http://www.blackwell-synergy.com/doi/abs/10.1111/j.1360-0443.2006.01360.x Addiction Volume 101 Page 608 - April 2006 doi:10.1111/j.1360-0443.2006.01360.x Volume 101 Issue 4 Letters to the Editor BUPRENORPHINE IN PREGNANCY: THE ADVANTAGES JAMES J. NOCON ------------ NOCON, JAMES J. (2006) BUPRENORPHINE IN PREGNANCY: THE ADVANTAGES. Addiction 101 (4), 608-608. doi: 10.1111/ j.1360-0443.2006.01360.x ----------- Herget G. Methadone and buprenorphine added to the WHO list of essential medicines.: HIV AIDS Policy Law Rev. 2005 Dec;10(3):23-4. In March 2005, methadone and buprenorphine were recently added as "complimentary" medicines to the 14th Model List of Essential Medicines (LEM) released by the World Health Organization (WHO). Studies have shown that these drugs increase adherence to antiretroviral therapy as well as reduce the risk of HIV infection among injection drug users (IDUs). ------------ J Pharm Pharmacol. 2006 Mar;58(3):295-302. In-vitro and in-vivo characterization of a buprenorphine delivery system. Kleppner SR, Patel R, McDonough J, Costantini LC. Titan Pharmaceuticals, Inc, 400 Oyster Point Blvd, Suite 505, South San Francisco, CA 94080, USA. Buprenorphine is a mu-opioid receptor partial agonist with enhanced safety and comparable efficacy to methadone for treatment of opioid dependence. The sublingual formulation of buprenorphine, approved for treatment of opioid dependence, produces variable buprenorphine blood levels and requires frequent dosing that limits patient compliance. To achieve stable buprenorphine levels that may improve patient outcome, an implantable sustained buprenorphine delivery system was developed. Each implant consists of ethylene vinyl acetate copolymer and 90 mg buprenorphine HCl, and measures 26 mm in length and 2.4 mm in diameter. Steady-state release in-vitro was 0.5 mg/implant/day. In-vivo pharmacokinetics and safety were examined for up to 52 weeks in beagle dogs receiving 8, 16 or 24 subcutaneous implants. Plasma buprenorphine concentrations correlated with the number of implants administered. Peak buprenorphine concentrations were generally reached within 24 h after implantation. Steady-state plasma levels were attained between 3 and 8 weeks, and were maintained for study duration, with a calculated mean release rate of 0.14+/-0.04 mg/implant/day. There were no test-article-related adverse effects. This delivery system can provide long-term stable systemic buprenorphine levels, and may increase patient compliance, thereby improving outcome for opioid-dependent patients. ------------ Biol Psychiatry. 2006 Mar 11; Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System. Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M. From the Department of Experimental Medicine and Public Health (RC, DE, MM), University of Camerino, Camerino, Italy. BACKGROUND: Activation of the NOP receptor by its endogenous ligand nociceptin/orphanin FQ reduces ethanol intake in genetically selected alcohol preferring Marchigian Sardinian alcohol preferring (msP) rats. Here we evaluated whether buprenorphine, a partial agonist at mu-opioid and NOP receptors, would reduce ethanol consumption in msP rats via activation of NOP receptors. METHODS: Marchigian Sardinian alcohol preferring rats trained to drink 10% alcohol 2 hours/day were injected with buprenorphine (.03, .3, 3.0, or 6.0 mg/kg intraperitoneally [IP]) 90 min before access to ethanol. RESULTS: Similar to prototypical mu-agonists, the two lowest doses of buprenorphine significantly increased ethanol consumption (p < .01); in contrast, the two highest doses reduced it (p < .05). Pretreatment with naltrexone (.25 mg/kg IP) prevented the increase of ethanol intake induced by .03 mg/kg of buprenorphine (p < .001) but did not affect the inhibition of ethanol drinking induced by 3.0 mg/kg of buprenorphine. Conversely, pretreatment with the selective NOP receptor antagonist UFP-101 (10.0 or 20.0 mug/rat) abolished the suppression of ethanol drinking by 3.0 mg/kg of buprenorphine. CONCLUSIONS: Buprenorphine has dualistic effects on ethanol drinking; low doses increase alcohol intake via stimulation of classic opioid receptors, whereas higher doses reduce it via activation of NOP receptors. We suggest that NOP agonistic properties of buprenorphine might be useful in the treatment of alcoholism. PMID: 16533497 [PubMed - as supplied by publisher] ------------ Addict Behav. 2006 Mar 6; [Epub ahead of print] Related Articles, Links Click here to read Well-being, psychosocial factors, and side-effects among heroin-dependent inpatients after detoxification using buprenorphine versus clonidine. Ponizovsky AM, Grinshpoon A, Margolis A, Cohen R, Rosca P. Mental Health Services, Ministry of Health, 2 Ben Tabai St., Jerusalem, 93591, Israel. Previous studies comparing buprenorphine and clonidine provided little information about subjective factors associated with the effective management of opioid withdrawal. This study sought to compare detoxification programs using these medications with regard to side-effects and related distress, general well-being, perceived self-efficacy and social support. A total of 200 treatment-seeking heroin-dependent patients, aged 18-50, were randomly assigned to buprenorphine or clonidine inpatient withdrawal treatments over 10days followed by 11days of relapse prevention measures. A semi-structured interview and a battery of self-rating scales assessing parameters of the interest were administered to the patients who completed the 10-day detoxification protocol with buprenorphine (n=90) and clonidine (n=50). Chi-square statistics and analysis of covariance were performed to examine between-group differences. Compared with patients treated with clonidine, patients who received buprenorphine developed significantly less side-effects and related distress, and had higher senses of well-being, self-efficacy and social support. The findings suggest that buprenorphine is preferable for inpatient detoxification due to its side-effects profile and positive effects on well-being and psychosocial variables. These early benefits of buprenorphine could enable consequent maintenance treatment. PMID: 16524668 [PubMed - as supplied by publisher] ------------ Ann Pharmacother. 2006 Mar;40(3):392-6. Epub 2006 Feb 28. Related Articles, Links Click here to read Effect of Buprenorphine and Antiretroviral Agents on the QT Interval in Opioid-Dependent Patients. Baker JR, Best AM, Pade PA, McCance-Katz EF. Addiction Psychiatry, Virginia Commonwealth University, Richmond, VA. BACKGROUND: Cardiac arrhythmias have been linked to treatment with methadone and levacetylmethadol. HIV-positive patients often have conditions that place them at risk for QT interval prolongation including HIV-associated dilated cardiomyopathy, coronary artery disease as a consequence of highly active antiretroviral (ARV) therapy-associated metabolic syndrome, and uncorrected electrolyte abnormalities. As of February 14, 2006, no cases of adverse events related to QT interval prolongation have been reported in patients receiving buprenorphine, an opioid partial agonist and the newest drug approved for the treatment of opioid dependence. OBJECTIVE: To evaluate the effects of buprenorphine/naloxone alone and in combination with 1 of 5 ARV agents (efavirenz, nelfinavir, delavirdine, ritonavir, lopinavir/ritonavir) on the QT interval. METHODS: This study was prospective, open-label, and within-subject in design, with subjects serving as their own controls. In 50 HIV-negative, opioid-dependent subjects, electrocardiogram recordings were obtained at baseline, after receiving buprenorphine/naloxone for 2 weeks, and then following buprenorphine/naloxone plus ARV administration for 5-15 days at steady-state. QTc interval measurements were compared using mixed-model, repeated-measures ANOVA. Recent cocaine use and gender were considered covariates. RESULTS: Buprenorphine/naloxone alone and often in the presence of evidence for recent use of cocaine did not significantly alter the QT interval (p = 0.612). Buprenorphine/naloxone in combination with ARVs caused a statistically, but not clinically, significant increase (p = 0.005) in the QT interval. Subjects receiving buprenorphine/naloxone in combination with either delavirdine or ritonavir had the greatest increase in QTc intervals. CONCLUSIONS: Prolonged QT intervals were not observed in opioid-dependent subjects receiving buprenorphine/naloxone alone. QT interval increases were observed with buprenorphine/naloxone in combination with either delavirdine or ritonavir, which inhibit CYP3A4. PMID: 16507617 [PubMed - in process] ----------- J Subst Abuse Treat. 