The Impact of High Potency Synthetic Opioids (HPSO) on Pharmacotherapies for Opioid Use Disorder: A Scoping Review

Abstract

Background:

The clinical implications of high potency synthetic opioids (HPSO) on medications for opioid use disorder (MOUD) is not well understood. Although pharmacological interactions are plausible, the clinical significance of such interaction has not been systematically elucidated. This scoping review investigates the relationship between HPSO exposure and various MOUD treatment outcomes.

Methods:

We followed PRISMA Extension for Scoping Reviews (PRISMA-ScR) for scoping reviews with extensive a priori search strategy of databases: MEDLINE, Embase, PsycInfo, Web of Science, CINAHL, and Cochrane.

Results:

From 9,149 studies, 34 fulfilled the inclusion criteria. Synthesized data reveals several critical insights: First, there's a variable but high occurrence (38-80%) of HPSO usage among individuals on MOUD. Second, MOUDs are linked to a decreased risk of overdoses and deaths associated with HPSO. Third, HPSO consumption is correlated with the risk of precipitated withdrawal when starting buprenorphine. Fourth, low dose buprenorphine is being recognized as one method to avoid moderate withdrawal symptoms prior to treatment. Lastly, significant gaps exist in human experimental data concerning the effects of HPSO on key factors critical for treating OUD-craving, withdrawal symptoms, and pain.

Conclusions:

Current evidence supports MOUD safety and effectiveness in reducing non-medical opioid use. Further research is needed to explore HPSO’s influence on the acute factors preceding non-medical opioid use, such as cravings, withdrawal symptoms, and pain. This research could inform the optimization of MOUD dosing strategies. Achieving consensus and harmonizing data across clinical and research protocols could diminish variability, enhancing our understanding of HPSOs effect on MOUD treatment outcomes.

1. INTRODUCTION

The prevalence of opioid use disorder (OUD) in the U.S. continues to rise, causing an unprecedented societal, economic, and humanitarian crisis.¹ Sustained initially by prescription opioids and heroin, the opioid crisis has been fueled, in recent years, by the contamination of the illicit drug supply with high-potency synthetic opioids (HPSO).² Since the early 2010s, HPSO have emerged as the main culprit in opioid overdose deaths accounting for the majority of all overdose deaths in the U.S..³ According to the National Center for Health Statistics, there were 100,306 drug overdose deaths in the U.S. from April 2020 to April 2021, almost twice the number of casualties in the Vietnam War.^4,5 Likewise, the unprecedented escalation of drug overdose deaths in the wake of the COVID-19 pandemic has been attributed to the rise in the availability of HPSO in the illicit drug supply.

The potency of HPSOs at the mu-opioid receptor (MOR) can range from 100 to 10,000 times more potent than morphine.⁶ HPSOs are highly lipophilic, hence the propensity to cross blood-brain barrier faster than most other opioids — as reflected in rapid equilibration between plasma and cerebral fluid, and rapid accumulation in adipose and muscle tissue, especially following repeated use.² Taken together, these characteristics contribute to these compounds’ high addictive potential, overdose risk, and other specific clinical challenges from slow elimination processes.^7,8

Recent reports about HPSO being compounded with other substances, such as cocaine, methamphetamine, and benzodiazepines have added another layer of complexity to the burgeoning opioid crisis.⁹ There is also an increase in primary users of HPSO as results emerging from cross-sectional studies indicate that over half of persons with OUD deliberately seek HPSO, probably due to their low cost and robust reinforcing effects.^9,10 Methadone and buprenorphine have been available to treat OUD since 1972 and 2002 respectively, both were developed decades before HPSO became widely available. Still, the real-world effectiveness of medications for opioid use disorder (MOUD) to counteract non-medical use of HPSO remains understudied.

This scoping review consolidates observational evidence regarding the effects of HPSO on the clinical outcomes for patients with OUD. We highlight knowledge gaps and provide recommendations for research methodologies, clinical management, and understanding the mechanisms at play, aiming to steer future research towards more definitive findings.

2. METHODS

This scoping review is being reported in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR).¹¹ The eligibility criteria for included studies were: 1) participants were adults aged 18 years or older; 2) participants were exposed to HPSO determined either by self-report or urine drug screen (UDS); alternatively, there was population-level evidence of a high prevalence of HPSO in drug supplies; and 3) the studies were available as peer-reviewed, and full reports regardless of language. Conversely, reports were excluded if :1) they were non-human preclinical studies; 2) participants were less than 18 years old; 3) if they were not peer-reviewed or original repots (e.g., review articles or viewpoints).

2.1. Search strategy and Study Selection

The protocol for this scoping review was published in Open Science Framework (OSF) https://doi.org/10.17605/OSF.IO/A2P7X. MEDLINE, Embase, and APA PsycInfo were searched on the Ovid platform. In addition, Web of Science Core Collection, CINAHL Complete, and Cochrane databases were searched. A medical librarian (M.S.F) was consulted on the search methodology and ran a medical subject heading (MeSH) analysis of known key articles provided by the research team. Scoping searches were done in each database and an iterative process was applied to translate and refine the searches. To maximize sensitivity, the formal search used controlled vocabulary terms and synonymous free-text words to capture the concepts of “fentanyl” and “treatment modalities”. The search strategy was peer reviewed by a second librarian, not otherwise associated with the project, using the Peer Review Checklist for Search Strategy (PRESS) standard.¹² Reviewers used the included studies to check for additional relevant cited and citing articles. The search was conducted on March 6, 2023, with no language or date limits.

