Managing Opioid Withdrawal Symptoms During the Fentanyl Crisis: A Review

References

• Ahmad FBCJ, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. 2023.
   Google Scholar
• Gladden RM, Martinez P, Seth P. Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid-Involved Overdose Deaths - 27 States, 2013-2014. MMWR Morb Mortal Wkly Rep. 2016;65(33):837–843. doi:10.15585/mmwr.mm6533a2
   PubMed Web of Science ®Google Scholar
• Jones CM, Bekheet F, Park JN, Alexander GC. The Evolving Overdose Epidemic: synthetic Opioids and Rising Stimulant-Related Harms. Epidemiol Rev. 2020;42(1):154–166. doi:10.1093/epirev/mxaa011
   PubMed Web of Science ®Google Scholar
• Jannetto PJ, Helander A, Garg U, Janis GC, Goldberger B, Ketha H. The Fentanyl Epidemic and Evolution of Fentanyl Analogs in the United States and the European Union. Clin Chem. 2019;65(2):242–253. doi:10.1373/clinchem.2017.281626
   PubMed Web of Science ®Google Scholar
• Higginbotham JA, Markovic T, Massaly N, Moron JA. Endogenous opioid systems alterations in pain and opioid use disorder. Front Syst Neurosci. 2022;16:1014768. doi:10.3389/fnsys.2022.1014768
   PubMed Web of Science ®Google Scholar
• Peng J, Sarkar S, Chang SL. Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Depend. 2012;124(3):223–228. doi:10.1016/j.drugalcdep.2012.01.013
   PubMed Web of Science ®Google Scholar
• Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):675.
   Web of Science ®Google Scholar
• Morgan MM, Christie MJ. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol. 2011;164(4):1322–1334. doi:10.1111/j.1476-5381.2011.01335.x
   PubMed Web of Science ®Google Scholar
• Williams JT, Ingram SL, Henderson G, et al. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev. 2013;65(1):223–254. doi:10.1124/pr.112.005942
   PubMed Web of Science ®Google Scholar
• Pergolizzi JV Jr, Raffa RB, Rosenblatt MH. Opioid withdrawal symptoms, a consequence of chronic opioid use and opioid use disorder: current understanding and approaches to management. J Clin Pharm Ther. 2020;45(5):892–903. doi:10.1111/jcpt.13114
   PubMed Web of Science ®Google Scholar
• Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies. N Engl J Med. 2016;374(13):1253–1263. doi:10.1056/NEJMra1507771
   PubMed Web of Science ®Google Scholar
• Koob GF. Anhedonia, Hyperkatifeia, and Negative Reinforcement in Substance Use Disorders. Curr Top Behav Neurosci. 2022;58:147–165. doi:10.1007/7854_2021_288
   PubMedGoogle Scholar
• Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35(2):253–259. doi:10.1080/02791072.2003.10400007
   PubMed Web of Science ®Google Scholar
• Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293–308. doi:10.3109/00952998709001515
   PubMed Web of Science ®Google Scholar
• Hall OT, Entrup P, Farabee K, et al. The Perceived Role of Withdrawal in Maintaining Opioid Addiction among Adults with Untreated Opioid Use Disorder: a Survey of Syringe Exchange Program Participants. Subst Use Misuse. 2024;59(2):312–315. doi:10.1080/10826084.2023.2269571
   PubMed Web of Science ®Google Scholar
• Alrawashdeh M, Rhee C, Klompas M, et al. Association of Early Opioid Withdrawal Treatment Strategy and Patient-Directed Discharge Among Hospitalized Patients with Opioid Use Disorder. J Gen Intern Med. 2023;38(10):2289–2297. doi:10.1007/s11606-023-08059-w
   PubMed Web of Science ®Google Scholar
• Harris M. Normalised pain and severe health care delay among people who inject drugs in London: adapting cultural safety principles to promote care. Soc Sci Med. 2020;260:113183. doi:10.1016/j.socscimed.2020.113183
   PubMed Web of Science ®Google Scholar
• Kimmel SD, Kim JH, Kalesan B, Samet JH, Walley AY, Larochelle MR. Against Medical Advice Discharges in Injection and Non-injection Drug Use-associated Infective Endocarditis: a Nationwide Cohort Study. Clin Infect Dis. 2021;73(9):e2484–e2492. doi:10.1093/cid/ciaa1126