2006 Mar;30(2):159-163. Related Articles, Links Click here to read Slow tapering from methadone maintenance in a program encouraging indefinite maintenance. Calsyn DA, Malcy JA, Saxon AJ. Department of Veterans Affairs, Puget Sound Health Care System, Seattle, WA 98108, USA; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98108, USA; University of Washington Alcohol and Drug Abuse Institute, Seattle, WA 98105, USA. Longitudinal studies have indicated that most opioid agonist-using patients are not able to successfully complete tapering attempts. Little is known, however, about tapering within a treatment environment that is supportive of indefinite agonist treatment and medication tapering. In this study, all records of patients beginning a slow methadone taper were reviewed (N = 30). No patient successfully completed methadone tapering. Four patients (13.3%) successfully switched to buprenorphine/naloxone, one of whom tapered off buprenorphine/naloxone. Three patients (10%) were continuing their taper at the study's end. One patient transferred to another program, one was administratively discharged, and one had his taper stopped for mishandling doses. The remaining patients (n = 20, 66.7%) stopped their tapers for the following reasons: feeling unstable/withdrawal symptoms (n = 4, 13.3%), drug use/positive urinalysis results (n = 12, 40%), psychiatric instability (n = 3, 10%), and pain management (n = 1, 3.3%). Only one patient prematurely left treatment secondary to a failed taper attempt. Patients attempting tapers should be informed about the difficulty involved and be monitored closely for signs of instability. For a few patients, a taper to a lower methadone dose and a switch to buprenorphine/naloxone are obtainable. Program policies that support both tapering attempts and indefinite maintenance are described in this article. PMID: 16490679 [PubMed - as supplied by publisher] ----------- Cas Lek Cesk. 2006;145(1):59-60. Related Articles, Links [Abuse of buprenorphine becomes a problem of the Czech Republic] [Article in Czech] Nespor K, Csemy L. Psychiatricka lecebna Bohnice, Praha. nespor.k@seznam.cz Buprenorphine (Subutex) is according to epidemiological data and clinical experience abused on a large scale in the Czech Republic and for some drug dependent persons it becomes a principal intravenously applied drug. This problem can be resolved by more appropriate training of physicians who prescribe the drug and especially by the introduction of the combination buprenorphine and naloxone (Suboxone) which is not abused intravenously. The registration of Suboxone in the Czech Republic was not initiated by the manufactures so far. PMID: 16468244 [PubMed - indexed for MEDLINE] ----------- iochem Pharmacol. 2006 Apr 14;71(8):1255-64. Epub 2006 Feb 7. Related Articles, Links Click here to read The effect of methadone and buprenorphine on human placental aromatase. Zharikova OL, Deshmukh SV, Nanovskaya TN, Hankins GD, Ahmed MS. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA. Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17beta-estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent K(m) values were 0.2+/-1 and 6+/-3muM, respectively. V(max) values for E(2) and E(3) formation were 70+/-16 and 28+/-10pmol/mg proteinmin, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E(2) and 16-OHT to E(3). The K(i) for methadone inhibition of E(2) and E(3) formation were 393+/-144 and 53+/-28muM, respectively, and for BUP the K(i) was 36+/-9 and 6+/-1muM. The higher potency of the two opiates and their metabolites in inhibiting E(3) formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E(3) formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens. PMID: 16455059 [PubMed - in process] ----------- Am J Vet Res. 2006 Feb;67(2):222-9. Related Articles, Links Effects of preoperative epidural administration of racemic ketamine for analgesia in sheep undergoing surgery. Guedes AG, Pluhar GE, Daubs BM, Rude EP. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108-1016, USA. OBJECTIVE: To investigate the effects of preoperative epidural administration of racemic ketamine to provide analgesia in sheep undergoing experimental hind limb orthopedic surgery. ANIMALS: 12 adult sheep (weight range, 51.4 to 67.2 kg). PROCEDURE: Sheep were anesthetized with guaifenesin, thiopental, and isoflurane; after induction of anesthesia, sheep received a lumbosacral epidural injection of ketamine (1 mg/kg; n = 6) or saline (0.9% NaCl) solution (1 mL/7 kg; 6 [control group]). Respiratory and cardiovascular variables were recorded before and at intervals during and for 6 hours after anesthesia. During that 6-hour postoperative period, analgesia was evaluated subjectively with a numeric ranking scale that included assessments of comfort, posture, movement, and response to wound palpation; buprenorphine was administered when a score > 3 (maximum score, 10) was achieved. Rectal temperature, heart and respiratory rates, and lameness were evaluated daily for 2 weeks after surgery. RESULTS: At all evaluations, cardiovascular and respiratory variables were comparable between the 2 groups. Compared with control sheep, time to first administration of rescue analgesic was significantly longer and total dose of buprenorphine administered during the 6- hour postoperative period was significantly decreased for ketamine-treated sheep. During the second week following surgery, ketamine-treated sheep had significantly less lameness than control sheep. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep undergoing hind limb surgery, preoperative epidural administration of ketamine appears to provide analgesia in the immediate postoperative period and has residual analgesic effects, which may contribute to more rapid return of normal function in surgically treated limbs. PMID: 16454625 [PubMed - in process] ------------ Am J Drug Alcohol Abuse. 2006;32(1):1-6. Related Articles, Links Support for buprenorphine and methadone prescription to heroin-dependent patients among New York City physicians. Coffin PO, Blaney S, Fuller C, Vadnai L, Miller S, Vlahov D. New York Academy of Medicine, New York, New York, 10029, USA. poc2@columbia.edu Methadone and buprenorphine are treatments for heroin-dependent patients. Methadone is available through highly-regulated treatment centers while buprenorphine was approved in 2002 for prescription by certified physicians. Just prior to the approval of buprenorphine, we conducted a random postal survey of 770 physicians in New York City to determine willingness to prescribe methadone or buprenorphine for heroin-dependent patients to be picked up at a pharmacy. Among 247 respondents, 36.3% would consider prescribing methadone and 17.9% were unsure, while 25.8% would consider prescribing buprenorphine and 31.8% were unsure. Willingness to prescribe methadone or buprenorphine was associated with more recent year of licensure (p = 0.044; p = 0.033), working in a hospital or clinic as opposed to an office setting (p = 0.009; p = 0.024), and being the director of a clinic or program (p = 0.031; p = 0.008). This preliminary study suggests that a substantial proportion of New York City physicians would prescribe methadone or buprenorphine to heroin-dependent patients. PMID: 16450639 [PubMed - indexed for MEDLINE] ------------- Am J Addict. 2006 Jan-Feb;15(1):61-70. Related Articles, Links Click here to read Transferring methadone-stabilized pregnant patients to buprenorphine using an immediate release morphine transition: an open-label exploratory study. Jones HE, Suess P, Jasinski DR, Johnson RE. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. A transition from methadone to buprenorphine without intervening withdrawal symptoms is critical for advancing the treatment of opioid-dependent patients. Four pregnant inpatients were transferred from methadone (65-85 mg) to five days of immediate release morphine (IRM) and then to buprenorphine (12-28 mg). Withdrawal scores decreased during the five days of IRM and subsequently increased over the first three days on buprenorphine. The transitional use of IRM appears safe for both mother and fetus. Withdrawal symptoms appeared during buprenorphine induction; however, these data suggest that the intensity of withdrawal symptoms may be lessened by the dose and frequency of buprenorphine administration. (Am J Addict 2006;15:61-70). PMID: 16449094 [PubMed - in process] --------------- Am J Addict. 