Buprenorphine Precipitated Opioid Withdrawal: Tips for Prevention and Management for the Emergency Clinician

We are proud to announce our winner for the Essentials of Emergency Medicine Fellow Competition. We received numerous, high-quality submissions for the Essentials of Emergency Medicine competition.  Over the next several weeks we will be publishing each of these. Today, we feature our winner: Buprenorphine Precipitated Opioid Withdrawal, by Dr. Tony Spadaro (@TSpadaro91).

Dr. Spadaro is a current EM resident (PGY-3) at the University of Pennsylvania.

Authors: Tony Spadaro, MD, MPH (@TSpadaro91, EM Resident Physician at the Hospital of the University of Pennsylvania) and Jeanmarie Perrone, MD, FACEP, FACMT (EM and Toxicology Attending at the Hospital of the University of Pennsylvania) // Reviewed by Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

A 47-year-old man with a history of Opioid Use Disorder (OUD), bipolar disorder, and hypertension presents to your Emergency Department (ED) complaining of opioid withdrawal and wants to be started on buprenorphine-naloxone (Suboxone). His vital signs include: 98.6F, HR: 94/min, BP: 146/82mmHg, and RR: 14/min. His initial Clinical Opiate Withdrawal Scale (COWS) score is 6. He reports that he uses 8-10 bags of fentanyl IV per day, with his last use about 18 hours prior to presentation. Despite a relatively low COWS score, the patient is still complaining of moderate withdrawal symptoms.  You order 4mg-1mg of buprenorphine-naloxone. Thirty minutes later you re-evaluate the patient and see that he is diaphoretic, tachycardic, restless, and complaining of abdominal cramping and leg pains and his repeat COWS score is 17. “Doc, give me something, I feel worse”. What are your next steps?

Background and Pathophysiology

Precipitated Opioid Withdrawal (POW) can be caused by an abrupt displacement of opioid agonist binding at the opioid receptor by either exposure to a partial opioid agonist (buprenorphine, nalbuphine) or antagonist (naloxone, naltrexone) in a patient that has opioid dependence and has residual opioid effects from a full agonist.¹ This article will focus on precipitated opioid withdrawal from buprenorphine.

Buprenorphine is a highly effective medication for the treatment of opioid use disorder (OUD) and can reduce the morbidity and mortality associated with OUD.^2,3 There is interest in buprenorphine initiation in the ED, as the ED serves as a critical low barrier access point with the health care system for many people with OUD.  Protocols have been developed to initiate buprenorphine in the ED.¹  Major clinical societies such as ACEP, AAEM, and ACMT have released clinical policies, statements, and white papers in support of using buprenorphine in the management of OUD in the ED.^4-6

Buprenorphine has a unique pharmacologic profile: it is a partial mu-opioid receptor agonist and has very high affinity for the mu-opioid receptor.¹ The partial agonism of the mu-opioid receptor relieves cravings, decreases withdrawal symptoms, and treats pain with a ceiling effect on respiratory depression and euphoria compared to full opioid agonists.^2,3 Buprenorphine’s high affinity for the mu-opioid receptor causes it to displace lower affinity full agonists (e.g., heroin) which can lead to POW in patients with opioid dependance who have adapted to the presence of full agonism, as the partial agonism of buprenorphine will not be strong enough to prevent withdrawal symptoms from the acute displacement of the full agonist.⁷ Symptoms of POW start to develop 10-15 minutes after sublingual buprenorphine and can last for 8-24 hours.³ Anxiety, nausea, vomiting, diarrhea, and agitation can develop during POW.³ POW is typically defined as a an increase in COWS of 6 or more after receiving buprenorphine.⁸ There have been case reports of Takotsubo cardiomyopathy and pulmonary edema from massive catecholamine release with POW.^9,10 Therefore, to avoid buprenorphine POW, patients seeking buprenorphine treatment must wait until they start experiencing withdrawal before initiating treatment.¹

In order to avoid POW, healthcare providers are instructed to wait until a patient is experiencing moderate to severe withdrawal, often defined as a Clinical Opioid Withdrawal Score (COWS) of 13 or greater; mild withdrawal is defined as a COWS 5-12.^3,8,11 This presents a challenge for the initiation of buprenorphine for clinicians hoping to start buprenorphine during the acute care visit and for patients who want to minimize the amount of time they are experiencing withdrawal. Use of longer acting opioids such as methadone as well as use of benzodiazepines have been associated with complicated inductions.   In one of the largest retrospective studies of buprenorphine initiation in the office setting,  close to 10% of patients experienced POW.⁸ There are additional concerns that the increasing prevalence of fentanyl in the illicit opioid supply can complicate buprenorphine induction.^11-14 Fentanyl is a highly lipophilic mu-opioid agonist, although typically used as a short acting analgesic, it has been shown to have prolonged renal clearance with chronic use.¹⁵ See table 1 for conditions associated with POW.^8,15 See table 2 for patient characteristics associated with lower risk.^1,8,12

Table 1: Conditions Associated with the development of POW.