   PubMed Web of Science ®Google Scholar
• Simon R, Snow R, Wakeman S. Understanding why patients with substance use disorders leave the hospital against medical advice: a qualitative study. Subst Abus. 2020;41(4):519–525. doi:10.1080/08897077.2019.1671942
   PubMed Web of Science ®Google Scholar
• Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Network Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622
   PubMed Web of Science ®Google Scholar
• Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014;2014(2):CD002207. doi:10.1002/14651858.CD002207.pub4
   PubMedGoogle Scholar
• Stein M, Herman D, Conti M, Anderson B, Bailey G. Initiating buprenorphine treatment for opioid use disorder during short-term in-patient ‘detoxification’: a randomized clinical trial. Addiction. 2020;115(1):82–94. doi:10.1111/add.14737
   PubMed Web of Science ®Google Scholar
• Neimark G, Tjoa C. Treating Fentanyl Withdrawal. J Behav Health Serv Res. 2020;47(4):614–615. doi:10.1007/s11414-020-09710-8
   PubMed Web of Science ®Google Scholar
• Sue KL, Cohen S, Tilley J, Yocheved A. A Plea From People Who Use Drugs to Clinicians: new Ways to Initiate Buprenorphine Are Urgently Needed in the Fentanyl Era. J Addict Med. 2022;16(4):389–391. doi:10.1097/ADM.0000000000000952
   PubMed Web of Science ®Google Scholar
• Bromley LKM, Regenstreif L, Srivastava A, Wyman J. Methadone Treatment for People Who Use Fentanyl: Recommendations. META: PHI, editor. Toronto, ON; 2021.
   Google Scholar
• Calcaterra SL, Bottner R, Martin M, 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;17(9):679–692. doi:10.1002/jhm.12908
   PubMed Web of Science ®Google Scholar
• Ciccarone D. The triple wave epidemic: supply and demand drivers of the US opioid overdose crisis. Int J Drug Policy. 2019;71:183–188. doi:10.1016/j.drugpo.2019.01.010
   PubMed Web of Science ®Google Scholar
• Oakley B, Wilson H, Hayes V, Lintzeris N. Managing opioid withdrawal precipitated by buprenorphine with buprenorphine. Drug Alcohol Rev. 2021;40(4):567–571. doi:10.1111/dar.13228
   PubMed Web of Science ®Google Scholar
• 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;37(1):143–150. doi:10.1016/j.ajem.2018.10.013
   PubMed Web of Science ®Google Scholar
• Whitley SD, Sohler NL, Kunins HV, et al. Factors associated with complicated buprenorphine inductions. J Subst Abuse Treat. 2010;39(1):51–57. doi:10.1016/j.jsat.2010.04.001
   PubMed Web of Science ®Google Scholar
• Varshneya NB, Thakrar AP, Hobelmann JG, Dunn KE, Huhn AS. Evidence of Buprenorphine-precipitated Withdrawal in Persons Who Use Fentanyl. J Addict Med. 2022;16(4):e265–e268. doi:10.1097/ADM.0000000000000922
   PubMed Web of Science ®Google Scholar
• Bormann NL, Gout A, Kijewski V, Lynch A. Case Report: buprenorphine-precipitated fentanyl withdrawal treated with high-dose buprenorphine. F1000Res. 2022;11:487. doi:10.12688/f1000research.120821.2
   PubMedGoogle Scholar
• Spadaro A, Long B, Koyfman A, Perrone J. Buprenorphine precipitated opioid withdrawal: prevention and management in the ED setting. Am J Emerg Med. 2022;58:22–26. doi:10.1016/j.ajem.2022.05.013
   PubMed Web of Science ®Google Scholar
• Nemlekar SS, Mehta R, Dave KR, Chaudhari F. Opioid withdrawal and its stabilization on sublingual buprenorphine in intravenous drug users: a South Gujarat Perspective. j Arch Psychiatry Psychother. 2020;22(1):63–69. doi:10.12740/app/109265
   Web of Science ®Google Scholar
• Hammig R, Kemter A, Strasser J, et al. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Subst Abuse Rehabil. 2016;7:99–105. doi:10.2147/SAR.S109919
   PubMed Web of Science ®Google Scholar
