Randomized, placebo-controlled trial of gabapentin during outpatient buprenorphine-assisted taper and transition to injectable naltrexone

Abstract

Background:

Gabapentin may help manage opioid withdrawal symptoms, but its effectiveness during buprenorphine taper and transition to naltrexone is uncertain.

Objectives:

To assess gabapentin’s efficacy in improving outcomes for lifetime prescription opioid use disorder (POUD) during outpatient buprenorphine taper and transition to extended-release naltrexone.

Methods:

This 12-week randomized, double-blind, placebo-controlled trial enrolled 117 (55% male) POUD participants. Weeks 1–3, participants attended clinic 5 days/week for medication, therapy, and assessments, including weekly craving and thrice-weekly opioid withdrawal and supervised urine screens. Participants were inducted onto buprenorphine (12 mg), randomized to receive either placebo or gabapentin (800 mg BID), and underwent a 10-day buprenorphine taper. In week 4, participants transitioned from oral to extended-release naltrexone. Chi-square and generalized estimating equation models assessed outcomes. A subset with baseline fentanyl tests was also examined for fentanyl’s impact on outcomes.

Results:

Of 117 participants, 75 (64.1%) completed the buprenorphine taper (41 gabapentin, 34 placebo), and 24 (20.5%) transitioned to naltrexone (12 gabapentin, 12 placebo). No significant group differences were observed in taper completion, naltrexone transition, craving, withdrawal, or opioid use. Fentanyl-positive participants had lower taper completion (47.8% vs. 75.8%, OR=0.286, p=0.033) and more opioid-positive urines (z=−4.24, p<0.0001). Fentanyl-positive participants on gabapentin had higher COWS (z=3.70, p=0.001) and SOWS (z= 3.73, p=0.001) scores, while fentanyl-negative participants on gabapentin had lower SOWS scores than those on placebo (z= −3.52, p=0.002).

Conclusions:

Fentanyl exposure impairs buprenorphine taper success and worsens withdrawal, in the presence of gabapentin, underscoring the need to tailor OUD treatment in fentanyl-exposed patients. (Clinicialtrials.gov ID NCT02543944).

Introduction:

Opioid use disorder (OUD) remains a significant public health issue, worsened by rising misuse of prescription opioids (POs) [1] and illicit fentanyl [2]. Although overshadowed by the dramatic rise in fentanyl misuse, POs still ranked second to cannabis for misuse or use disorder in 2020 [1]. Over 14% of emergency department visits in 2021 were opioid-related, with fentanyl-related visits peaking in the 4th quarter [3], especially among 26- to 44-year-olds [3]. In 2023, over 69% of overdose deaths involved fentanyl, and nearly 10% of opioid overdose deaths involved POs [2]. Overdose deaths involving POs have remained stable through 2022 after significantly increasing to all-time highs from 2002 to 2016 [4]. These findings highlight the urgent need to enhance OUD treatments, including prescription opioid use disorder (POUD), especially as illicit fentanyl is increasingly mixed with or sold as other substances, including POs, heroin, methamphetamine, cocaine, or counterfeit pills [5].

People who misuse opioids may experience serious health consequences, including developing dependence, engaging high-risk behaviors [3, 6], experiencing overdose [7, 8], and even death [9, 10]. In 2021–2022, past-year nonmedical PO use was highest among adults (26+ years), followed by those 18–25 [11]. Buprenorphine is effective for withdrawal, yet relapse rates post-taper remain high [12]. Buprenorphine withdrawal remains a frequent clinical challenge, particularly for individuals attempting to taper off the medication in outpatient settings [13]. While buprenorphine is highly effective for OUD maintenance treatment [14], some individuals express a strong preference to discontinue use due to personal reasons, stigma, side effects, or a desire to transition to naltrexone [15, 16]. However, in clinical practice, there is no standardized tapering protocol, and withdrawal symptoms remain a key barrier. Gabapentin, widely used for neuropathic pain and anxiety, might serve as an adjunct in opioid dependence. Our pilot study found that gabapentin, an anticonvulsant that blocks the alpha-2 delta subunit of calcium channels, reduced opioid use during a 10-day buprenorphine taper [17–21]. Other studies support gabapentin as an effective adjunct in buprenorphine taper [22, 23].

