BIC Position Statement on the Use of Benzodiazepines in Patients Receiving Buprenorphine
Laura C. Huff M.D. [a], Peter R. Martin, M.D., M.S.[b],, A. J. Reid Finlayson, M.D., M.M.H.C.[c]
[a]Benzodiazepine Information Coalition, Director
[b]Vanderbilt University School of Medicine, Professor of Psychiatry and Pharmacology
[c]Vanderbilt University School of Medicine, Associate Professor of Clinical Psychiatry and Behavioral Health
The danger of combining benzodiazepines and opioids is well known. In August 2016, the FDA issued a boxed warning, citing that the combination may lead to “excessive sleepiness, respiratory depression, coma, and death”. The addition of benzodiazepines to opioids increases the risk of psychomotor impairment, overdose, and suicide [2-5] Nearly 30% of overdose deaths associated with opioids also involve benzodiazepines.  Benzodiazepine use is also associated with lower success rates with medication assisted treatment (MAT) of opioid use disorder. ]
Deaths due to the combined use of buprenorphine and benzodiazepines is supported by preclinical laboratory research that suggests that co-administration of benzodiazepine agents can remove buprenorphine’s “protective ceiling” effect on respiratory depression in the same pattern as co-administration with methadone.
A series of case reports in France documented 6 overdose deaths due to the combination of buprenorphine and benzodiazepines. Another 12-month study documented an increase in the frequency of ED visits related to the combination of buprenorphine and benzodiazepines. This harmful association between benzodiazepines and buprenorphine is confirmed independently by emergency room data.
Some prescribers have advocated for concurrent benzodiazepine maintenance during buprenorphine substitution management. One recent single-practice case study suggested improved treatment adherence and lower mortality for patients who combined benzodiazepine use with opioid maintenance therapy. That retrospective report is based on plausible but untestable assumptions that benzodiazepine treatment combined with opiate substitution treatment must have terminated when the practice closed, but during previous treatment, “supplementation with illicit benzodiazepines (based on self-report) seemed rare.” In contrast, the larger Harvard report found no increase in treatment retention among patients who concurrently used benzodiazepines with buprenorphine treatment, but the combined therapy was associated with significantly more emergency room visits and accidental injuries, especially among female patients during the 12 month study.
Of note, the FDA package insert recommends no use of sedatives while taking buprenorphine. There is a dearth of literature regarding the specific combination of buprenorphine and benzodiazepines, and we endorse the need for further long-term prospective studies.
Studies estimate that between 18-50% of opioid users presenting for MAT are also misusing benzodiazepines. Benzodiazepines alone carry with them the risk of tolerance, suicide [11,12] seizures after abrupt cessation, and a protracted withdrawal syndrome that may last for months in some individuals. Discontinuation symptoms following cessation of benzodiazepines can be encountered even in those who take these medicines strictly according to prescription.
We recognize that this problem is extremely complex. Many of those with opioid use disorder and/or dependency present with benzodiazepine misuse or dependency, while fear and other symptoms of anxiety are common features of opioid withdrawal. Benzodiazepines are not recommended as first line treatment for Anxiety Disorders, Bipolar Disorder or Posttraumatic Stress disorder, all of which are more frequently associated with Substance Use Disorders.
Because benzodiazepines can cause sedation, cognitive effects, dependence, and loss of anxiolytic efficacy, guidelines for management of anxiety disorders generally support adjunct benzodiazepines only when necessary, with restriction to short-term, scheduled dosing, in those with low risk of misuse.<sup>8, 14</sup>
We have reviewed the 2015 ASAM National Practice Guidelines for the Use of Medications in the Treatment of Addiction Involving Opioid Use and the 2013 IRETA report entitled Management of Benzodiazepines in Medication-Assisted Treatment. Most of these guidelines are very reasonable, with the exception of the recommended rate of benzodiazepine tapering. We have listed our recommendations below for the management of buprenorphine and benzodiazepines based on our review of the literature, published guidelines and our experience with benzodiazepines.
According to ASAM guidelines, patients using benzodiazepines should “receive more intensive monitoring during office-based treatment with buprenorphine to minimize risk of adverse events. Alternatively, patients with these co-occurring disorders may be better treated in a setting with greater supervision”.15
Outpatients who are chemically-dependent on benzodiazepines:
a. Should not have their medication stopped abruptly due to risk of seizure and death, and the benzodiazepine should be tapered once reaching a stable dose of buprenorphine. Concurrent intensive psychological therapy is advisable.
b. Consider changing to a long-acting benzodiazepine for tapering. We recommend diazepam according to the Ashton manual due to the ability to make small dosage reductions.
c. Long-term, dependent benzodiazepine users should be tapered. This process may require a year or more in a few highly sensitive individuals. We differ from the IRETA guidelines in that we recommend tapering at a rate of <5-10% every 2-4 weeks based on patient symptoms.[13,17-18]
Some success in safely reducing post-acute benzodiazepine withdrawal symptoms has been reported with buspirone, melatonin, beta-adrenergic blockers, and anticonvulsant agents. Inpatient detoxification may be particularly indicated for benzodiazepine dependent patients with severe comorbid mental illness that is compromised by ongoing benzodiazepine use. In the inpatient setting short-term use of phenobarbital may be effective for detoxification.