• Cohen SM, Weimer MB, Levander XA, Peckham AM, Tetrault JM, Morford KL. Low Dose Initiation of Buprenorphine: a Narrative Review and Practical Approach. J Addict Med. 2022;16(4):399–406. doi:10.1097/ADM.0000000000000945
   PubMed Web of Science ®Google Scholar
• Baumgartner K, Salmo E, Liss D, et al. Transdermal buprenorphine for in-hospital transition from full agonist opioids to sublingual buprenorphine: a retrospective observational cohort study. Clin Toxicol. 2022;60(6):688–693. doi:10.1080/15563650.2022.2028802
   PubMed Web of Science ®Google Scholar
• Webster L, Hjelmstrom P, Sumner M, Gunderson EW. Efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet for the treatment of adults with opioid dependence: a randomized trial. J Addict Dis. 2016;35(4):325–338. doi:10.1080/10550887.2016.1195608
   PubMed Web of Science ®Google Scholar
• Herring AA, Vosooghi AA, Luftig J, et al. High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder. JAMA Network Open. 2021;4(7):e2117128. doi:10.1001/jamanetworkopen.2021.17128
   PubMed Web of Science ®Google Scholar
• Hassman H, Strafford S, Shinde SN, Heath A, Boyett B, Dobbins RL. Open-label, rapid initiation pilot study for extended-release buprenorphine subcutaneous injection. Am J Drug Alcohol Abuse. 2023;49(1):43–52. doi:10.1080/00952990.2022.2106574
   PubMed Web of Science ®Google Scholar
• D’Onofrio G, Hawk KF, Perrone J, et al. Incidence of Precipitated Withdrawal During a Multisite Emergency Department-Initiated Buprenorphine Clinical Trial in the Era of Fentanyl. JAMA Network Open. 2023;6(3):e236108. doi:10.1001/jamanetworkopen.2023.6108
   PubMed Web of Science ®Google Scholar
• Ahmadi J, Jahromi MS, Ghahremani D, London ED. Single high-dose buprenorphine for opioid craving during withdrawal. Trials. 2018;19(1):675. doi:10.1186/s13063-018-3055-z
   PubMedGoogle Scholar
• Mariani JJ, Mahony A, Iqbal MN, Luo SX, Naqvi NH, Levin FR. Case Series: rapid Induction Onto Long Acting Buprenorphine Injection for High Potency Synthetic Opioid Users. Am J Addict. 2020;29(4):345–348. doi:10.1111/ajad.13018
   PubMed Web of Science ®Google Scholar
• Su MK, Lopez JH, Crossa A, Hoffman RS. Low dose intramuscular methadone for acute mild to moderate opioid withdrawal syndrome. Am J Emerg Med. 2018;36(11):1951–1956. doi:10.1016/j.ajem.2018.02.019
   PubMed Web of Science ®Google Scholar
• Chalabianloo F, Fadnes LT, Hoiseth G, et al. Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway. Subst Abuse Treat Prev Policy. 2021;16(1):39. doi:10.1186/s13011-021-00367-w
   PubMed Web of Science ®Google Scholar
• Laks J, Kehoe J, Farrell NM, et al. Methadone initiation in a bridge clinic for opioid withdrawal and opioid treatment program linkage: a case report applying the 72-hour rule. Addict Sci Clin Pract. 2021;16(1):73. doi:10.1186/s13722-021-00279-x
   PubMed Web of Science ®Google Scholar
• Taylor JL, Laks J, Christine PJ, 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;236:109497. doi:10.1016/j.drugalcdep.2022.109497
   PubMed Web of Science ®Google Scholar
• Enns B, Krebs E, Whitehurst DGT, et al. Cost-effectiveness of flexible take-home buprenorphine-naloxone versus methadone for treatment of prescription-type opioid use disorder. Drug Alcohol Depend. 2023;247:109893. doi:10.1016/j.drugalcdep.2023.109893
   PubMed Web of Science ®Google Scholar
• Panwala V, Joudrey P, Kowalski M, Bach P, Amram O. Changes to methadone maintenance therapy in the United States, Canada, and Australia during the COVID-19 pandemic: a narrative review. J Subst Use Addict Treat. 2023;152:209086. doi:10.1016/j.josat.2023.209086
   PubMedGoogle Scholar
• GovTrack. S. 644: modernizing Opioid Treatment Access Act. Available from: https://www.govtrack.us/congress/bills/118/s644. Accessed February 1, 2024.
