Benzodiazepine use during buprenorphine treatment for opioid dependence: Clinical and safety outcomes
Introduction
Prescribing benzodiazepines during office-based opioid treatment (OBOT) (Gunderson and Fiellin, 2008) with buprenorphine is a practice that evokes intense discussion in clinical settings. Fatal overdoses from mixing benzodiazepines with buprenorphine, especially through concurrent intravenous administration, are a major safety concern (Reynaud et al., 1998b). The Food and Drug Administration required a warning for physicians to use caution when prescribing buprenorphine with benzodiazepines (Reckitt-Benckiser, 2010). Additionally, many clinicians believe that benzodiazepine prescriptions should be avoided because benzodiazepines hinder development of psychological coping strategies (Otto et al., 2005, Soyka, 2010), can be misused (Brunette et al., 2003, Chen et al., 2011) and can contribute to relapse (Brands et al., 2008). In contrast, others argue that use of long-acting benzodiazepine can be helpful in some circumstances, especially to retain people with co-occurring severe anxiety disorders who are receiving treatment for opioid dependence (Bleich et al., 2002, Liebrenz et al., 2010). For instance, 12-month retention in buprenorphine treatment among people with generalized anxiety disorder is low compared to people with major depressive disorder (39% vs. 72%; Gerra et al., 2006) and to the 12-month retention rate reported in several buprenorphine treatment samples (43–49%; Alford et al., 2011, Fiellin et al., 2008, Gerra et al., 2006). In the context of this ongoing debate, some OBOT programs avoid both prescribing benzodiazepines and admitting those who already have a prescription. Alternatively, some programs will accept those who already have a benzodiazepine prescription, while encouraging gradual benzodiazepine reduction within a limited time period (Tyrer, 2010), subject to certain conditions aimed at enhancing safety and limiting aberrant drug use behaviors (Lintzeris and Nielsen, 2010). Furthermore, some clinicians prescribe benzodiazepine maintenance to people with co-occurring anxiety disorders during buprenorphine treatment, believing it helps maintain retention and prevents relapse.
Benzodiazepine use is common among patients prescribed buprenorphine for opioid dependence. For example, in a Norwegian prescription database, 30% of patients on buprenorphine received a benzodiazepine prescription during the previous year (Bramness and Kornor, 2007). Early in treatment, patients receiving buprenorphine treatment frequently request a benzodiazepine prescription to mitigate anxiety and insomnia symptoms (Lintzeris and Nielsen, 2010). Misuse of benzodiazepines is also common; in a French sample, 31% of patients on buprenorphine had problematic use of benzodiazepines in the past month (Lavie et al., 2009).
While benzodiazepines and buprenorphine are each safer than their respective alternatives, barbiturates and methadone, the misuse of benzodiazepines with buprenorphine has resulted in dangerous consequences. Benzodiazepines, unlike barbiturates, do not cause respiratory depression when taken alone (Gasser et al., 1975, Murray et al., 1987), although benzodiazepine use has been associated with sedation, psychomotor impairment, and accidental injuries (Oster et al., 1990). Similarly, buprenorphine is safer than methadone when taken by itself; its partial agonism at central mu opioid receptors results in a “ceiling effect” on respiratory depression (Bell et al., 2009).