2006 Jan-Feb;15(1):1-7. Related Articles, Links Click here to read Inpatient Initiation of Buprenorphine Maintenance vs. Detoxification: Can Retention of Opioid-Dependent Patients in Outpatient Counseling Be Improved? Caldiero RM, Parran TV, Adelman CL, Piche B. Department of Psychiatry, University of Washington School of Medicine, Seattle, Washington. Buprenorphine-naloxone is an office-based opioid agonist released in 2003 in the United States for the maintenance of heroin- and other opioid-dependent patients. Concern has been raised that the medication will distract or otherwise inhibit patients from participating in a holistic recovery program or abstinence-based counseling. Using a retrospective chart review, the first thirty opioid-dependent patients induced on buprenorphine maintenance therapy in an inpatient detoxification unit were compared to thirty age- and gender-matched patients who underwent detoxification (with a tramadol taper) and referral to intensive outpatient treatment. The clinical outcomes were a comparison of completion rates for an intensive outpatient program (IOP) and retention in treatment after twelve weeks of aftercare therapy. Patients induced on buprenorphine maintenance over three days had similar relief of withdrawal symptoms to patients detoxified from opioids over five days with tramadol. Patients maintained on buprenorphine had a markedly increased initiation of IOP and remained in outpatient treatment longer than patients who were detoxified (8.5 wks vs. 0.4 wks, p < 0.001). This study indicates that induction and maintenance on buprenorphine may be more effective than detoxification for engaging and retaining patients in abstinence-based comprehensive outpatient addiction treatment. (Am J Addict 2006;15:1-7). PMID: 16449087 [PubMed - in process --------------- Addiction. 2006 Feb;101(2):275-81. Related Articles, Links Click here to read Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study. Fischer G, Ortner R, Rohrmeister K, Jagsch R, Baewert A, Langer M, Aschauer H. Department of Psychiatry, Medical University of Vienna MUW, Vienna, Austria. AIMS: To evaluate the efficacy and safety of methadone versus buprenorphine treatment in pregnant opioid-dependent women. DESIGN: Randomized, double-dummy, double-blind, flexible-dosing comparison study. SETTING: Addiction Clinic at the Medical University of Vienna, Austria. PARTICIPANTS: Eighteen women were assigned randomly to receive either methadone (n = 9) or buprenorphine (n = 9) during weeks 24-29 of pregnancy. After dropouts, data were available from 14 cases (six in the methadone and eight in the buprenorphine group). INTERVENTION: Sublingual buprenorphine tablets (8-24 mg/day) or oral methadone solution (40-100 mg/day), with matched placebos. MEASUREMENTS: Mothers: retention in treatment, urine toxicology and nicotine use. Neonates: Routine birth data, neonatal abstinence syndrome (NAS) in severity and duration. FINDINGS: There was somewhat greater retention in the buprenorphine group but significantly lowered use of additional opioids in the methadone group (P = 0.047).Neonates: There was earlier onset of NAS in neonates born to the methadone (mean 60 hours) than to the buprenorphine groups (mean 72 hours after last medication); 43% did not require NAS-treatment with short treatment duration in both groups (mean 5 days). CONCLUSION: This preliminary study had limited power to detect differences but the trends observed suggest this kind of research is practicable and that further studies are warranted. PMID: 16445556 [PubMed - in process] ----------- Subst Use Misuse. 2006;41(2):223-44. Related Articles, Links Click here to read Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants. Giacomuzzi S, Kemmler G, Ertl M, Riemer Y. University Department of Psychiatry, Innsbruck, Austria. salvatore.giacomuzzi@uibk.ac.at With use of a randomized study design, quality of life (QOL) and physical symptoms of opioid addicts at admission were compared with slow-release oral morphine, methadone, and sublingual buprenorphine maintenance program participants after 6 months of treatment. The study was conducted from February to July 2004 in the outpatient drug user treatment center at University Department of Psychiatry at Innsbruck, providing maintenance treatment programs and detoxification in Tyrol, Austria. One hundred twenty opioid users seeking treatment were compared with 120 opioid-dependent patients retained for 6 months on a slow-release oral morphine, methadone, or sublingual buprenorphine maintenance program. The German version ("Berlin Quality of Life Profile") of the Lancashire Quality of Life Profile was used, and illicit opioid use was determined by urinalysis. Physical symptoms were measured by using the Opioid Withdrawal Scale. Urinalyses revealed a significantly lower consumption of cocaine and opioids in all three substitution groups than in patients at admission (p < 0.001 and p < or = 0.004, respectively). Both the buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission for stomach cramps (p < or = 0.002), muscular tension (p < or = 0.027), general pain (p < or = 0.001), feelings of coldness (p < or = 0.000), heart pounding (p < or = 0.008), runny eyes (p < or = 0.047), and aggressions (p < or = 0.009). Patients who received slow-release oral morphine treatment generally showed the least favorable QOL scores compared with patients at admission or sublingual buprenorphine and methadone clients. Patients in the sublingual buprenorphine or methadone program showed nearly the same QOL scores. The buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission regarding leisure time (p < or = 0.019), finances (p < or = 0.014), mental health (p < or = 0.010), and overall satisfaction (p < or = 0.010). Slow-release oral morphine is a well-established treatment for pain, but more research is required to evaluate it as a treatment for heroin dependence. The present data indicate that slow-release oral morphine could have some disadvantages compared with sublingual buprenorphine and methadone in QOL, physical symptoms, and additional consumption. The results further suggest that buprenorphine treatment is as effective as methadone in effects on quality of life and physical symptoms. PMID: 16393744 [PubMed - in process] ----------- Exp Clin Psychopharmacol. 2005 Nov;13(4):293-302. Related Articles, Links Click here to read Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence. Marsch LA, Stephens MA, Mudric T, Strain EC, Bigelow GE, Johnson RE. Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. marsch@ndri.org This study examined (1) predictors of treatment outcome for opioid-dependent participants in a single-site controlled trial comparing methadone, buprenorphine, and LAAM treatments and (2) the extent to which various subpopulations of patients may have more successful outcomes with each medication. The relationships between patient demographics, drug use history, and psychological status and outcome measures of treatment retention, opiate use, and cocaine use were assessed. We believe this study to be the first to demonstrate that predictors of treatment success appear to be largely similar in LAAM, buprenorphine, and methadone treatment for opioid dependence. We did not find any factors that would strongly guide selection of one medication over others. Copyright 2005 APA, all rights reserved. Publication Types: * Randomized Controlled Trial PMID: 16366759 [PubMed - indexed for MEDLINE] ----------- Drug Alcohol Depend. 