2.2. Data Management

The final search retrieved a total of 9149 references (Figure 1), which were pooled in EndNote and de-duplicated [www.endnote.com]. This set was uploaded to Covidence [www.covidence.org] for screening, which identified additional duplicates, leaving 5072 references for screening. Using Covidence, two screeners (C.H. and E.C.) independently reviewed the titles, abstracts and full text of the eligible articles that meet inclusion criteria. Any conflicts were resolved through consensus or by a third independent reviewer (O.J. or J.D.). Standardized forms were used by all reviewers for the data abstraction- demographic information, study methodology, intervention details (if applicable), specific MOUD dose, frequency, and pattern of titration and maintenance doses (if described), and specific clinical outcomes. Finally, the type and source of financial support for publications were noted. Two authors (C.H. and E.C.) extracted data independently from each eligible article. To ensure consistency, each article selected were then independently reviewed and areas of differences were resolved by a third reviewer (O.J. or J.D.).

Figure 1.

RESULTS

A total of 34 articles met criteria for inclusion in this scoping review (Table 1). Articles showed wide variability in study designs including case series, observational cohort studies, and secondary analysis of randomized controlled trials (RCT). The primary outcomes of the studies included prevalence of HPSO exposure, feasibility of novel buprenorphine induction protocols, retention in treatment, HPSO-related opioid overdose and mortality, abstinence, and HPSO exposed persons’ satisfaction with MOUD treatment.

Table 1:

Study characteristics

Study reference	Study design	Primary outcome	Study Sample	Protocol (if applicable)	Main Results	Other notes
Case Series
Danilewitz, M et al, 2020	Case report	Buprenorphine induction	29-year-old with OUD	D1: 16mg bup in divided doses. D2: 30mg. D3: 32mg. D4: 40mg	No withdrawals at 40mg	Difficulties dissolving entire 40 mg dose under tongue. Concerns for hepatotoxicity
Brar et al, 2020	Case Series	Buprenorphine induction	7 adults with OUD in outpatient. UDS +fentanyl	Standard protocol: Day 1 (0.5mg x1), Day 2 (0.5 BID), Day 3 (1 BID), Day 4 (2 BID), Day 5 (3 BID), Day 6 (4 BID), Day 7 (12mg x1), Day 8 variable.	Induction well tolerated, follow up, no fentanyl use.	Full agonist opioids continued at same dose and discontinued on Day 8.
Mariani J. et al, 2020	Case series	Buprenorphine induction	5 adults with OUD in outpatient setting	Patient 1: Induction at COWS > 6 with 2mg SL bup. Total daily bup > 8 for 3 days prior to giving ER-bup. 2 patients: received ER-bup on day 2 3 patients received ER-bup on day 3. Protocol modified to more rapid administration of ER-bup after observing that participants receiving 16mg for 2 or 3 days have no issues tolerating ER-bup	Both patients tolerated transition to ER bup. there is no clinical advantage in delaying ER-bup, with risk of failed induction in delaying ER-bup.
Mariani J. et al, 2021	Case series	Buprenorphine induction	5 adults with OUD in outpatient setting	ER-bup injection after 24 mg SL bup on the same day.	All patients retained for 12 weeks of trial	All patients received 2 more scheduled ER-bup injections
Antoine, et al, 2021	Case series	Buprenorphine induction	4 adults with severe OUD and +fentanyl	Standard protocol*	2 patients had PW on standard protocol, 2 had no PW on modified protocol
Kaliamurthy, et al, 2022	Case series	Buprenorphine induction	2 adults at a MMTP clinic with fentanyl UDS.	Standard protocol: SL bup/nal 2mg-0.5mg film cut into quarters, starting at 0.5mg on D1, increased over 7-10 days to 16mg, then methadone (kept at same dose during titration) discontinued.	Both patients tolerated transition to bup	Both patients were on methadone 125 mg and 25 mg
Shearer D, et al 2022	Case series	Buprenorphine induction	3 patients with OUD	bup 2 mg x 1; bup 2 x 2; bup2 x 1 + 16 mg x 1 + 4 mg x2 + 2 mg mg x3 --> 24mg x 3 months	bup can cause precipitated w/d in patients using HPSO
Suen L et al, 2022	Case series	Buprenorphine induction	12 patients with OUD	Rapid microdosing protocol utilizing divided doses of bup while they did not require stopping other opioid use (blister packaging was used)	50% had no w/d during initiation. 58% retained in care at 30 days. 42% retained on bup treatment in 30 days	92% using fentanyl at intake
Adams, K et al, 2023	Case series	Buprenorphine induction	45 hospitalized adults. 49% OUD only, 11% chronic pain only, 40% with both. 80% with h/o heroin or non-prescribed fentanyl use.		(80%) patients completed the transition to sublingual buprenorphine with a median completion dose of 16 mg daily.	Only 53% had documented COWS; Severe withdrawal-none; mild or moderate withdrawal-62.5%) no withdrawal-37.5%)
Azar, P et al, 2023	Case series	Buprenorphine induction	2 adult patients with OUD and acute pain and UDS +fentanyl	Ultra-rapid induction: Patient 1-SL bup 0.5 −1 mg q3h, then given 12 mg at hour 24 for cumulative 18.5 mg within 24 hours. Over next 24hr, received total 32 mg. Discharged on bup 20 mg. Patient 2: SL bup/nal 0.5 q1h and 4mg at hour 5 for total 7.75 mg within 6 hours. Over next 24hr, received total 32, on day 3 received total 16, discharged on 12 BID.	Patient 1: COWS <5 during induction Patient 2: COWS peaked at 8 during induction	Both patients received simultaneous hydromorphone PRN during induction but weaned off prior to discharge.
Kahan, M et al, 2023	Case series	Buprenorphine induction	2 adults with intravenous fentanyl use	Patient 1: Took bup 8mg at home, after an hour got a total of 28 mg bup (4mg at 30mins, 4mg at 3 hours, 8mg at 3hr 20 mins, 8mg at 4 hours, and 4mg at 7 hours after presenting to ED). Patient 2: received 16mg bup at COWS 25, followed by 8mg 1 hour and 8mg 2 hours after initial dose (32mg within 2 hours).	Both individuals tolerated large doses of bup and received 300 mg extended release bup on discharge after 32 mg bup the morning after (4-5 hours after induction). They both received second dose of ER bup 4 weeks later.	Both patients were already in active opioid withdrawals.
Thakrar A, 2023	Case series	Primary outcome: safe administration of naloxone, over-sedation, or a fall. Secondary outcomes were Patient directed discharges (PDD) and respective length of stay (LOS), discharges on methadone or buprenorphine, and discharges with naloxone.	23 patients with OUD selected based on risk assessment: prior PDDs, presence of an acute pain indication, or the amount of illicit opioids used	Short acting opioid agonist treatment (sOAT) was administered at median doses of 200–320 morphine milligram equivalents per 24-h period	The PDD rate was 44% with median LOS 5 days (compared to PDD rate 69% with median LOS 3 days for prior admissions), 65% of sOAT cases were discharged on buprenorphine or methadone (compared to 33% for prior admissions), and 65% of sOAT cases were discharged with naloxone (com- pared to 19% for prior admissions).	Utox + fentanyl (82.6%)
Observational Studies
Arfken C. et al, 2017	Cross-sectional	To describe the characteristics of patients and prevalence of +fentanyl in an MMTP	368 adults with OUD enrolled in an MMTP	NA	38% have at least 1 +fentanyl UDS, 26.1% with 2 or more +fentanyl. +fentanyl associated with shorter clinic retention, multiple admissions to clinic	Cocaine was secondary/tertiary drug of choice. Fentanyl detection more likely in first 30 days following admission. Methadone dose unspecified
Krause D. et al, 2017	Cross-sectional	To describe prevalence and correlates of fentanyl use among patients at 3 OTPs in Germany using surveys and UDS	960 adults with OUD receiving OAT (73.5% methadone, 17.5% bup, 9% diamorphine)	NA	37.9% of 401 surveyed (qualitative) reported prior concomitant fentanyl use but only 6.8% of 960 UDS +fentanyl. Diamorphine maintenance subgroup less likely to use fentanyl	+fentanyl all UDS confirmed or self-report.
Stone C, 2018	Retrospective cohort	Outcomes: retention in treatment at 6 months, evidence of sustained abstinence, relapse, methadone dosage required to achieve sustained abstinence; and the number of days required to achieve abstinence.	154 unique intake events (representing 147 patients).	NA	89% of those who remained in treatment at 6 months achieved abstinence. No significant difference was seen for dose or time to achieve abstinence. Relapse was common (57%). Repeated exposure to fentanyl was seen frequently (71%) while in MMT before and after achieving abstinence.	80% (n = 123) tested positive for fentanyl at intake. Methadone dose at abstinence, median 90 mg for those +fentanyl only and 100 mg other opiates only
Silverstein S et al, 2019	Qualitative surveys	Explore buprenorphine self-treatment of people with OUD who use HPSO	63 participants	NA	Proliferation of HPSO in opioid supply Difficulty to use BUP as harm-reduction or self-Tx strategy due to precipitated withdrawal w/ HPSO	intentional and unintentional HPSO via self-report
Wakeman, S, 2019	Retrospective cohort	Primary: Treatment retention and opioid abstinence at 6 months. Secondary: Retention and abstinence at 1 and 3 months; bup dose at initiation and at 1, 3, and 6 months.	251 adults with OUD, newly started on OBOT, and had tox report within 30 days prior to starting bup.	NA; chart review once fentanyl testing was made available.	Fentanyl+ (N = 48). At 6m: 37.5% retention → 54.5% abstinent. Other opioid+ (N = 19). At 6m: 47.4% retention → 60% abstinent. Opioid Negative (N = 184). At 6m: 50.5% retention → 92.6% abstinent. No difference in 6-month retention. Fentanyl+ had lower abstinence than Opioid Negative at 6 months.
