by both point estimate and probabilistic methods, and the uncertainty of the calculated values was estimated. The point estimate for the acute consumer exposure, calculated using the 97.5th percentiles of morphine concentration and of poppy seed consumption and taking into account the reduction of morphine content by processing, was 78.64 µg (kg bw)⁻¹ day⁻¹ for adults, and 116.90 µg (kg bw)⁻¹ day⁻¹ for children. Based on probabilistic estimations, the 97.5th and 99th percentile exposures ranged between 18.3-25.4 and 25.6-47.4 µg (kg bw)⁻¹ day⁻¹ for adults, and between 32.9 and 66.4 µg (kg bw)⁻¹ day⁻¹ for children, respectively. As a no observed effect level (NOEL) had not been established, the significance of exposure could not be assessed.

  8. Narcotic tapering in pregnancy using long-acting morphine

    PubMed Central

    Dooley, Roisin; Dooley, Joe; Antone, Irwin; Guilfoyle, John; Gerber-Finn, Lianne; Kakekagumick, Kara; Cromarty, Helen; Hopman, Wilma; Muileboom, Jill; Brunton, Nicole; Kelly, Len

    2015-01-01

    Abstract Objective To document the management of and outcomes for patients receiving narcotic replacement and tapering with long-acting morphine preparations during pregnancy. Design A prospective cohort study over 18 months. Setting Northwestern Ontario. Participants All 600 births at Meno Ya Win Health Centre in Sioux Lookout, Ont, from January 1, 2012, to June 30, 2013, including 166 narcotic-exposed pregnancies. Intervention Narcotic replacement and tapering of narcotic use with long-acting morphine preparations. Main outcome measures Prenatal management of maternal narcotic use, incidence of neonatal abstinence syndrome, and other neonatal outcomes. Results The incidence of neonatal abstinence syndrome fell significantly to 18.1% of pregnancies exposed to narcotics (from 29.5% in a previous 2010 study, P = .003) among patients using narcotic replacement and tapering with long-acting morphine preparations. Neonatal outcomes were otherwise equivalent to those of the nonexposed pregnancies. Conclusion In many patients, long-acting morphine preparations can be safely used and tapered in pregnancy, with a subsequent decrease in observed neonatal withdrawal symptoms. PMID:25821873

  9. 21 CFR 1304.31 - Reports from manufacturers importing narcotic raw material.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... grams of anhydrous morphine alkaloid): (1) Beginning inventory; (2) Gains on reweighing; (3) Imports; (4... derivative including morphine, codeine, thebaine, oxycodone, hydrocodone, medicinal opium, manufacturing... anhydrous morphine alkaloid for manufacturing opium and medicinal opium): (1) Beginning inventory; (2)...

  10. 21 CFR 1304.31 - Reports from manufacturers importing narcotic raw material.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... grams of anhydrous morphine alkaloid): (1) Beginning inventory; (2) Gains on reweighing; (3) Imports; (4... derivative including morphine, codeine, thebaine, oxycodone, hydrocodone, medicinal opium, manufacturing... anhydrous morphine alkaloid for manufacturing opium and medicinal opium): (1) Beginning inventory; (2)...

  11. 21 CFR 1304.31 - Reports from manufacturers importing narcotic raw material.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... grams of anhydrous morphine alkaloid): (1) Beginning inventory; (2) Gains on reweighing; (3) Imports; (4... derivative including morphine, codeine, thebaine, oxycodone, hydrocodone, medicinal opium, manufacturing... anhydrous morphine alkaloid for manufacturing opium and medicinal opium): (1) Beginning inventory; (2)...

  12. 21 CFR 1304.31 - Reports from manufacturers importing narcotic raw material.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... grams of anhydrous morphine alkaloid): (1) Beginning inventory; (2) Gains on reweighing; (3) Imports; (4... derivative including morphine, codeine, thebaine, oxycodone, hydrocodone, medicinal opium, manufacturing... anhydrous morphine alkaloid for manufacturing opium and medicinal opium): (1) Beginning inventory; (2)...

  13. 21 CFR 1304.31 - Reports from manufacturers importing narcotic raw material.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... grams of anhydrous morphine alkaloid): (1) Beginning inventory; (2) Gains on reweighing; (3) Imports; (4... derivative including morphine, codeine, thebaine, oxycodone, hydrocodone, medicinal opium, manufacturing... anhydrous morphine alkaloid for manufacturing opium and medicinal opium): (1) Beginning inventory; (2)...

  14. Effects of LAAM and methadone utilization in an opiate agonist treatment program.

    PubMed

    Valdivia, J F; Khattak, S

    2000-01-01

    The development and approval of levo-alpha-acetylmethadol (LAAM) as a pharmacotherapeutic agent in opioid agonist therapy provided an alternative to methadone. Clinicians recognized the potential benefits that LAAM, a synthetic mu agonist with pharmacological properties which differ from those of methadone,could have in the treatment management of addicts in opioid agonist therapy. We report our experience utilizing LAAM from 1995 to 1999 at the Hines VA opioid agonist therapy clinic. The addition of LAAM to the clinic's treatment armamentarium has resulted in management options that have improved the areas of patient recruitment, patient retention, patient traffic, take-home medication, detoxification, and treatment outcomes.

  15. Illicit use of methadone and buprenorphine among adolescents and young adults in Sweden

    PubMed Central

    2013-01-01

    Background Illicit use of methadone and buprenorphine has been described as a growing problem in Sweden in recent years, and has been associated with an increased drug-related mortality. Critics claim that the substances have become popular among adolescents and that they function as a gateway to heroin use. The aim of this study is to investigate, firstly, the extent to which illicit use of methadone and buprenorphine occurs among adolescents and young adults in Sweden, and secondly, at what stage in a user’s drug career these substances tend to appear. Methods The study is based on surveys and structured interviews on drug use among various populations of young people, in addition to qualitative interviews with 86 informants who, in their professional capacity, encounter adolescents or young adults who are using illicit drugs. Results Illicit use of methadone and buprenorphine is rare among young people in Sweden. According to high school surveys, less than 0.1% have tried these substances. Among young drug users in general, few have tried the substances, and there is nothing to indicate that they act as gateway drugs. Among adolescents and young adults with severe drug problems, however, the illicit use of methadone and buprenorphine is more common (54% in a compulsory care sample). These substances normally enter the drug career late, and few use them as their main drug of choice. Other prescription drugs, like benzodiazepines and tramadol, are used by adolescents to a far greater extent. Diversion and illicit use of methadone and buprenorphine is not seen as a serious problem by the professionals interviewed. A general view is that the substances are mainly used by people with a heroin or polydrug addiction, often for “self-medication” purposes. However, several informants express concern that methadone and buprenorphine may cause fatalities among young drug users without an opioid tolerance. Conclusions Illicit use of methadone and buprenorphine among

