Review of Opioid Withdrawal Treatments – Past, Current, & Future

KATHRYN FULTON, BS  

Sidney Kimmel Medical College, Class of 2026

SUMMARY POINTS

• Early efforts in opioid withdrawal treatment focused on managing symptoms.  

• Buprenorphine and methadone induction is now the standard of care for withdrawal treatment and a critical linkage point to long-term treatment for opioid use disorder (OUD). 

• Buprenorphine is commonly used in Emergency Departments (EDs), but regimens have changed with increasing fentanyl use and incidence of precipitated withdrawal.

• An evolving illicit drug market, federal regulations, and patient and physician concerns are barriers to effective, accessible withdrawal treatments. 

• Innovations in treatment are critical to expand access to OUD treatment and reduce all-cause mortality.

ANALYSIS

Background

Opioid-related hospitalizations have increased in the last decade with 5-10% of hospitalized patients having opioid use disorder (OUD). In a recent study of opioid-related presentations in Philadelphia Emergency Departments (EDs), 70% were for opioid withdrawal (1). Uncontrolled withdrawal contributes to high rates of patient-directed discharge and all-cause mortality (2). 

Opioid withdrawal consists of acute physiologic and psychiatric symptoms which can be caused by abstinence of opioids following chronic use or precipitated after administering an opioid antagonist or partial agonist (3,4). Symptoms include sympathetic hyperactivity (agitation, cravings, etc), influenza-like symptoms, and gastrointestinal discomfort. The Clinical Opiate Withdrawal Scale (COWS) is an objective scale used to grade symptom severity and guide treatment (5,6). The onset of withdrawal symptoms depends on the drug used and timing of last use, spanning 12 hours for short-acting opioids (i.e. heroin) to 24-72 hours for long-acting opioids (i.e. fentanyl). 

This analysis will discuss the primary medications considered for opioid withdrawal treatment and how recommendations have changed to optimize patient care and adapt to increasing opioid-related hospitalizations, changing regulations on medications for opioid use disorder (MOUD), and an evolving illicit drug market. 

History of Opioid Withdrawal Treatments

Long-acting opioid agonists and α2-adrenergic agonists have been widely used over the years for opioid withdrawal treatment. Methadone is a full opioid agonist. Buprenorphine is a partial opioid agonist with high affinity, allowing it to displace opioids bound, and low intrinsic activity, creating a “ceiling effect” on sedation and respiratory depression (7–9). Buprenorphine is often formulated with naloxone, which is inert when ingested and prevents injection diversion (6,10). α2-Adrenergic agonists like clonidine and lofexidine suppress norepinephrine release to treat withdrawal, but clonidine is not FDA-approved and has significant side effects like hypotension (4,11). 

Clonidine was one of the earliest agents used off-label for opioid withdrawal treatment in the 1980s (11). Then, treatment of withdrawal in EDs primarily focused on symptomatic relief. Opioid agonists were limited to inpatient and outpatient programs. In 2000, Congress passed the Drug Addiction Treatment Act (DATA 2000), allowing buprenorphine and methadone to be prescribed for opioid withdrawal treatment in non-outpatient settings for up to 72 hours. ED physicians were uniquely positioned to address acute withdrawal and offer linkage to long-term MOUD (7,12,13). Multiple studies have since proven buprenorphine effective across healthcare settings and superior to clonidine for treatment retention and reducing withdrawal symptoms (14, 15). Buprenorphine is also safer and easier to administer than methadone, making it ideal for use in EDs (3,15,16). 

Current Regimens: Buprenorphine

The current standard of care for withdrawal treatment is buprenorphine or methadone with psychosocial support and nonopioid adjunctive medications (3, 4, 5). There is increasing evidence that ED buprenorphine use is safe, cost-effective, and a critical entry point to long-term MOUD care (15,17). Despite wide support for the standard buprenorphine induction regimen, guidance on dosing and timing is evolving and subject to limitations (3,5,7,18,19). 