2005 Dec 9; [Epub ahead of print] Related Articles, Links Click here to read Impaired decision-making in opiate-dependent subjects: Effect of pharmacological therapies. Pirastu R, Fais R, Messina M, Bini V, Spiga S, Falconieri D, Diana M. "G. Minardi" Laboratory of Cognitive Neuroscience, Department of Drug Sciences, University of Sassari, Italy; Ser.T. A.S.L No. 7, Carbonia (CA), Italy. Cognitive dysfunction is a major feature of drug addiction. In the present paper, we compared the decision-making ability using the Iowa gambling task of methadone- and buprenorphine-maintained individuals to non opiate-dependent drug-free controls. Buprenorphine-maintained individuals performed better than methadone-maintained individuals, and not differently than non opiate-dependent controls. In addition, methadone-maintained individuals had more perseverative errors on the Wisconsin card sorting task (WCST) as compared with non opiate-dependent drug-free controls whereas buprenorphine-maintained individuals had intermediate scores. Scores on Weschler adult intelligence scale (WAIS-R) were similar for methadone- and buprenorphine-maintained individuals whereas drug-free controls had significantly higher scores. In addition, both opiate-dependent groups performed more poorly than drug-free controls on the Benton visual retention test (BVRT). The results suggest that buprenorphine in contrast to methadone improves decision-making, and thus may be more effective in rehabilitation programs of opiate-dependent subjects and this improvement may be related to its distinct pharmacological action as a k antagonist. PMID: 16343811 [PubMed - as supplied by publisher] ----------- Editorial Is methadone too dangerous for opiate addiction? The case for using a safer alternative, buprenorphine, is strong The first 150 words of the full text of this article appear below. Methadone is an effective treatment for heroin addiction, and it remains the mainstay of drug treatment for opiate dependence in the United Kingdom.1 The lethal dose of methadone is estimated at 50 mg for an opiate-naive adult.2 Nevertheless, many authorities recommend that methadone doses should be gradually increased to maintenance doses of 80-120 mg1—that is, twice the lethal dose for non-users. The greatly increased risk to users from methadone, particularly black market methadone, thus remains a major concern. Buprenorphine is a partial agonist that has a lower potential for causing respiratory depression than many other opioids, including methadone and heroin.3 It is increasingly used in the United Kingdom to treat opiate dependence, with guidelines for clinical management in primary and secondary care summarised by Ford et al4 and Taikato et al.5 It is time it replaced methadone as the mainstay of drug . . . [Full text of this article] BMJ 2005;331:1352-1353 (10 December), doi:10.1136/bmj.331.7529.1352 http://bmj.bmjjournals.com/cgi/content/extract/331/7529/1352 ---------- Pharmacol Ther. 2005 Oct;108(1):119-28. Related Articles, Links Click here to read Challenges in the adoption of new pharmacotherapeutics for addiction to alcohol and other drugs. Saxon AJ, McCarty D. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98108, USA. andrew.saxon@med.va.gov The adoption of pharmacotherapies for the treatment of alcohol and drug use disorders has progressed slowly despite the approval of new and effective medications. This paper begins with overviews of the prevalence of alcohol and drug abuse and dependence, the costs of addiction to the nation, and the value of treatment services. The role of pharmacotherapy in the treatment of addictive diseases is examined, and factors that affect the adoption and use of medications for alcohol and drug treatment are identified and discussed. Investigations that tested the effectiveness of buprenorphine for treatment of opioid dependence in new settings illustrate physician and counselor training and mentorship strategies that may promote the adoption of medications in the treatment of alcohol and drug use disorders. The paper concludes with a discussion of barriers and ways to surmount the barriers and to foster greater use of medications in alcohol and drug treatment. Publication Types: * Review PMID: 16055196 [PubMed - indexed for MEDLINE] ---------- Am J Psychiatry. 2005 Aug;162(8):1432-40. Related Articles, Links Click here to read Medication development for addictive disorders: the state of the science. Vocci FJ, Acri J, Elkashef A. Division of Pharmacotherapies and Medical Consequences of Drug Abuse, 6001 Executive Blvd., Rm. 4133, MSC 9551, Bethesda, MD 20892-9551, USA. fv6k@nih.gov In 1989, the National Institute on Drug Abuse (NIDA) established its Medications Development Program. This program has concentrated on developing pharmacotherapies for opiate and cocaine dependence and, more recently, for methamphetamine and cannabis dependence. The major goals of this program are to optimize existing treatments and to expand treatment options for physicians and patients. This review will concentrate on the development of pharmacotherapies for the following substance abuse disorders: opiate, cocaine, methamphetamine, and cannabis dependence. Left untreated, opiate and stimulant dependence are responsible for significant morbidity and mortality. For example, use of illicit opiates is associated with an increased risk of hepatitis C infection, HIV infection, and other medical consequences, e.g., an overdose. The NIDA Medications Development Program has had success in developing, with pharmaceutical partners, levomethadyl acetate, buprenorphine, and buprenorphine/naloxone for opiate dependence. Moreover, several marketed medications have shown promise in reducing cocaine use. Of interest, these medications likely operate through diverse neurochemical mechanisms, suggesting that combination therapy may be a rational next step that could increase treatment gains further in cocaine-dependent patients. The Medications Development Program has also identified multiple neuronal mechanisms that are altered by chronic administration of drugs of abuse. Advances in neuroscience have identified changes in conditioned cueing, drug priming, stress-induced increases in drug intake, and reduced frontal inhibitory mechanisms as all being possible for the development of, maintenance of, and possible relapse to, addiction. Potential medications that modulate these mechanisms are highlighted. Publication Types: * Review PMID: 16055764 [PubMed - indexed for MEDLINE] --------- Drug Alcohol Rev. 2005 May;24(3):267-74. Related Articles, Links Click here to read From opioid maintenance to abstinence: a literature review. Kornor H, Waal H. Unit for Addiction Medicine, University of Oslo, Norway. hege.kornor@psykiatri.uio.no It appears that the literature on agonist maintenance therapies for opioid dependence pays more attention to outcomes during, rather than after, treatment. This review aims to (a) estimate to what extent opioid abstinence can be expected from former maintenance patients, (b) examine possible relationships between patient and treatment characteristics and abstinence rates and (c) assess the need for research in the field of abstinence-orientated maintenance treatment in general, and time-limited buprenorphine maintenance treatment in particular. Database searches supplemented by cross-references resulted in 12 studies included in the review. The studies were mostly naturalistic follow-up studies of former methadone maintenance patients, authored by US researchers in the 1970s. Buprenorphine was used in only one of the studies, and then as a transition between methadone and abstinence. There were considerable variations in definition and assessment of abstinence. Pooled abstinence rates ranged from 22% to 86%. The single factor associated most frequently with abstinence was voluntary participation in detoxification programmes with eligibility criteria ('therapeutic detoxification'). When 'therapeutic detoxification' was compared to 'non-therapeutic detoxification' the pooled abstinence rates were 48% and 22%, respectively. Abstinence-orientated maintenance therapy may be suitable for a subgroup of patients, but there is a substantial need for research updates. Publication Types: * Review PMID: 16096130 [PubMed - indexed for MEDLINE] ---------- Drug Alcohol Depend. 2005 Sep 1;79(3):303-10. Epub 2005 Mar 31. Related Articles, Links Click here to read Examining the influence of drop-outs in a follow-up of maintained opiate users. Encrenaz G, Rondeau V, Messiah A, Auriacombe M. Laboratoire de Psychiatrie and Jeune Equipe 2358, Bordeaux, France. Gaelle.Encrenaz@isped.u-bordeaux2.fr INTRODUCTION: In most longitudinal studies of problem opiate users, drop-outs are frequent, but not taken into account. However, missing data can induce important bias in parameters estimates. OBJECTIVE: The aim of this study was to examine the influence of drop-outs in the statistical analysis of a follow-up of opiate users in maintenance treatment. METHODS: Participants were 519 patients who had sought maintenance treatment between 1994 and 2001. Drug use was studied using the drug composite score of the Addiction Severity Index. A classical data analysis (linear mixed effects model for repeated measurements) was compared with a selection model, which consists, in this case, of a joint modelling of the score and of the drop-out probability in order to reduce bias induced by drop-outs. RESULTS: At 18 months, 38% of the patients were available for evaluation. Drop-outs were associated with low drug use and were informative. Each model showed that the score decreased over time and that it was associated with psychiatric problems. Unlike the classical method, the joint model showed no significant association between the score and age or treatment setting. CONCLUSIONS: These results show the importance of accounting for informative drop-outs in data analysis before drawing conclusions from such studies. PMID: 16102374 [PubMed - indexed for MEDLINE] --------- J Clin Psychopharmacol. 