Many individuals with OUD express reluctance to remain on opioid agonist therapy long-term [24]. However, transitioning to naltrexone is challenging due to withdrawal severity and the need for a 7-day opioid-free period before initiation. Despite the common use of buprenorphine maintenance therapy, a subset of patients actively seeks to taper off buprenorphine and transition to naltrexone. Studies have shown that structured tapering protocols followed by naltrexone maintenance can be effective for certain populations. For instance, Sigmon et al. found that a 4-week buprenorphine taper regimen improved treatment retention and opioid abstinence compared to shorter taper durations [25]. Similarly, another clinical trial highlighted that while maintenance therapy is generally more effective, some patients successfully taper off buprenorphine and maintain abstinence, indicating the clinical relevance of tapering as an alternative for select individuals [26]. These findings suggest that while tapering off buprenorphine may not be standard practice, it is a desired option for certain patients.

Our study aimed to evaluate whether a buprenorphine taper with gabapentin augmentation could facilitate this transition. Thus, we conducted a randomized, double-blind, placebo-controlled trial to assess gabapentin’s potential in improving outcomes for individuals with POUD undergoing buprenorphine taper and transition to naltrexone. Historically, individuals in Arkansas primarily reported using POs; however, about halfway through the study, some participants also began reporting fentanyl use, while heroin use remained rare. Given the rise in fentanyl use during the trial, we also analyzed the impact of baseline fentanyl urine toxicology screens (UTS) on outcomes.

Methods:

Participants:

One hundred seventeen individuals with OUD seeking treatment with medication were enrolled between February 2016 and February 2021 in a 12-week randomized, double-blind, placebo-controlled trial to assess the efficacy of gabapentin during an outpatient buprenorphine taper and the feasibility of transitioning to injectable naltrexone. Participants (18–65 years) met DSM-5 criteria for current moderate/severe OUD and lifetime prescription OUD. Lifetime POUD was defined according to DSM-5 criteria, requiring that at any point during their lifetime, participants had met the diagnostic criteria for POUD over a 12-month period. Inclusion criteria included a benzodiazepine- and barbiturate-negative urine screen before starting study medications, no severe adverse reactions, no over-the-counter or prescription drugs with major interactions, and stable medical conditions. Exclusion criteria included major psychiatric disorders (psychosis, schizophrenia, bipolar disorder), suicidal ideation or attempts in the past year, seizure disorders, and physiological dependence on alcohol or substances other than opioids, tobacco, or cannabis. Required tests included normal ECG, BUN, creatinine, and liver enzymes (less than three times the upper limit of normal). Participants assigned female at birth were required to not be pregnant and to use effective birth control. Participants could receive up to $610 in fixed monetary payments for attendance at all screening/intake visits, transition phase visits, weekly visits during naltrexone phase, follow-up visits, and for all blister pack returns. Participants also received unfixed compensation based on a “fishbowl” contingency management procedure for attending clinic visits [27, 28]. In the fishbowl procedure, participants had the opportunity over the course of the taper and transition phase to draw up to 72 chips, which had varying dollar amounts from $1.00-$100.00 (or “Good Job!”) written on them, according to an escalating ratio schedule. The protocol was approved by the University of Arkansas for Medical Sciences Institutional Review Board.

Design and Procedures:

Once eligibility was confirmed, participants underwent a 2- to 4-hour intake, where a research assistant provided a study explanation, informed consent, and exclusion criteria evaluation. Participants were fully informed that the study’s goal was to transition them to naltrexone, and they consented with this understanding. Many individuals expressed a preference for antagonist therapy over opioid agonist maintenance, which motivated their participation. Participants completed lab exams, including urinalysis, UTS, ECG, and bloodwork (SMA-20, CBC). While the initial UTS included tests for opioids (methadone, opiates, morphine, buprenorphine, oxycodone), a fentanyl screen was added partway through the trial due to increased fentanyl use. A study physician conducted psychiatric and medical evaluations before medication started. Screening was typically completed within a week.

During weeks 1–3, participants visited the UAMS Center for Addiction Services and Treatment (CAST) 5–6 days per week for medication, therapy, and assessments. All participants were inducted onto buprenorphine and randomized to receive gabapentin or placebo using computerized urn randomization to balance groups on sex, opioid-withdrawal symptom severity, cannabis-use status, anxiety ratings and tobacco-use status. They started study medication (gabapentin or placebo) on day 3, began a 10-day buprenorphine taper on day 10, and received the final buprenorphine dose on day 19. Opioid-abstinent participants then received increasing doses of oral naltrexone on days 22–25, followed by a naltrexone injection on day 26 [29].

