Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
buprenorphine/naloxone; atazanavir; ritonavir; drug interactions
To examine the influence of top managers’ characteristics on the adoption of buprenorphine for opioid dependence among U.S. outpatient substance abuse treatment units, this investigation analyzed a cross-sectional national study of 547 such units in the 2004–2005 wave of the Drug Abuse Treatment System Survey. Administrators reported their demographics, training, and treatment orientation, as well as features of the unit and its pattern of use of buprenorphine. Nationally, 15.8% of programs offered any buprenorphine services. Greater adoption of buprenorphine correlated with directors’ younger age, longer tenure, male gender, and weaker endorsement of abstinence as the most important treatment goal. Availability of naltrexone and medical services also correlated positively with buprenorphine adoption. The authors conclude that leaders’ characteristics are related to the adoption of innovative practices in addiction treatment programs. Future work should examine whether leadership development for community addiction programs might speed up the diffusion of buprenorphine and other innovative, evidence-based practices.
In adults receiving buprenorphine-naloxone maintenance, buprenorphine pharmacokinetics were not changed significantly by 15-day coadministration of darunavir-ritonavir or fosamprenavir-ritonavir. The pharmacokinetics of the protease inhibitors did not differ from those in matched controls receiving only the protease inhibitors.
Background. This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir.
Methods. The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone–maintained, human immunodeficiency virus (HIV)–negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non–opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine.
Results. There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine.
Conclusions. Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.
Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS.
pregnancy; substance abuse; HIV disease; cocaine; methadone; buprenorphine; drug interactions
Methadone maintenance treatment is the most widely available pharmacotherapy for opioid addiction and has been shown over a period of 40 years to be an effective and safe treatment. While women comprise approximately 40% of clients currently being treated in MMT programs, comparatively little research geared specifically toward this group has been published. This article begins with an overview of neurobiological studies on opioid addiction, including a discussion of gender differences, followed by a review of the pharmacology of methadone The authors then examine the particular needs and differences of women being treated in MMTs, including co-dependence with other substances, women’s health issues and psychosocial needs unique to this population. In conclusion, research shows that women have different substance abuse treatment needs in comparison to their male counterparts. One New York City MMT program that has attempted to address these differences is highlighted.
women; methadone maintenance; pharmacotherapy; gender differences; addiction; opiate addiction
The diversion, misuse, and non-medically supervised use of buprenorphine and buprenorphine/naloxone by opioid users are reviewed. Buprenorphine and buprenorphine/naloxone are used globally as opioid analgesics and in the treatment of opioid dependency. Diversion of buprenorphine and buprenorphine/naloxone represents a complex medical and social issue, and has been widely documented in various geographical regions throughout the world.
We first discuss the clinical properties of buprenorphine and its abuse potential. Second, we discuss its diversion and illicit use on an international level, as well as motivations for those activities. Third, we examine the medical risks and benefits of buprenorphine’s non-medically supervised use and misuse. These risks and benefits include the effect of buprenorphine’s use on HIV risk and the risk of its concomitant use with other medications and drugs of abuse. Finally, we discuss the implications of diversion, misuse, and non-medically supervised use (including potential measures to address issues of diversion); and potential areas for further research.
Buprenorphine; buprenorphine/naloxone; diversion; injection drug use; self treatment; Suboxone; Subutex; opioid dependence; opioid abuse; opiate abuse; opiate dependence
Given that buprenorphine + naloxone is prescribed for opioid-dependent pregnant women, it is important to examine the extent to which it differs from buprenorphine alone, methadone, or methadone-assisted withdrawal on neonatal and maternal outcomes. Summary statistics on maternal and neonatal outcomes were collected from 7 previously published studies examining treatment for opioid-dependent pregnant women that represented a range of research methodologies. Outcomes from these studies were compared to the same outcomes for 10 women treated with the combined buprenorphine + naloxone product. There were no significant differences in maternal outcomes for buprenorphine + naloxone compared to buprenorphine, methadone, or methadone-assisted withdrawal. Preliminary findings suggest no significant adverse maternal or neonatal outcomes related to the use of buprenorphine + naloxone for the treatment of opioid dependence during pregnancy. However, further research should examine possible differences between buprenorphine + naloxone and buprenorphine alone or methadone in fetal physical development.