  16. Methadone Maintenance for HIV Positive and HIV Negative Patients in Kyiv: Acceptability and Treatment Response

    PubMed Central

    Dvoriak, Sergii; Karachevsky, Andrey; Chhatre, Sumedha; Booth, Robert; Metzger, David; Schumacher, Joseph; Chychula, Nina; Pecoraro, Anna; Woody, George

    2014-01-01

    Background With up to 40% of opioid injectors infected with HIV, Ukraine has one of the most concentrated HIV epidemics in the world, mainly due to unsterile injection practices and a historical absence of effective prevention services. Harm reduction programs, including syringe exchange and a small buprenorphine treatment program, were introduced in 2004 and methadone maintenance was allowed in 2007. Despite an initial expansion, by 2009, only 3221 injectors were receiving methadone treatment. A growing body of research on methadone maintenance has found high retention rates with reduction in opioid use and HIV risk behaviors. We report on the acceptability and initial outcome of methadone treatment as a function of HIV status, an issue that has not yet been reported for injectors in Ukraine. Methods Longitudinal observational study of a 12-week course of methadone treatment in 25 HIV+ and 25 HIV− opioid addicted individuals recruited from a harm reduction program and the city AIDS Center. Drug use and HIV risk were assessed at baseline and weeks 4, 8, 12 and 20; all patients were offered continued methadone maintenance in the Kyiv city program at the end of 12 weeks. Results Fifty-four individuals were asked if they were interested in the study and 50, demographically similar to other samples of opioid addicted Ukrainians, agreed to participate. Two died of non-study related causes; the other 48 completed assessments at weeks 4, 8 and 12, and 47 completed followups at week 20. Significant reductions were seen in use of heroin (p<. 0001), other opiates/analgesics (p< 0.0001), and HIV risk behaviors (drug, sex, total; all p <0.0001). All 48 patients chose to continue methadone after the 12-weeks of study medication ended. Unlike most opioid treatment studies, sexual risk was somewhat higher than injecting risk at study intake. Conclusions Methadone maintenance was well accepted by HIV+ and HIV− opioid dependent individuals and has the potential for significant

  17. Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity

    PubMed Central

    Mouly, Stéphane; Bloch, Vanessa; Peoc'h, Katell; Houze, Pascal; Labat, Laurence; Ksouda, Kamilia; Simoneau, Guy; Declèves, Xavier; Bergmann, Jean Francois; Scherrmann, Jean-Michel; Laplanche, Jean-Louis; Lepine, Jean-Pierre; Vorspan, Florence

    2015-01-01

    Aims Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. Methods Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day−1 methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. Results Methadone maintenance dose was correlated to the highest dose ever used (r2 = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27–18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01–2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day−1 in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = −0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. Conclusions Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP

  18. [Quality of buprenorphine and morphine as components of combined anesthesia].

    PubMed

    Knoche, E; Dick, W; Rummel, C; Konietzke, D

    1988-02-01

    Perioperative effects of buprenorphine during and after combined anesthesia for gynecological laparotomies were compared to those of morphine. In a controlled, randomized study two similar groups of patients received flunitrazepam (0.016 mg/kg) and either buprenorphine (0.008 mg/kg) or morphine (0.333 mg/kg); all patients were ventilated with a N2O/O2-mixture. To maintain adequate anesthesia, additional injections of buprenorphine or morphine and a volatile anesthetic agent (enflurane, less than 1.0 vol.%) were administered as needed. In some patients in both groups the injection of thiopental (1-2 mg/kg) became necessary for induction of anesthesia. Hemodynamic parameters showed a slight but not significant increase during intubation and remained stable intraoperatively (Figs. 1 and 2). The frequencies of additional intraoperative injections of buprenorphine or morphine and modalities of enflurane administration were similar in both groups. Based on an awakeness score, recovery from anesthesia was similar in both groups (Fig. 3). All patients were pain-free for a long period postoperatively (pain score 1-2, duration 6-10 h) (Fig. 4). In both groups respiratory depression could be demonstrated by means of ventilatory CO2 response (Figs. 6 and 7). The respiratory depression was of no clinical importance and seems to have been due to the combination of a long-acting benzodiazepine with an opiate. There were no differences in the occurrence of nausea and vomiting in both groups. Buprenorphine seems to be an alternative to morphine in combined anesthesia. PMID:3284406

  19. Influence of fentanyl and morphine on intestinal circulation

    SciTech Connect

    Tverskoy, M.; Gelman, S.; Fowler, K.C.; Bradley, E.L.

    1985-06-01

    The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of /sup 86/Rb and 9-micron spheres labeled with /sup 141/Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestines reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O/sub 2/up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation.

  20. Opiate receptor in praying mantis: effect of morphine and naloxone.

    PubMed

    Zabala, N A; Miralto, A; Maldonado, H; Nuñez, J A; Jaffe, K; Calderon, L D

    1984-05-01

    A praying mantis displays a "frightening reaction" called deimatic reaction (DR), any time that it is faced with a patterned visual stimulus that represents a potential damage for the insect. Results of the present paper show that the DR could be also elicited by an actual noxious (an electrical shock) and that this response is similar to that elicited by a potential nociceptive stimulus (a patterned visual stimulus). The DR elicited by the electric shock was used as a model for studying the analgesic effect of opiates. The mantis was placed in an apparatus that allowed us to give the insect an electrical shock and to measure the strength of its DR. During a first session the voltage threshold necessary to induce a full DR was determined, and then, the insect was injected with a certain solution. The voltage threshold was tested one, two and four hours after injection. Mantises that were injected with only distilled water showed no changes in their voltage threshold during the three tests. Injections of 300, 350 and 400 micrograms/g of morphine-HCl increased the voltage threshold in both a time-dependent and a dose related manner. A dose of 350 micrograms/g of morphine-HCl produced 50% of response inhibition after two hours of injections and is referred to as the median antinoxious dose ( AD50 ). Sixteen micrograms/g of naloxone given in conjunction with an AD50 of morphine, partially blocked the effect of morphine during the first hour and fully blocked it during the second hour. Thirty-two micrograms/g of naloxone fully blocked the morphine effect during the first and the second hour. However, more than 48 micrograms/g of naloxone alone also increased the voltage threshold in insects, similar to those described for vertebrates. PMID:6330763