During the taper phase, thrice-weekly supervised urine collection and assessments (withdrawal scales, craving measures, adverse effects) were conducted. A urine sample was positive for opioid use if fentanyl, methadone, opiates, morphine, or oxycodone were detected. Medication compliance was monitored through observed ingestion, urine toxicology screens, pill counts, and self-report. Riboflavin was added to gabapentin/placebo capsules, and weekly urine samples were analyzed for riboflavin levels.

No standard opioid taper protocol exists, so the procedures used were based on a previous taper protocol showing gabapentin efficacy [21]. The buprenorphine induction dose of 12 mg was selected based on prior clinical trials, demonstrating that this dose effectively managed withdrawal symptoms [21, 30, 31]. While higher doses are often used for maintenance [32–34], this study focused on facilitating a transition to naltrexone. Higher buprenorphine doses prolong opioid receptor occupancy, increasing the likelihood of precipitated withdrawal when transitioning to naltrexone [35]. By using a 12 mg buprenorphine dose, we aimed to minimize withdrawal while ensuring participants could successfully transition off buprenorphine and onto naltrexone [21]. The buprenorphine maintenance period was shortened to start the 10-day taper on day 10. This allowed better monitoring of symptoms during the taper, with the taper ending on day 19, providing a 3-day window for naltrexone initiation in week 4. Table 1 outlines the dosing strategy, which was adjusted after the first 16 participants to reduce the risk of moderate opioid withdrawal upon naltrexone initiation. Gabapentin/placebo was ingested under supervision 6 days per week, with take-home doses for evenings and weekends. On days when the clinic was closed, extra doses ensured adequate gabapentin blood levels were maintained. The initial gabapentin dose of 100 mg was given on day 3, and doses increased to 200 mg BID on day 4, 400 mg BID on day 5, 600 mg BID on day 6, and 800 mg BID on day 7. Participants remained on 1,600 mg/day until day 30, followed by a 5-day taper. Clonidine was a one-time dose during day 22 when participants ingested the first dose of oral naltrexone. This was a safety measure to reduce any potentially severe withdrawal.

Table 1.

Dosing Schedule

Week	MED	Day
		1	2	3	4	5	6	7
1	BUP	8 (I)	12 (l)	12 (M)	12 (M)	12 (M)	12 (M)	12 (M)
	GBP or PLA			200 (l)	400 (l)	800 (l)	1200 (l)	1600 (l)
2	BUP	12 (M)	12 (M)	8 (T)	8 (T)	6 (T)	6 (T)	6 (T)
	GBP or PLA	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)
3	BUP	4 (T)	2 (T)	2 (T)	1 (T)	1 (T)
	GBP or PLA	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)
4	NTX	6.25 (O/I)	6.25 (O/I)	12.5 (O/I)	25 (O/I)	380 (D)
	GBP or PLA	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)	1600 (M)
	Clonidine	0.1	0.1	0.1	0.1
5	NTX
	GBP or PLA	1600 (M)	1600 (M)	1200 (T)	800 (T)	600 (T)	400 (T)	200 (T)

All doses are measured in milligrams.

MED = medication; GBP = gabapentin; PLA = placebo; NTX = extended-release naltrexone

I = initiation, M = maintenance;T = taper

O = oral; D = depot

Note: The first 15 participants versus the subsequent 112 participants received 10 mg for days 3 and 4, 8 mg on day 5, 16 mg on day 6 (double dose to cover day 7), 6 mg on day 1 and 2 of week 3, 4 mg on days 3 and 4, and 2 mg on day 5 (last dose) of week 3, 112 participants received 8 mg for days 3 and 4, 6 mg on day 5, 12 mg on day 6 (double dose to cover both day 6 and 7), 4 mg on day 1 of week 3, 2 mg on days 2 and 3, and 1 mg on days 4 and 5 (last dose) of week 3.

Medications:

UAMS research pharmacists prepared all medication packets, including buprenorphine monotherapy tablets, gabapentin, placebo (microcrystalline cellulose), clonidine, and naltrexone injections. Riboflavin (25 mg) was added to all gabapentin and placebo capsules.

Assessments:

Assessments included general participant demographic data, substance use, and medical and psychiatric histories. The Psychiatric Research Interview for Substance and Mental Disorders for DSM-5 (PRISM-V-CV) was used to assess DSM-5 criteria for substance use and other disorders [36, 37].