2005 Oct;25(5):490-3. Related Articles, Links Click here to read Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: results of a randomized clinical trial. Soyka M, Hock B, Kagerer S, Lehnert R, Limmer C, Kuefner H. Psychiatric Hospital, University of Munich, Germany. asatkoordination@mpipsykl.mpg.de BACKGROUND: Cognitive impairment in drug-dependent patients under methadone maintenance treatment has been reported before. We assessed whether patients under buprenorphine, a partial mu-opioid agonist, perform better in cognitive tests measuring psychomotor performance as described in previous nonrandomized studies. METHODS: We performed a randomized clinical trial in 62 drug-dependent patients under either buprenorphine or methadone treatment. Sixteen patients dropped out of maintenance therapy, before the testing was performed, after 8 to 10 weeks of treatment. Several subtests of the Act & React Test System test battery were used measuring visual perception, selective attention, vigilance, reactivity, and stress tolerance. FINDINGS: Although there were no differences in cognitive function at baseline, patients under buprenorphine treatment showed partially better results in some of the domains tested. The used tests are relevant when assessing driving ability. There was a significant correlation between dose of buprenorphine and some test results. We also found a correlation between age and reaction time and between duration of opioid dependence and results in some subtests. INTERPRETATIONS (CONCLUSIONS): When comparing both treatments in drug dependent patients, buprenorphine produces partially less impairment on cognitive functions in some of the subtests of the psychomotor battery than methadone. This difference is specially relevant when it comes to driving ability and social functioning. Publication Types: * Clinical Trial * Randomized Controlled Trial PMID: 16160628 [PubMed - indexed for MEDLINE] --------- Toxicol Appl Pharmacol. 2005 Sep 15; [Epub ahead of print] Related Articles, Links Click here to read Buprenorphne is protective against the depressive effects of norbuprenorphine on ventilation. Megarbane B, Marie N, Pirnay S, Borron SW, Gueye PN, Risede P, Monier C, Noble F, Baud FJ. INSERM U705, CNRS UMR 7157, Universite Paris VII, Hopital Fernand Widal, Paris, France; Reanimation Medicale et Toxicologique, Hopital Lariboisiere, 2 Rue Ambroise Pare, 75010 Paris, France. High dose buprenorphine is used as substitution treatment in heroin addiction. However, deaths have been reported in addicts using buprenorphine. The role of norbuprenorphine, an N-dealkyl metabolite of buprenorphine, was hypothesized to explain these fatal cases. We determined the median intravenous lethal dose (LD(50)) of norbuprenorphine in male Sprague-Dawley rats. The effects of a single intravenous dose of 3 or 9 mg/kg norbuprenorphine alone on arterial blood gases were studied. Finally, the effect of pre- and post-administrations of buprenorphine on norbuprenorphine-induced changes on arterial blood gases were analyzed. Norbuprenorphine's LD(50) was 10 mg kg(-1). Norbuprenorphine 3 mg kg(-1) produces the rapid onset of sustained respiratory depression, as demonstrated at 20 min by a maximal significant increase in PaCO(2) (8.4 +/- 0.9 versus 5.7 +/- 0.1 kPa), decrease in arterial pH (7.25 +/- 0.06 versus 7.44 +/- 0.01), and hypoxia (8.3 +/- 0.6 versus 11.1 +/- 0.2 kPa). Buprenorphine not only protected against the effects of 3 mg kg(-1) norbuprenorphine in a dose-dependent manner but also reversed the effects when given afterward. Binding experiments suggest a role for mu- and to a lesser extent for delta-opioid receptors in buprenorphine protective effect against norbuprenorphine-induced respiratory depression. In conclusion, our data clearly show that norbuprenorphine alone causes important deleterious effects on ventilation in rats. However, buprenorphine protective effect calls into question the role for norbuprenorphine in respiratory toxicity associated with buprenorphine use. PMID: 16169027 [PubMed - as supplied by publisher] ---------- Addict Biol. 2005 Jun;10(2):149-55. Related Articles, Links Induction of patients with moderately severe methadone dependence onto buprenorphine. Glasper A, Reed LJ, de Wet CJ, Gossop M, Bearn J. Drug Dependency Unit, St. George's Hospital, Clare House, Cranmer Terrace, Tooting, London, UK. Current clinical practice allows patients with low levels of physiological dependence on opioids (equivalent to methadone doses of 30 mg/d or less) to be transferred to buprenorphine. This study investigated the response of opioid-dependent patients receiving doses of methadone between 30-70 mg/d when transferred to buprenorphine at doses between 12-16 mg/d. Twenty-three patients receiving inpatient opioid detoxification agreed to take part in a trial of facilitated transfer to buprenorphine. Following the last morning dose of methadone, buprenorphine was substituted in doses increasing from 4 mg to a maximum of 16 mg, with adjunctive lofexidine (maximum of 2.4 mg/d). All except two patients successfully completed transfer to buprenorphine. To investigate the effect of initial methadone dose, the group was split into intermediate dose (ID; 30 - 49 mg/d; n = 10) and high dose (HD; 50-70 mg/d; n = 11) groups. Average stabilisation dose of buprenorphine for the sample who completed transfer was 14.0 mg/d (SD 2.3) and average daily lofexidine dose during transfer was 0.57 mg (SD 0.39). The HD group used significantly more lofexidine to complete transfer compared to the ID group. Increased opioid withdrawal symptoms, of mild severity as measured by the Short Opiate Withdrawal Scale (SOWS), were found in the HD group compared with the ID group during the first and last day of buprenorphine stabilisation. However, average SOWS scores for the whole of the period of transfer were not significantly different from those during the period of stabilisation on buprenorphine in either the ID or HD groups. This study suggests that transfer to buprenorphine is relatively uncomplicated from daily methadone doses of 30-70 mg in an inpatient setting and may be facilitated by use of lofexidine. This procedure may allow a larger proportion of opioid-dependent patients access to buprenorphine treatment. PMID: 16191667 [PubMed - indexed for MEDLINE] ---------- 1: Addict Biol. 2005 Jun;10(2):157-64. Related Articles, Links Mood and affect during detoxification of opiate addicts: a comparison of buprenorphine versus methadone. Seifert J, Metzner C, Paetzold W, Borsutzky M, Ohlmeier M, Passie T, Hauser U, Becker H, Wiese B, Emrich H, Schneider U. Department of Clinical Psychiatry and Psychotherapy, Hannover Medical School, Germany. Seifert.Juergen@mh-hannover.de Twenty-six in-patients with Diagnostic and Statistical Manual version IV (DSM-IV) criteria for opioid dependence were selected at random to receive either a combination of an 11-day low-dose buprenorphine and a 14-day carbamazepine regimen (n = 14) or a combination of an 11-day methadone and a 14-day carbamazepine regimen (n = 12) in a double-blind, randomized 14-day in-patient detoxification treatment. Patients with buprenorphine and carbamazepine showed a significantly better psychological state after the first and second weeks of treatment. Above all, the buprenorphine-treated patients demonstrated a less marked tiredness, sensitiveness and depressive state as well as a more prominent elevated mood during the detoxification process. Seven non-completers (after 7 days: four of 12 = 33.3%; after 14 days: seven of 12 = 58.3%) were treated with methadone and carbamazepine and five non-completers (after 7 days: two of 14 = 14.3%; after 14 days: five of 14 = 35.7%) received buprenorphine and carbamazepine. The difference in the overall dropout rate after day 14 was not significant. The present study supports the hypothesis that the combination of buprenorphine and carbamazepine leads to a better clinical outcome than does a combination of methadone and carbamazepine in the detoxification of opioid addicts with additional multiple drug abuse. The buprenorphine and carbamazepine-regimen provides a more effective short-term relief of affective disturbances than does methadone and carbamazepine. No severe side effects occurred during the treatment period in both groups. Publication Types: * Clinical Trial * Randomized Controlled Trial PMID: 16191668 [PubMed - indexed for MEDLINE] ----------- Schmerz. 