  1. Evaluation of menstrual cycle effects on morphine and pentazocine analgesia

    PubMed Central

    Ribeiro-Dasilva, MC; Shinal, RM; Glover, T; Williams, RS; Staud, R; Riley, JL; Fillingim, RB

    2011-01-01

    Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08 mg/kg) or pentazocine (0.5 mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model ANOVAs. NOC women showed slightly greater heat pain sensitivity in the follicular vs. luteal phase, while the reverse pattern emerged for OC women (p=0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (p < .05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs. the luteal phase (p=0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (p=0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude. PMID:21239109

  2. Memory impairment and reduced exploratory behavior in mice after administration of systemic morphine.

    PubMed

    Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Fujii, Mei; Goto, Akiko; Kanda, Yusuke; Koizumi, Akira; Kuroiwa, Hirotoshi; Mibayashi, Satoko; Muranishi, Yumi; Otaki, Soichiro; Sumikawa, Minako; Tanaka, Koh-Ichi; Nishiyama, Nobuyoshi; Uhl, George R; Takemura, Motohiko

    2015-01-01

    In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or β-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by μ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety.

  3. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    PubMed

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy. PMID:27424012

  4. PKC-mediated potentiation of morphine analgesia by St. John's Wort in rodents and humans.

    PubMed

    Galeotti, Nicoletta; Farzad, Mersedeh; Bianchi, Enrica; Ghelardini, Carla

    2014-01-01

    Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John's Wort (SJW) or its main component hypericin. Phosphorylation of the γ subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.

  5. Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats

    PubMed Central

    Prasoon, Pranav; Gupta, Shivani; Kumar, Rahul; Gautam, Mayank; Kaler, Saroj; Ray, Subrata Basu

    2016-01-01

    Objectives: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action. Methods: Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry. Results: Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1–4). Expression of SP was increased in the morphine + fosaprepitant group. Conclusions: The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.

  6. Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice

    PubMed Central

    Vahdati Hassani, Faezeh; Hashemzaei, Mahmoud; Akbari, Edris; Imenshahidi, Mohsen; Hosseinzadeh, Hossein

    2016-01-01

    Objective: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da) and N-methyl-D-aspartate (NMDA) contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice. Materials and Methods: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine. The effects of different doses of berberine (5, 10, and 20 mg/kg) on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test. Results: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg) did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg) 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine-induced CPP. Conclusion: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction. PMID:27222833

  7. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    SciTech Connect

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-04-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-(/sup 14/C)xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in /sup 14/CO/sub 2/ excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an ..cap alpha../sub 2/-adrenergic agonist.

  8. Memory Impairment and Reduced Exploratory Behavior in Mice after Administration of Systemic Morphine

    PubMed Central

    Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Fujii, Mei; Goto, Akiko; Kanda, Yusuke; Koizumi, Akira; Kuroiwa, Hirotoshi; Mibayashi, Satoko; Muranishi, Yumi; Otaki, Soichiro; Sumikawa, Minako; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Uhl, George R; Takemura, Motohiko

    2015-01-01

    In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or β-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by μ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety. PMID:25987850

  9. Tolerance to behavioral effects of clonidine after chronic administration of morphine.

    PubMed

    McKearney, J W

    1985-04-01

    Male rats (Buffalo strain) were studied under a procedure in which each 30th lick of a drinking tube resulted in the delivery of 0.01 ml water. The effects of clonidine HC1 (0.003-0.3 mg/kg, IP) were determined before, during and after exposure to conditions in which a morphine sulfate solution (0.5 mg/ml in 0.4% saccharin) was the only source of fluid. After either 10 or 80 days exposure to the chronic morphine regimen, rats were maintained under a repetitive cycle in which the morphine was available for 3 days and then removed for 4 days. The subjects consumed an average of 100 mg/kg/day morphine during the times it was available. The effects of clonidine were redetermined once weekly, on the 4th day after removal of the morphine solution. The effects of clonidine were also determined after morphine was removed for more prolonged periods (18-67 days). Chronic exposure to the morphine solution resulted in a 4- to 5-fold shift to the right in the dose-effect curve for clonidine (decreased responding). ED50 values returned to pre-morphine levels when rats were tested at longer post-morphine times (e.g., 18 days). Under the conditions of this experiment, chronic exposure to morphine produced marked cross-tolerance to the behavioral effects of clonidine.

  10. Synthetic geopolymers for controlled delivery of oxycodone: adjustable and nanostructured porosity enables tunable and sustained drug release.

    PubMed

    Forsgren, Johan; Pedersen, Christian; Strømme, Maria; Engqvist, Håkan

    2011-03-15

    In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2:1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial.

  11. Prescription opioids. III. Disposition of oxycodone in oral fluid and blood following controlled single-dose administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-04-01

    Oxycodone (OC) is recommended to be included as an analyte tested in the proposed Substance Abuse and Mental Health Services Administration (SAMHSA's) Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OF) Specimens. This study demonstrates the time course of OC and metabolites, noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM), in near-simultaneous paired OF and whole blood (BL) specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS) (limit of detection = 1 ng/mL OF, 5 ng/mL BL). A single dose of OC 20 mg controlled-release was administered to 12 healthy subjects followed by specimen collections for 52 h. Analyte prevalence was as follows: OF, OC > NOC > OM; and BL, OC > NOC > NOM. OC and NOC were frequently detected within 15-30 min in OF and 30 min to 2 h in BL. NOM and OM appeared between 1.5-5 h post-dose. The mean OF-to-BL (OF:BL) ratios and correlations were 5.4 for OC (r = 0.719) and 1.0 for NOC (r = 0.651). The period of detection for OF exceeded BL by ∼2-fold at similar cutoff concentrations. At a 1 ng/mL cutoff for OF, the mean detection time was 34 h for OC and NOC. These data provide new information that should facilitate interpretation of OC test results.