buprenorphine; methadone; opioid dependence; pregnancy; neonates
Heroin dependence is a major health and social problem associated with increased morbidity and mortality that adversely affects social circumstances, productivity, and healthcare and law enforcement costs. In the UK and many other Western countries, both methadone and buprenorphine are recommended by the relevant agencies for detoxification from heroin and for opioid maintenance therapy. However, despite obvious benefits due to its unique pharmacotherapy (eg, greatly reduced risk of overdose), buprenorphine has largely failed to overtake methadone in managing opioid addiction. The experience from the developing world (based on data from India) is similar. In this article we compare the advantages and disadvantages of the use methadone and buprenorphine for the treatment of opioid addiction from both a developed and developing world perspective; and explore some of the reasons why buprenorphine has not fulfilled the expectations predicted by many in the addictions field.
Addiction; buprenorphine; detoxification; maintenance; methadone; opiate
The present investigation examines baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths.
This study of 69 opioid-dependent youths is a secondary analysis of data collected during a National Institute on Drug Abuse (NIDA) Clinical Trials Network study. Outpatients aged 15-21 were randomized to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper). Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity).
Most (75.4%) reported having either “some” (n=40, 58.0 %) or “extreme” (n=12, 17.4%) pain on enrollment. Maximum daily dose of buprenorphine-naloxone (19.7 mg) received by patients reporting “extreme” pain at baseline was significantly higher than the dose received by patients reporting “some” pain (15.0 mg) and those without pain (12.8 mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain.
These data suggest that the presence of pain predicts buprenorphine-naloxone dose levels in opioid-dependent youth, and that patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses.
Buprenorphine; Naloxone; Opioid dependence; Treatment; Dose
The National Institute on Drug Abuse (NIDA) established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to bring researchers and treatment providers together to develop a clinically relevant research agenda. Initial CTN efforts addressed the use of buprenorphine, a mu-opioid partial agonist, as treatment for opioid dependence. Strong evidence of buprenorphine's therapeutic efficacy was demonstrated in clinical trials involving several thousand opioid-dependent participants, and in 2002, the FDA approved buprenorphine for the treatment of opioid dependence. With the advent of a sublingual tablet containing both buprenorphine and naloxone to mitigate abuse and diversion (Suboxone®), buprenorphine appeared poised to be the first-line treatment for opioid addiction. Notwithstanding its many attributes, certain implementation barriers remained to be addressed in CTN studies, and these efforts have brought a body of knowledge on buprenorphine to front-line clinicians. The purpose of this article is to review CTN-based buprenorphine research and related efforts to overcome challenges to the implementation of buprenorphine therapy in mainstream practice. Furthermore, this paper explores current issues and future challenges that may require additional CTN efforts.
In October 2002, the U.S. Food and Drug Administration approved buprenorphine-naloxone (Suboxone®) sublingual tablets as an opioid dependence treatment available for use outside traditionally licensed opioid treatment programs. The NIDA Center for Clinical Trials Network (CTN) sponsored two clinical trials assessing buprenorphine-naloxone for short-term opioid detoxification. These trials provided an unprecedented field test of its use in twelve diverse community-based treatment programs. Opioid-dependent men and women were randomized to a thirteen-day buprenorphine-naloxone taper regimen for short-term opioid detoxification. The 234 buprenorphine-naloxone patients averaged 37 years old and used mostly intravenous heroin. Direct and rapid induction onto buprenorphine-naloxone was safe and well tolerated. Most patients (83%) received 8 mg buprenorphine-2 mg naloxone on the first day and 90% successfully completed induction and reached a target dose of 16mg buprenorphine-4 mg naloxone in three days. Medication compliance and treatment engagement was high. An average of 81% of available doses was ingested, and 68% of patients completed the detoxification. Most (80.3%) patients received some ancillary medications with an average of 2.3 withdrawal symptoms treated. The safety profile of buprenorphine-naloxone was excellent. Of eighteen serious adverse events reported, only one was possibly related to buprenorphine-naloxone. All providers successfully integrated buprenorphine-naloxone into their existing treatment milieus. Overall, data from the CTN field experience suggest that buprenorphine-naloxone is practical and safe for use in diverse community treatment settings, including those with minimal experience providing opioid-based pharmacotherapy and/or medical detoxification for opioid dependence.
