Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation

Gregory and colleagues [1] conducted a systematic review of published original research between 2002 and 2023 that reported on the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder (OUD). Secondary outcomes explored were baseline type of opioids used, buprenorphine induction dose, initial Clinical Opiate Withdrawal Scale (COWS) score, location of induction (e.g. home, healthcare setting), definition and severity of precipitated withdrawal and adverse events. A total of 26 studies were included where the majority were conducted within the United States (US) (84.6%, n = 22) and (80.7%, n = 21) were cohort studies with only 19.2% (n = 5) being RCTs. The majority of participants reported heroin use at baseline with four studies having participants who reported fentanyl use. A variety of types of induction protocols were used from standard, high dose, to micro induction strategies and there were various initial induction doses of buprenorphine ranging from 0.75 to 24 mg, with the majority reporting 2 to 8 mg, far lower than the recommended induction target of 16 mg [2] or more recent recommended 24 mg dose or higher in persons who use fentanyl [3, 4].

The bottom line of this systematic review was that there was hardly any precipitated withdrawal (range of 0%–13.2%) out of an overall total sample size of 4497 individuals. In fact, 11 of the 26 studies representing 2117 persons, reported no opioid withdrawal at all. Further, the majority of the 87 cases of reported precipitated withdrawal were in outpatient settings with only one person who received buprenorphine via a home induction protocol requiring inpatient hospitalization. This information is important and is in line with many other studies showing that the prevalence of precipitated withdrawal is relatively low when initiating buprenorphine, and clinicians should not be guided by fear that they will cause withdrawal when deciding about initiation of this life-saving treatment. If a person wants and needs buprenorphine treatment for their OUD and is denied treatment, then they are at high risk of overdose and death.

The significance of these findings cannot be overstated. Although there has been recent good news of a 10% reduction of overdose deaths in the United States from 2023 to 2024 [5], over one million Americans have died from drug overdoses [6]. The majority of all overdose deaths involve an opioid largely driven by the presence of illicitly manufactured synthetic fentanyl, which contributes to almost 90% of fatal opioid overdoses in the United States. All three forms of US Food and Drug Administration approved medications for opioid-use disorder (MOUD): buprenorphine, methadone and extended-release naltrexone, which reduce opioid craving, opioid use, overdose and death. Additionally, buprenorphine and methadone also treat opioid withdrawal because of their opioid agonist properties. Buprenorphine has been found to be the most effective form of MOUD [7] through reducing death from overdose by 50% [8] and can be provided in various care settings from primary care to specialty substance use treatment programs. Unfortunately, however, only 22% of the 2.5 million American adults with OUD receive MOUD treatment [9].

There have been numerous reported reasons why so few people who could benefit from this effective treatment are not receiving it; however, one of the main issues is reluctance from clinicians to initiate treatment for fear of precipitating opioid withdrawal as discussed in Gregory et al. [1]. There is a reason to be concerned if buprenorphine is given too soon or at too high a dose among patients who report use of full opioid agonists and after cessation of full agonists like fentanyl [10-12]. Although this review only included studies published up through 2023, more recent studies continue to show that there is relatively low precipitated withdrawal among persons with OUD who use fentanyl either during traditional sublingual buprenorphine induction as well as with long-acting injectable forms of buprenorphine in the emergency room [13, 14] and in-patient settings [15, 16]. Careful strategies to ensure a low likelihood of precipitated withdrawal while treating OUD can lead to successful treatment [17, 18]. It is our job as clinicians to ensure our patients have access to this life saving form of treatment when they ask for it as opposed to not providing treatment for fear of eliciting withdrawal. Although this is, of course, an important consideration, there are numerous strategies published that involve patient shared decision making and education to successfully start treatment safely. Withholding buprenorphine treatment in someone who wants and needs it only puts that person at risk of overdose and death. Let us not let fear guide us, rather let the evidence guide us to ensure our patients get the treatment they need when they need it.

Sandra Springer has provided paid scientific consultation to Alkermes, and received in-kind study drug donations from Alkermes and Indivior Pharmaceutical Company for National Institutes of Health funded research.