Table 2: Patient characteristics associated with low risk of POW.

Prevention Strategies

The optimal strategy to prevent POW is proper patient assessment and patient selection. Guidelines exist to help clinicians decide when and who to treat. Reviewing the evidence can best inform ED clinician practice. See table 3 for different dosing regimen strategies.^{1,11,12,16-19}

Patients who are very anxious or who report prior POW need additional reassurance and the support to know that if POW occurs, they can be rapidly treated.

Table 3: Buprenorphine Dosing Regimens.

*Can also use Belbuca^ä, a buccal buprenorphine formulation that comes in 75mcg, 150mcg, 300mcg, 450mcg films, may have limited availability in outpatient pharmacies or hospital formularies

 Randomized Controlled Trials

A landmark study by D’Onofrio et al. in 2015 demonstrated reduced days of illicit opioid use and higher rates of engagement in outpatient addiction treatment following buprenorphine treatment in the ED.¹⁶ Of the 329 patients enrolled in the study 34% presented to the ED seeking treatment for OUD, the rest of the patients were identified via screening or after an overdose.¹⁶ Twenty-five percent of the patients enrolled reported only using prescription opioids.¹⁶Patients is this study were placed in one of three arms 1) screening and referral to treatment 2) screening, brief intervention, and referral to treatment or 3) screening, brief intervention, ED initiated buprenorphine, and referral to treatment.¹⁶ Patients in the buprenorphine group were given their first dose in the ED if they were in moderate to severe withdrawal (typically defined as COWS greater than 8), although COWS scores were not reported, and 57% of participants in this group were not in enough withdrawal and were given instructions to take their first dose of 8mg at home.¹⁶ No events of POW were reported in this study.¹⁶

Guideline survey

Since the 2015 RCT was published many EDs have developed their own protocol for the initiation of buprenorphine.¹⁷ A 2021 survey of 31 protocols among different EDs participating in a National Institute on Drug abuse (NIDA) research network was conducted to describe the range of practices in ED buprenorphine initiation as of October 2020 when the study was conducted.¹⁷ Thirty of 31 sites required a COWS score documented prior to administration, 27 sites recommended a minimum COWS score of 8, with 3 sites recommending a minimum COWS score of 5,11, or 12.¹⁷Nineteen sites had protocols with recommendations for how long to wait since last illicit opioid use prior to the first buprenorphine dose, with most recommending 12 hours for short-acting opioids, and 24 for long-acting opioids, and 48-72 hours for methadone.¹⁷ Initial buprenorphine dose varied in the protocols from 2-16mg (most common 4mg), additionally 45% of protocols varied their buprenorphine dose by COWS score, with most recommending 4mg for COWS 8-12 and 8mg for COWS > 12.¹⁷ Of note, some of these protocols were developed before fentanyl became more prevalent in the drug supply.

Microdosing

One alternative strategy of preventing buprenorphine POW is to start at small “microdoses” of buprenorphine prior to the development of withdrawal from full opioid agonist use.¹⁸ Microdosing was first described by Hammig et al as the “Bernese method”, initially as a strategy to avoid having to wait for withdrawal to develop rather than avoid the risk of POW.¹⁸ A case series by Antoine et al describes 4 patients who used primarily fentanyl who were induced on buprenorphine, 2 patients experienced POW when started on 4mg of buprenorphine and 2 patients who started on a lower dose regimen of 2mg and did not experience POW.¹³ A study by Moe et al performed a feasibility study of microdosing vs standard dosing buprenorphine, in phase 1 of the study patients were non-consecutively enrolled until a prespecified number of patients were enrolled and then in phase 2 patients were randomly assigned to either a microdosing regimen of 0.5mg buprenorphine twice daily and slowly increasing to 12mg twice daily by day 6 or a standard dose which they defined as initially taking 2mg and going up to 12mg on the first day and staying at that dose thereafter.¹² Although the aim of the study was to prove feasibility and interpretation limited by small numbers, more patients in the microdosing group 8/25 (32%) remained in therapy at 30 days compared to 5/21 (23.8%) in the standard dose group.¹² Of note in this study, if patients were in more severe withdrawal, defined as COWS> 12 they were not eligible for the microdosing pathway.¹² Patients in the microdosing pathway were given 0.5mg tablets and instructed to take the first dose at their convenience and increase at home.¹²  Of note the tablet formulation used in the study is available in Canada but not the US.

