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Drug cues play an important role in relapse to drug use. Naltrexone is an opioid antagonist that is used to prevent relapse in opioid dependence. Central opioidergic pathways may be implicated in the heightened drug cue-reactivity, but the effects of the opioid receptors' blockade on the brain responses to drug cues in opioid dependence are unknown. To pursue this question, we studied 17 abstinent i.v. heroin users with brain functional magnetic resonance imaging (fMRI) during exposure to visual heroin-related cues and matched neutral images before and 10-14 days after an injection of extended-release naltrexone (XRNTX). Whole brain analysis of variance of fMRI data showed main effect of XRNTX in the medial frontal gyrus, precentral gyrus, cuneus, precuneus, caudate and the amygdala. fMRI response was decreased in the amygdala, cuneus, caudate and the precentral gyrus and increased in the medial frontal gyrus and the precuneus. Higher plasma levels of naltrexone's major metabolite, 6-beta-naltrexol, were associated with larger reduction in the fMRI response to drug cues after XRNTX in the precentral, caudate and amygdala clusters. The present data suggest that XRNTX pharmacotherapy of opioid-dependent patients may, respectively, decrease and potentiate prefrontal and limbic cortical responses to drug cues and that this effect might be related to the XRNTX metabolism. Our findings call for further evaluation of the brain fMRI response to drug-related cues and of the 6-beta-naltrexol levels as potential biomarkers of XRNTX therapeutic effects in patients with opioid dependence.

Oral melatonin (MEL) can improve daytime sleep, but the hormone's short elimination half-life limits its use as a hypnotic in shift workers and individuals with jet lag or other sleep problems. Here we show, in healthy subjects, that transdermal delivery of MEL during the daytime can elevate plasma MEL and reduce waking after sleep onset, by promoting sleep in the latter part of an 8-h sleep opportunity. Transdermal MEL may have advantages over fast-release oral MEL in improving sleep maintenance during adverse circadian phases. © 2009 American Society for Clinical Pharmacology and Therapeutics.

Aims Buprenorphine is marketed in a sublingual formulation for treatment of opioid dependence. A transdermal formulation has been developed that may provide extended relief from opioid withdrawal, reduce required clinic visits and improve adherence, while having less potential for diversion and abuse. This study evaluated the safety and biodelivery (blood levels) of this transdermal buprenorphine formulation (i.e. buprenorphine patch), and its apparent efficacy in suppressing the opioid withdrawal syndrome. Design Open-label, first-in-humans trial. Setting A residential research facility. Participants Nine physically dependent opioid-users completed the 10-day opioid detoxification study. Intervention Each volunteer received a single patch application that remained in place for 3 days. The formulation has shown an average delivery of 1.9 mg/day of buprenorphine over 3 days in pre-clinical evaluation. Measures Physiological, behavioral, subjective and observer ratings of opioid withdrawal and opioid agonist effects were collected. Findings Overall, the patch appeared safe and well tolerated. There were no serious adverse events, and no opioid intoxication following patch application. Oxygen saturation, heart rate, blood pressure, skin temperature and pupil diameter remained well within normal ranges. Buprenorphine blood levels peaked 48 hours after patch application at a concentration of 0.60 ng/ml. Volunteers' self-reports of the presence and severity of withdrawal symptoms were reduced by approximately 50% on the 3 days of patch application. Withdrawal symptoms increased marginally upon patch removal. Administration of opioid rescue medication was eliminated within 6 hours of patch application, and increased slightly upon patch removal. Conclusions The significant biodelivery of buprenorphine and the suppression of the opioid withdrawal syndrome during patch application and its reappearance after patch removal indicate clinically useful pharmacodynamic activity. Transdermal buprenorphine may be a useful opioid detoxification treatment that reduces compliance concerns, and delivers buprenorphine in a formulation less likely to be diverted to illicit use.

