Evaluation of an injection depot formulation of buprenorphine: placebo comparison

AIMS: Buprenorphine is a mu-opioid partial agonist that is marketed in a sublingual formulation as a treatment for opioid dependence. A microcapsule depot sustained-release formulation has been developed which may offer effective treatment of opioid dependence while also minimizing risks of illicit diversion or patient non-compliance. The present study examined the efficacy of depot buprenorphine in suppressing the opioid withdrawal syndrome and in attenuating the effects of exogenous opioid challenge. DESIGN: A placebo-controlled, double-blind, randomized trial. SETTING: A closed residential research facility. PARTICIPANTS: A total of 15 opioid-dependent participants were enrolled into the 6-week study. INTERVENTION: Fifteen participants were randomized to receive a single subcutaneous depot injection containing buprenorphine (58 mg) or placebo. Two participants, both of whom received placebo, terminated participation after depot administration. Thirteen participants (six buprenorphine, seven placebo) completed the 6-week study and were assessed throughout the study for signs and symptoms of opioid withdrawal and for response to weekly subcutaneous challenges with 3 mg hydromorphone. MEASUREMENT: Subjective, physiological and observer-rated indices of opioid withdrawal and opioid agonist effects. FINDINGS: Depot buprenorphine provided more effective relief from opioid withdrawal than placebo, as evidenced by significantly fewer buprenorphine participants requiring supplemental medications for withdrawal suppression after depot administration compared to participants receiving placebo. In the weekly hydromorphone challenge sessions, depot buprenorphine significantly reduced opioid response on measures of subjective effects and pupillary diameter. CONCLUSIONS: Results from this double-blind, placebo-controlled study indicate that depot buprenorphine is effective in providing both withdrawal suppression and opioid blockade. Future studies examining additional doses and repeated dosing regimens with depot buprenorphine are warranted.     

Evaluation of a transdermal buprenorphine formulation in opioid detoxification

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.     

Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine

Aims. Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawalsymptomatology during buprenorphine dose induction, maintenance treatment (daily and alternate-day dosing) and withdrawal . Design. Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52 . Setting. Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD . Participants. Eleven male, heroin-dependent volunteers participating in a research study . Intervention. Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine) . Measurements. Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter . Findings. The mean steady-state buprenorphine plasma concentration (24 hours) after daily administration of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively . Conclusions. During daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.     

Naltrexone depot for treatment of alcohol dependence: a multicenter, randomized, placebo-controlled clinical trial

BACKGROUND: Studies of the efficacy of naltrexone for alcohol dependence have yielded variable findings, which may be due, in part, to variation in compliance with oral naltrexone. Efforts to improve naltrexone compliance have included the development of injectable, long-acting depot formulations. METHODS: We conducted a multicenter trial in 315 subjects who were randomly assigned to receive an intramuscular injection of a depot formulation containing naltrexone (n = 158) or a placebo formulation (n = 157) monthly for 3 months. All patients received five sessions of manual-guided motivational enhancement therapy during the 12 weeks of the study. The outcomes of interest were based on self-reported alcohol use and gamma-glutamyl transpeptidase level. Missing data or data from subjects who discontinued the study were conservatively treated as heavy-drinking days. RESULTS: Groups were comparable on pretreatment demographic and clinical measures. The medication was well tolerated; 73.7% of subjects received all injections. The time to the first heavy-drinking day, the percentage of subjects with no heavy drinking throughout the study, and gamma-glutamyl transpeptidase levels favored the naltrexone depot, although the effects did not reach statistical significance. There was a significant advantage for naltrexone depot treatment on the time to the first drinking day. Naltrexone depot subjects also had significantly fewer drinking days during treatment and a significantly greater abstinence rate than the placebo group (18% vs. 10%). CONCLUSIONS: This is the first multicenter study of a depot formulation of naltrexone for the treatment of alcohol dependence. Using a conservative intent-to-treat analysis, the study showed an advantage for the active medication. Further research with this formulation is warranted.     

The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double‐blind, placebo‐controlled, cross‐over study. Setting An in‐patient research unit at the University of Kentucky. Participants Healthy adults (n = 10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject‐ and observer‐rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time‐ and dose‐dependent increases on subjective and physiological mu‐opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time–course were observed. Buprenorphine bioavailability was 38–44% and T_max was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non‐dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine/naloxone administration may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine, in opioid‐dependent individuals.     

Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence

High-dose methadone is well known to cause testosterone deficiency and sexual dysfunction in opioid-dependent men. Buprenorphine is a new drug for the pharmacotherapy of opioid dependence. Its influence on the gonadal axis has not been investigated to date. We therefore assayed testosterone, free testosterone, estradiol, SHBG, LH, FSH, and prolactin in 17 men treated with buprenorphine. Thirty-seven men treated with high-dose methadone and 51 healthy blood donors served as controls. Sexual function and depression were assessed using a self-rating sexual function questionnaire and the Beck Depression Inventory. Patients treated with buprenorphine had a significantly higher testosterone level [5.1 +/- 1.2 ng/ml (17.7 +/- 4.2 nmol/liter) vs. 2.8 +/- 1.2 ng/ml (9.7 +/- 4.2 nmol/liter); P < 0.0001] and a significantly lower frequency of sexual dysfunction (P < 0.0001) compared with patients treated with methadone. The testosterone level of buprenorphine-treated patients did not differ from that of healthy controls. In conclusion, we demonstrated for the first time that buprenorphine, in contrast with high-dose methadone, seems not to suppress plasma testosterone in heroin-addicted men. To this effect, buprenorphine was less frequently related to sexual side effects. Buprenorphine might therefore be favored in the treatment of opioid dependence to prevent patients from the clinical consequences of methadone-induced hypogonadism.     

Management of Acute Postpartum Pain in Patients Maintained on Methadone or Buprenorphine During Pregnancy

Background: Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients. Objectives: To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate postpartum period. Methods: Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- (n = 8) and methadone-maintained (n = 10) patients over the first five days postpartum were examined. Results: Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use. Conclusions and Scientific Significance: Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.     

Course and treatment of buprenorphine/naloxone withdrawal: an analysis of case reports

Currently published information on buprenorphinenaloxone withdrawal recommends a gradually decreasing dosage over weeks to months. In this case report, abrupt cessation of buprenorphine/naloxone at various doses, and after variable durations of treatment, resulted in mild opiate withdrawal lasting over approximately 1-2 days that did not require additional opioid medication or only specific symptom-relieving, non-opioid, medications. Lengthy withdrawal regimens might prolong withdrawal symptoms unnecessarily, perhaps increasing the risk of re-addiction. Controlled studies of buprenorphine/naloxone withdrawal regimens over varying time frames would help to illuminate the most effective means of opioid discontinuation and inform clinical care. (Am J Addict 2012;00:1-3).     

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine‐maintained intravenous heroin abusers

Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double‐blind, cross‐over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine‐maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self‐administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self‐administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ‘drug liking’ and ‘desire to take the drug again’ were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.     

Naltrexone in the treatment of opioid‐dependent pregnant women: the case for a considered and measured approach to research

The present paper considers naltrexone to treat opioid dependence during pregnancy. The public health problem of opioid dependence and its treatment during pregnancy is reviewed first. Next, the naltrexone and opioid dependence treatment literature is summarized, with overviews of the pre‐clinical and clinical research on prenatal naltrexone exposure. Finally, considerations and recommendations for future medication research for the treatment of opioid dependence in pregnant women are provided. The efficacy of long‐acting injectable naltrexone relative to placebo, its blockade of opioid agonist euphoric effects, its lack of abuse and tolerance development and its modest adverse effect profile make it a potential medication for opioid‐dependent pregnant women. However, it is not without seriously concerning potential drawbacks, including the difficulty surrounding medication induction that may lead to vulnerability with regard to relapse, physical dependence re‐establishment, increased risk behaviors, treatment dropout and resulting opioid overdose. Before embarking on future research with this medication, the benefits and risks for the mother–embryo/fetus/child dyad should be weighed carefully. Should future research be conducted, a multi‐level commitment to proactive ethical research is needed to reach the ultimate goal of improving the lives of women and children affected by opioid dependence.     

Substance use of disorders in HIV-infected patients: impact and new treatment strategies

Substance use of disorders--including alcohol, cocaine, and opiod dependencies--are common in HIV-infected patients. Untreated substance use disorders result in poor HIV disease treatment outcomes; however, several new treatment strategies have emerged in recent years. Combined medication and counseling therapies are effective for alcohol and opioid dependencies, and counseling treatments are effective for cocaine dependence. Office-based treatment with buprenorphine offers the opportunity for coordinated treatment of HIV disease and opioid dependence. This article summarizes a presentation by David A. Fiellin, MD, in March 2004 at the International AIDS Society-USA New York course.     