During the taper phase, assessments occurred weekly or thrice weekly. Thrice-weekly urine samples were analyzed for the presence of substances by Redwood Toxicology Laboratory. Urine samples collected during weeks 2 and 3 were preserved with oxalic acid, frozen, and assayed for riboflavin levels [36]. The Craving and Use Scale, measuring craving frequency, intensity (0–20 scale), and duration, was obtained weekly. Thrice-weekly assessments included supervised urine samples to test for opioids and other substances, the Subjective Opiate Withdrawal Scale (SOWS) [38] with 16 items rated from 0 (not at all) to 4 (extremely), and the Clinician Opiate Withdrawal Scale (COWS), an observer-rated scale with 11 items [38]. Fentanyl testing was conducted using testing strips and confirmatory laboratory testing was not performed. CLIA-waived fentanyl urine test cassettes manufactured by Lochness Medical Supplies Inc. were used to detect recent fentanyl use offering a sensitivity of 1 ng/mL, storage conditions of 35.6–86°F, and compatible with human urine samples (FYL-1CAP156–25) [39].

Data Analyses:

Baseline differences were assessed using contingency tables (χ² test or Fisher exact test) for categorical variables and the Wilcoxon Rank-sum test for age. Study retention was analyzed using Kaplan-Meier Survival analysis, with group differences assessed by the Log-Rank test.

For study outcomes, only participants who received gabapentin/placebo and completed at least one assessment during the buprenorphine taper were included. Contingency tables determined differences in taper completion and naltrexone transition between treatment groups. COWS data were analyzed using a negative binomial generalized estimating equations (GEE) model with medication group and study visit as predictors, while SOWS data used a zero-inflated negative binomial two-stage model. UTS data were analyzed using GEE repeated measures logistic regression. Craving data were log-transformed and analyzed with repeated measures models. Riboflavin concentrations were analyzed using a Rank Sum test. Statistical significance was set at p<0.05, with trends noted at p=0.05–0.1. Analyses were conducted using SAS 9.4 software.

Analytic Strategy for Sample Subset:

Secondary analyses were conducted on 56 participants with a baseline fentanyl UTS. Baseline characteristics, including fentanyl UTS, were analyzed using χ² or Fisher exact tests for categorical variables and the Wilcoxon Rank-sum test for age. Study retention was assessed using Kaplan-Meier survival analyses by medication group, fentanyl UTS, and their combination. Logistic regression modeled the effects of medication group, fentanyl UTS, and their interaction on taper completion and naltrexone receipt.

COWS and SOWS data were analyzed using a negative binomial GEE model with medication group, fentanyl UTS, and study visit as factors. P-values were adjusted using the Tukey procedure. UTS data were analyzed via GEE repeated measures logistic regression with medication group, fentanyl UTS, and study visit as factors. Higher-order effects of study visit were eliminated based on significance and model fit. Craving measures were analyzed with repeated measures models, log-transformed for length and times, while intensity required no transformation.

Results:

Whole Sample

Subject Characteristics:

Of 126 individuals who signed consent, 125 were randomized to gabapentin (n=65) or placebo (n=60). Five gabapentin participants did not complete buprenorphine initiation, and 19 were withdrawn or withdrew. The remaining 41 completed the taper phase. Three placebo participants were non-starters, and 23 were withdrawn or withdrew, leaving 34 who completed the taper. In total, 75 (64.1%) participants completed the taper phase. There were no significant demographic differences between medication groups. Among eligible participants who started buprenorphine induction, an average of $241.25 in monetary compensation was received.

Outcomes:

Taper completion rates were similar between gabapentin (68.3%) and placebo (59.6%) groups (χ²=0.9580, p=0.328). Likewise, the percentage transitioning to injection naltrexone post-taper did not differ between gabapentin (89.2%) and placebo (85.3%) groups (p=0.729).

During the taper, no significant medication group differences in opioid-positive UTS were found (p=0.768). However, time effects were significant, showing a decline in week 1, a nadir in week 2, and a slight rebound in week 3. COWS and SOWS scores also showed no group differences, though both declined after week 1, with a nadir in COWS (p<0.0001) and a rebound in SOWS in week 3 (p<0.0001).

Craving intensity and length did not differ by group but significantly decreased in weeks 2 and 3 compared to week 1 (p<0.0001). There was significant interaction between medication group and time for the number of cravings (p=0.048), with placebo showing a larger decrease from week 1 to week 2 relative to gabapentin, although gabapentin reached parity in craving number by week 3.