Patients should not be continued on benzodiazepines long-term due to the risk of adverse effects as described above.
Physicians should undergo training regarding the safe tapering of benzodiazepines, especially in the context of opioid use.
Patients should be given informed consent, intensive education, and literature about the extensive risks of benzodiazepines combined with MAT5.
Any patient presenting for MAT who is not already taking benzodiazepines should not be given a prescription for a benzodiazepine.
Benzodiazepine Information Coalition is a 501(c)(3) nonprofit organization. Our mission is to provide information about benzodiazepines, particularly the drug’s potential to cause long-term disability and its dangerous side effects.
FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use. Aug 2016. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm518697.htm
Walton G, Hayakashi K, Bach P, et al. The Impact of Benzodiazepine Use on Mortality Among Polysubstance Users in Vancouver, Canada. Public Health Rep. 2016; 131:491-9
Riley E, Evans J, Hahn J, et al. A Longitudinal Study of Multiple Drug Use and Overdose Among Young People Who Inject Drugs. Am J Public Health 2016; 5:915-17.
Jones J, Mogali S, Comer, S. Polydrug Abuse: A review of opioid and benzodiazepine combination use. Drug Alcohol Depend 2012; 125:8-18.
Management of Benzodiazepines in Medication-Assisted Treatment. Institute for Research, Evaluation, and Training in Addictions 2013.
Lintzeris, N., Mitchell, T.B., Bond, A., Nestor, L., Strang, J., 2006. Interactions on mixing diazepam with methadone or buprenorphine in maintenance patients. J. Clin. Psychopharmacol. 26, 274–283.
Reynaud M, Petit G, Potard D. Six Deaths Linked to Concomitant Use of Buprenorphine and Benzodiazepines. Addiction 1998; 93:1385-92.
Schumann-Olivier Z, Hoeppner B, Weiss R, et al. Benzodiazepine Use During Buprenorphine Treatment for Opioid Dependence: Clinical Safety and Outcomes. Drug Alcohol Depend 2013; 132:580-6.
Crane EH. Emergency Department Visits Involving Buprenorphine. 2013 Jan 29. In: The CBHSQ Report. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK384655/
Bakker A, Streel, E. Benzodiazepine maintenance in opiate substitution treatment: Good or Bad? A retrospective primary care case-note review. Psychopharmacology 2017; 31: 62-66.
Dodds T. Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature. Prim Care Companion CNS Disord 2017;19:e1-6.
McCall, W, Benca, R, Rosenquist, P, et al. Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA. Am J Psychiatry 2017;174:18-25.
Ashton H. The Ashton Manual 2002. Available from: http://www.benzo.org.uk/manual/
Swinson, RP. Clinical Practice Guidelines. Management of Anxiety Disorders. Can. J. Psychiatry 51 (2006) 9S-91S.
National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use 2015. American Society of Addiction Medicine.
Lintzeris N, Nielson S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict 2010; 19:59-72.
Peart R. Crossover Schedules. Available from: http://www.benzosupport.org/crossover_schedules.htm
Tapering Solutions 2016. Benzodiazepine Information Coalition. Available from: https://www.benzoinfo.com/single-post/2016/09/06/Tapering
Pollmann A, Murphy A, Bergman, J, et al. Deprescribing benzodiazepines and Z-drugs in community-dwelling adults: a scoping review. BMC Pharmacology and Toxicology 2015; 16:19.
Kawasaki S, Jacapraro J, Rastegar D. Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification. J Subst Abuse Treat 2012; 43:331-4.
Christy Huff, MD, FACC is a board-certified cardiologist who resides in Fort Worth, Texas. She attended medical school at the University of Texas Southwestern Medical School in Dallas where she graduated Alpha Omega Alpha in 2001. She completed an internal medicine residency at Washington University in St. Louis in 2004. Her cardiology training was completed at U.T. Southwestern in 2008, with a focus in advanced cardiovascular imaging and noninvasive cardiology. She was in private practice as a cardiologist in Fort Worth from 2008-2011. Following the birth of her child, she made the decision to become a stay at home mom.
Dr. Huff is currently experiencing benzodiazepine withdrawal firsthand after she was prescribed Xanax for insomnia related to a major health crisis in 2015. After developing concerning symptoms and receiving no answers from her primary care doctor and a prominent neurologist, she began to research benzodiazepines and discovered her symptoms were consistent with benzodiazepine withdrawal syndrome. With the help of a local psychiatrist, she is slowly tapering off benzodiazepines using Valium. Christy’s personal experience has led her to realize the dangers of these drugs and the severity of the benzodiazepine withdrawal syndrome, neither of which were emphasized during her medical training. She is an advocate of better education of physicans regarding the dangers of benzodiazepines and how to safely taper patients off these drugs, and stronger regulation of the prescribing of benzodiazopines.