To improve the analysis of naltrexone and its primary metabolite 6beta-naltrexol, a sensitive and specific method for the analysis of subnanogram-per-milliliter concentrations of these analytes in human, rat, and rabbit plasma was developed utilizing liquid chromatography (LC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS-MS). Plasma samples were extracted utilizing a liquid-liquid extraction technique. Chromatographic separation was achieved using an isocratic solvent system consisting of dilute formic acid and methanol pumped through an ODS-AQ HPLC column. ESI-MS-MS was in the positive ion mode followed by collision-induced dissociation of the protonated molecular ions for naltrexone, 6beta-naltrexol, and their deuterated analogues. This method was validated using Good Laboratory Practice approved methods and was compared to an existing gas chromatography (GC)-MS method by analyzing plasma samples collected from a clinical study. Specificity determined from comparing blank plasma fortified with internal standard to samples fortified with internal standard and analyte at the lower limit of quantitation (LLOQ) from six different human, rat, and rabbit sources demonstrated sufficient signal-to-noise to set the LLOQ at 0.1 ng/mL. This assay has a quantitative range of 0.1-100 ng/mL. The inter- (human only) and intra-assay precision and accuracy in plasma varied by less than 13, 11, and 16% at the LLOQ for both analytes and by less than 10, 10, and 9% at higher concentrations for human, rat, and rabbit plasma, respectively. No loss of analyte was observed after 24 h of room temperature storage in human, rat, and rabbit plasma or three cycles of freezing and thawing of human plasma prior to extraction. Human samples that had been extracted were stable for at least five days when stored frozen at -20 degrees C or for at least two days when stored at room temperature on an autosampler. The GC-MS and LC-MS-MS methods correlated in the measured plasma concentrations of both naltrexone and 6beta-naltrexol. This method has been validated and subsequently used in the determination of the pharmacokinetics of Depotrex in rabbits. In rabbits, the parent compound shows dose-dependent pharmacokinetics as seen in humans, but rabbits have much lower unconjugated metabolite, 6beta-naltrexol, than that seen in humans.

Nalmefene is an opioid antagonist used in the treatment of alcoholism and opioid overdose. A highly sensitive method was developed to measure nalmefene in human and rabbit plasma and rabbit serum. Nalbuphine was used as internal standard. Liquid-liquid extraction was applied using n-butyl chloride/acetonitrile (4:1). High-performance liquid chromatography interfaced by electrospray ionization to a tandem mass spectrometer was used for quantitation. Primary validation experiments were conducted using human plasma then it was cross-validated in rabbit plasma and rabbit serum. Specificity (peak-area ratio of blank plasma or serum to its internal standard as percent of peak-area ratio of blank plasma or serum fortified with 0.1 ng/mL nalmefene to its internal standard) ranged from 2.09 to 5.29 with a mean of 3.21% for human plasma and from 4.08 to 6.63 with a mean of 5.55% for rabbit plasma and from 2.47 to 6.17 with a mean of 3.62% for rabbit serum. The mean recovery for nalmefene was 80% in human plasma. The calibration range was from 0.1 to 100 ng/mL. Intrarun accuracy of the lower limit of quantitation (0.1 ng/mL) in all matrices was within 18.0% of target with intrarun precision within 13.6%. At 0.3, 35, and 75 ng/mL, the intrarun accuracy in all matrices was within 11.9% of target with intrarun precision within 6.6%. The inter-run accuracy in human plasma was within 8.0% of target with inter-run precision within 6.6%. Nalmefene was stable in human and rabbit plasma and rabbit serum for up to 24 h at room temperature and in human plasma after three freeze-thaw cycles. Following intravenous injection of 5 mg/kg nalmefene to rabbits, the mean area under curve for 0 to 24 h was 1116 (ng)(mL)(-1)(h), and the mean plasma clearance was 67.9 (mL)(min)(-1)(kg)(-1).

Buprenorphine, a partial mu-opioid agonist, has been shown effective for treatment of opioid dependence but also has some abuse potential. A novel formulation of buprenorphine, using a polymer microcapsule depot sustained-release technology, has been developed which may offer effective treatment of opioid dependence while also minimizing risks of patient noncompliance and illicit diversion. This open-label, first-in-human study evaluated the safety and pharmacokinetics of a single-dose buprenorphine depot in physically dependent opioid abusers. The present study also examined the efficacy of depot buprenorphine in suppressing symptoms of opioid withdrawal, attenuating the effects of exogenous opioid challenge, and providing clinical detoxification. Five opioid-dependent volunteers each received a single subcutaneous depot injection containing 58 mg of buprenorphine and were assessed for at least four weeks for signs and symptoms of opioid withdrawal, first residentially and then as outpatients. Depot buprenorphine appeared to provide effective relief from opioid withdrawal, with no participant requiring additional medication for withdrawal relief following depot administration. The depot was safe and well-tolerated, with no significant side effects, signs of intoxication, or respiratory depression. In the opioid challenge sessions, depot buprenorphine appeared to produce substantial opioid blockade that persisted for 6 weeks post-depot administration. Results from the present study suggest that depot buprenorphine offers significant promise for enhancing the delivery of effective opioid agonist treatment while minimizing risk for abuse of the medication.