  12. Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release

    PubMed Central

    Forsgren, Johan; Pedersen, Christian; Strømme, Maria; Engqvist, Håkan

    2011-01-01

    In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2∶1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial. PMID:21423616

  13. Pain catastrophizing and pain coping among methadone-maintained patients*

    PubMed Central

    Garnet, Brian; Beitel, Mark; Cutter, Christopher J.; Savant, Jonathan; Peters, Skye; Schottenfeld, Richard S.; Barry, Declan T.

    2010-01-01

    Objective The aim of this study was to examine the association of pain catastrophizing and pain coping strategies with characteristic pain intensity (an average of worst, least, and typical pain intensity in the past week) and recent pain-related disability (an average of three measures of past week pain interference) in opioid dependent patients enrolled in a methadone maintenance treatment program (MMTP) who reported recent pain. Design Cross-sectional survey. Patients One hundred and eight MMTP patients who reported recent pain. Measures Participants completed measures of demographics, pain status (i.e. “chronic severe pain” [pain lasting at least 6 months with at least moderate pain intensity or significant pain interference in the past week] vs. “some pain” [pain in the past week not meeting the threshold of chronic severe pain]), characteristic pain intensity, recent pain-related disability, somatization, depression, catastrophizing, and pain coping strategies. Results Catastrophizing explained a significant proportion of the variance in characteristic pain intensity (14%) and recent pain-related disability (11%) after controlling for demographics, pain status, somatization, and depression. Mirroring the findings of studies of non-opioid dependent chronic pain patients, greater catastrophizing was associated with greater pain intensity and increases in recent pain-related disability. On average, the chronic severe pain group reported higher levels of catastrophizing than the some pain group. Conclusion Consistent with studies of patients with chronic pain who are not opioid dependent, our findings emphasize the importance of assessing and addressing catastrophizing in MMTP patients with pain. PMID:21087402

  14. 77 FR 67397 - Manufacturer of Controlled Substances; Notice of Application; Johnson Matthey, Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-09

    ...) II Drug Schedule Diphenoxylate (9170) II Hydrocodone (9193) II Meperidine (9230) II Methadone (9250) II Methadone intermediate (9254) II Morphine (9300) II Thebaine (9333) II The company plans...

  15. Metabolism and Disposition of Prescription Opioids: A Review.

    PubMed

    DePriest, A Z; Puet, B L; Holt, A C; Roberts, A; Cone, E J

    2015-07-01

    Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subjectto drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5'-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation.

  16. Metabolism and Disposition of Prescription Opioids: A Review.

    PubMed

    DePriest, A Z; Puet, B L; Holt, A C; Roberts, A; Cone, E J

    2015-07-01

    Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subjectto drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5'-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation. PMID:26227254

  17. Concurrent Heroin Use and Correlates among Methadone Maintenance Treatment Clients: A 12-Month Follow-up Study in Guangdong Province, China

    PubMed Central

    Luo, Xiaofeng; Zhao, Peizhen; Gong, Xiao; Zhang, Lei; Tang, Weiming; Zou, Xia; Chen, Wen; Ling, Li

    2016-01-01

    Objective: To assess concurrent heroin use and correlates among Methadone Maintenance Treatment (MMT) clients in Guangdong Province, China. Method: Demographic and drug use data were collected with a structured questionnaire, and MMT information was obtained from the MMT clinic registration system in Guangdong. Human immunodeficiency virus (HIV-) and hepatitis C virus (HCV) infected status and urine morphine results were obtained from laboratory tests. Logistic regressions were employed to investigate the factors associated with concurrent heroin use. Results: Among the 6848 participants, 75% continued using heroin more than once during the first 12 months after treatment initiation. Concurrent heroin use was associated with inharmonious family relationship (OR (odds ratio) = 1.49, 95% CI (confidence intervals): 1.24–1.78), HIV positivity (OR = 1.25, 95% CI: 1.01–1.55), having multiple sex partners (OR = 1.34, 95% CI: 1.07–1.69), having ever taken intravenous drugs (OR = 0.81, 95% CI: 0.69–0.95), higher maintenance dose (OR = 1.13, 95% CI: 1.01–1.28) and poorer MMT attendance (OR<20% = 1.32, 95% CI: 1.13–1.53; OR20%– = 1.33, 95% CI: 1.14–1.54; OR50%– = 1.69, 95% CI: 1.44–2.00). Among those who used heroin concurrently, the same factors, and additionally being older (OR35– = 1.26, 95% CI: 1.11–1.43; OR≥45 = 1.63, 95% CI: 1.30–2.05) and female (OR = 1.60, 95% CI: 1.28–2.00), contribute to a greater frequency of heroin use. Conclusions: Concurrent heroin use was prevalent among MMT participants in Guangdong, underscoring the urgent needs for tailored interventions and health education programs for this population. PMID:27005649

  18. Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing

    PubMed Central

    Begg, Evan J; Malpas, Timothy J; Hackett, L Peter; Ilett, Kenneth F

    2001-01-01

    Aims To measure the interdose milk to plasma ratio (M/P) of R- and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure. Methods Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of ≥40 mg day−1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0–4, 4–8, 8–12, 12–16, 16–20, and 20–24 h after dose. R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/PAUC was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg−1. Results For immature milk (n = 8) the M/PAUC for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/PAUCs for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). Conclusions Breastfeeding during medium to high dose methadone appears to be ‘safe’ according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk-benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome. PMID:11736879

  19. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

    PubMed Central

    Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

    2015-01-01

    Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

  20. The Relationship between Sugar-Containing Methadone and Dental Caries: A Systematic Review

    ERIC Educational Resources Information Center

    Tripathee, Sheela; Akbar, Tahira; Richards, Derek; Themessl-Huber, Markus; Freeman, Ruth

    2013-01-01

    Objectives: To review the evidence of a relationship between sugar-containing methadone and dental caries. Data sources: A systematic search of Cochrane Library, PubMed, PsychINFO, EMBASE, MEDLINE, Current Controlled Trials, WHO, OHRN, SIGLE and ERIC databases was conducted from January 1978 up to June 2010. Study selection: Articles were assessed…

  1. Patterns in admission delays to outpatient methadone treatment in the United States.

    PubMed

    Gryczynski, Jan; Schwartz, Robert P; Salkever, David S; Mitchell, Shannon Gwin; Jaffe, Jerome H

    2011-12-01

    Waiting lists for methadone treatment have existed in many U.S. communities, but little is known nationally about what patient and service system factors are related to admission delays that stem from program capacity shortfalls. Using a combination of national data sources, this study examined patterns in capacity-related admission delays to outpatient methadone treatment in 40 U.S. metropolitan areas (N = 28,920). Patient characteristics associated with admission delays included racial/ethnic minority status, lower education, criminal justice referral, prior treatment experience, secondary cocaine or alcohol use, and co-occurring psychiatric problems. Injection drug users experienced fewer delays, as did self-pay patients and referrals from health care and addiction treatment providers. Higher community-level utilization of methadone treatment was associated with delay, whereas delays were less common in communities with higher utilization of alternative modalities. These findings highlight potential disparities in timely admission to outpatient methadone treatment. Implications for improving treatment access and service system monitoring are discussed.