Adverse Events:

In week 1, there were 35 adverse events in the gabapentin group and 25 in the placebo group, with all classified as mild except for one moderate event (vomiting) in the gabapentin group. In weeks 2 and 3, adverse events were 12 (gabapentin) vs. 11 (placebo) and 5 (gabapentin) vs. 7 (placebo), respectively, with all events classified as mild. No opioid overdoses, either fatal or non-fatal, were reported during the trial. Furthermore, there was no evidence of gabapentin contributing to overdose risk within the study population.

Protocol Adherence:

Forty-one gabapentin and 34 placebo participants adhered to the protocol and completed the buprenorphine taper. Out of 815 scheduled medication days for gabapentin participants, 35 (4.3%) were missed, while 23 (3.5%) of 654 scheduled days were missed in the placebo group.

Average riboflavin levels in gabapentin (week 2: 5.28 μg/ml; week 3: 4.51 μg/ml) and placebo (week 2: 3.77 μg/ml; week 3: 3.45 μg/ml) were above the positive threshold of 0.97 μg/ml. The percentage of samples below this threshold was 17.8% (gabapentin) vs. 24.4% (placebo) in week 2, and 25% (gabapentin) vs. 41.2% (placebo) in week 3. There were no significant differences between groups in riboflavin concentration or threshold frequency during either week.

Baseline Fentanyl UTS Subsample

Subject Characteristics:

In the gabapentin group, 42.9% had a baseline fentanyl-positive UTS, compared to 39.3% in the placebo group (p=0.786), with no significant differences in taper completion rates between groups (p=0.577). Study retention did not differ by medication group or fentanyl status.

Outcomes:

Of the 56 participants with baseline fentanyl UTS, 36 completed the taper, with 30.6% being fentanyl-positive. Fentanyl-positive participants were less likely to complete the taper than fentanyl-negative ones (47.8% vs. 75.8%, p=0.033). No interaction between medication group and fentanyl status was found.

The probability of receiving naltrexone post-taper did not differ by fentanyl status (p=0.193) or medication group (p=0.593). Fentanyl-positive participants had a higher percentage of opioid-positive urine results (p<0.0001), with no medication group effect (p=0.491). Time effects reflected a decrease in week 1, followed by a slight rebound in week 3.

COWS scores were higher for fentanyl-positive participants z=2.47, p=0.014), with a significant interaction between fentanyl status and medication group for the gabapentin group (z=3.70, p=0.001), but no difference in the placebo group (z=0.80, p=0.423). SOWS scores were lower in the gabapentin group for fentanyl-negative participants (z= −3.52, p=0.002, and higher for fentanyl-positive participants (z= 3.73, p=0.001), with no differences in the placebo group.

No significant differences were observed for craving intensity or times by medication or fentanyl status, but craving intensity and times decreased significantly from week 1 to weeks 2 (intensity: t=−6.84, df=105, p<0.0001, times: t=−5.41, df=105, p<0.0001) and 3 (intensity: t=−6.86, df=105, p<0.0001, times: t=−5.03, df=105, p<0.0001). Craving length also decreased over time (week 1 to week 2: t=−2.79, df=89, p=0.008, week 1 to week 3: t=−2.79, df=89, p=0.008), and a significant interaction between fentanyl status and medication group was found for craving duration (t= −2.65, df=47, p=0.011), with shorter episodes in fentanyl-positive participants in the gabapentin group.

Discussion:

Despite decreases in PO medication dispensing rates [40], nonmedical PO use continues to rank second to marijuana use [41] and overdose deaths remain high [2]. No optimal opioid taper strategy has been identified to date and opioid withdrawal during tapering continues to be common and contribute to relapse. Improving strategies to manage withdrawal is critical to enhancing treatment outcomes, particularly during transition to opioid antagonist treatment with extended release naltrexone. This study aimed to determine whether adjunctive gabapentin could improve buprenorphine taper outcomes and facilitate transition to extended-release naltrexone. Contrary to our hypothesis, there were no significant differences in taper completion or naltrexone initiation between gabapentin (1,600 mg/day) and placebo.

