To use or not to use buprenorphine for illegally manufactured fentanyl

The US opioid overdose crisis has been a triple wave phenomenon consisting of prescription opioids, heroin, and synthetic opioids. There is now a rising concern about a “fourth wave” driven by illegally manufactured fentanyl (IMF).¹ Starting in 2013, IMF began gaining popularity in the United States, both in its pure form and mixed with heroin. Additionally, IMF is cheaper, and its cost continues to decline, with a concurrent rise in mortality from 2014 to the present day.^1,3 This fourth wave recently hit a peak of more than 100,000 estimated drug overdose deaths in a 12-month period for the first time with over 64% of these deaths involving IMF. Fentanyl is 30–40 times more potent by weight than heroin and can induce severe physiologic dependence. The high potency of IMF can lead to rapid overdose, evidenced by 56% of the deceased being pulseless on arrival of first responders.⁴ IMF also presents special challenges to healthcare providers prescribing buprenorphine (BUP) treatment. In particular, BUP’s high binding affinity to the mu-opioid receptor (MOR) appears important in its relationship to fentanyl. BUP’s binding affinity to the MOR is 6.2 times greater than fentanyl. This means that BUP easily displaces fentanyl from the MOR, precipitating withdrawal in fentanyl-dependent individuals.² This pharmacologic feature makes BUP induction particularly difficult in heavy fentanyl users. We must find ways to improve BUP induction in fentanyl users because medication-assisted treatment (e.g. BUP) is superior in improving outcomes, such as reduction in opioid use and overdoses relative to psychosocial strategies.⁵

Toward this end, a recent case report discusses the use of high-dose BUP in a patient with potential fentanyl use as a means of managing BUP-precipitated withdrawal and achieving recovery.⁶ With the widespread use of IMF, this case report highlights the need for modified induction protocols to allow primary care providers (PCPs) to more effectively use BUP in managing these patients.

According to the current guidelines, individuals with opioid use disorder (OUD) are advised to take their first BUP dose after the onset of opioid withdrawal, which occurs 12–24 h after their last heroin use. If the opioid being used has a long half-life (e.g. IMF) one has to wait longer. Inducting an IMF user into BUP treatment is difficult, as there is a lack of data regarding BUP’s effectiveness in IMF users⁷ and a commonly held belief among many fentanyl users is that “BUP does not work for fentanyl”.⁸ BUP is a partial agonist at the MOR and has low intrinsic activity. In contrast, fentanyl has a rapid, intense onset, but it then quickly redistributes into peripheral and adipose tissue. These act as physiological stores, and their subsequent slow release of fentanyl appears to be responsible for its long terminal half-life. This predisposes IMF users to experience BUP-precipitated withdrawal even after a significant period of fentanyl abstinence. Hence, stopping fentanyl use can lead to severe cravings, which may be less responsive to BUP. This risk was first discovered by fentanyl users on the streets, and several case reports have confirmed this.⁹

This case report⁶ mirrors the findings of a recent emergency department (ED)-based study by Herring et al., which utilized an accelerated induction procedure with high doses of oral BUP to achieve a therapeutic level in less than 3–4 h during ED stay, rather than the 3–4 days required in the normal induction protocol. 63.2% of inductions were done using more than 12 mg of sublingual BUP and 23.8% were done with doses ≥28 mg. They found only five cases of precipitated withdrawal out of 391 patients. Out of these five, four cases happened after a dose of 8 mg. The fifth patient experienced precipitated withdrawal when 24 mg of BUP was given, however, a review indicated that his concurrent stimulant use may have played a role. The authors then effectively utilized additional BUP (for a total dose of 28 mg) to successfully treat the precipitated withdrawal, and all patients were discharged in stable or improved conditions. This study established the safety of high-dose BUP, and significantly simplified the complicated, long induction regime for the benefit of both providers and patients.¹⁰