Macrodosing

A high-dose, or “macrodosing” strategy, was described by Herring et al in 2021 in order to more rapidly stabilize patients on a dose of buprenorphine, rather than up titrate over 2-3 days.¹⁹ This was a retrospective chart review of patients in mild to severe opioid withdrawal at a center that had both a standard induction and high dose buprenorphine pathway.¹⁹ It was up to the treating clinician to determine clinical appropriateness of buprenorphine induction with initial doses recommended of 4-8mg and were instructed to be reassessed in 30-45 minutes.¹⁹ Additional doses up to 24mg of buprenorphine were given.¹⁹ Of 579 patients there were 5 (0.8%) cases of PW, 4 of these cases occurred in patients who were treated on a standard induction pathway and received 8mg total and the fifth case occurred after a patient had received 32mg of buprenorphine.¹⁹ This study found a shorter length of stay in patients who were on the high-dose pathway, presumably due to faster control of their withdrawal symptoms.¹⁹ The results could be confounded by the non-random nature of clinicians choosing the dosing regimen for their patients, however this could be a promising pathway for treatment of OUD.

Managing Precipitated Opioid Withdrawal

While there is no randomized data to guide the management of buprenorphine POW, experience from the management of non-precipitated withdrawal as well as POW from naltrexone and naloxone can inform practice. Patient reassurance and a therapeutic alliance are an important foundation given that the first dose of buprenorphine caused these symptoms.

Evidence for Additional Buprenorphine Doses

Buprenorphine has been well established as an effective treatment for opioid withdrawal and thus it is an attractive option to Macrodosing give additional doses of buprenorphine to treat precipitated withdrawal if the first dose of buprenorphine made symptoms worse.¹ Extrapolating from the management of naltrexone induced POW, 3 case reports and one case series described the use of buprenorphine to treat precipitated withdrawal, with resolution of precipitated withdrawal within hours using doses of 4mg to 22mg.^20-23 Buprenorphine has also been described as a treatment for naloxone precipitated opioid withdrawal in a case report.²⁴ In case reports of buprenorphine to manage buprenorphine POW, doses of 8-16mg were given with improvement of symptoms within 1-2 hours of receiving the additional doses.^11,25

Adjunctive Medications

Non-opioid adjunctive medications to manage POW can be chosen based on the symptoms that occur during POW.¹Expert reviews of the management of OUD and society guidelines make recommendations for different medications, although little high-quality evidence exists.^1,3,5 See table 4 for adjunctive medications for POW.^1,3,5 Care should be taken when combining high doses of benzodiazepines with higher doses of buprenorphine as respiratory depression can occur. Case reports exist of using ketamine and propofol for severe POW, although close monitoring would be needed after use.^5,26

Table 4: Adjunctive Medications for POW.

Case Conclusion

The patient is given an additional 16mg-4mg of buprenorphine-naloxone, 8mg of ondansetron, 4mg of loperamide, clonidine 0.1mg, and 975mg of acetaminophen with improvement of their symptoms over the next 2 hours. A repeat COWS score is now 3. The patient is enrolled in a bridge clinic for further management of the OUD and discharged on 16mg-4mg of buprenorphine-naloxone until their appointment in 3 days.

Summary

• Buprenorphine is highly effective for the treatment of OUD but can occasionally cause precipitated opioid withdrawal in some patients.
• Longer acting opioid use such as methadone and chronic fentanyl use may increase the risk of POW.
• Microdosing or Macrodosing are alternative dosing options for preventing POW.
• Should POW develop in your patient, it can be managed with additional doses of buprenorphine, antiemetics, NSAIDS, antihistamines, and benzodiazepines.

References

1. Herring AA, Perrone J, Nelson LS. Managing Opioid Withdrawal in the Emergency Department With Buprenorphine. Ann Emerg Med. 2019;73(5):481-487. doi:10.1016/j.annemergmed.2018.11.032
2. 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 and Alcohol Dependence. 2007;86(2-3):239-244. doi:10.1016/j.drugalcdep.2006.06.014
3. Cisewski DH, Santos C, Koyfman A, Long B. Approach to buprenorphine use for opioid withdrawal treatment in the emergency setting. American Journal of Emergency Medicine. 2019;37(1):143-150. doi:10.1016/j.ajem.2018.10.013
4. Hawk K, Hoppe J, Ketcham E, et al. Consensus Recommendations on the Treatment of Opioid Use Disorder in the Emergency Department. Ann Emerg Med. 2021;78(3):434-442. doi:10.1016/j.annemergmed.2021.04.023
5. Strayer RJ, Hawk K, Hayes BD, et al. Management of Opioid Use Disorder in the Emergency Department: A White Paper Prepared for the American Academy of Emergency Medicine. J Emerg Med. 2020;58(3):522-546. doi:10.1016/j.jemermed.2019.12.034
6. Wax PM, Stolbach AI, Schwarz ES, Warrick BJ, Wiegand TJ, Nelson LS. ACMT Position Statement: Buprenorphine Administration in the Emergency Department. J Med Toxicol. 2019;15(3):215-216. doi:10.1007/s13181-019-00712-3
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21. Santos, Cynthia, and Stephanie H. Hernandez. “A case of unintentional naltrexone-induced opioid withdrawal successfully treated with buprenorphine in an emergency department setting.” Clinical Toxicology. Vol. 52. No. 4. 52 Vanderbilt Ace, New York, NY 10017 USA: Informa Healthcare, 2014.
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