Gabapentin is FDA-approved with minimal drug interactions [42] and has shown promise in enhancing opioid analgesia [43, 44] and treating withdrawal in pilot studies [21, 22, 45, 46]. Gabapentin is commonly used for chronic pain and anxiety, which are also symptoms of opioid withdrawal [47, 48]. Previous studies, including our pilot, demonstrated lower opioid use with gabapentin [21], but the 1,600 mg/day dose in this trial may have been insufficient. In the present study, gabapentin was well tolerated with few adverse events or major differences between gabapentin- or placebo-reported adverse events. However, gabapentin has gained attention in recent years due to its potential for sedative effects and misuse, particularly when combined with opioids. Reports indicate that gabapentin is increasingly co-used with opioids, with some individuals seeking its enhanced euphoric effects or its ability to potentiate opioid-induced respiratory depression [49, 50]. Given this emerging public health concern, it is essential to carefully balance the potential benefits of gabapentin in opioid withdrawal management against its risks of sedation and misuse. Although there have been reports of misuse of gabapentin [49, 50], there was little evidence for it in this study. Higher doses (up to 3,600 mg/day) have been effective in other conditions [29], and future research should explore whether higher doses of gabapentin could yield better results, given the low adverse event rate and high tolerability observed. However, given the increased recognition of gabapentin misuse, any future dose escalation studies must include careful monitoring of adverse effects, sedation, and potential misuse behaviors. Additionally, screening for polysubstance use, particularly co-administration with opioids or benzodiazepines, should be a priority in study protocols.

Opioid withdrawal involves complex mechanisms, including sympathetic overdrive from the locus coeruleus [51–54]. α-2 adrenergic agonists like clonidine directly address this, while gabapentin indirectly dampens the nervous system’s overall excitability [55]. Thus, α-2 adrenergic agonists like clonidine might be specifically effective for certain withdrawal symptoms linked to sympathetic overdrive, while gabapentin might offer broader neuro-modulatory benefits. Indeed, in practice opioid withdrawal is often treated with a combination of agents [56, 57]. Thus, gabapentin could still play a role as part of a multi-medication approach to withdrawal [34, 56].

A potential confounder in this study was the increasing prevalence of fentanyl use, which became common during the trial and is a major contributor to opioid overdoses [2]. While heroin played a pivotal role nationally in the opioid overdose crisis, particularly when many individuals transitioned from POs to heroin due to increased regulation and reduced availability of POs which led to a surge in heroin-related overdoses between 2010 and 2015 [58], fentanyl, not heroin, started to become more prevalent in Arkansas where individuals with OUD almost exclusively misused POs. Thus, fentanyl use may negatively impact treatment outcomes [59–63], and our secondary analyses showed fentanyl-positive participants had worse taper outcomes, more opioid-positive urines, and more severe withdrawal. The emergence of fentanyl likely overshadowed any benefits of gabapentin, particularly at the 1,600 mg/day dose. Indeed, gabapentin-treated participants with fentanyl exposure had a higher prevalence of opioid-positive urine screens relative to placebo treated, fentanyl exposed, participants.

Study Strengths and Limitations:

This randomized, double-blind, placebo-controlled trial was strengthened by its rigorous design and balanced baseline demographics. The study was adequately powered to detect medium effect sizes, and compliance was closely monitored. However, the design requirement for frequent visits, and the lack of clonidine or other adjunct medications for withdrawal limits comparisons to real-world settings where such medications are standard, leaving the potential synergistic effects of gabapentin and adjunct treatments for future investigation. In addition, the selection of 12 mg buprenorphine induction dose, while based on our prior work [21] and the need to reduce buprenorphine receptor occupancy to facilitate the taper strategy in our trial may not reflect real-world clinical practice where higher, unfixed induction doses (e.g., 16–24 mg) are more commonly used, particularly for patients exposed to fentanyl. Nevertheless, the results of this study may still inform clinical practice.

Other limitations affect the conclusions. While nonmedical opioid use in Arkansas was primarily prescription-based, the rise in fentanyl use during the trial led to adding fentanyl UTS mid-study. As a result, data from participants before fentanyl UTS were unavailable for comparison, limiting definitive conclusions about fentanyl’s impact. However, results indicate baseline fentanyl use is associated with worse outcomes, and future studies should consider study designs to address the impact of fentanyl use on treatment outcomes with novel MOUD induction and transition strategies.