Time is one limitation as unduction is a multi-day process. Inadequate dose escalations can result in patient discomfort and early treatment cessation. Studies, however, indicate a high-dose induction pathway reaches a therapeutic dose within hours, extends the duration of buprenorphine, and is safe and effective in ED settings (1,9,12,19). 

Another limitation is precipitated withdrawal. Patients must be in moderate to severe withdrawal and abstain from opioids before buprenorphine induction to avoid buprenorphine precipitated withdrawal (BPOW) (4,8,11).  This occurs when buprenorphine displaces remaining opioids from receptors and  causes rapid, severe withdrawal symptoms which can prompt patient-directed discharge (1). Although uncommon, BPOW is extremely uncomfortable and a growing concern among physicians and patients, particularly fentanyl users (21,22). Fentanyl takes longer to “wash out” than other opioids and has an increased risk of BPOW. As a result, the Substance Abuse and Mental Health Service Administration (SAMHSA) recently altered its recommendations to initiate buprenorphine later at a higher COWS score (9,10,22). Also, low-dose or microdose inductions have been used to prevent BPOW by using initial doses too low to precipitate withdrawal. As buprenorphine is titrated up, the patient can continue using opioids (illicit or prescribed), effectively avoiding withdrawal (3,23). Both high and low dose induction methods are safe alternatives to prevent BPOW, however, further research and alternatives are needed (1,9,22,24). 

Current Regimens: Methadone 

Methadone is the only other FDA-approved medication with similar efficacy to buprenorphine, but it remains underutilized. Current methadone prescribing in EDs is largely for individuals already taking methadone. However, multiple studies have demonstrated successful same-day methadone induction for withdrawal management in bridge clinics and EDs with rapid referral to outpatient care and high treatment retention (1,9,12). Regulation of methadone continues to be the primary barrier to expansion into EDs. DATA 2000 continues to be underutilized and methadone administration is restricted to licensed sites with limited hours and waiting lists (8,9). Further, methadone induction requires ED infrastructure to connect patients to outpatient treatment (12,13). Although methadone has more regulatory barriers, side effects, and drug interactions than buprenorphine, it has several advantages. It can be started without prolonged abstinence and there is no risk of precipitated withdrawal (3,9). More research and legislative efforts are needed to expand access to methadone and increase collaboration between EDs and outpatient treatment centers. 

General Barriers & Limitations

Despite advancements in opioid withdrawal regimens, barriers to expansion of treatment exist. Stigma about “replacing one opioid with another” remains a concern of patients and clinicians, emphasizing the need for evidence-based MOUD training (7,21). Withdrawal patients have also expressed concerns about undertreated psychiatric symptoms and the severity of symptoms upon discontinuing MOUD (7,21). This highlights the importance of ancillary medication and counseling on the short and long-term effects of MOUD. Moreover, physicians are concerned about undertreating pain. However, updated American Society of Addiction Medicine guidelines indicate providers can safely manage pain by using higher buprenorphine or methadone doses and opioid pain medications as needed (25). Lastly, a lack of competent, confident clinicians adversely impacts effective withdrawal management. In recent studies, however, resident educational interventions have resulted in increased knowledge and confidence treating opioid withdrawal (26,27).

Innovations in Opioid Withdrawal Treatment 

In the fentanyl era, methadone and buprenorphine do not provide adequate relief for all patients experiencing opioid withdrawal. Changes in the dosing and timing of buprenorphine regimens have been promising. Extended-release buprenorphine injections are also being evaluated in clinical trials as an alternative induction method allowing earlier, shorter treatment (20). Recent studies show short-acting opioids as a complement to MOUD can provide immediate relief of withdrawal symptoms and address severe pain. However, further studies are needed to evaluate usage when pain is not present (2).

Additionally, the illicit drug market has seen the emergence of Xylazine, which is often mixed with fentanyl or heroin, necessitating further studies regarding its impact on withdrawal. Recent case studies have supported coupling α2-adrenergic agonists with buprenorphine micro-induction for dual management of Xylazine and opioid withdrawal (28,29). 