Peckham A. et al, 2020	Retrospective cohort	Transitioning from SL bup to ER-bup	40 adults with OUD already taking SL bup (dose and duration varied) in outpatient setting.	Conventional ER-bup: 300 mg monthly x2, followed by 100 mg monthly. Delayed Conventional ER-bup: 300 mg monthly x3, followed by 100 mg monthly. Empiric High-Dose ER-bup: 300 mg monthly	14 DC’d after 1 or 2 doses. 14 conventional (3 later switched to empiric HD). 4 delayed. 10 empiric HD. 22 needed supplemental SL bup (including 9/10 who have been on SL bup for < 7 days).	39 (97.5%) reported OUD w/ “heroin/fentanyl” (unclear when last use). 21 had tox available on day of first ER-bup: All +bup, but only 4 +fentanyl.
Stone C et al, 2020	Retrospective cohort	Primary: Treatment retention, sustained remission, return to use, methadone dosage required; and number of days to achieve remission. Secondary: Mortality.	154 unique intake events (representing 151 patients).	NA	75% of patients achieved remission. 1-year retention was 53% for fentanyl-exposed individuals and 47% for those not exposed. 99% who remained in treatment at 12 months achieved remission. 4 patients died after leaving MMT prematurely.	80% +fentanyl at intake
Pearce L.A et al, 2020	Retrospective cohort	All cause and cause specific crude mortality rate and retention in treatment	55347 patients with OUD	NA	Risk of mortality lower during periods on MOUD. MMT 4.7 vs 9.5 BUP/NX 2.9 vs 11.3. Highest mortality risk in week after stopping MOUD.	HPSO prevalent in drug supply
Mackay L. 2021	Prospective cohort	Self-reported treatment satisfaction among patients with OUD with fentanyl exposure	804 participants with OUD (1930 observations)	NA	Incidence of dissatisfaction: methadone 30.8%, buprenorphine 19.1%, SROM 20.9%, and iOAT 11.9%.	OAT dissatisfaction was significantly associated with OAT discontinuation. OAT discontinuation was significantly associated with fentanyl exposure
Herring, A, 2021	Prospective cohort	Buprenorphine treatment of fentanyl withdrawal by EMS and 30-day treatment engagement	54 patients with OUD in acute moderate-severe withdrawal.	NA	No cases of precipitated withdrawal, excessive respiratory depression or sedation. At 30 days, 39.2% of fentanyl users treated with bup were engaged in outpatient addiction treatment	Self-report of fentanyl (51.8% reported fentanyl use in the last 72 hours)
Young S, 2021	Retrospective cohort	Fentanyl+ UDT.	915 participants from 3 existing cohorts (age 14+) who reported frequent use of non-prescribed opioids and had Utox at baseline.		Baseline rates of UDT +fentanyl was high regardless of OAT vs no OAT. Only bup/nal a/w lower odds of +fentanyl UDT in both unadjusted/adjusted.	Methadone had lower odds of +fentanyl UDT (unadjusted only). Injectable OAT and SROM not a/w decreased +fentanyl compared to no OAT.
Gomes, T et al, 2022	Prospective cohort	opioid overdose while on treatment	[18880 (9404 methadone and 9476 with bup)] 7517 initiating bup, matched with 7517 initiating methadone	NA	Incidence rate of overdose for bup was less than for methadone while on treatment, and for first 30 days of treatment. Secondary outcomes: individuals initiating bup had higher incident rate of discontinuation, less outpatient visits, less healthcare interactions, higher rate of weekly take-homes. Incidence rate for overdose was higher following treatment discontinuation.	Unregulated drug supply is dominated by fentanyl
Jablonski, L. A et al, 2022	Retrospective cohort	Tolerability of low-dose induction of IV bup in hospitalized patients with OUD	59 patients with OUD and no recent bup, 79.7% with acute pain, 41% with chronic pain	Rapid, moderate, slow dosing strategies based on institutional protocol	91.5% completed LDI. 72.9% met tolerability criteria	Self-reported HPSO
Varshneya N et al, 2022	Cross sectional survey	Self-reported precipitated withdrawal	1679 individuals seeking treatment for OUD	NA	Severe w/d symptoms when taking bup within 24 hours or 24 to 48 hours after fentanyl use compared to methadone
Taylor, J et al, 2022	Prospective cohort	Referral completion within 72 hr, OTP linkage within 1m, OTP retention at 1m.	142 patients over 150 episodes seeking methadone for emergency opioid withdrawal management.	Feasibility of methadone initiation under 72-hour rule in bridge clinic (received referrals from ED and Healthcare for Homeless, dispense methadone daily x3 days with linkage to OTP).	92% had referral completion within 72 hr, of which 86.8% had successful OTP linkage, of which 66.7% remained in treatment at 1m.	84.9% (62/73) had past 12m UDS +fentanyl.
Snyder H. et al, 2023	Retrospective cohort	Primary outcome: Treatment Engagement (follow-up) at 7- and 30-day follow-up	896 participants with OUD	High dose initiation (8-32 mg) in the ER	Among those treated with buprenorphine (492), 30-day follow-up similar in HPSO (41.4%]) vs non-HPSO groups (37.2%)	HPSO self-reported
Sokolski E. et al, 2023	Retrospective cohort	Feasibility of initiation of a rapid low-dose buprenorphine protocol in the hospital setting	24 patients with OUD	Day 1- 0.48mg Day 2- 3mg Day 3- 6mg Day 4- 9mg additional full Agonist Opioid (avg MME 171)	19 (79%) completed rapid bup titration. 2 (40%) patients with recent HPSO use failed initiation and transitioned to methadone.	13 (54%) self-reported fentanyl use. Self-reported HPSO use
Noel M. et al, 2023	Retrospective cohort	Tolerance of low dose overdose bup initiation in outpatient pharmacy	27 adults with OUD; 63% experiencing houselessness	Day1 0.5 SL Day2 0.5mg BID Day3 0.5 BID+ 1mg qhs D4 2mg BID D5 3mg BID D6- 4mg BID + Full agonist through D6	14/26 patients completed protocol. 79% had no w/d symptoms, 21% mild w/d symptoms, 0 mod/severe. 29% cessation of full agonist opioid use 71% reported reduction in use. In 30 days, 86% working with clinician and 71% remained on BUP.	7 patients remain in care (day 30-180) but did not complete protocol due to w/d symptoms, desire for return to use, or preference for higher BUP dosages
Hartley, J et al, 2023	Prospective cohort	Buprenorphine induction with low-dose combined with high-dose induction	82 patients with OUD admitted to detox unit	24hr low-dose bup initiation using 1mg doses, followed by high-dose bup (up to 20mg) within first hour of D2. 40 patients with fentanyl compared to 42 patients not reporting fentanyl initiated on standard protocol	4/40 low/high vs 6/42 standard required adjunctive benzodiazepines 3/40 low/high left AMA vs 6/42 on standard. No patients on low/high required HLOC vs 3/42 on standard	Patients reported using fentanyl only or primarily, immediately prior to admission, and not yet in withdrawal.
Chambers et al, 2023	Retrospective cohort	Dose based treatment retention	6499 patients initiating treatment between 2016 and 2020	NA	Patients with OUD prescribed 16 mg buprenorphine at greater risk of treatment discontinuation compared to 24 mg	Period of widespread fentanyl availability in Rhode Island
Randomized Controlled Trials
Cook R et al, 2021	Secondary analysis of RCT*	Time to MOUD initiation, the total number of medication administrations received over 24 weeks; and MOUD retention	111 adults with HIV and OUD in outpatient and residential settings. 64% with UDS +fentanyl	NA	Initiation: 70% initiated MOUD-56% bup, 33% XR-NTX, 10% methadone. MOUD persistence: buprenorphine= 2.6 months XR-NTX injections=3.3 Methadone=4.5 months MOUD Retention: 47% retained on MOUD at 6 months- 41% buprenorphine, 100% methadone and 42% on XR-NTX. Mean daily dose of buprenorphine =14.6 mg, methadone=73.3 mg	Initiation: +fentanyl at baseline were half as likely to initiate MOUD compared to −fentanyl +Fentanyl individuals less likely to initiate XR-NTX No evidence that fentanyl affected buprenorphine initiation MOUD persistence: Baseline fentanyl use had little impact on Baseline +fentanyl less likely to initiate any MOUD and had no significant impact on retention if initiated.
Socias E. m et al, 2022	Secondary analysis of RCT*	MOUD initiation and discontinuation	209 participants with OUD	NA	In adjusted models, no interaction between fentanyl and MOUD was observed for any of the outcomes	HPSO Determined by Utox (55.4% had a positive fentanyl)