  2. Psychological Symptoms in Methadone Maintenance Patients: Prevalence and Change over Treatment.

    ERIC Educational Resources Information Center

    Corty, Eric; And Others

    1988-01-01

    Twice interviewed methadone maintenance patients in three cities using Addiction Severity Index. Of subjects followed, 35.4 percent reported having experienced recent psychological symptoms. Found no relation between length of time in treatment at first interview and psychiatric severity. Over one-year period, treatment that subjects received from…

  3. Prize Reinforcement Contingency Management for Cocaine Dependence: Integration with Group Therapy in a Methadone Clinic

    ERIC Educational Resources Information Center

    Petry, Nancy M.; Martin, Bonnie; Simcic, Francis

    2005-01-01

    In this study, the authors evaluated a low-cost contingency management (CM) procedure for reducing cocaine use and enhancing group therapy attendance in 77 cocaine-dependent methadone patients. Patients were randomly assigned to 12 weeks of standard treatment or standard treatment with CM, in which patients earned the opportunity to win prizes…

  4. Gabapentin improves Cold-pressor Pain Responses in Methadone-maintained Patients

    PubMed Central

    Compton, Peggy; Kehoe, Priscilla; Sinha, Karabi; Torrington, Matt A.; Ling, Walter

    2010-01-01

    Individuals on methadone maintenance for the treatment of addiction (MM) are demonstrated to be hyperalgesic to cold-pressor pain in comparison to matched controls and ex-opioid addicts, a finding described as clinical evidence of opioid-induced hyperalgesia (OIH). Interestingly, opioids induce hyperalgesia via many of the same neuro-inflammatory and central sensitization processes that occur with the development of neuropathic pain. Evaluated in this study was the efficacy of a key pharmacotherapy for neuropathic pain, gabapentin (GPN), to reverse OIH in MM patients. Utilizing a clinical trial design and double blind conditions, changes in cold-pressor pain threshold and tolerance following a five-week trial of GPN (titrated to 2400mg/day) were evaluated at peak and trough methadone plasma levels in a well-characterized MM sample. Drug abstinence was encouraged via an escalating payment schedule, and compliance monitored via pill counts and GPN plasma levels; entered into the analyses were only those subjects compliant and abstinent throughout the study (approx 45%). Utilizing change scores from baseline, significant improvements in cold-pressor pain threshold and pain tolerance were observed at both peak and trough methadone levels (p < 0.05). Notably, drop-out rates due to medication side effects were low (2%) and the medication was well-tolerated. These results support that GPN, as prescribed for the treatment of neuropathic pain, is effective in decreasing OIH in patients who are abstinent and stable in methadone treatment. PMID:20163921

  5. Voucher-Based Contingent Reinforcement of Smoking Abstinence among Methadone-Maintained Patients: A Pilot Study

    ERIC Educational Resources Information Center

    Dunn, Kelly E.; Sigmon, Stacey C.; Thomas, Colleen S.; Heil, Sarah H.; Higgins, Stephen T.

    2008-01-01

    This study evaluated the efficacy of a contingency management (CM) intervention to promote smoking cessation in methadone-maintained patients. Twenty participants, randomized into contingent (n = 10) or noncontingent (n = 10) experimental conditions, completed the 14-day study. Abstinence was determined using breath carbon monoxide and urine…

  6. Self-Efficacy and Illicit Opioid Use in a 180-Day Methadone Detoxification Treatment.

    ERIC Educational Resources Information Center

    Reilly, Patrick M.; And Others

    1995-01-01

    Studied self-efficacy and treatment outcomes in a sample of opioid addicts. Results show self-efficacy influenced subsequent drug use in parallel with previous behavior. Suggests that psychological constructs like self-efficacy may hold promise for understanding and decreasing illicit opioid use during long-term methadone detoxification treatment.…

  7. Impact of a methadone maintenance program on an Aboriginal community: a qualitative study

    PubMed Central

    Landry, Michel; Veilleux, Nadia; Arseneault, Julie-Eve; Abboud, Saneea; Barrieau, André; Bélanger, Mathieu

    2016-01-01

    Background: Methadone maintenance treatment programs implemented in Aboriginal communities have proven to be beneficial for the control of opioid addiction and its associated consequences, but the perceptions and opinions of different community members about these programs remain elusive. The goal of this study was to determine the perceptions of members of a First Nation community in New Brunswick, Canada, on the implementation of a methadone maintenance treatment program and its effects on the community. Methods: We conducted a qualitative study using semistructured focus group discussions with 3 distinct groups composed of health care professionals and influential community members, patients in the methadone maintenance treatment program and community members at large. Thematic analysis of discussion transcripts was performed. Results: A total of 22 partipants were included in the 3 focus groups. All groups of participants expressed that patients in the program are stigmatized and marginalized. Discussions also revealed widespread misconceptions about the program. Participants associated the program with improvements in community-level outcomes and in parenting abilities of patients, but also with difficulties preserving family unity. Interpretation: Despite being culturally adapted to the community, elements surrounding the methadone maintenance treatment program in this First Nation community appear to be misunderstood and stigmatized. It may be beneficial to provide community education on these programs to assure community buy-in for the successful implementation of harm reduction programs in Aboriginal communities. PMID:27730106

  8. The 2-Year Test-Retest Reliability of the Psychopathy Checklist-Revised in Methadone Patients.

    ERIC Educational Resources Information Center

    Rutherford, Megan; Cacciola, John S.; Alterman, Arthur I.; McKay, James R.; Cook, Terry G.