Methadone treatment reduces HIV risk but the effects of primary care-based buprenorphine/naloxone on HIV risk are unknown. The purpose of the current study was to determine whether primary care-based buprenorphine/naloxone was associated with decreased HIV risk behavior. We conducted a longitudinal analysis of 166 opioid dependent persons (129 men and 37 women) receiving buprenorphine/naloxone treatment in a primary care clinic. We compared baseline, 12 and 24-week overall, drug-related and sex-related HIV risk behaviors using the AIDS/HIV Risk Inventory (ARI). Buprenorphine/naloxone treatment was associated with significant reductions in overall and drug-related ARI scores from baseline to 12 and 24-weeks. Intravenous drug use in the past 3 months was endorsed by 37%, 12%, and 7%, of patients at baseline, 12 weeks and 24 weeks, respectively; p < 0.001. Sex while you or your partner were “high” was endorsed by 64%, 13%, and 15% of patients at baseline, 12 weeks and 24 weeks, respectively; p<0.001. Inconsistent condom use during sex with a steady partner was high at baseline and did not change over time. We conclude that primary care-based buprenorphine/naloxone treatment is associated with decreased drug-related HIV risk but additional efforts may be needed to address sex-related HIV risk when present. (ClinicalTrials.gov number, NCT00023283).
Buprenorphine; HIV/AIDS; Risk Reduction Behavior; Treatment; Prevention
This series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication.
Opioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-hour blood sampling studies: 1. for buprenorphine pharmacokinetics and 2. following 15 days of rifampin 600 mg daily or rifabutin 300 mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics.
Rifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p=<0·001) and onset of opiate withdrawal symptoms in 50% of participants (p=0·02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p<0·001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p=0·009), although rifabutin and its active metabolite concentrations remained in the therapeutic range.
Rifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed.
buprenorphine/naloxone; rifampin; rifabutin; tuberculosis; opioid addiction; drug interactions
Opioid addiction is a worldwide problem. Agonist opioid treatment (AOT) is the most widespread and frequent pharmacotherapeutic approach. Methadone has been the most widely used AOT, but buprenorphine, a partial μ-opiod agonist and a κ-opiod antagonist, is fast gaining acceptance. The objective was to assess the budgetary impact in Spain of the introduction of buprenorphine-naloxone (B/N) combination.
A budgetary impact model was developed to estimate healthcare costs of the addition of B/N combination to the therapeutic arsenal for treating opioid dependent patients, during a 3-year period under the National Health System perspective. Inputs for the model were obtained from the specialized scientific literature. Detailed information concerning resource consumption (drug cost, logistics, dispensing, medical, psychiatry and pharmacy supervision, counselling and laboratory test) was obtained from a local expert panel. Costs are expressed in euros (€, 2010).
The number of patients estimated to be prescribed B/N combination was 2,334; 2,993 and 3,589 in the first, second and third year respectively. Total budget is €85,766,129; €79,855,471 and €79,137,502 in the first, second and third year for the scenario without B/N combination. With B/N combination the total budget would be €86,589,210; €80,398,259 and €79,708,964 in the first, second and third year of the analyses. Incremental cost/patient comparing the addition of the B/N combination to the scenario only with methadone is €10.58; €6.98 and €7.34 in the first, second and third year respectively.
Addition of B/N combination would imply a maximum incremental yearly cost of €10.58 per patient compared to scenario only with methadone and would provide additional benefits.