Lastly, it is important to acknowledge studies evaluating withdrawal treatments have largely focused on symptom relief and MOUD treatment retention. Future research should evaluate desired patient outcomes. One study suggests α2 agonists might be more appropriate for managing withdrawal to decrease opioid dose whereas opioid agonists might be preferable for opioid discontinuation (11). 

Discussion

Untreated opioid withdrawal is associated with premature patient-directed discharge and higher all-cause mortality. This is a missed opportunity in OUD care (8,18). Opioid agonists like methadone and buprenorphine are life-saving medications used for withdrawal management, but these regimens are not the only solution and require continued evaluation (8). 

Opioid withdrawal treatment alone is insufficient to treat OUD. Effective OUD treatment requires transitioning the patient to long-term treatment with MOUD. The proper identification and treatment of withdrawal, however, is a critical opportunity to engage patients regarding transition (8,3,4,9).

As the illicit drug market, OUD patient treatment goals, and federal regulations continue to change, innovations in opioid treatment regimens are critical to expand access to care and reduce all-cause mortality. Clinicians and healthcare institutions should prioritize treatment of opioid withdrawal and establish the infrastructure to facilitate entry into long-term treatment. This is the truly life-saving impact of MOUD. 

References

1. Faude S, Delgado MK, Perrone J, McFadden R, Xiong RA, O’Donnell N, et al. Variability in opioid use disorder clinical presentations and treatment in the emergency department: A mixed-methods study. Am J Emerg Med. 2023 Apr;66:53–60.

2. Kleinman RA, Wakeman SE. Treating Opioid Withdrawal in the Hospital: A Role for Short-Acting Opioids. Ann Intern Med. 2022 Feb;175(2):283–4.

3. Carswell N, Angermaier G, Castaneda C, Delgado F. Management of opioid withdrawal and initiation of medications for opioid use disorder in the hospital setting. Hosp Pract (Minneap). 2022 Oct;50(4):251–8.

4. Kampman K, Jarvis M. American society of addiction medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015 Oct;9(5):358–67.

5. Calcaterra SL, Bottner R, Martin M, Englander H, Weinstein ZM, Weimer MB, et al. Management of opioid use disorder, opioid withdrawal, and opioid overdose prevention in hospitalized adults: A systematic review of existing guidelines. J Hosp Med. 2022 Sep;17(9):679–92.

6. Substance Abuse Mental Health Services Administration. SAMHSA Buprenorphine Quick Start Guide. 2003;

7. Cisewski DH, Santos C, Koyfman A, Long B. Approach to buprenorphine use for opioid withdrawal treatment in the emergency setting. Am J Emerg Med. 2019 Jan;37(1):143–50.

8. Herscher M, Fine M, Navalurkar R, Hirt L, Wang L. Diagnosis and management of opioid use disorder in hospitalized patients. Med Clin North Am. 2020 Jul;104(4):695–708.

9. Church B, Clark R, Mohn W, Potee R, Friedmann P, Soares WE. Methadone induction for a patient with precipitated withdrawal in the emergency department: A case report. J Addict Med. 2023 Jun 1;17(3):367–70.

10. Herring A. Medication-Assisted Treatment of Opioid Addiction. 2016 Aug 1 [cited 2023 Jun 27]; Available from: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.chcf.org/wp-content/uploads/2017/12/PDF-EDMATOpioidProtocols.pdf

11. Srivastava AB, Mariani JJ, Levin FR. New directions in the treatment of opioid withdrawal. Lancet. 2020 Jun;395(10241):1938–48.

12. Taylor JL, Laks J, Christine PJ, Kehoe J, Evans J, Kim TW, et al. Bridge clinic implementation of “72-hour rule” methadone for opioid withdrawal management: Impact on opioid treatment program linkage and retention in care. Drug Alcohol Depend. 2022 Jul 1;236:109497.