    1999-01-01

    Examined the two-year test-retest reliability of the Psychopathy Checklist-Revised (R. Hare, 1991)(PCL-R) in 200 men and 25 women methadone patients. Stability of the PCL-R was generally good, but the measure was somewhat more reliable as a continuous measure than a dichotomous measure. (SLD)

  9. Evidence-Based Drug Treatment Practice and the Child Welfare System: The Example of Methadone

    ERIC Educational Resources Information Center

    Lundgren, Lena M.; Schilling, Robert F.; Peloquin, Susan D.

    2005-01-01

    This article examined the extent to which methadone maintenance (MM) is considered a treatment alternative for drug-dependent parents, as reflected in the social work and child welfare literature and in child welfare policies. Findings were derived from a review of 15 social work journals published from 1996 through 2002 and from a review of child…

  10. Randomized Trial of Contingent Prizes versus Vouchers in Cocaine-Using Methadone Patients

    ERIC Educational Resources Information Center

    Petry, Nancy M.; Alessi, Sheila M.; Hanson, Tressa; Sierra, Sean

    2007-01-01

    Contingency management (CM) interventions frequently utilize vouchers as reinforcers, but a prize-based system is also efficacious. This study compared these approaches. Seventy-four cocaine-dependent methadone outpatients were randomly assigned to standard treatment (ST), ST plus a maximum of $585 in contingent vouchers, or ST plus an expected…

  11. Impact of a Vocational Counselor on Employment-Related Outcomes among Methadone Patients.

    ERIC Educational Resources Information Center

    Appel, P. W.; Smith, R.; Schmeidler, J. B.; Randell, J.

    2000-01-01

    Studied the effects of placement of a vocational rehabilitation counselor (VRC) in methadone maintenance clinics for 333 and 358 patients. Results suggest that placement of a VRC in clinic settings is a cost effective change to vocational and educational services. (SLD)

  12. Contracting for Treatment Termination to Reduce Illicit Drug Use among Methadone Maintenance Treatment Failures.

    ERIC Educational Resources Information Center

    Dolan, Michael P.; And Others

    1985-01-01

    Evaluated the effectiveness of a contingency contracting intervention on reducing illicit drug use by methadone maintenance outpatients. Illicit drug use was significantly reduced during the 30-day intervention and remained below baseline levels during 60-day follow-up. (Author/MCF)

  13. Methadone: The Drug and Its Therapeutic Uses In the Treatment of Addiction. Series 31, No. 1.

    ERIC Educational Resources Information Center

    Gamage, James R.; Zerkin, E. Lief

    This fact sheet from the National Clearinghouse for Drug Abuse Information discusses methadone, a therapeutic drug for the treatment of narcotic addiction. It reviews the pharmacology of the drug as well as physiological and psychological effects, patterns of use, and adverse effects (toxicity and poisoning). It examines the success rates of…

  14. Intervention for Infants and Toddlers Exposed to Methadone in Utero: Three Case Studies.

    ERIC Educational Resources Information Center

    Burns, M. Susan; And Others

    1996-01-01

    Three case studies describe intervention with infants/toddlers who were exposed to methadone in utero. Intervention included providing therapeutic nursery services and addressing developmental and mental health needs of the children and the high-risk family systems, including parents' knowledge of child development and parents' emotional support…

  15. UHPLC-MS/MS quantification of buprenorphine, norbuprenorphine, methadone, and glucuronide conjugates in umbilical cord plasma.

    PubMed

    Kyle, Amy Redmond; Carmical, Jennifer; Shah, Darshan; Pryor, Jason; Brown, Stacy

    2015-10-01

    Opioid use during pregnancy can result in the newborn being physically dependent on the substance, thus experiencing drug withdrawal, termed neonatal abstinence syndrome (NAS). Buprenorphine and methadone are two drugs used to treat opioid withdrawal and are approved for use in pregnancy. Quantification of these compounds in umbilical cord plasma would help assess in utero exposure of neonates in cases of buprenorphine or methadone use during pregnancy. An LC-MS/MS method using solid-phase extraction sample preparation was developed and validated for the simultaneous quantification of methadone, buprenorphine, norbuprenorphine, and glucuronide metabolites in umbilical cord plasma. The average accuracy (percentage error) and precision (relative standard deviation) were <15% for each validated concentration. Our data establishes a 2 week maximum freezer storage window in order to achieve the most accurate cord plasma concentrations of these analytes. Additionally, we found that the umbilical cord tissue analysis was less sensitive compared with analysis with umbilical cord blood plasma, indicating that this may be a more appropriate matrix for determination of buprenorphine and metabolite concentrations. This method was successfully applied to the analysis of cord blood from women with known buprenorphine or methadone use during pregnancy. PMID:25808363

  16. Effect of Subchronic Intravenous Morphine Infusion and Naloxone-Precipitated Morphine Withdrawal on P-gp and Bcrp at the Rat Blood-Brain Barrier.

    PubMed

    Chaves, Catarina; Gómez-Zepeda, David; Auvity, Sylvain; Menet, Marie-Claude; Crété, Dominique; Labat, Laurence; Remião, Fernando; Cisternino, Salvatore; Declèves, Xavier

    2016-01-01

    Chronic morphine regimen increases P-glycoprotein (P-gp) and breast cancer-resistance protein (Bcrp) expressions at the rat blood–brain barrier (BBB) but what drives this effect is poorly understood. The objective of this study is to assess subchronic continuous morphine infusion and naloxone-precipitated morphine withdrawal effects on P-gp/Bcrp contents and activities at the rat BBB. Rats were treated either with (i) a continuous i.v. morphine for 120 h, (ii) escalating morphine dosing (10-40 mg/kg, i.p., 5 days), (iii) a chronic morphine regimen (10 mg/kg s.c., 5 days) followed by a withdrawal period (2 days) and treatment for 3 additional days. Animal behavior was assessed after naloxone-precipitated withdrawal (1 mg/kg, s.c.). P-gp/Bcrp expressions and activities were determined in brain microvessels by qRT-PCR, Western blot, UHPLC–MS/MS, and in situ brain perfusion of P-gp or Bcrp substrates. Results show continuous i.v. morphine did not change P-gp/Bcrp protein levels in rat brain microvessels, whereas naloxone-precipitated withdrawal after escalating or chronic morphine dose regimen increased Mdr1a and Bcrp mRNA levels by 1.4-fold and 2.4-fold, respectively. Conversely, P-gp/Bcrp protein expressions remained unchanged after naloxone administration, and brain uptake of [3H]-verapamil (P-gp) and [3H]-mitoxantrone (Bcrp) was not altered. The study concludes subchronic morphine infusion and naloxone-precipitated morphine withdrawal have poor effect on P-gp/Bcrp levels at the rat BBB.