   Google Scholar
• Gauthier G, Eibl JK, Marsh DC. Improved treatment-retention for patients receiving methadone dosing within the clinic providing physician and other health services (onsite) versus dosing at community (offsite) pharmacies. Drug Alcohol Depend. 2018;191:1–5. doi:10.1016/j.drugalcdep.2018.04.029
   PubMed Web of Science ®Google Scholar
• Strang J, Hall W, Hickman M, Bird SM. Impact of supervision of methadone consumption on deaths related to methadone overdose (1993-2008): analyses using OD4 index in England and Scotland. BMJ. 2010;341:c4851. doi:10.1136/bmj.c4851
   PubMed Web of Science ®Google Scholar
• Simon C, Vincent L, Coulter A, et al. The Methadone Manifesto: treatment Experiences and Policy Recommendations From Methadone Patient Activists. Am J Public Health. 2022;112(S2):S117–S122. doi:10.2105/AJPH.2021.306665
   PubMedGoogle Scholar
• Jones CM, Compton WM, Han B, Baldwin G, Volkow ND. Methadone-Involved Overdose Deaths in the US Before and After Federal Policy Changes Expanding Take-Home Methadone Doses From Opioid Treatment Programs. JAMA Psychiatry. 2022;79(9):932–934. doi:10.1001/jamapsychiatry.2022.1776
   PubMed Web of Science ®Google Scholar
• Administration SAa MHS. Methadone take-home flexibilities extension guidance. 2021. Available from: https://www.samhsa.gov/medication-assisted-treatment/statutes-regulations-guidelines/methadone-guidance. Accessed February 1, 2024.
   Google Scholar
• Krawczyk N, Rivera BD, Levin E, Dooling BCE. Synthesising evidence of the effects of COVID-19 regulatory changes on methadone treatment for opioid use disorder: implications for policy. Lancet Public Health. 2023;8(3):e238–e246. doi:10.1016/S2468-2667(23)00023-3
   PubMed Web of Science ®Google Scholar
• Socias ME, Wood E, Dong H, et al. Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): protocol for a non-inferiority randomized clinical trial. Contemp Clin Trials. 2020;91:105993. doi:10.1016/j.cct.2020.105993
   PubMed Web of Science ®Google Scholar
• Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev. 2013;2(6):CD009879. doi:10.1002/14651858.CD009879.pub2
   Google Scholar
• Zarghami M, Masoum B, Shiran MR. Tramadol versus methadone for treatment of opiate withdrawal: a double-blind, randomized, clinical trial. J Addict Dis. 2012;31(2):112–117. doi:10.1080/10550887.2012.665728
   PubMed Web of Science ®Google Scholar
• Dean L, Kane M, et al. Tramadol Therapy and CYP2D6 Genotype. In: Pratt V, Scott SA, Pirmohamed M, editors. Medical Genetics Summaries [Internet]. National Center for Biotechnology Information; 2021.