A French case series reported details of six overdose deaths related to concomitant use of buprenorphine and benzodiazepines (Reynaud et al., 1998a). When buprenorphine and benzodiazepines were co-administered to rats, the protective bell-shaped dose response effect on respiration was eliminated (Nielsen and Taylor, 2005). Human laboratory studies demonstrated that even when buprenorphine is taken at therapeutic doses, co-administration with supra-therapeutic doses of benzodiazepines can remove buprenorphine's “ceiling effect” on respiratory depression in the same pattern as co-administration with methadone (Lintzeris et al., 2006). In Finland, where buprenorphine is the primary opioid of abuse (Yokell et al., 2011), a retrospective analysis of opioid-associated deaths recorded in the national postmortem toxicology database found 1363 opioid-positive cases, of which 182 had buprenorphine poisoning as the cause of death; either a benzodiazepine or alcohol was found in all but one case, and were present in 82 and 58% of cases, respectively (Hakkinen et al., 2012). The median concentrations of buprenorphine and benzodiazepines in these poisonings were in the therapeutic range (Hakkinen et al., 2012). In contrast, a controlled human laboratory study with eight patients prescribed buprenorphine who were orally co-administered diazepam at therapeutic doses (≤20 mg) did not demonstrate an effect of diazepam on oxygen saturation compared with placebo, even though sedation and performance deficits emerged as the dose was increased (Lintzeris et al., 2006). Additionally, in a cross-sectional survey of 250 people with opioid dependence, overdose events from benzodiazepine use were self-reported ten times less frequently during buprenorphine versus methadone treatment (Nielsen et al., 2007). Taken together, these data suggest, even with therapeutic doses of buprenorphine, co-administration of benzodiazepines may result in lethal overdose when used either at supra-therapeutic dosages or at therapeutic dosages through intravenous injection or in combination with sedatives; however, lethal overdose would be unexpected to occur in the context of controlled oral co-administration of therapeutic dosages of benzodiazepines and buprenorphine. Therefore, clinical investigation of the safety of benzodiazepine treatment prescribed at therapeutic doses during buprenorphine treatment is necessary.
Using a chart review with a naturalistic, quasi-experimental design, we attempted to evaluate the relationship between benzodiazepine prescribing and clinical and safety outcomes during buprenorphine treatment, while also evaluating for effects of historical benzodiazepine misuse. We investigated the relationship between past-year benzodiazepine misuse and benzodiazepine prescription in several areas. Our primary clinical outcomes were 12-month treatment retention and number of months without positive urine toxicology screens for illicit opioids. Our primary safety outcomes were emergency department (ED) visits during treatment and ED visits related to overdose and accidental injury. We hypothesized that the best clinical and safety outcomes would occur among those without any benzodiazepine use history. We further hypothesized that there would be more ED visits due to overdose and accidental injuries, more opioid-positive toxicology screens, and poorer treatment retention among those with both a benzodiazepine prescription and history of benzodiazepine misuse as compared with those without either a benzodiazepine prescription or a history of benzodiazepine misuse.
Section snippets
Sample selection
This sequential-admission retrospective study was conducted with admissions to a collaborative care OBOT program (Alford et al., 2011, Schuman-Olivier et al., 2010) from November 2007 to June 2010. Two nurse care managers collaborated with multiple buprenorphine prescribers, coordinating urine toxicology screening, monitoring treatment adherence, overseeing medication management and facilitating communication with addiction counselors. Prescribers were affiliated with an academic community
Sample characteristics
Patients with a benzodiazepine misuse history differed from those without a misuse history in several ways (Table 1). Patients with benzodiazepine misuse history more frequently reported misuse of cocaine, amphetamine, and alcohol. Additionally, they more frequently had cocaine positive intake toxicology screens.
Patients with OBOT-approved benzodiazepine prescriptions at intake differed from those without benzodiazepine prescriptions in several ways: they were more frequently female, more
Discussion
This investigation of clinical outcomes and safety indicators for patients with varying levels of benzodiazepine prescription and benzodiazepine misuse history had several key findings.