^*Comparing Treatments for HIV-Infected Opioid Users in an Integrated Care Effectiveness Study (CHOICES)

^*Optimizing Patient Centered-Care: A Pragmatic Randomized Control Trial Comparing Models of Care in the Management of Prescription Opioid Misuse (OPTIMA)

MOUD- medication for opioid use disorder

RCT- Randomized controlled trial

UTOX-urine toxicology

XR-NTX Naltrexone extended release

Bup- buprenorphine

3.1. Buprenorphine Treatment Among Persons Exposed to HPSO

3.1.1. Low-Dose Buprenorphine Induction (LDI)

Many of the studies reviewed highlighted the clinical challenge of starting buprenorphine in people with OUD exposed to HPSO. Individuals who have recently used fentanyl have been reported to develop clinically significant withdrawal symptoms when initiated on buprenorphine using traditional standard protocols, and this has been noted by practicing clinicians and among people with OUD themselves. In a large longitudinal study of individuals with OUD, 93.7% of whom reported using fentanyl, the experience and fear experiencing precipitated withdrawal during self-treatment was noted as a major deterrent to treatment.¹³

Twelve case series and case reports described the feasibility of low-dose induction (LDI) protocols in outpatient, inpatient, community settings, by pharmacist-led and Emergency Medical Technician (EMT)-led personnel. LDI is suggested to be effective based the novel pharmacology of buprenorphine-the hypothesis that repetitive small doses, given at sufficient dosing intervals would accumulate at the receptor without precipitating withdrawals.¹⁴

Seven case reports/series presented protocols that address concerns for buprenorphine induction in individuals with OUD exposed to fentanyl using either a standard or rapid LDI protocol. The standard LDI protocols consisted of prescribing increasing doses of buprenorphine over the period of at last 5 days with concurrent use of either prescribed or non-prescribed full agonist opioid. In three studies, buprenorphine induction proceeded in an incremental fashion with progressively increasing doses of 0.5 mg once daily on day 1 to between 12 – 32 mg daily over five to seven days. ^15-17 However, in two studies that utilized 2 mg buprenorphine in timed intervals, buprenorphine induction was well tolerated in only one patient who had a COWS of 13 at the initiation of buprenorphine.¹⁸ A similar protocol (2 mg initiation) precipitated opioid withdrawal leading to treatment discontinuation in three patients, despite each patient experiencing moderate opioid withdrawal at the initiation of buprenorphine (COWS of 13, 19 and 14 respectively).¹⁹ Rapid LDI in persons with OUD exposed to HPSO were described by Suen and Azar et al.^20,21 Both protocols instituted rapid inductions reaching therapeutic doses of buprenorphine within 3 days and in 24 hours respectively without any documented precipitated withdrawals.