Buprenorphine-naloxone; Methadone; Budgetary impact; Opioid dependence; Spain
This study was conducted to determine whether drug interactions of clinical importance occur between buprenorphine, an opioid partial agonist medication used in treatment of opioid dependence, and the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=7) participated in 24-hour sessions to determine the pharmacokinetics of buprenorphine alone and of buprenorphine and nevirapine following administration of 200 mg nevirapine daily for 15 days. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined prior to and following nevirapine administration. Modest decreases were observed for AUC for buprenorphine and its metabolites. There was a trend for more rapid clearance of both buprenorphine (p = .08) and buprenorphine-3-glucuronide (p = .08). While no single effect reached statistical significance, the joint probability that the consistent declines in all measures of exposure were due to chance was extremely low, indicating that nevirapine significantly reduces overall exposure to buprenorphine and buprenorphine metabolites. Clinically significant consequences of the interaction were not observed. Buprenorphine did not alter nevirapine pharmacokinetics. Dose adjustments of either buprenorphine or nevirapine are not likely to be necessary when these drugs are coadministered for the treatment of opiate dependence and HIV disease.
The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long term efficacy and patient discomfort remains a significant therapy challenge. Buprenorphine’s effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the US is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence, however, randomized clinical trials are needed.
opioid; opiate; pharmacotherapy; heroin
Accumulating evidence indicates important gender differences in substance use disorders. Little is known, however, about gender differences and opioid use disorders.
To compare demographic characteristics, substance use severity, and other associated areas of functioning (as measured by the Addiction Severity Index–Lite; ASI) among opioid-dependent men and women participating in a multisite effectiveness trial.
Participants were 892 adults screened for the National Institute on Drug Abuse’s (NIDA) Clinical Trials Network (CTN) investigation of the effectiveness of two buprenorphine tapering schedules.
The majority of men and women tested positive for oxycodone (68% and 65%, respectively) and morphine (89% each). More women than men tested positive for amphetamines (4% vs. 1%, p<0.01), methamphetamine (11% vs. 4%, p<0.01) and phencyclidine (8% vs. 4%, p=0.02). More men than women tested positive for methadone (11% vs. 6%, p=0.05) and marijuana (22% vs. 15%, p=0.03). Craving for opioids was significantly higher among women (p<0.01). Men evidenced higher alcohol (p<0.01) and legal (p=0.04) ASI composite scores, whereas women had higher drug (p<0.01), employment (p<0.01), family (p<0.01), medical (p<0.01), and psychiatric (p<0.01) ASI composite scores. Women endorsed significantly more current and past medical problems.
Important gender differences in the clinical profiles of opioid-dependent individuals were observed with regard to substance use severity, craving, medical conditions, and impairment in associated areas of functioning. The findings enhance understanding of the characteristics of treatment-seeking men and women with opioid dependence, and may be useful in improving identification, prevention, and treatment efforts for this challenging and growing population.
The profile of opioid dependence in the United States is changing. Abuse of prescription opioids is more common than that of illicit opioids. Recent data indicate that there are approximately 1.6 million individuals with prescription opioid abuse or dependence and 323,000 with heroin abuse or dependence. Despite this prevalence, nearly 80% of these individuals go untreated. One option for expanding treatment is the use of buprenorphine and the buprenorphine/naloxone combination. Buprenorphine is a partial opioid agonist that can be prescribed by trained Internists and dispensed at pharmacies.
The case-based discussion in this paper addresses the clinical presentation of a patient with opioid dependence and describes the relatively new practice of office-based treatment with buprenorphine/naloxone. It examines the different components of treatment, the role of the Internist in providing this treatment, and the logistics of treating this growing and multi-faceted patient population.
Prior studies have shown an increased vulnerability among males, to adverse outcomes during the postnatal period. The majority of children exposed to opioids and other medication in utero develop a neonatal abstinence syndrome (NAS), yet individual predisposition for NAS is poorly understood. This investigation examines the role of neonatal sex in the postnatal period, for neonates exposed to standardized opioid maintenance treatment in utero with a focus on the neonatal abstinence syndrome (NAS) regarding severity, medication requirements and duration.