High dropout rates and low stabilization on naltrexone reflect the challenges of this outpatient opioid taper as a treatment strategy, with the resurgence in opioid-positive UTS and withdrawal symptoms towards the end of the 10-day taper suggesting this approach is suboptimal for outpatient naltrexone transitions [64, 65]. Recent studies show more rapid tapers with adjunct medications improve naltrexone transition success rates [56, 66–69], but show low success rates among individuals with heroin use disorder, which likely applies to individuals who use fentanyl as well [68, 69]. Although the exclusion of adjunct medications allowed for a focused evaluation of gabapentin, this limits generalizability to studies that use such medications, which are routine in clinical practice [70, 71]. Despite prior research supporting buprenorphine taper protocols for some individuals, our findings highlight the difficulties in achieving a successful transition to naltrexone in an outpatient setting. Future studies with higher doses of gabapentin or adjunct medications may benefit from more rapid taper and transition strategies to improve outcomes, particularly in outpatient settings where naltrexone initiation rates are still generally lower than in inpatient settings [49].

A notable limitation of this study is that the secondary analysis of fentanyl UTS was not pre-specified in the original grant or study protocol. This analysis was conducted in response to the significant rise in fentanyl use reported by participants midway through the trial, which necessitated the addition of fentanyl screening to better assess its impact on treatment outcomes. As a result, some participants enrolled earlier in the study did not undergo fentanyl testing, potentially leading to incomplete data for baseline fentanyl exposure. This post hoc analysis, while informative, should be interpreted with caution, as it was not initially designed as a primary study objective.

Conclusions:

Gabapentin at 1,600 mg/day did not significantly improve opioid withdrawal outcomes or aid transition to injection naltrexone compared to placebo in individuals with OUD undergoing a 10-day buprenorphine taper and 5-day naltrexone transition. The taper duration may have been suboptimal, as opioid use and withdrawal symptoms resurged near the end. The rise in fentanyl use, among participants with a history of POUD, was linked to worse outcomes and may have diminished gabapentin’s potential benefits. Future trials should stratify participants by baseline fentanyl use, test higher gabapentin doses alongside adjunct medications, and adopt more rapid buprenorphine taper and naltrexone transition protocols.

Figure 1.

Flow chart of participant’s progress through the taper phase of the randomized clinical trial. BUP=buprenorphine; GBP = gabapentin; PLA= placebo. Nonstarters = no shows or those who refused; Design exclusion = positive for opioids.

Figure 2.

Percentage of participants retained during the 3-week taper phase and transition to injection naltrexone in each of the two medication groups. Y-axis: percentage of participants; X-axis: days of the taper phase, naltrexone transition phase, and gabapentin taper. Study retention did not significantly differ by medication group.

Figure 3.

The effects of gabapentin (GBP, closed circles) and placebo (PLA, open circles) in the whole sample of participants (N=117) on Urine Toxicology Screens for Opioids (A.), Y-axis: percentage of opioid-positive urine toxicology screens, X-axis: the sequence of the screen collected thrice weekly per week, all values represent the total percent positive; the Clinician Opiate Withdrawal Scale (COWS, B.), the Subjective Opiate Withdrawal Scale (SOWS, C.), Y-axis: the average score; X-axis: the sequence of the assessment administration per week. There were no significant differences between gabapentin and placebo groups in opioid-positive UTS, COWS, or SOWS scores, though all measures showed expected time-related changes during the taper. All values represent the means + SEM.

Figure 4.

The effects of gabapentin (GBP, closed symbols) and placebo (PLA, open symbols) in a subsample of participants (N = 56) on urine toxicology screens and opioid withdrawal scores, stratified by baseline fentanyl status (fentanyl-positive = circles (left) and fentanyl-negative = squares (right).

(A) Urine Toxicology Screens: Y-axis: percentage of opioid-positive urine toxicology screens; X-axis: sequence of screens collected three times per week. Participants who were fentanyl-positive had significantly higher rates of opioid-positive screens (p < 0.0001), while no significant effect of medication group was observed within either subgroup (p = 0.491). All values represent the total percent positive.

(B) Clinician Opiate Withdrawal Scale (COWS): Y-axis: average score; X-axis: sequence of assessment administration per week. Fentanyl-positive participants had significantly higher COWS scores overall (p = 0.014), with a significant interaction between fentanyl status and medication group in the gabapentin group (p = 0.001); no significant difference was observed in the placebo group.

(C) Subjective Opiate Withdrawal Scale (SOWS): Y-axis: average score; X-axis: sequence of assessment administration per week. Among fentanyl-negative participants, those receiving gabapentin reported significantly lower SOWS scores (p = 0.002). In contrast, fentanyl-positive participants in the gabapentin group reported significantly higher SOWS scores (p = 0.001).