Rationale: Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. Objective: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex®). Methods: Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, six participants received 192 mg naltrexone base and six participants received 384 mg naltrexone base. For safety, the low dose of depot naltrexone was tested before the high dose. The effects of heroin (0, 6.25, 12.5, 18.75, 25 mg, IV) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Active heroin doses were administered in ascending order during the week, while placebo could be administered on any day. Subjective, performance, and physiological effects were measured both before and after heroin administration. The hypotheses were that depot naltrexone would antagonize the effects of heroin, and that the high dose of depot naltrexone would produce a more effective and longer-lasting antagonism than the low dose. Results: The low and high doses of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Plasma levels of naltrexone remained above 1 ng/ml for approximately 3 and 4 weeks after administration of 192 mg and 384 mg naltrexone. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side-effects. Conclusions: These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting antagonism of the effects of heroin.

Drug cues play an important role in relapse to drug use. Naltrexone is an opioid antagonist that is used to prevent relapse in opioid dependence. Central opioidergic pathways may be implicated in the heightened drug cue-reactivity, but the effects of the opioid receptors' blockade on the brain responses to drug cues in opioid dependence are unknown. To pursue this question, we studied 17 abstinent i.v. heroin users with brain functional magnetic resonance imaging (fMRI) during exposure to visual heroin-related cues and matched neutral images before and 10-14 days after an injection of extended-release naltrexone (XRNTX). Whole brain analysis of variance of fMRI data showed main effect of XRNTX in the medial frontal gyrus, precentral gyrus, cuneus, precuneus, caudate and the amygdala. fMRI response was decreased in the amygdala, cuneus, caudate and the precentral gyrus and increased in the medial frontal gyrus and the precuneus. Higher plasma levels of naltrexone's major metabolite, 6-beta-naltrexol, were associated with larger reduction in the fMRI response to drug cues after XRNTX in the precentral, caudate and amygdala clusters. The present data suggest that XRNTX pharmacotherapy of opioid-dependent patients may, respectively, decrease and potentiate prefrontal and limbic cortical responses to drug cues and that this effect might be related to the XRNTX metabolism. Our findings call for further evaluation of the brain fMRI response to drug-related cues and of the 6-beta-naltrexol levels as potential biomarkers of XRNTX therapeutic effects in patients with opioid dependence.

A feasibility study was conducted to pilot test the ability of 5 sites to recruit, treat, and retain opioid-dependent offenders in a trial of extended-release injectable naltrexone (XR-NTX). The participants, 61 previously opioid-dependent individuals under legal supervision in the community, received up to 6 monthly injections of Depotrex brand naltrexone and completed a 6-month follow-up interview. Six-month outcomes showed that those who completed treatment had significantly fewer opioid-positive urines and were less likely to have been incarcerated than those who had not completed treatment. The findings indicate that XR-NTX holds promise as a feasible, effective treatment option for opioid-dependent offenders.

RATIONALE: Managed withdrawal (i.e., detoxification) from opioid dependence is a widespread clinical procedure that is a necessary step for those pursuing abstinence. Buprenorphine is one effective detoxification treatment, however, consensus regarding effective detoxification procedures is lacking. OBJECTIVES: This study evaluated the efficacy of a buprenorphine transdermal formulation (i.e., patch) in suppressing opioid withdrawal, its safety and tolerability, and its biodelivery when applied for 7 days. METHODS: Physically dependent opioid (heroin) users (n = 12) completed a 10-day opioid detoxification in a residential research unit. Each received a single patch application that remained in place for 7 days. Blood samples were drawn prior to patch application and once daily thereafter. Assessments, four times daily, included: the amount of rescue medications ordered to treat withdrawal discomfort; self-report and observer ratings of opioid withdrawal and agonist effects; and vital sign measures. RESULTS: Overall, the patch appeared safe and well-tolerated. Buprenorphine plasma levels peaked 48 h after patch application at 0.59 ng/ml. Indices of withdrawal (self-reports, observer ratings, rescue medication) were significantly reduced within 24 h of patch application, continued to decline thereafter, and did not reappear following patch removal. CONCLUSIONS: This study confirms that transdermal buprenorphine is safe and clinically effective, and suggests that a 7-day application may provide an effective and comfortable means of detoxification. This patch formulation would appear to be a useful opioid detoxification treatment by reducing compliance concerns, and administering buprenorphine in a formulation less likely to be diverted to illicit use.