2005 Nov 10; [Epub ahead of print] Related Articles, Links Click here to read [Transdermal buprenorphine during pregnancy.] [Article in German] Ebner E, Wiedmann M. Praxis fur Anasthesiologie, Stolberg, . Buprenorphine has been widely used and studied for over 20 years and has been shown to be an effective opioid analgesic. Some years ago a buprenorphine formulation for transdermal therapy of chronic cancer-related and non-cancer-related pain became available. We report the case of a woman who received a lower dosed transdermal buprenorphine patch (3/5 of a 35 microg/h patch corresponding to release of 21 microg/h buprenorphine) during pregnancy without any complication for herself or the child. The patient has now being using the transdermal system for more than 2 years and has reported continuous excellent pain relief. The buprenorphine patch was well tolerated and produced no effect on vigilance over the whole period of administration. PMID: 16283207 [PubMed - as supplied by publisher] ------------ Forensic Sci Int. 2005 Nov 7; [Epub ahead of print] Related Articles, Links Click here to read Fatal poisoning in Nordic drug addicts in 2002. Steentoft A, Teige B, Holmgren P, Vuori E, Kristinsson J, Hansen AC, Ceder G, Wethe G, Rollmann D. Institute of Forensic Medicine, University of Copenhagen, Department of Forensic Chemistry, Frederik Vs Vej 11, Copenhagen, Denmark. The present study from 2002 includes medicolegally examined fatal poisonings among drug addicts in the five Nordic countries: Denmark, Finland, Iceland, Norway and Sweden. A common definition "drug addict" is applied by the participating countries. The number of deaths, age, sex, place of death, main intoxicant and other drugs present in the blood are recorded in order to obtain national data, as well as comparable Nordic data and data comparable to earlier studies from 1997 and 1991. The Icelandic results are commented on separately due to the low number of cases. The most fatal overdoses are seen in Norway, in both the death rate (number per 100,000 inhabitants=8.44) and in absolute number (n=232). The comparable figures for the other four countries are Denmark 5.43 (n=175), Iceland 3.6 (n=6), Finland 2.93 (n=94) and Sweden 2.56 (n=136). In earlier studies from 1991 and 1997, the highest death rate is seen in Denmark, with Norway as number two. Denmark is the only country where the death rate decreases from 1997 to 2002. A relatively large increase in deaths in the younger age groups (<30 years) is noted from 1997 to 2002, except in Denmark, where only a small increase in overdose deaths in very young people (15-19 years) is observed. Females account for 12-20% of the overdoses (three out of six deaths in Iceland). Relatively fewer deaths are recorded in the capital areas in 2002 than in 1997 and 1991, suggesting more geographically widespread drug use in the Nordic countries. Heroin/morphine is the single most frequently encountered main intoxicant, varying from 10% of the cases in Finland to 72% of the cases in Norway. Finland differs from the other countries in that a high percentage of the fatal overdoses in Finland are not caused by an illicit drug; buprenorphine overdoses are seen, and relatively few deaths resulting from heroin are seen. Methadone is the main intoxicant in 41% of the Danish overdose cases, 15% of the Norwegian cases, 4% of the Swedish cases and none of the Finnish overdose cases, an observation probably linked to different national prescription rules for methadone. The analytical screening reveals extended polydrug use. Frequently seen substances, in addition to the main intoxicant are amphetamine, tetrahydrocannabinol (THC), benzodiazepines and ethanol. PMID: 16289615 [PubMed - as supplied by publisher] ------------ J Gen Intern Med. 2005 Nov;20(11):1038-41. Related Articles, Links Click here to read Buprenorphine retention in primary care. Stein MD, Cioe P, Friedmann PD. Division of General Internal Medicine, Rhode Island Hospital, Providence, RI 02903, USA. mstein@lifespan.org BACKGROUND: This study assesses the rate and predictors of treatment retention for primary care patients with opioid dependence-prescribed buprenorphine, a long-acting partial opioid agonist. METHODS: Observational cohort study of patients prescribed buprenorphine/naloxone and followed for 6 months in the period after the adoption of buprenophine/naloxone by a primary care practice in Rhode Island. Practice policy precluded patient discharges due to continuing drug use. RESULTS: Patients (n=41) had a mean duration of opioid use of 15.7 years and most had a history of heroin use (63.4%). Thirty-nine percent of patients transferred from methadone maintenance. At 24 weeks, 59% remained in treatment. Nearly half of dropouts occurred in the first 30 days. Participants with opiate-positive toxicologies at week 1 were more likely to drop out of the program (P<.01) and had a significantly shorter retention time (P<.01) on average. Among other drug use and drug treatment variables, employment and addiction counseling during treatment were significantly associated with treatment retention (P=.03). CONCLUSION: Retention rates in a real world, primary care-based buprenorphine maintenance practice reflect those reported in clinical trials. Abstinence during the first week of treatment and receipt of counseling were critical to patient retention. PMID: 16307630 [PubMed - in process] ------------ Prog Neuropsychopharmacol Biol Psychiatry. 2006 Mar;30(2):265-72. Epub 2005 Nov 23. Related Articles, Links Click here to read Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study. Gerra G, Leonardi C, D'Amore A, Strepparola G, Fagetti R, Assi C, Zaimovic A, Lucchini A. Addiction Treatment Centre, AUSL Parma, Italy. The present study compared retrospectively in a clinical non-experimental setting the efficacy of buprenorphine (BUP) in different subgroups of dually diagnosed and non-dually diagnosed opioid-dependent patients: all the subjects included in the study showed severe long-lasting heroin addiction and 68.4% were affected by psychiatric comorbidity. Participants (206) (mean age 32.2+/-8.9, 177 males-29 females) were applicants to a long-term buprenorphine treatment program (mean doses 7.9+/-0.42 mg). Aim of the study was to evaluate dual diagnosis variables possibly influencing retention rate and abstinence from illicit drugs. The patients were divided into 5 subgroups on the basis of dual diagnosis: group 1: major depression (MD) 29.61%; group 2: generalized anxiety (GAD) (11.2%); group 3: personality disorders (PD), antisocial-borderline (21.84%); group 4: schizophrenia (SC)(6.3%); group 5: substance use disorder without overt psychiatric comorbidity (SUD) (31.1%). Group 1 patients affected by MD showed the highest retention rate at 12 months (72.1%) in comparison with the other groups of patients: group 2 GAD (39.1%), group 3 PD (17.8%), group 4 SC (7.7%) and group 5 SUD, without comorbidity (45.3%) (p=0.006, p<0.001, p<0.001, p=0.002). Similarly, at 12 months, the patients affected by MD showed less risk of illicit opioid use (16.4%) than those affected by GAD (34.8%), PD (42.2%), SC (53.8%) and SUD without comorbidity (34.4%) (p=0.06, p=0.003, p=0.008, p=0.017). When evaluated on the whole sample, retention rate was not influenced by dose. In contrast, the higher BUP doses were associated with less risk of illicit opioid use, than lower doses (p<0.001). Multivariate analysis and factor analysis showed a greater association of outcome measures (retention rate and negative urines rate) with comorbid diagnosis (depression) (respectively 0.64) than with buprenorphine doses (respectively 0.54). Our data need to be interpreted with caution because of the retrospective methodology applied to a clinical non-experimental setting. BUP seems to be more effective in opioid-dependent patients affected by depression, probably due to the kappa opioid-receptors antagonist action, counteracting dysphoria, negativism and anxiety. High doses of BUP appear to predict a better outcome, in terms of negative urines, but not in terms of retention. PMID: 16309810 [PubMed - in process] ------------ J Subst Abuse Treat. 2005 Dec;29(4):307-12. Related Articles, Links Click here to read Buprenorphine tablet versus liquid: a clinical trial comparing plasma levels, efficacy, and symptoms. Chawarski MC, Moody DE, Pakes J, O'Connor PG, Schottenfeld RS. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. We evaluated peak plasma concentrations, trough concentrations, and the 24-hour area under the concentration curve (AUC(0-24 h)) during maintenance with sublingual (SL) liquid or tablet formulations in 57 opiate-dependent volunteers. Study participants were assigned randomly to one of three SL daily buprenorphine dose pairs and maintained for 2 weeks with the liquid formulation followed by 2 weeks with the corresponding tablet dose. Plasma samples were obtained after at least 10 days of maintenance with the liquid formulation and after at least 10 days of that with the tablet formulation. The bioequivalence of the tablet compared with the liquid doses ranged from 57% to 75% based on peak concentrations, from 102% to 108% based on trough concentrations, and from 66% to 86% based on 24-hour AUC, but there was a large intersubject and intrasubject variability in plasma concentrations, with greater variability following tablets than liquid. Measures of withdrawal symptoms or illicit opioid use were not associated with buprenorphine dose, formulation, or plasma buprenorphine levels. PMID: 16311183 [PubMed - in process] ------------- Addict Biol. 2005 Dec;10(4):365-71. Related Articles, Links Opioid plasma concentrations in methadone-and buprenorphine-maintained patients. Jagsch R, Gombas W, Schindler SD, Eder H, Moody DE, Fischer G. Faculty of Psychology, Clinical and Health Psychology, University of Vienna, Vienna, Austria. reinhold.jagsch@univie.ac.at This is the first trial to compare the relationship of opioid plasma concentrations in methadone-versus buprenorphine-maintained subjects. Sixty subjects (19 females and 41 males) seeking treatment who met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for opioid dependence were recruited and treated at the Drug Addiction Outpatient Clinic at the University of Vienna. Of these, 44 (11 female and 33 male) were included in the analyses of plasma concentrations. Subjects received either daily sublingual buprenorphine (2 mg or 8 mg tablets; maximum daily dose: 8 mg) or oral methadone (racemic R-/S-methadone) and were maintained on a stable dose after an induction period of 2 weeks. Mean dose and mean plasma concentrations were correlated on an individual and collective basis. Correlation was 0.51 for buprenorphine, whereas the score for methadone was 0.69. Intra-individual variation was much higher for buprenorphine (p<0.0001), while the concentration-to-dose ratio was very small. Based on the differences of the pharmacokinetics of blood plasma of the two agents, we tried to explain the differences in the acceptance of treatment, which was significantly lower in the buprenorphine-maintained group. No such differences could be evaluated between completers and dropouts in buprenorphine-maintained subjects, neither concerning withdrawal scores nor dose, plasma concentration, concentration-to-dose ratios or intra-individual variation. PMID: 16318959 [PubMed - in process] ------------- Br J Pharmacol. 2006 Mar;147(6):671-80. Related Articles, Links Click here to read Differential activation of G-proteins by mu-opioid receptor agonists. Saidak Z, Blake-Palmer K, Hay DL, Northup JK, Glass M. [1] 1The Liggins Institute, University of Auckland, Auckland, New Zealand [2] 2Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. We investigated the ability of the activated mu-opioid receptor (MOR) to differentiate between myristoylated G(alphai1) and G(alphaoA) type G(alpha) proteins, and the maximal activity of a range of synthetic and endogenous agonists to activate each G(alpha) protein.Membranes from HEK293 cells stably expressing transfected MOR were chaotrope extracted to denature endogenous G-proteins and reconstituted with specific purified G-proteins. The G(alpha) subunits were generated in bacteria and were demonstrated to be recognised equivalently to bovine brain purified G(alpha) protein by CB(1) cannabinoid receptors. The ability of agonists to catalyse the MOR-dependent GDP/[(35)S]GTP(gamma)S exchange was then compared for G(alphai1) and G(alphaoA).Activation of MOR by DAMGO produced a high-affinity saturable interaction for G(alphaoA) (K(m)=20+/-1 nM) but a low-affinity interaction with G(alphai1) (K(m)=116+/-12 nM). DAMGO, met-enkephalin and leucine-enkephalin displayed maximal G(alpha) activation among the agonists evaluated. Endomorphins 1 and 2, methadone and beta-endorphin activated both G(alpha) to more than 75% of the maximal response, whereas fentanyl partially activated both G-proteins.Buprenorphine and morphine demonstrated a statistically significant difference between the maximal activities between G(alphai1) and G(alphaoA). Interestingly, DAMGO, morphine, endomorphins 1 and 2, displayed significant differences in the potencies for the activation of the two G(alpha). Differences in maximal activity and potency, for G(alphai1) versus G(alphaoA), are both indicative of agonist selective activation of G-proteins in response to MOR activation.These findings may provide a starting point for the design of drugs that demonstrate greater selectivity between these two G-proteins and therefore produce a more limited range of effects.British Journal of Pharmacology (2006) 147, 671-680. doi:10.1038/sj.bjp.0706661; published online 16 January 2006. PMID: 16415903 [PubMed - in process] ------------- Brain Res. 2005 Nov 23;1063(1):84-95. Epub 2005 Nov 2. Related Articles, Links Click here to read Clorazepate affects cell surface regulation of delta and kappa opioid receptors, thereby altering buprenorphine-induced adaptation in the rat brain. Quentin T, Debruyne D, Lelong-Boulouard V, Poisnel G, Barre L, Coquerel A. UMR CEA E2-FRE CNRS 2698 Research Group, Center Cyceron, 15 Boulevard Henry Becquerel, 14070 Caen cedex, France. quentin@cyceron.fr Concomitant abuse of buprenorphine (BPN) and benzodiazepines (BZD) may relate to a pharmacodynamic interaction between the two. The objective of the present work was to investigate the acute and chronic effects of clorazepate (CRZ) alone or in combination with BPN on selective kappa opiate tritiated ligand [3H]-U69 593 and delta opiate radioligand [3H]-deltorphine II binding in the rat brain. Bmax (maximal receptor density) and Kd (the dissociation constant) were directly determined at different brain regions of interest (ROI) selected for high densities of kappa and/or delta receptors in rats treated with BPN and/or CRZ. The agents were administered either once or for 21 consecutive days. Differences in Bmax and Kd (for both specific ligands) were related to drug treatment and receptor location. Globally, single BPN administration induced no changes in kappa or delta opiate receptor binding, whereas repeated BPN administration up-regulated kappa receptor density and decreased delta affinity. At the kappa receptor level, repeated administration of CRZ acted only on Kd, whereas the delta receptor was up-regulated. Repeated addition of CRZ to BPN had no effect on kappa receptor Bmax versus chronic controls. By significantly decreasing Bmax, CRZ nullified the effect of chronic BPN on the kappa receptor. The modifications were strongest in the nucleus accumbens, where both types of receptor occur. Treatments had region-selective effects in some brain areas, such as the amygdala, periaqueductal gray matter, hypothalamus and caudate putamen. Increased mu and delta receptor densities would be expected to provide reinforcement by enhancing reward, and impairment of kappa receptor availability would be expected to decrease aversion. The effects described are likely to influence addictive behavior among people abusing BZD and BPN. PMID: 16269137 [PubMed - indexed for MEDLINE] ------------- Clin Infect Dis. 2005 Jul 1;41 Suppl 1:S89-95. Related Articles, Links Click here to read Treatment of opioid dependence and coinfection with HIV and hepatitis C virus in opioid-dependent patients: the importance of drug interactions between opioids and antiretroviral agents. McCance-Katz EF. Division of Addiction Psychiatry, Virginia Commonwealth University, Richmond, VA 23219, USA. emccancekatz@vcu.edu The occurrence of human immunodeficiency virus (HIV) disease and hepatitis C is common in injection drug users, most of whom are opioid dependent. Methadone pharmacotherapy has been the most widely used treatment for opioid addiction in this population. Methadone has significant, adverse drug-drug interactions with many antiretroviral therapeutic agents that can contribute to nonadherence and poor clinical outcomes in this high-risk population. The present article summarizes current knowledge about interactions between methadone