   Google Scholar
• Kleinman RA, Wakeman SE. Treating Opioid Withdrawal in the Hospital: a Role for Short-Acting Opioids. Ann Intern Med. 2022;175(2):283–284. doi:10.7326/M21-3968
   PubMed Web of Science ®Google Scholar
• Thakrar AP. Short-Acting Opioids for Hospitalized Patients With Opioid Use Disorder. JAMA Intern Med. 2022;182(3):247–248. doi:10.1001/jamainternmed.2021.8111
   PubMed Web of Science ®Google Scholar
• Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309–318. doi:10.1016/S0140-6736(17)32812-X
   PubMed Web of Science ®Google Scholar
• Rudolf G, Walsh J, Plawman A, et al. A novel non-opioid protocol for medically supervised opioid withdrawal and transition to antagonist treatment. Am J Drug Alcohol Abuse. 2018;44(3):302–309. doi:10.1080/00952990.2017.1334209
   PubMed Web of Science ®Google Scholar
• Mannelli P, Wu LT, Peindl KS, Swartz MS, Woody GE. Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial. Drug Alcohol Depend. 2014;138:83–88. doi:10.1016/j.drugalcdep.2014.02.002
   PubMed Web of Science ®Google Scholar
• Mannelli P, Swartz M, Wu LT. Withdrawal severity and early response to treatment in the outpatient transition from opioid use to extended release naltrexone. Am J Addict. 2018;27(6):471–476. doi:10.1111/ajad.12763
   PubMed Web of Science ®Google Scholar
• Sullivan M, Bisaga A, Pavlicova M, et al. Long-Acting Injectable Naltrexone Induction: a Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine. Am J Psychiatry. 2017;174(5):459–467. doi:10.1176/appi.ajp.2016.16050548
   PubMed Web of Science ®Google Scholar
• Bisaga A, Mannelli P, Yu M, et al. Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: a Phase 3 randomized trial. Drug Alcohol Depend. 2018;187:171–178. doi:10.1016/j.drugalcdep.2018.02.023
   PubMed Web of Science ®Google Scholar
• Safari F, Mottaghi K, Malek S, Salimi A. Effect of ultra-rapid opiate detoxification on withdrawal syndrome. J Addict Dis. 2010;29(4):449–454. doi:10.1080/10550887.2010.509278
   PubMed Web of Science ®Google Scholar
• Bisaga A, Sullivan MA, Cheng WY, et al. A placebo controlled trial of memantine as an adjunct to oral naltrexone for opioid dependence. Drug Alcohol Depend. 2011;119(1–2):e23–9. doi:10.1016/j.drugalcdep.2011.05.019
   PubMedGoogle Scholar
• Bisaga A, Sullivan MA, Glass A, et al. A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence. J Subst Abuse Treat. 2014;46(5):546–552. doi:10.1016/j.jsat.2014.01.005
   PubMed Web of Science ®Google Scholar
• Gorodetzky CW, Walsh SL, Martin PR, Saxon AJ, Gullo KL, Biswas K. A Phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend. 2017;176:79–88. doi:10.1016/j.drugalcdep.2017.02.020
   PubMed Web of Science ®Google Scholar
• Fishman M, Tirado C, Alam D, et al. Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: a Randomized Controlled Clinical Trial. J Addict Med. 2019;13(3):169–176. doi:10.1097/ADM.0000000000000474
   PubMed Web of Science ®Google Scholar
• Guo S, Manning V, Yang Y, et al. Lofexidine versus diazepam for the treatment of opioid withdrawal syndrome: a double-blind randomized clinical trial in Singapore. J Subst Abuse Treat. 2018;91:1–11. doi:10.1016/j.jsat.2018.04.012
   PubMed Web of Science ®Google Scholar
• Sanders NC, Mancino MJ, Gentry WB, et al. Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine-assisted detoxification procedure. Exp Clin Psychopharmacol. 2013;21(4):294–302. doi:10.1037/a0033724
   PubMed Web of Science ®Google Scholar
• Kheirabadi GR, Moazeni S, Salehi M, Mahaki B. Pregabalin Does Not Reduce Opioid Withdrawal Symptoms: a Randomized Controlled Trial. Addictive Disorders Their Treatment. 2019;18(4):205–211. doi:10.1097/adt.0000000000000166
   Web of Science ®Google Scholar