Benzodiazepines,Methadone and Buprenorphine: Interactions and Clinical Management

Benzodiazepines (BZDs) are widely used by heroin users not in treatment, and by patients in methadone and buprenorphine (BPN) treatment. This review examines the epidemiology of BZD use by opioid users, and the range of harms that are associated with BZD use in this group, including the association of BZD use with opioid‐related mortality. Preclinical and clinical data regarding pharmacokinetic and pharmacodynamic interactions between methadone, buprenorphine, and BZDs are reviewed. An overview of treatment approaches for managing BZD use in this population is presented, including strategies for minimizing abuse and addressing BZD dependence. (Am J Addict 2009;19:59–72)     

Concurrent buprenorphine and benzodiazepines use and self-reported opioid toxicity in opioid substitution treatment

AIMS: To examine concurrent buprenorphine and benzodiazepine consumption and to compare opioid toxicity symptoms induced by methadone and buprenorphine, examining factors associated with the reporting of these symptoms. DESIGN: Self-report cross-sectional survey. SETTING: Five needle syringe programmes and five opioid substitution treatment services in Melbourne, Australia. PARTICIPANTS: A total of 250 people who had experience with methadone or buprenorphine. Eligibility criteria were current or previous methadone or buprenorphine use. MEASUREMENTS: Structured questionnaire covering: demographic characteristics; current treatment and drug use; concurrent use of buprenorphine and benzodiazepines, including route of administration and source of medications; and opioid toxicity symptoms reported in association with methadone and buprenorphine consumption. FINDINGS: Of those reporting buprenorphine use, two-thirds reported concurrent benzodiazepine use, with a median dose reported of 30 mg diazepam equivalents. A greater number of opioid toxicity symptoms were reported in relation to methadone consumption compared with buprenorphine. Those reporting opioid toxicity with buprenorphine were more likely to report intravenous use compared with those reporting opioid toxicity with methadone. CONCLUSIONS: The risk of opioid toxicity appeared greater with methadone compared with buprenorphine, despite high levels of benzodiazepine consumption and injection being reported in relation to buprenorphine use. The prevalence of buprenorphine injection and the normalization of methadone-induced sedation are two findings that merit further investigation. Establishing recommendations as to the safest and most effective way to manage benzodiazepine-using people in opioid substitution treatment is necessary for the optimization of treatment for opioid dependence in polydrug-using individuals.     

Pharmacologic treatments for heroin and cocaine dependence

Given the difficulty of achieving sustained recovery, pharmacotherapy of opioid and cocaine addiction is more effective when combined with behavioral and psychosocial approaches. Effective pharmacotherapies for opioid dependence and withdrawal include methadone, L-alpha acetylmethadol (LAAM), naltrexone, buprenorphine, and clonidine. Treatment of cocaine addiction includes anti-craving agents, dopamine agonists or blocking agents, antidepressants, and treatment of co-morbid psychiatric disorders, but all with mixed results. In this paper, we discuss the use of medication in the context of general principles of opioid and cocaine addiction treatment. Both established medications and promising directions in pharmacotherapy will be addressed.     

Efficacy and tolerability of naltrexone in the treatment of alcohol dependence: oral versus injectable delivery

Oral naltrexone, an opioid antagonist, reduces relapse and heavy drinking in alcohol-dependent patients. However, oral delivery is associated with poor compliance and adverse events. To enhance treatment outcome and reduce side effects, injectable extended-release naltrexone formulations have been developed. Currently, there are no studies available directly comparing oral and injectable formulations of naltrexone in alcohol-dependent patients. This paper reviews the efficacy and adverse events of oral versus injectable extended-release naltrexone. Therefore, data were extracted from two recently published reviews about oral naltrexone in the treatment of alcohol dependence. Pooled outcomes were compared with reported outcomes of recent studies on injectable extended-release naltrexone. Injectable naltrexone seems to be effective in the management of alcohol dependence. Although inconclusive, the available results indicate that the expected advantages of injectable naltrexone over oral naltrexone still have to be proven. Randomized studies with direct comparisons of oral and injectable naltrexone are urgently needed.     

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

Maintenance therapy with methadone or buprenorphine‐based regimens reduces opioid dependence and associated harms. The perception that methadone is more effective than buprenorphine for maintenance treatment has been based on low buprenorphine doses and excessively slow induction regimens used in early buprenorphine trials. Subsequent studies show that the efficacy of buprenorphine sublingual tablet (Subutex®) or buprenorphine/naloxone sublingual tablet (Suboxone®) is equivalent to that of methadone when sufficient buprenorphine doses, rapid induction, and flexible dosing are used. Although methadone remains an essential maintenance therapy option, buprenorphine‐based regimens increase access to care and provide safer, more appropriate treatment than methadone for some patients. (Am J Addict 2010;00:1–12)