Four studies reported the treatment of hospitalized patients with OUD or pain exposed to HPSO. All but one of these used the rapid buprenorphine induction strategy. One study utilized the methods described by Weimer and colleagues, patients were started on buccal buprenorphine and successfully transitioned to sublingual formulation.^22-24 In another cohort of hospitalized patients admitted for infections, rapid LDI was done using intravenous buprenorphine based on rapid, moderate, and slow induction protocols developed at the institution for 24, 36 and 48 hours of inductions respectively.²⁵ A method of “low/high” induction was also described in a detoxification program that began with a 24-hour LDI using 1-mg buprenorphine doses, initiated immediately on admission, directly after use of fentanyl and titrating up to 20 mg buprenorphine within the first hour on day two of admission.²⁶

3.1.2. Extended-Release Buprenorphine Injection Induction

High dose buprenorphine induction was described as a viable option for buprenorphine induction in HPSO exposed individuals, especially as a quick protocol to start patients with OUD exposed to HPSO on extended-release buprenorphine. A case report described 2 adults with intravenous fentanyl use, the first patient tolerated rapid escalation of buprenorphine doses up to a total of 28 mg within the first hour of induction and the second case tolerated up to 32 mg within two hours of induction. Both individuals received 300 mg extended-release buprenorphine afterward rapid induction and were retained in treatment a month later. Two studies by Mariani and colleagues highlighted a similar protocol including a rapid buprenorphine induction followed by extended-release buprenorphine.^27,28

3.1.3. Higher Buprenorphine Doses and Treatment Retention

Case reports and anecdotal reports from clinicians have suggested that higher doses of buprenorphine may be needed in the era of HPSO to counteract the impact of withdrawals and opioid cravings.^29,30 Chambers and colleagues in a large study of patients with OUD initiating buprenorphine treatment during a period of high fentanyl prevalence showed that patients prescribed the recommended dose of 16 mg were at significantly greater risk of treatment discontinuation within 180 days than those prescribed a higher dose of 24 mg.³¹

3.2. Methadone Treatment Among Persons Exposed to HPSO

Five studies described methadone use in patients with OUD exposed to HPSO. They reported the prevalence of HPSO in cohorts of people with OUD on methadone, including individual characteristics, methadone maintenance dose, as well as other treatment outcomes including treatment retention, and number of days to retention. Among the studies reviewed, the prevalence of fentanyl positivity- either by urine drug testing or self-report ranged from 38% to 80% among the cohort of those in active methadone treatment.^32-36 Some of the results showed that younger individuals in methadone treatment programs were more likely to test positive for fentanyl,³⁷ and patients with fentanyl positivity had a shorter treatment retention.³² In a longitudinal follow up of a cohort of patients attending a methadone treatment clinic with 80% fentanyl positivity, 53% of those who were fentanyl-positive at intake were retained in treatment at 12-months and 99% of those who remained in treatment achieved remission at 12 months.^34,35

3.2. Comparing Methadone vs. Buprenorphine Treatment Among Persons Exposed to HPSO

Five studies compared methadone and buprenorphine, both first line MOUDs, across a variety of outcomes. Varshneya and colleagues confirmed that compared to methadone, individuals who have recently used fentanyl were more likely to report withdrawal symptoms with buprenorphine. Patients self-reported severe withdrawal symptoms when taking buprenorphine within 24 hours after fentanyl use and within 24 to 48 hours after fentanyl use.³⁸

In a large population based retrospective cohort study of patients with OUD in a region where the drugs supply has a high prevalence of HPSO, Pearce and colleagues, examined all-cause and cause-specific mortality rate and treatment retention. Of all the patients on treatment with methadone and buprenorphine, the all-cause standardized mortality ratio was substantially lower while on treatment compared to when off treatment. In fact, these results show that during the periods of fentanyl contamination of drug supplies, the protective effect of MOUD was more noticeable- with a 65% increase in relative risk of mortality at the end of the study period during period of high fentanyl prevalence compared to before fentanyl.³⁹ Standardized mortality ratios were 4.7 and 9.5 on and off methadone compared to 2.9 and 11.3 on and off buprenorphine, respectively. Thus the risk of mortality after starting and stopping buprenorphine was lower compared to methadone, highlighting possible buprenorphine’s superior safety profile.³⁹

Gomes and colleagues, in a population-based propensity-score matched cohort study that compares the risks and benefits of methadone versus buprenorphine in a cohort with fentanyl dominated drug supply, showing that the risk of opioid overdose while on treatment or within the first 30 days of treatment was lower among buprenorphine recipients compared to methadone recipients, although treatment retention was higher among methadone recipients.³⁶