13. Marshall KD, Derse AR, Iserson KV, Kluesner N, Vearrier L. Medications for addiction treatment initiated from the emergency department: Ethical considerations. Am J Emerg Med. 2020 Feb;38(2):343–8.

14. Edwards FJ, Wicelinski R, Gallagher N, McKinzie A, White R, Domingos A. Treating opioid withdrawal with buprenorphine in a community hospital emergency department: an outreach program. Ann Emerg Med. 2020 Jan;75(1):49–56.

15. Berg ML, Idrees U, Ding R, Nesbit SA, Liang HK, McCarthy ML. Evaluation of the use of buprenorphine for opioid withdrawal in an emergency department. Drug Alcohol Depend. 2007 Jan 12;86(2–3):239–44.

16. Love JS, Perrone J, Nelson LS. Should buprenorphine be administered to patients with opioid withdrawal in the emergency department? Ann Emerg Med. 2018 Jul;72(1):26–8.

17. Spadaro A, Faude S, Perrone J, Thakrar AP, Lowenstein M, Delgado MK, et al. Precipitated opioid withdrawal after buprenorphine administration in patients presenting to the emergency department: A case series. Journal of the American College of Emergency Physicians Open. 2023 Feb;4(1):e12880.

18. Herring AA, Perrone J, Nelson LS. Managing opioid withdrawal in the emergency department with buprenorphine. Ann Emerg Med. 2019 May;73(5):481–7.

19. Herring AA, Vosooghi AA, Luftig J, Anderson ES, Zhao X, Dziura J, et al. High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder. JAMA Netw Open. 2021 Jul 1;4(7):e2117128.

20. D’Onofrio G, Hawk KF, Herring AA, Perrone J, Cowan E, McCormack RP, et al. The design and conduct of a randomized clinical trial comparing emergency department initiation of sublingual versus a 7-day extended-release injection formulation of buprenorphine for opioid use disorder: Project ED Innovation. Contemp Clin Trials. 2021 May;104:106359.

21. Goldfine CE, Chapman BP, Taylor MM, Bradley ES, Carreiro SP, Rosen RK, et al. Experiences with Medications for Addiction Treatment Among Emergency Department Patients with Opioid Use Disorder. West J Emerg Med. 2023 Feb 22;24(2):236–42.

22. Spadaro A, Long B, Koyfman A, Perrone J. Buprenorphine precipitated opioid withdrawal: Prevention and management in the ED setting. Am J Emerg Med. 2022 Aug;58:22–6.

23. Randhawa PA, Brar R, Nolan S. Buprenorphine-naloxone “microdosing”: an alternative induction approach for the treatment of opioid use disorder in the wake of North America’s increasingly potent illicit drug market. CMAJ. 2020 Jan 20;192(3):E73.

24. Heeney M, Herring A, Anderson E. 159 Ketamine Use for Buprenorphine-Precipitated Opioid Withdrawal: A Case Series of 10 Patients. Ann Emerg Med. 2022 Oct;

25. Crotty K, Freedman KI, Kampman KM. Executive summary of the focused update of the ASAM national practice guideline for the treatment of opioid use disorder. J Addict Med. 2020;14(2):99–112.

26. Fujita AW, LaRosa A, Carter A. Treating withdrawal and pain in inpatients with opioid use disorder: A brief educational intervention for internal medicine residents. MedEdPORTAL. 2021 Mar 10;17:11123.

27. Jennings L, Warner T, Bacro-Duverger B. Identification and treatment of opioid withdrawal and opioid use disorder in the emergency department. MedEdPORTAL. 2020 May 15;16:10899.

28. New York State Department of Health. Xylazine: What Clinicians Need to Know. 2022;

29. Ehrman-Dupre R, Kaigh C, Salzman M, Haroz R, Peterson L-K, Schmidt R. Management of Xylazine Withdrawal_in_a.19.pdf. Journal of Addiction Medicine. 2022;