Does High-Dose Buprenorphine Cause Respiratory Depression?

Abstract

Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.

Sleep disordered breathing in patients receiving therapy with buprenorphine/naloxone

“…The discovery of SDB in patients receiving buprenorphine should not be surprising; however, it is widely regarded as a safe and effective opioid [11,13,33]. Furthermore, many clinicians may not be familiar with the unique pharmacologic profile of this particular opioid and its potential for respiratory toxicity [12,20,33,34].…”

The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom

“…In the United States, more than 60 000 people died from an overdose in 2016: a fourfold increase in the last 15 years 28. While methadone is a full mu‐opioid agonist, buprenorphine is a partial mu‐opioid agonist, providing a ‘ceiling effect’ for respiratory depression and potentially limiting the effect of additional heroin use 29, 30. Qualitative studies in the United States suggest that patient preference for buprenorphine and methadone varies, and is influenced by peer attitudes, prior treatment experience and clinic dispensing practices 31, 32, 33.…”

Diversion of Methadone and Buprenorphine from Opioid Substitution Treatment: A Staff Perspective

“…4,5 Buprenorphine is less potent, but if mixed with alcohol or sedatives there is a risk of polydrug intoxication. 6 Both medications have high abuse potential and are sought after on the illicit drug market. Diversion-here defined as patients selling or sharing part or all of their medication-is therefore a significant risk.…”

“…20 The second strand of research is looking at the negative consequences of illicit use, mainly in the form of methadone-and buprenorphine-related mortality among users not in treatment. 6,8,[26][27][28][29][30][31][32] The majority of such fatalities are caused by polyintoxication involving a broad array of different substances, often sedatives and alcohol. 6,29,31,32 Such deaths have made up a significant percentage of the opioid-related mortality in some countries, not least Sweden; since 2011 the combined number of methadone-and buprenorphine-related fatalities have exceeded heroin-related deaths.…”