In contrast to this high-dose BUP approach, evidence is accumulating for another novel method for BUP induction to help patients using illicit opioids and even fentanyl called micro induction. This method calls for initiating small doses of BUP without waiting for emergence of opiate withdrawal symptoms. Due to the slow buildup of BUP at the MOR, no withdrawal is expected to be precipitated. Recent reviews demonstrated that while there are several promising case reports and case series (with one open-label trial) and many proposed protocols to follow, there is no consensus regarding a single method. The reviews also noted the need for further research and clinical caution as the possibility of emergence of mild withdrawal symptoms remains.^11,12

Even if BUP induction is successful, there are additional challenges related to continuation of BUP treatment. For heavy fentanyl users, stopping fentanyl use can lead to severe cravings, which may not be BUP responsive. Of note, BUP is a MOR partial agonist with low intrinsic activity at this receptor. Conversely, fentanyl is a full agonist at the MOR. The differential degree of MOR receptor agonism between these agents suggests that even maximal doses of BUP confer a level of opioid agonism that is lower than that of fentanyl. To the extent that fentanyl cravings correlate with the degree of MOR effects, it is questionable that BUP can adequately curb fentanyl cravings. Hence, BUP partial agonism and low intrinsic activity at the MOR can limit its effectiveness in improving fentanyl cravings.¹³

There are also physician-related barriers that may influence clinical decision-making about BUP use. A national survey showed that while 90% of PCPs report treating a patient with OUD in their practice in the past year, only 27.3% feel very comfortable treating OUD. Additionally, only 10.9% are waivered to prescribe BUP.¹⁴ The most commonly reported barriers to increased BUP prescribing were a lack of experience managing OUD; lack of co-management support from providers specializing in addiction, behavioural health, and psychiatry; and a concern for being inundated with BUP requests. However, clear, readily discernible guidelines can allay these concerns and enhance confidence in PCPs as prescribers. Additionally, as more physicians gain this confidence and are comfortable with utilizing BUP, there will be more prescribers in the community and there is less chance of being overwhelmed with BUP requests. Another significant concern preventing widespread use of BUP by PCPs is diversion (when medication is redirected from its intended destination for personal use, sale, or distribution to others); with a study reporting that about half of the prescribers strongly agreed that they would terminate a patient when they suspect diversion.¹⁵ However, a narrative review identified how illicitly acquired BUP is still mainly used to self-medicate opioid withdrawal symptoms or maintain abstinence and not to achieve any euphoric effects.¹⁶ In fact, it is possible that people who were receiving BUP but were terminated from a programme after losing insurance or out of concern for diversion, are now buying it illicitly to maintain their abstinence.

In conclusion, IMF is primarily implicated in fatal overdoses in the fourth wave of the opioid overdose epidemic. Empirically validated measures to reduce harm and overdose (e.g. BUP) are essential. Supporting PCPs who are on the front line fighting this wave is imperative to reverse the current trend of opioid overdoses. Increasing access to BUP is instrumental in reversing this trend, as it will help every individual who uses opioids, including IMF. The need of the hour is to ease barriers to BUP access by providing confidence to PCPs that BUP is safe to prescribe to IMF users, and that changes can be made to the recommended BUP protocol to manage precipitated opioid withdrawal. As it stands now, desperate patients are pleading with clinicians to be receptive to emerging BUP induction methods to help them access this life-saving treatment.¹⁷ Further research including larger trial results may solidify the empirical basis of novel methods and allow for the development of guidelines to promote the use of modified induction protocols to reduce barriers to BUP prescribing and to encourage increased acceptability of BUP by PCPs.

Funding

The study was funded by departmental resources.

Ethical approval

Ethical approval was not required for this literature review and letter to the editor.

Conflict of interest

The first and third authors are ABPM-certified addiction psychiatrists. The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. The authors certify that the submission is original work and is not under review at any other publication.

Data availability

These data were derived from the following resources available in the public domain: https://pubmed.ncbi.nlm.nih.gov/. The authors declare that this literature review is not based on original data.

References