In a post hoc analysis of the OPTIMA trial (Optimizing Patient Centered-Care: A Pragmatic Randomized Control Trial Comparing Models of Care in the Management of Prescription Opioid Misuse treatment), Socias and colleagues, measured the impact of baseline fentanyl exposure on initiation and discontinuation across MOUD- buprenorphine and methadone among individuals with prescription-type OUD. In their unadjusted analyses, fentanyl exposure was associated with reduced likelihood of treatment initiation, shorter duration of treatment but the effects were no longer statistically significant in adjusted models, and no interaction between fentanyl and MOUD was observed for any of the outcomes.⁴⁰

Finally, MacKay and colleagues, described levels of dissatisfaction among patients on MOUDs. With specific MOUD type, dissatisfaction at baseline range from methadone 30.8%, buprenorphine 19.1%, oral morphine 20.9%, and injectable MOUD (i.e., diacetylmorphine or hydromorphone) 11.9%. More than half of individuals were exposed to fentanyl and those who were dissatisfied with their treatment were more likely to be exposed to fentanyl.⁴¹

3.3. Extended-Release Intramuscular Naltrexone

The only study that included naltrexone was a secondary analysis of data from a multisite clinical trial to describe associations between fentanyl use and initiation and retention on MOUD. The trial compared extended-release naltrexone (XR-NTX) with buprenorphine or methadone (treatment as usual) to achieve HIV viral suppression among people with OUD and uncontrolled HIV disease.⁴² Among participants in this study, 64% tested positive for fentanyl at baseline. Those with baseline fentanyl positivity were 11 times less likely to initiate XR-NTX than those negative for fentanyl. Furthermore, the study showed no evidence that fentanyl use impacted the likelihood of initiation of buprenorphine or methadone (treatment as usual) and baseline fentanyl use was not associated retention on any MOUD.⁴²

4. DISCUSSION

The current study appraised and summarized published reports to estimate the impact of HPSO on medication treatments for OUD, given the new landscape of the illicit drug market wherein HPSOs have replaced other opioids. Our review showed a paucity of high-quality data to address our research question, hence we relied on data derived from individual case reports, and observational studies. First, there's a high occurrence (38-80%) of HPSO usage among individuals undergoing MOUD. Second, MOUDs are linked to a decreased risk of HPSO-related overdoses and deaths. Third, HPSO use is correlated with the risk of precipitated withdrawal when starting buprenorphine. Fourth, LDI of buprenorphine is recognized as a safe method to avoid the requirement for patients to be in moderate withdrawal symptoms prior to treatment. Lastly, the review highlights a significant gap in human experimental data concerning the effects of HPSO on key factors critical for treating OUD, such as craving, withdrawal symptoms, and pain management.

To our knowledge, this is the first scoping review of the impact of HPSO on several clinical indices including MOUD effectiveness, ease of induction, MOUD acceptance and retention in treatment. We have identified several gaps in knowledge, and our findings provide methodological, clinical, and mechanistic implications to guide future observational and experimental research.

4.1. Methodological Implications

We found that the included studies reported inconsistent outcomes associated with HPSO exposure, and that most reports were observational in design. Future high-quality methods to assess acute and long-treatment outcomes related to HPSO exposure are needed. As we expand our understanding of the new wave of HPSO, inadvertent exposures, and HPSO-polysubstance mixtures, understanding the role of available MOUDs becomes a scientific urgency that will require both naturalistic and experimental approaches. The impact of HPSO on a wide range of outcomes such as treatment retention, using prospective designs, and well-defined timepoints (e.g., 12 weeks and 6 months consistent with prior clinical MOUD studies). Further, human laboratory studies may be employed to examine whether HPSO admixture significantly alters the known pharmacokinetics and pharmacodynamics of the new mixed compound and if such exposure is associated with changes in clinically relevant, acute and dynamic processes such as opioid withdrawal, craving, and pain responses, which can be measured and manipulated in the laboratory, along with robust experimental control of important pharmacological factors (e.g., MOUD dose, quantification of fentanyl and its metabolites, and pharmacokinetic interactions).⁴³Such translational studies hold promise to enable the application of precision medicine, using personalized biomarkers to tailor MOUD dosing.

4.2. Clinical Implications

This review lends support to currently approved pharmacological treatments for OUD among individuals exposed to HPSO. Although anecdotal reports have questioned the efficacy of MOUD with HPSO exposure, the preponderance of the evidence shows that pharmacotherapy is still the most consequential intervention, given that it reduces the risk of death by opioid overdose. The question of optimal dosing of MOUDs in the context of HPSO remains an open one, worthy of further examination (Table 2). Recent data from Chambers et al showed that 24 mg buprenorphine retained patients (using HPSO) longer in treatment than doses up to 16 mg.³¹ Additional data (albeit less convincing) from case reports have suggested even doses up to 40 mg daily in patients with OUD.^29,30

Table 2:

Proposed themes for future high-quality studies addressing HPSO and MOUD interactions.