• Kheirabadi GR, Salehi M, Bahrami M, Maracy MR. Gabapentin, Pregabalin, and Placebo in Reducing Opioid Withdrawal Symptoms in Opioid-dependent Individuals: a Randomized-controlled Trial. Addictive Disorders Their Treatment. 2018;17(2):55–64. doi:10.1097/adt.0000000000000127
   Google Scholar
• Huhn AS, Finan PH, Gamaldo CE, et al. Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper. Sci Transl Med. 2022;14(650):eabn8238. doi:10.1126/scitranslmed.abn8238
   PubMed Web of Science ®Google Scholar
• Lin SK, Pan CH, Chen CH. A double-blind, placebo-controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal. J Clin Psychopharmacol. 2014;34(4):508–512. doi:10.1097/JCP.0000000000000144
   PubMed Web of Science ®Google Scholar
• Klein LR, Cole JB, Driver BE, et al. An open-label randomized trial of intramuscular olanzapine versus oral clonidine for symptomatic treatment of opioid withdrawal in the emergency department. Clin Toxicol. 2019;57(8):697–702. doi:10.1080/15563650.2018.1547828
   PubMed Web of Science ®Google Scholar
• Kianbakht S, Hajiaghaee R, Akhondzadeh S. Efficacy and safety of Sophora alopecuroides var. alopecuroides seed extract for opioid detoxification: a randomized, double-blind, and placebo-controlled clinical trial. Phytother Res. 2020;34(5):1108–1113. doi:10.1002/ptr.6578
   PubMed Web of Science ®Google Scholar
• Hashem-Dabaghian F, Kianbakht S. A randomized controlled trial on the seeds of Sophora alopecuroides var. alopecuroides for the treatment of acute heroin withdrawal syndrome. Complement Ther Clin Pract. 2023;51:101740. doi:10.1016/j.ctcp.2023.101740
   PubMed Web of Science ®Google Scholar
• Bergeria CL, Tan H, Antoine D, et al. A double-blind, randomized, placebo-controlled, pilot clinical trial examining buspirone as an adjunctive medication during buprenorphine-assisted supervised opioid withdrawal. Exp Clin Psychopharmacol. 2023;31(1):194–203. doi:10.1037/pha0000550
   PubMed Web of Science ®Google Scholar
• Kheirabadi G, Najafian N, Khodadadi F. The Effect of Adding Memantine to Clonidine in Reducing Withdrawal Symptoms in Opioid-Dependent Patients: a Double-Blind Randomized Controlled Trial. J Clin Psychopharmacol. 2021;41(6):644–649. doi:10.1097/JCP.0000000000001466
   PubMed Web of Science ®Google Scholar
• Morabbi MJ, Razaghi E, Moazen-Zadeh E, et al. Pexacerfont as a CRF1 antagonist for the treatment of withdrawal symptoms in men with heroin/methamphetamine dependence: a randomized, double-blind, placebo-controlled clinical trial. Int Clin Psychopharmacol. 2018;33(2):111–119. doi:10.1097/YIC.0000000000000200
   PubMed Web of Science ®Google Scholar
• Liu S, Li L, Shen W, Shen X, Yang G, Zhou W. Scopolamine detoxification technique for heroin dependence: a randomized trial. CNS Drugs. 2013;27(12):1093–1102. doi:10.1007/s40263-013-0111-9
   PubMed Web of Science ®Google Scholar
• Samuels ER, Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol. 2008;6(3):235–253. doi:10.2174/157015908785777229
   PubMed Web of Science ®Google Scholar
• Rasmussen K. The role of the locus coeruleus and N-methyl-D-aspartic acid (NMDA) and AMPA receptors in opiate withdrawal. Neuropsychopharmacology. 1995;13(4):295–300. doi:10.1016/0893-133X(95)00082-O
   PubMed Web of Science ®Google Scholar
• Farrand A, Jacquemet V, Verner R, Owens M, Beaumont E. Vagus nerve stimulation parameters evoke differential neuronal responses in the locus coeruleus. Physiological Reports. 2023;11(5):e15633. doi:10.14814/phy2.15633
   PubMed Web of Science ®Google Scholar
• Fornai F, Ruffoli R, Giorgi FS, Paparelli A. The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation. Eur J Neurosci. 2011;33(12):2169–2178. doi:10.1111/j.1460-9568.2011.07707.x
   PubMed Web of Science ®Google Scholar
• U.S. Food & Drug Administration, Drug Relief - Percutaneous Nerve Stimulator for Opioid Withdrawal https://www.accessdata.fda.gov/cdrh_docs/pdf17/K173861.pdf 2018 Accessed 20 11 2023.