  17. Involvement of cyclic AMP systems in morphine physical dependence in mice: prevention of development of morphine dependence by rolipram, a phosphodiesterase 4 inhibitor

    PubMed Central

    Mamiya, Takayoshi; Noda, Yukihiro; Ren, Xiuhai; Hamdy, Moustafa; Furukawa, Shoei; Kameyama, Tsutomu; Yamada, Kiyofumi; Nabeshima, Toshitaka

    2001-01-01

    In this study, we examined whether morphine dependence was inhibited by rolipram, a cyclic AMP selective phosphodiesterase inhibitor in mice, since a role for the cyclic AMP systems in the development of morphine dependence has been reported. Mice, which received morphine (10 mg kg−1 s.c.) twice a day for 5 days showed withdrawal syndromes such as jumping, rearing and forepaw tremor following naloxone challenge (5 mg kg−1 i.p.) on the 6th day. Such mice exhibited a significant elevation of cyclic AMP levels in the thalamus compared to control mice. However, co-administration of rolipram (1 mg kg−1 i.p.) with morphine for 5 days significantly attenuated the severity of the withdrawal syndrome and the increase in the cyclic AMP levels after the administration of naloxone. In naïve mice, acute morphine treatment (10 mg kg−1 s.c.) decreased cyclic AMP levels in the thalamus and cerebral cortex 10 min later. The decrease of cyclic AMP levels induced by acute morphine treatment was blocked by co-administration of rolipram (1 mg kg−1 i.p.). However, acute rolipram did not affect the naloxone-precipitated morphine withdrawal syndrome. These results suggest that the elevation of the cyclic AMP levels is involved in the development of morphine withdrawal syndrome and that blockade of the morphine-induced reduction of cyclic AMP levels by chronic rolipram inhibits the development of dependence and the behavioural and biochemical changes induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence. PMID:11226142

  18. Methadone Induction in Primary Care for Opioid Dependence: A Pragmatic Randomized Trial (ANRS Methaville)

    PubMed Central

    Carrieri, Patrizia Maria; Michel, Laurent; Lions, Caroline; Cohen, Julien; Vray, Muriel; Mora, Marion; Marcellin, Fabienne; Spire, Bruno; Morel, Alain; Roux, Perrine

    2014-01-01

    Objective 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. Methods 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. Results 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). Conclusions 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

  19. Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

    PubMed Central

    Wang, R.; Luo, W.-L.; Wastall, P.; Kandoussi, H.; DeMicco, M.; Bruce, R. D.; Hwang, C.; Bertz, R.; Bifano, M.

    2015-01-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized Cmax for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  20. Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

    PubMed

    Garimella, T; Wang, R; Luo, W-L; Wastall, P; Kandoussi, H; DeMicco, M; Bruce, R D; Hwang, C; Bertz, R; Bifano, M

    2015-09-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  1. Effect of isolation on pain threshold and on different effects of morphine.

    PubMed

    Coudereau, J P; Monier, C; Bourre, J M; Frances, H

    1997-08-01

    1. The effect of three periods of isolation (8, 15 and 30 days) were studied in mice on the pain threshold and the sensitivity to morphine. 2. The pain threshold was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation. 3. The analgesic effect of morphine was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation. 4. The tolerance to morphine analgesia was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation (morphine-induced analgesia was reduced). 5. The physical dependence on morphine induced by precipitated withdrawal was unchanged after 8 and 15 days of isolation but decreased after 30 days of isolation. 6. It is suggested that isolation may modify the metabolism the metabolism/absorption of morphine in a different way according as the treatment is unique or chronic. PMID:9380794

  2. Protective Effect of Bacoside-A against Morphine-Induced Oxidative Stress in Rats.

    PubMed

    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.

  3. Protective Effect of Bacoside-A against Morphine-Induced Oxidative Stress in Rats

    PubMed Central

    Sumathi, T.; Nathiya, V. C.; Sakthikumar, M.

    2011-01-01

    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. Ca2+ and Mg2+ ATPases) activities in rat. The results of the present study indicate that bacoside-A protects the brain from oxidative stress induced by morphine. PMID:22707825

  4. Modulation of ethanol-intake by morphine: Evidence for a central site of action

    SciTech Connect

    Wild, K.D.; Reid, L.D. )

    1990-01-01

    Previous studies have shown that subcutaneous administration of low doses of morphine increase, while subcutaneous naloxone decreases, ethanol-intake in rats. However, the site of action of morphine modulation of ethanol-intake remains unclear. In an attempt to elucidate this issue, seven graded doses of morphine were given intracerebroventricularly to rats 15 min prior to an opportunity to consume water and sweetened alcoholic beverage for 2 hr. Two lower doses of intracerebroventricular morphine reliably increased ethanol-intake, while higher doses decreased intake of water. Preference ratios were reliably increased by morphine doses of 1 {mu}g and higher. The present data provide support for a central site of morphine modulation of ethanol-intake.

  5. Different neural systems mediate morphine reward and its spontaneous withdrawal aversion.

    PubMed

    Vargas-Perez, Hector; Ting-A-Kee, Ryan; van der Kooy, Derek

    2009-05-01

    The opponent-process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non-drug-dependent rats were examined using a place-conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non-dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non-dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself.