Buprenorphine is marketed in a sublingual formulation for treatment of opioid dependence. A transdermal formulation has been developed that may provide extended relief from opioid withdrawal, reduce required clinic visits and improve adherence, while having less potential for diversion and abuse. This study evaluated the safety and biodelivery (blood levels) of this transdermal buprenorphine formulation (i.e. buprenorphine patch), and its apparent efficacy in suppressing the opioid withdrawal syndrome.Open-label, first-in-humans trial.A residential research facility.Nine physically dependent opioid-users completed the 10-day opioid detoxification study.Each volunteer received a single patch application that remained in place for 3 days. The formulation has shown an average delivery of 1.9 mg/day of buprenorphine over 3 days in pre-clinical evaluation.Physiological, behavioral, subjective and observer ratings of opioid withdrawal and opioid agonist effects were collected.Overall, the patch appeared safe and well tolerated. There were no serious adverse events, and no opioid intoxication following patch application. Oxygen saturation, heart rate, blood pressure, skin temperature and pupil diameter remained well within normal ranges. Buprenorphine blood levels peaked 48 hours after patch application at a concentration of 0.60 ng/ml. Volunteers' self-reports of the presence and severity of withdrawal symptoms were reduced by approximately 50% on the 3 days of patch application. Withdrawal symptoms increased marginally upon patch removal. Administration of opioid rescue medication was eliminated within 6 hours of patch application, and increased slightly upon patch removal.The significant biodelivery of buprenorphine and the suppression of the opioid withdrawal syndrome during patch application and its reappearance after patch removal indicate clinically useful pharmacodynamic activity. Transdermal buprenorphine may be a useful opioid detoxification treatment that reduces compliance concerns, and delivers buprenorphine in a formulation less likely to be diverted to illicit use.

Aim Buprenorphine is an effective medication for treatment of opioid dependence. An injectable depot formulation of buprenorphine has been developed using biodegradable polymer microcapsule technology. This formulation may offer effective treatment of opioid dependence and enhance treatment delivery while minimizing risks of patient non-adherence or illicit diversion of the medication. This report provides a characterization of the biodelivery of this injectable depot in humans and of the relationship of drug blood levels to pharmacodynamic indices. Method and participants The data are from two studies in which 11 opioid-dependent volunteers each received a single depot injection containing 58 mg of buprenorphine, and include previously unreported detailed plasma concentration data over a 6-week time-course following depot administration and examination of their relationship to pharmacodynamic indices. Findings Mean plasma buprenorphine increased gradually following depot administration, peaked at 2–3 days with a mean concentration of 1.25 ng/ml and then decreased gradually, approaching undetectable levels (

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This 12-week study examined the bioavailability, tolerability, and potential efficacy of an injectable sustained-release preparation (SRP) of naltrexone (NTX). Twenty alcohol-dependent subjects took NTX 50 mg po daily for 2 weeks, followed by a 2-week, no-medication Washout Period, a 4-week Injection Period, and a 4-week Follow-up Period. Fifteen subjects (75%) received a single subcutaneous injection of 206 mg of sustained-release NTX, and five subjects (25%) received a placebo injection. All subjects also received eight weekly coping skills sessions during the Oral NTX, and the Washout and Injection Periods. Results: After injection, NTX plasma concentrations exceeded a mean of 1 ng/ml for 21 days. Adverse effects produced by the SRP of NTX were comparable with those resulting from oral NTX therapy. Compared with placebo, the SRP of NTX significantly reduced the frequency of heavy drinking days during the Injection and Follow-up Periods. Conclusions: The results of this preliminary study support the potential clinical utility of the SRP of NTX for treatment of alcohol dependence.

Two intratubal devices, one covered with a flock made from ethylene vinyl acetate and the other constructed of titanium-aluminum-vanadium alloy with an etched surface were evaluated after being placed in the Fallopian tubes of pigtail monkeys. In some instances, the devices were medicated with 10% silver nitrate or 50% quinacrine hydrochloride. The microflock device anchored in the tube mechanically, but there is no evidence that either the polymeric or metal alloy device formed an actual attachment with Fallopian tube epithelium. It is suggested that a mechanical design approach to ITDs might be more productive than one which assumes a tissue-device bond.