First, when comparing patients with and without a benzodiazepine prescription, we found no significant differences in our primary clinical outcomes, including treatment retention and illicit opioid or cocaine use during 12 months of treatment. People with anxiety disorders who received benzodiazepine
Role of funding source
Funding for this study was provided through several sources. Dr. Schuman-Olivier conducted this research while receiving salary support through a Harvard Medical School Dupont-Warren Psychiatry Research Fellowship. Dr. Weiss supported the study with funding through NIDA Grants K24DA022288 and U10 DA15831 (RW). In her role as director of statistics at MGH Center for Addiction Medicine, Bettina Hoeppner contributed to statistical analysis while supported by K01DA027097 (BH). Use of REDCAP
Contributors
All authors were involved in the design of the study and contributed the protocol. Zev Schuman-Olivier managed the literature searches and summaries of previous related work. Zev Schuman-Olivier managed the chart review process, sample selection, and database management with collaboration from Jacob Borodovsky and Mark Albanese. Zev Schuman-Olivier and Bettina Hoeppner undertook the statistical analysis, and Zev Schuman-Olivier wrote the first draft of the manuscript. Zev Schuman-Olivier, Jacob
Conflict of interest
Dr. Schuman-Olivier: “I have received salary as medical director at WestBridge Community Services, a non-profit dual diagnosis community treatment program. I have no conflict of interest to report.
Dr. Hoeppner: “I have no conflicts of interest.”
Dr. Weiss: “I have served as a consultant to Titan Pharmaceuticals and Reckitt Benckiser. None of these funding sources provided support for my involvement in this manuscript. In addition, none of these funding sources were involved in the study design;
Acknowledgements
We appreciate the contribution of Kevin Wall to data entry and database auditing. We thank Francyne Puopolo, RN, Lola Roland, RN and David Mysells, MD for their consultation during the data entry process. We appreciate mentoring and editorial support from the MGH Center for Addiction Medicine, especially A. Eden Evins, MD, MPH and John Kelly, PhD.
References (43)
- et al.
Comparing overdose mortality associated with methadone and buprenorphine treatment
Drug Alcohol Depend.
(2009) - et al.
Benzodiazepine prescription for patients in opioid maintenance treatment in Norway
Drug Alcohol Depend.
(2007) - et al.
Clinical impairment of benzodiazepines—relation between benzodiazepine concentrations and impairment in apprehended drivers
Drug Alcohol Depend.
(2002) - et al.
Mortality prior to, during and after opioid maintenance treatment (OMT): a national prospective cross-registry study
Drug Alcohol Depend.
(2008) - et al.
Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: a retrospective study
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2006) - et al.
Benzodiazepine use among opiate-dependent subjects in buprenorphine maintenance treatment: correlates of use, abuse and dependence
Drug Alcohol Depend.
(2009) - et al.
Gender differences in pharmacokinetics of maintenance dosed buprenorphine
Drug Alcohol Depend.
(2011) - et al.
The effect of buprenorphine and benzodiazepines on respiration in the rat
Drug Alcohol Depend.
(2005) - et al.
Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation
Behav. Res. Ther.
(2010) - et al.
Mortality and causes of death among users of methadone maintenance treatment in Israel, 1999–2008
Drug Alcohol Depend.
(2012)
Self-treatment: illicit buprenorphine use by opioid-dependent treatment seekers
J. Subst. Abuse Treat.
Collaborative care of opioid-addicted patients in primary care using buprenorphine: five-year experience
Arch. Intern. Med.
Prescribing of tranquillizers to women and men
CMAJ
Cognitive effects of long-term benzodiazepine use: a meta-analysis
CNS Drugs
Benzodiazepine abuse in a methadone maintenance treatment clinic in Israel: characteristics and a pharmacotherapeutic approach
Isr. J. Psychiatry relat. Sci.
The impact of benzodiazepine use on methadone maintenance treatment outcomes
J. Addict. Dis.
Benzodiazepine use and abuse among patients with severe mental illness and co-occurring substance use disorders
Psychiatr. Serv.
Benzodiazepine use and misuse among patients in a methadone program
BMC Psychiatry
Long-term treatment with buprenorphine/naloxone in primary care: results at 2–5 years
Am. J. Addict.
Respiratory effects of lorazepam, pentobarbital, and pentazocine
Clin. Pharmacol. Ther.
Patients who use drugs during inpatient substance abuse treatment
Am. J. Psychiatry
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