Study Type	Clinical Trials	Observational Studies	Human Laboratory Studies
Thematic exploration	Optimal MOUD dosing among individuals exposed to HPSO	Large prospective cohort studies to uncover prevalence and correlates of HPSO exposure among those on MOUD	Impact of HPSO on laboratory measures of opioid craving, opioid withdrawal, and pain sensitivity
	Novel MOUD targeting receptors other than MOR		Application of precision medicine and biomarkers to determine appropriate dosing of MOUD
	Clinical trials administering promising medications for OUD (SROM, diacetylmorphine and others)	Determination of treatment retention, correlates of treatment drop-out, relapse and overdose	Potential altered pharmacokinetic properties of HPSO admixed with other drugs (e.g., cocaine, cannabis, xylazine); impact on their pharmacodynamic effects in humans
	Compare and synthesize protocols for buprenorphine initiation in variable clinical contexts	Barriers to treatment: ethnic/racial, and social determinants of health
Other clinical measures	Observer- and patient-rated opioid withdrawal symptoms Precipitated withdrawal, operationalized as 10 points (15% MPE) and 6 points (12% MPE) on the SOWS and COWS, respectively, that occurred within 60 min of opioid antagonist administration1 Patient satisfaction with current MOUD treatment

Abbreviations: COWS-clinical opiate withdrawal scale; HPSO-high potency synthetic opioids; MOUD- medication for opioid use disorder; MPE- maximum percent effect; SOWS- subjective opiate withdrawal scale

One of the most prominent clinical challenges in the wake of an evolved illicit drug landscape is the induction of buprenorphine. Individuals with OUD exposed to HPSO have been shown to experience withdrawals on buprenorphine treatment, an experience that makes some decline buprenorphine treatment.⁴⁴ Whereas several induction protocols are emerging, the clinical effectiveness of these alternative approaches to traditional induction has not been systematically studied. Another rarely discussed impact of HPSO is the possibility of expanding medication options to include diacetylmorphine and slow-release oral morphine, third line MOUDs in Canada. As shown in the study by Krause and colleagues, patients on diamorphine were least likely to use fentanyl when compared with other MOUDs.³³ Furthermore, the relative paucity of data on naltrexone among individuals exposed to HPSO is noted.

4.3. Mechanistic Implications

This scoping review also highlights the need to understand, at the mechanistic level, how MOUDs exert their effects against the backdrop of HPSO domination of community drug supplies. Although prior studies have investigated the relationship between MOR occupancy and the mitigation of opioid rewarding effects of opioids and improvement OUD treatment outcomes^45,46, it is important to note that these studies highlight challenges in establishing MOR-occupancy guided, precise dosing guidelines for buprenorphine. Additionally, participants in these studies were likely not exposed to HPSO, given the rarity of HPSOs in drug supplies at the time. Clarifying the level of MOR occupancy that optimizes the treatment response when HPSO are implicated may guide the dosing and schedule of administration of MOUD- which could be modified using data-driven approaches (e.g., the MOR dissociation half-life of MOUD and HPSO, and their relationship with specific clinical outcomes).⁴⁷ Further, as reviewed elsewhere, methadone and buprenorphine’s distinct effects on MOR downregulation and desensitization, could ostensibly influence the treatment response in patients exposed to HPSO use.⁴⁸ The MOR occupancy by MOUD to counteract specific outcomes (withdrawal, opioid-derived reward, or pain) may be different for low potency opioids compared and for HPSO. Of note, however, as shown by Olofsen and colleagues, with high enough MOR occupancy by buprenorphine, fentanyl is unable to sufficiently activate enough MOR to cause fatal respiratory depression, thus buprenorphine exerts a protective effect even at very high plasma concentrations of fentanyl.⁴⁹ Finally, whether HPSO induces long-term changes in rewarding and nociceptive systems, thereby altering the analgesic response, remains an area worthy of scientific exploration (Table 2).⁵⁰

4.4. Limitations

Notwithstanding the methodological strengths of this review, our results are limited to observational studies, post-hoc analyses from clinical trials not initially intended to evaluate HPSO's impact on MOUD outcomes and only FDA approved MOUD. The studies lacked uniformity in reporting clinical outcomes and employed various definitions of favorable treatment outcomes. Furthermore, the current body of literature does not specifically address the effects of HPSO on several processes relevant to OUD treatment (withdrawal symptoms, craving, and pain). These acute factors are crucial to consider since the management of OUD is inherently dynamic, and the propensity for non-medical opioid use can be instantly influenced by HPSO exposure. Finally, the methodology for this scoping review was limited to adults, who are older than 18 years old. We acknowledge that the ramifications of the rising use of HPSO among younger people is deserving of further rigorous investigation.

5. CONCLUSIONS

The widespread availability of HPSO has profoundly altered the dynamics of the illicit drug market and traditional approaches to OUD treatment. Clinical evidence underscores the importance of MOUD in reducing the mortality linked to the non-medical use of HPSOs. Yet, there is a pressing research gap concerning the influence of HPSOs on various phases of buprenorphine and methadone treatment and on critical phenomena such as opioid cravings, withdrawal, and pain, all of which impact the likelihood of non-medical opioid use. Future research should rigorously explore MOUD protocols for patients exposed to HPSO. Integrating mechanistic studies with human trials will be crucial in filling these knowledge gaps and in crafting evidence-based clinical guidelines that can improve treatment efficacy.