and antiretroviral medications. Buprenorphine is the newest agent available for the treatment of opioid dependence and may have fewer adverse interactions with antiretroviral agents. Buprenorphine has a significant pharmacokinetic interaction with efavirenz but no pharmacodynamic interaction; therefore, simultaneous administration of these drugs is not associated with opioid withdrawal, as has been observed with methadone. This promising finding may simplify the treatment of opioid-dependent patients with HIV disease and should also improve clinical outcomes for persons coinfected with HIV and hepatitis C virus. PMID: 16265622 [PubMed - in process] -------------- Brain Res. 2005 Aug 9;1052(2):222-31. Related Articles, Links Click here to read Acute and chronic administration of clorazepate modifies the cell surface regulation of mu opioid receptors induced by buprenorphine in specific regions of the rat brain. Debruyne D, Quentin T, Poisnel G, Lelong-Boulouard V, Barre L, Coquerel A. Pharmacology Department, University Hospital Centre, Caen, France. debruyne-d@chu-caen.fr The aim of the present study was to investigate the acute and chronic effects of clorazepate (CRZ) alone or in combination with buprenorphine (BPN) on binding of the selective mu opiate tritiated ligand [3H]-DAMGO in the rat brain. Using 0.1 to 5 nM [3H]-DAMGO concentrations and a beta-imager, Bmax (maximal receptor density) and K(D) (the dissociation constant) were directly determined at different regions of interest (ROI) in the brains of rats treated with BPN and/or CRZ administered either once or over 21 consecutive days. Differences in Bmax and K(D) were related to both treatment and location. Acute BPN induced a down-regulation (62% mean decrease in Bmax observed on the whole brain) of mu opiate receptors. CRZ induced a mean 39% decrease in Bmax associated with substantially decreased affinity, particularly after acute administration (136% mean K(D) increase). Addition of CRZ to BPN [mean Bmax decreases of 34% (acute) and 29% (chronic)] induced significantly less down-regulation than did BPN alone, while altering affinity. These changes were maximal in the amygdaloid nucleus. Significant and persistent decreases in Bmax and affinity were also detected in the hippocampus, hypothalamus and thalamus. In the thalamus, an opposite regulation of Bmax was observed that was maximal with the combination. As the regions where changes were greatest have been specifically implicated in memory and socio-emotional functions and/or vegetative and endocrine adaptations, there is reason to suspect that the addition of CRZ to BPN may have clinical consequences. On the one hand, it may have some impact on drug abuse and misuse behaviors towards treatments including heroin substitute and BZD, and on the other, amplify the BPN effect-particularly hedonic or toxic-mainly after sporadic BPN-BZD abuses. These pharmacodynamic findings may explain, at least in part, the well-established preference of patients for the BPN-benzodiazepine combination and the toxicity with which it is associated. PMID: 16023087 [PubMed - indexed for MEDLINE] -------------- Anaesth Intensive Care. 2005 Feb;33(1):17-25. Related Articles, Links High-dose buprenorphine: perioperative precautions and management strategies. Roberts DM, Meyer-Witting M. Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Herston, Brisbane, Queensland. Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered. Publication Types: * Review PMID: 15957687 [PubMed - indexed for MEDLINE] -------------- Pharmacopsychiatry. 2005 Mar;38(2):100-2. Related Articles, Links Click here to read Naltrexone treatment of combined alcohol and opioid dependence: deterioration of co-morbid major depression. Schurks M, Overlack M, Bonnet U. Naltrexone is frequently used for the treatment of opioid or alcohol dependence. However, the reports on its potential to worsen affective disorders are contradicting. Here we report on a patient with combined alcohol and opioid dependence whose co-morbid major depression deteriorated reversibly and repeatedly under naltrexone. By exchanging buprenorphine for naltrexone, his depression and craving for alcohol and opioids disappeared. This underlines the close interaction between depression, substance dependence and the opioid system. Publication Types: * Case Reports * Letter PMID: 15744636 [PubMed - indexed for MEDLINE] ---------------- Biol Pharm Bull. 2005 Feb;28(2):212-6. Related Articles, Links Click here to read Effect of nonspecific binding to microsomes and metabolic elimination of buprenorphine on the inhibition of cytochrome P4502D6. Umeda S, Harakawa N, Yamamoto M, Ueno K. Drug Discovery Research Department, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan. sh.umeda@teijin.co.jp Recently, the pharmaceutical industry has employed the high-throughput method for the evaluation of cytochrome P450 (CYP) inhibition, using a combination of the heterologously expressed enzyme and a fluoregenic substrate. When buprenorphine (BN), a potent mixed agonist-antagonist analgesic, was evaluated by this method, it exhibited potent inhibition of CYP2D6 with an IC50 value of 0.25 microM in recombinant CYP2D6-expressing insect cell microsomes (rCYP2D6 microsomes). In contrast, the IC50 value was 22.7 microM in human liver microsomes (HLM) using a classical method. Although the substrate concentrations in each study were set to near the Km values, there was a large discrepancy in IC50 values. When we investigated the effect of nonspecific binding to microsomes on the inhibitory potency, with a view to clarifying this discrepancy, the unbound fraction in microsomes (fu,mic) was 0.06-0.21 and 0.99 in HLM and rCYP2D6 microsomes, respectively. The corrected IC50 value (1.74 microM) using free BN concentrations was much smaller than the uncorrected value. On the other hand, it was observed that the concentration of BN in HLM decreased rapidly due to metabolism by CYP3A4 while that in rCYP2D6 microsomes decreased only slightly. We then investigated the effect of incubation time on the inhibitory potency, since the rapid elimination of BN in HLM could have been a cause of the discrepancy. The IC50 value for BN was observed to decrease slightly from 22.7 to 17.1 microM, following the shortening of the incubation time from 10 to 2 min in HLM. We conclude that nonspecific binding to microsomes of the inhibitor could affect the inhibitory potency against CYP2D6. If this factor is considered, a more precise estimate of the risk of adverse drug interaction could be achieved. PMID: 15684471 [PubMed - indexed for MEDLINE] ------------- Eur J Clin Pharmacol. 2005 Feb;60(12):875-81. Epub 2005 Jan 19. Related Articles, Links Click here to read Effect of benzodiazepines on the metabolism of buprenorphine in human liver microsomes. Chang Y, Moody DE. Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA. OBJECTIVE: To determine whether enzyme inhibition explains the clinical adverse interaction of benzodiazepines and buprenorphine. METHODS: Buprenorphine was incubated in the presence of benzodiazepines (or metabolites) with human liver microsomes (HLMs). A number of benzodiazepines were screened at therapeutic concentrations after 0-min and 15-min preincubation times. For tentative metabolically activated inhibitors, the kinetics of inhibition was studied in a secondary incubation system. Buprenorphine and norbuprenorphine were quantified by means of liquid chromatography-mass spectrometry. RESULTS: Buprenorphine elimination and norbuprenorphine formation were at most reduced by 26% (i.e., weak or negligible inhibition). Evidence of metabolically activated inhibition suggested the need for further studies on the inhibitory kinetics. Midazolam caused time- and concentration-dependent inhibition of norbuprenorphine formation with pseudo-first-order kinetics, and K(I) and k(inact) values of 10.5 microM and 0.045 min(-1), respectively. Mixed-type inhibition of buprenorphine elimination (K(i) = 30-35 microM) and a noncompetitive inhibition of norbuprenorphine formation were also observed. For clonazepam (up to 10 microM), 3-hydroxy-7-acetamidoclonazepam (up to 10 microM), and alpha-hydroxy-triazolam (up to 1.0 microM), no time- or concentration-dependent inhibition of buprenorphine metabolism was found. CONCLUSION: A single benzodiazepine, midazolam, is a moderate mechanism-based inactivator of buprenorphine N-dealkylation. It is anticipated that repeated exposures to midazolam might alter the in vivo metabolism of buprenorphine. PMID: 15657781 [PubMed - indexed for MEDLINE] -------------