Effects of buprenorphine on opioid craving in comparison to other medications for opioid use disorder: A systematic review of randomized controlled trials

Abstract

Background

Craving is a distressing symptom of opioid use disorder (OUD) that can be alleviated with medications for OUD (MOUD). Buprenorphine is an effective MOUD that may suppress craving; however, treatment discontinuation and resumed opioid use is common during the early phases of treatment. More information on the craving response through the high-risk period of initiating buprenorphine may provide meaningful information on how to better target craving, which in turn may enhance outcomes. This systematic review investigated buprenorphine doses and formulations on craving during the induction and maintenance phases of treatment, and for context also compared the craving response to other MOUD (i.e., methadone, extended-release naltrexone [XR-NTX]).

Methods

PubMed, PsycInfo, Embase, and Cochrane Central databases were searched for randomized trials of buprenorphine versus placebo, various buprenorphine formulations/doses, or other MOUD that included a measure of opioid craving.

Results

A total of 10 studies were selected for inclusion. Buprenorphine and buprenorphine/naloxone (BUP/NAL) were each associated with lower craving than placebo over time. Craving was greater among those prescribed lower versus higher buprenorphine doses. In comparison to other MOUD, buprenorphine or BUP/NAL was linked to greater craving than methadone in 3 of the 6 studies. BUP/NAL was associated with greater reported craving than XR-NTX.

Discussion

Craving is reduced over time with buprenorphine and BUP/NAL, although other MOUD may provide greater reductions in craving. Although there is currently considerable variability in the measurement of craving, it may be a valuable concept to address with individuals receiving MOUD, especially early in treatment.

Introduction

The opioid epidemic is a significant public health crisis associated with excess morbidity and mortality within the United States (Hickton & Leary, 2015). Opioid overdose deaths increased by 35% from 2020 to 2021, with over 75,000 opioid overdose deaths in 2021 (Centers for Disease Control and Prevention, 2021). The economic burden of opioid use disorder (OUD) and opioid-related overdose is approximately $1.02 trillion annually, largely due to opioid overdose fatalities and reductions in quality of life from OUD (Florence, Luo, & Rice, 2021). Thus, effective OUD treatments are critical to combat this costly and deadly epidemic (Blanco and Volkow, 2019, Sordo et al., 2017).

Food and Drug Administration (FDA)-approved medications for OUD (MOUD) are the recommended first-line OUD treatment, which include the full opioid agonist methadone, the partial agonist buprenorphine, and the extended-release injectable formulation of the antagonist naltrexone (XR-NTX). All three MOUD have demonstrated enhanced treatment engagement, survival rates, and psychosocial functioning (Ling, Nadipelli, Aldridge, et al., 2020; Substance Abuse and Mental Health Services Administration [SAMHSA], 2021; Thomas et al., 2014). Buprenorphine has several advantages over XR-NTX and methadone, and its prescribing has trended upwards in recent years (Olfson et al., 2020, Roehler et al., 2020). First, unlike methadone, buprenorphine is not required to be dispensed through opioid treatment programs and can be prescribed in any clinical setting by prescribers with Drug Enforcement Agency certification (SAMHSA, 2021). Second, buprenorphine is combined with the antagonist naloxone to deter misuse of the medication (Center for Substance Abuse Treatment, 2004, Substance Abuse and Mental Health Services Administration, 2021). Third, as a partial opioid agonist, buprenorphine has a greater safety profile than full agonists such as methadone (Fairley et al., 2021, Thomas et al., 2014); therefore, buprenorphine may be a preferred MOUD for patients with multiple health comorbidities, as it has less side effects and drug-drug interactions than methadone (SAMHSA, 2021). Fourth, buprenorphine, which is available as a generic prescription and prescribed in public health clinics, may be more cost effective than XR-NTX, which is currently not available off patent in the U.S. (Jackson, Mandell, Johnson, Chatterjee, & Vanness, 2015).

A major concern with buprenorphine is the premature discontinuation and/or resumed opioid use in the initial weeks of initiation (Hser et al., 2016, Ling et al., 2020). In fact, nearly a quarter of patients initiating buprenorphine discontinue treatment within the first week, with up to 64% discontinuing services by 6 months (Stein et al., 2010, Timko et al., 2016). Therefore, it is crucial to identify and better understand modifiable factors that may impact early buprenorphine outcomes. Craving, the subjective desire or urge to use a drug (Drummond, 2001, Sayette et al., 2000), is one modifiable factor that may be important for exploration, given that stress enhances craving (MacLean, Armstrong, & Sofuoglu, 2019), and the initiation of buprenorphine may be a particularly challenging and stressful time for patients. In addition, craving is familiar to both practitioners and patients, appears to vary among patients with OUD, can be targeted in treatment, has been added to the substance use disorders section of DSM-5, and has been increasingly incorporated as an outcome measure in clinical trials (American Psychiatric Association., 2013, Northrup et al., 2015, Skinner and Aubin, 2010, Tiffany et al., 2012). Although craving may decrease with higher doses of buprenorphine (Ahmadi, Jahromi, Ghahremani, & London, 2018), it is not completely eliminated (Fareed, Vayalapalli, Casarella, Amar, & Drexler, 2010) and may affect outcomes. The few studies that have examined the relationship between craving and subsequent opioid use during buprenorphine treatment have found no relationship (Dreifuss et al., 2013) or a positive association between craving and opioid use (Baxley et al., 2019, Messina and Worley, 2019, Tsui et al., 2014),

To date, systematic reviews have explored craving in the context of MOUD, though the primary focus of these reviews has been on craving during methadone treatment (Fareed, Vayalapalli, Stout, et al., 2010), the impact of stress on craving and MOUD outcomes (MacLean et al., 2019), opioid craving assessment (Kleykamp et al., 2019), or a combination of FDA and non-FDA-approved MOUD (with the exception of methadone) on craving (Fareed, Vayalapalli, Casarella, et al., 2010). The current literature is lacking a review synthesizing buprenorphine’s impact on craving during the early phases of treatment, as well as a comparison of buprenorphine to all other FDA-approved MOUD on the outcome of craving. Therefore, the present review had two exploratory aims: 1) to examine how the initiation and maintenance of buprenorphine impacts opioid craving, and 2) determine if buprenorphine is more or less effective than other FDA-approved MOUD in reducing opioid craving at the onset of treatment. Findings may provide meaningful information on how to better target craving, which in turn may enhance buprenorphine outcomes. Further, findings may assist prescribers in choosing the best MOUD for their patients who report significant craving.