All values represent the mean ± SEM.

Figure 5.

The effects of gabapentin (GBP, closed symbols) and placebo (PLA, open symbols) in a subsample (N=56) with opioid positive drug screen results (Fentanyl positive result, FEN circles) on craving length, Y-axis: average minutes, X-axis: the week. Craving duration significantly decreased over time, with reductions observed from week 1 to week 2 and week 1 to week 3. All values represent the means + SEM.

Table 2.

Comparison of sample demographics (N = 117)

Variable	GBP (N = 60)	PLA (N = 57)	P-value
	N (%) or *Mean (SD)	N (%) or *Mean (SD)
Sex
Male	32 (53.3)	32 (56.1)	0.761
Female	28 (46.7)	25 (43.9)
Age (years)	32.95 (8.29)*	32.51 (7.25)*	0.889
Race/ethnicity
European descent	50 (83.3)	47 (82.5)	0.965
African descent	6 (10.0)	6 (10.5)
Hispanic descent	3 (5.0)	4 (7.0)
Asian descent	1 (1.7)	0 (0.0)
Education
High school or higher	51 (86.4)	51 (92.7)	0.274
Less than high school	8 (13.6)	4 (7.3)
Employment status
Employed	30 (50.8)	25 (45.5)	0.565
Unemployed	29 (49.2)	30 (54.5)
Living status
Cohabitating	23 (39.0)	16 (29.1)	0.266
Noncohabitating	36 (61.0)	39 (70.9)

GBP = gabapentin; PLA= placebo

SD= standard deviation

^*= value represents a mean and a standard deviation

Table 3.

Number of adverse events reported by week and treatment group

Adverse event	Week 1		Week 2		Week 3
	GBP	PLA	GBP	PLA	GBP	PLA
Agitation	_	_	_	_	_	_
Anxiety	_	_	_	_	1	_
Auditory and visual hallucinations	1	_	_	_	_	_
Back pain	1	_	_	_	_	_
Bilateral L.E. pitting edema	_	_	1	_	_	_
Blurred vision	_	_	_	1	_	_
Bright colored urine	1	_	_	_	_	_
Cardiovascular symptoms	_	_	_	_	_	_
Cold sweats	_	_	_	1	_	_
Constipation	2	_	1	_	_	_
Continuously hot throughout the day	_	_	_	1	_	_
Depressed mood	_	_	_	_	_	_
Diarrhea	1	_	_	_	_	_
Dizziness	_	1	1	_	_	_
Double vision	_	_	1	_	_	_
Dry mouth	1	_	_	_	_	_
Elevated heart rate	1	_	_	_	_	_
Fatigue	1	_	_	_	_	_
Flu like symptoms	1	_	_	_	_	_
Hands shaking	_	1	_	_	_	_
Headache	1	4	3	1	_	_
Heartburn	1	_	_	_	_	_
Impotence/loss of libido	1	_	_	_	_	_
Insomnia	2	_	_	_	_	1
Involuntary spasm of arms and legs at night	_	_	1	_	_	_
Irritability/anger	1	_	_	_	1	_
Listlessness/dysphoria	1	_	_	_	_	_
Loss of balance	_	1	_	_	_	_
Muscle twitches	2	_	1	_	_	_
Nausea/vomiting	1	2	_	1	_	1
Opioid withdrawal symptoms	7	11	1	2	1	5
Respiratory symptoms	_	1	_	_	_	_
Sedation	1	2	_	_	_	_
Severe shaking/trembling	_	_	_	1	_	_
Shortness of breath	_	_	_	1	_	_
Somnolence	2	1	2	_	_	_
Stomach cramps/pain	_	_	_	1	_	_
Stomach pain/soreness	_	_	_	_	_	_
Tightness in upper body	_	_	_	_	_	_
Twitching in hands/feet	_	_	_	_	1	_
Urinary incontinence/hesitancy	2	_	_	_	1	_
Urinary urgency/frequency	3	_	_	1	_	_
Weakness	_	1	_	_	_	_
Total number of events	35	25	12	11	5	7

GBP = gabapentin; PLA = placebo

Number of times adverse events were credited as possible, probable, or definite. Adverse events credited as unrelated or unlikely were not reported.

Week 1: All participants were initiated on BUP, GBP, and PLA. Week 2: All participants were maintained and tapered off BUP, while maintained on GBP or PLA. Week 3: All participants were tapered off BUP, while maintained on GBP or PLA.