   Google Scholar
• Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment. Am J Drug Alcohol Abuse. 2018;44(1):56–63. doi:10.1080/00952990.2017.1295459
   PubMed Web of Science ®Google Scholar
• Buono FD, Pickering R, Berlepsch R, Halligan S. Percutaneous electrical nerve field stimulation to reduce clinical opiate withdrawal: a case series. J Subst Use. 2022;27(5):501–504. doi:10.1080/14659891.2021.1961894
   Web of Science ®Google Scholar
• Tirado CF, Washburn SN, Covalin A, et al. Delivering transcutaneous auricular neurostimulation (tAN) to improve symptoms associated with opioid withdrawal: results from a prospective clinical trial. Bioelectronic Medicine. 2022;8(1):12. doi:10.1186/s42234-022-00095-x
   PubMedGoogle Scholar
• Gazi AH, Harrison AB, Lambert TP, et al. Transcutaneous cervical vagus nerve stimulation reduces behavioral and physiological manifestations of withdrawal in patients with opioid use disorder: a double-blind, randomized, sham-controlled pilot study. Brain Stimul. 2022;15(5):1206–1214. doi:10.1016/j.brs.2022.08.017
   PubMed Web of Science ®Google Scholar
• Meade CS, Lukas SE, McDonald LJ, et al. A randomized trial of transcutaneous electric acupoint stimulation as adjunctive treatment for opioid detoxification. J Subst Abuse Treat. 2010;38(1):12–21. doi:10.1016/j.jsat.2009.05.010
   PubMed Web of Science ®Google Scholar
• Bormann NL, Oesterle TS, Arndt S, Karpyak VM, Croarkin PE. Systematic review and meta-analysis: combining transcranial magnetic stimulation or direct current stimulation with pharmacotherapy for treatment of substance use disorders. Am J Addict. 2024. doi:10.1111/ajad.13517
   PubMed Web of Science ®Google Scholar
• Socias ME, Wood E, Le Foll B, et al. Impact of fentanyl use on initiation and discontinuation of methadone and buprenorphine/naloxone among people with prescription-type opioid use disorder: secondary analysis of a Canadian treatment trial. Addiction. 2022;117(10):2662–2672. doi:10.1111/add.15954
   PubMed Web of Science ®Google Scholar
• Thakrar AP, Faude S, Perrone J, et al. Association of Urine Fentanyl Concentration With Severity of Opioid Withdrawal Among Patients Presenting to the Emergency Department. J Addict Med. 2023;17(4):447–453. doi:10.1097/ADM.0000000000001155
   PubMed Web of Science ®Google Scholar
• Amass L, Pukeleviciene V, Subata E, et al. A prospective, randomized, multicenter acceptability and safety study of direct buprenorphine/naloxone induction in heroin-dependent individuals. Addiction. 2012;107(1):142–151. doi:10.1111/j.1360-0443.2011.03577.x
   PubMed Web of Science ®Google Scholar