Patients and Methods
This is a secondary analysis of data collected in a prospective randomized, double-blind, double-dummy multi-center trial examining the comparative safety and efficacy of methadone and buprenorphine during pregnancy (Maternal Opioid Treatment: Human Experimental research MOTHER – study). 131 neonates born to opioid-dependent women randomized at six US sites (n=74) and one European site (n=37) were analyzed. Sex-based differences in birth weight, length, head circumference, NAS duration, NAS severity, and treatment parameters of full-term neonates were assessed.
Males had a significantly higher birth weight (p=0.027) and head circumference (p=0.017) than females, with no significant sex difference in rates of preterm delivery. No significant sex-related differences were found for NAS development, severity, duration, or medication administered with non significant differences in concomitant drug consumption during pregnancy (p =0.959).
This unique prospective study shows similar postnatal vulnerability for both sexes, suggesting that factors other than sex are the major determinants of clinically significant NAS.
opioid dependence; methadone; buprenorphine; pregnancy; neonatal abstinence syndrome; sex differences
Opioid analgesics provide effective treatment for noncancer pain, but many physicians have concerns about adverse effects, tolerance, and addiction. Misuse of opioids is prominent in patients with chronic back pain and early recognition of misuse risk could help physicians offer adequate patient care while implementing appropriate levels of monitoring to reduce aberrant drug-related behaviors. In this review, we discuss opioid abuse and misuse issues that often arise in the treatment of patients with chronic back pain and present an overview of assessment and treatment strategies that can be effective in improving compliance with the use of prescription opioids for pain. Many persons with chronic back pain have significant medical, psychiatric and substance use comorbidities that affect treatment decisions and a comprehensive evaluation that includes a detailed history, physical, and mental health evaluation is essential. Although there is no “gold standard” for opioid misuse risk assessment, several validated measures have been shown to be useful. Controlled substance agreements, regular urine drug screens, and interventions such as motivational counseling have been shown to help improve patient compliance with opioids and to minimize aberrant drug-related behavior. Finally, we discuss the future of abuse-deterrent opioids and other potential strategies for back pain management.
Addiction to substances continues to be a significant public health concern in the United States. The following review of current pharmacological treatments discusses a range of substances: nicotine, alcohol, cocaine, and opioids. The goal is to provide an overview of currently available and new pharmacological treatments for substance use disorders, while also addressing the pharmacothera-peutic challenges remaining. The significant advances in pharmacotherapy have had limited utilization, however. For example, naltrexone for alcoholism is infrequently prescribed, buprenorphine for opiates still has relatively few qualified prescribers, and stimulants have no Food and Drug Administration-approved pharmacotherapy. These pharmacotherapies are needed, with the rate of even the relatively uncommon abuse of opiates now rising sharply.
addictive disorders; substance abuse
While street drugs appear unlikely to alter the metabolism of antiretroviral (ARV) medications, several ARVs may induce or inhibit metabolism of various street drugs. However, research on these interactions is limited. Case reports have documented life-threatening overdoses of ecstasy and gamma-hydroxybutyrate after starting ritonavir, an ARV that inhibits several metabolic enzymes. For opioid addiction, methadone or buprenorphine are the treatments of choice. Because a number of ARVs decrease or increase methadone levels, patients should be monitored for methadone withdrawal or toxicity when they start or stop ARVs. Most ARVs do not cause buprenorphine withdrawal or toxicity, even if they alter buprenorphine levels, with rare exceptions to date including atazanavir/ritonavir associated with significant increases in buprenorphine and adverse events related to sedation and mental status changes in some cases. There are newer medications yet to be studied with methadone or buprenorphine. Further, there are many frequently used medications in treatment of complications of HIV disease that have not been studied. There is need for continuing research to define these drug interactions and their clinical significance.
Drug interactions; Street drugs; Methadone; Buprenorphine; Anti-HIV agents
Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area.
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.
A randomized, double-blind, placebo-controlled, crossover study.
An in-patient research unit at the University of Kentucky.
Healthy adults (n=10) abusing, but not physically dependent on, intranasal opioids.
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.
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 Tmax was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively.
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.
Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of molecular biological techniques has advanced our knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, we have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.
Buprenorphine; partial agonist; agonist-antagonist; antinociception; tolerance; dependence; ORL-1 receptors; knockout mice