  6. Simultaneous analysis of codeine, morphine, and heroin after B-glucuronidase hydrolysis.

    PubMed

    Zezulak, M; Snyder, J J; Needleman, S B

    1993-11-01

    Analysis of the opiates, morphine and codeine, often proceeds by way of acid hydrolysis for release of the parent morphine from its glucuronide formed during metabolism. Following use, heroin is rapidly deacetylated to 6-monoacetylmorphine (6-MAM), which can be detected in the urine for a short time following injection of heroin. Only a small amount of 6-MAM may be further metabolized to morphine glucuronide. Thus, in general, the urine specimen has not been hydrolyzed prior to analysis for heroin, using a separate procedure from morphine and codeine. Simultaneous analysis of morphine, codeine, 6-MAM and heroin would be complicated by loss of identity between morphine and heroin when heroin converts to morphine following acid hydrolysis for removal of the glucuronide moiety from morphine glucuronide. Another significant problem in simultaneous analysis is the relative disparity in concentration between morphine/codeine and 6-MAM/heroin (which might be present in the urine specimen). In the proposed method of analysis, free morphine resulting from B-glucuronidase rather than acid hydrolysis of morphine glucuronide is derivatized with propionic anhydride to form dipropionylmorphine. Heroin that does not react with B-glucuronidase remains unhydrolyzed as the diacetylmorphine derivative. Some of the more exacting steps for the acid procedure are eliminated altogether making overall costs for the enzyme procedure comparable to those of the acid hydrolysis method. The enzyme reaction mixture is purified through a solid phase column system. The optimal conditions for concentration of enzyme, temperature of hydrolysis and pH are individually characterized for B-glucuronidase hydrolysis and the ions which identify the propionyl derivatives are characterized for the simultaneous analysis of morphine, codeine, 6-MAM and heroin. PMID:8263474

  7. Different neural systems mediate morphine reward and its spontaneous withdrawal aversion.

    PubMed

    Vargas-Perez, Hector; Ting-A-Kee, Ryan; van der Kooy, Derek

    2009-05-01

    The opponent-process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non-drug-dependent rats were examined using a place-conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non-dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non-dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself. PMID:19453632

  8. Forced exercise improves passive avoidance memory in morphine-exposed rats.

    PubMed

    Saadipour, K; Sarkaki, A; Alaei, H; Badavi, M; Rahim, F

    2009-09-01

    The aim of this study was to investigate the effect of short-term forced exercise protocol on passive avoidance retention in morphine-exposed rats. Effects of morphine on acquisition and retrieval of retention have been proven in the avoidance paradigms. Twenty four male Wistar rats weighing 250-300 g were used in this study. Animals were randomly divided into four groups including: (1) non-morphine-exposed without exercise (nA.nE) (2) non-morphine-exposed with exercise (nA.E) (3) morphine-exposed without exercise (A.nE) and (4) morphine-exposed with exercise (A.E). Rats ran as forced exercise on the motorized treadmill 1 h daily for ten days. Morphine-exposed animals received intraperitoneal morphine during first 5 days of the exercise period and their dependence to morphine was confirmed by naloxane admistration (10 mg kg(-1), i.p.) and withdrawal test. After 10 days of forced exercise, step down latency was tested and Inflexion Ratio (IR) was evaluated in each rat. Baseline step down latencies before any morphine exposing or exercise have shown no significant alteration in all groups. Inflexion Ratio (IR) ofnA.E group has increased significantly (p<0.001) at 1, 3, 7 and 14 days after receiving shock (learning) compared to nA.nE and A.E groups. Our data showed that short-term forced exercise on treadmill improved retention in both morphine-exposed and non morphine-exposed rats at least up to 7 days and more than 14 days, respectively. Alteration in retention between exercised groups may attribute the release of adrenal stress hormones such as epinephrine and corticosterone because of the emotional arousal.

  9. Feasibility of Promoting Smoking Cessation Among Methadone Users Using Multimedia Computer-Assisted Education

    PubMed Central

    Lapshin, Oleg; Cha, Eunme

    2008-01-01

    Background The prevalence of smoking is very high among methadone users. As a method of delivering health education, computers can be utilized effectively. However computer-assisted education in methadone users has not been evaluated systematically. Objective This study was aimed at assessing feasibility and patient acceptance of an interactive educational module of a multi-component smoking cessation counseling computer program for former illicit drug users treated in an outpatient methadone clinic. Methods The computer-mediated education for hazards of smoking utilized in this study was driven by major constructs of adult learning theories. The program interface was tailored to individuals with minimal computer experience and was implemented on a touch screen tablet PC. The number of consecutive methadone-treated current smokers enrolled in the study was 35. After providing socio-demographic and smoking profiles, the patients were asked to use the educational program for 40 minutes. The impact of the computer-mediated education was assessed by administering a pre- and post-intervention Hazards of Smoking Knowledge Survey (HSKS). An attitudinal survey and semi-structured qualitative interview were used after the educational session to assess the opinions of participants about their educational experience. Results The computer-mediated education resulted in significant increase of HSKS scores from 60.5 ± 16.3 to 70.4 ± 11.7 with t value 3.69 and P < .001. The majority of the patients (78.8%) felt the tablet PC was easy to use, and most of the patients (91.4%) rated the educational experience as good or excellent. After controlling for patient baseline characteristics, the effect of computer-mediated education remained statistically significant. Conclusions Computer-assisted education using tablet PCs was feasible, well-accepted, and an effective means of providing hazards of smoking education among methadone users. PMID:18984556

  10. Auditory target processing in methadone substituted opiate addicts: The effect of nicotine in controls

    PubMed Central

    Müller, Bernhard W; Specka, Michael; Steinchen, Nicolai; Zerbin, Dieter; Lodemann, Ernst; Finkbeiner, Thomas; Scherbaum, Norbert

    2007-01-01

    Background The P300 component of the auditory evoked potential is an indicator of attention dependent target processing. Only a few studies have assessed cognitive function in substituted opiate addicts by means of evoked potential recordings. In addition, P300 data suggest that chronic nicotine use reduces P300 amplitudes. While nicotine and opiate effects combine in addicted subjects, here we investigated the P300 component of the auditory event related potential in methadone substituted opiate addicts with and without concomitant non-opioid drug use in comparison to a group of control subjects with and without nicotine consumption. Methods We assessed 47 opiate addicted out-patients under current methadone substitution and 65 control subjects matched for age and gender in an 2-stimulus auditory oddball paradigm. Patients were grouped for those with and without additional non-opioid drug use and controls were grouped for current nicotine use. P300 amplitude and latency data were analyzed at electrodes Fz, Cz and Pz. Results Patients and controls did not differ with regard to P300 amplitudes and latencies when whole groups were compared. Subgroup analyses revealed significantly reduced P300 amplitudes in controls with nicotine use when compared to those without. P300 amplitudes of methadone substituted opiate addicts were in between the two control groups and did not differ with regard to addit