Synergistic Effect of Ketamine and Buprenorphine Observed in the Treatment of Buprenorphine Precipitated Opioid Withdrawal in a Patient With Fentanyl Use

Abstract

BackgroundOptimal treatment of buprenorphine precipitated opioid withdrawal (BPOW) is unclear. Full agonist treatment of BPOW is limited by buprenorphine’s high-affinity blockade at mu-opioid receptors (μORs). Buprenorphine’s partial agonism (low intrinsic efficacy) at μORs can limit the effectiveness of even massive doses once BPOW has begun. Adjunct medications, such as clonidine, are rarely effective in severe BPOW. Ketamine is an N-methyl-D-aspartate receptor antagonist with a potentially ideal pharmacologic profile for treatment of BPOW. Ketamine reduces opioid withdrawal symptoms independently of direct μOR binding, synergistically potentiates the effectiveness of buprenorphine μOR signaling, reverses (resensitizes) fentanyl induced μOR receptor desensitization, and inhibits descending pathways of hyperalgesia and central sensitization. Ketamine’s rapid antidepressant effects potentially address depressive symptoms and subjective distress that often accompanies BPOW. Ketamine is inexpensive, safe, and available in emergency departments. To date, neither ketamine as treatment for BPOW nor to support uncomplicated buprenorphine induction has been described.Case DescriptionWe report a case of an illicit fentanyl-using OUD patient who experienced severe BPOW during an outpatient low-dose cross taper buprenorphine induction (ie, “microdose”). The BPOW was successfully treated in the emergency department with a combination of ketamine (0.6 mg/kg intravenous over 1 hour) combined with high-dose buprenorphine (16 mg sublingual single dose); 3 days later he was administered a month-long dose of extended-release subcutaneous buprenorphine which was repeated monthly (300 mg). At 90 days the patient remained in treatment and reported continuous abstinence from fentanyl use.ConclusionsThis single case observation raises important questions about the potential therapeutic role of ketamine as a treatment for BPOW. BPOW is an important clinical problem for which there is currently only limited guidance and no universally accepted approach. Prospective study comparing the effectiveness of differing pharmacologic approaches to treat BPOW is urgently needed.

Precipitated opioid withdrawal after buprenorphine administration in patients presenting to the emergency department: A case series

“…For other patients, it is possible that gradually worsening or undertreated withdrawal symptoms were interpreted as PW. 16 , 19 In those instances, concern for PW may prevent clinicians and patients from proceeding with additional doses of buprenorphine. 7 Overall, our findings suggest that it may be challenging for acute care clinicians to pinpoint where patients are on the arc of this withdrawal syndrome.…”

“…Our findings suggest that PW did occur among patients with moderate to severe opioid withdrawal. For other patients, it is possible that gradually worsening or undertreated withdrawal symptoms were interpreted as PW 16,19 . In those instances, concern for PW may prevent clinicians and patients from proceeding with additional doses of buprenorphine 7 .…”

“Just give them a choice”: Patients' perspectives on starting medications for opioid use disorder in the ED

“…This is emerging in the literature as an important issue, as it makes both people with OUD and clinicians hesitant to initiate buprenorphine 39–42 . Fortunately, research addressing the treatment of precipitated withdrawal is a rapidly evolving; “micro” and “macro” dosing of buprenorphine may be effective, and IV ketamine has also been used with good effect 43–47 . However, the actual risk of precipitated withdrawal for an individual patient is based on history of drug use (which drugs and when) and may be difficult for a clinician to predict.…”

“…[39][40][41][42] Fortunately, research addressing the treatment of precipitated withdrawal is a rapidly evolving; "micro" and "macro" dosing of buprenorphine may be effective, and IV ketamine has also been used with good effect. [43][44][45][46][47] However, the actual risk of precipitated withdrawal for an individual patient is based on history of drug use (which drugs and when) and may be difficult for a clinician to predict. This has implications for SDM in this context: clinicians will need to effectively treat precipitated withdrawal and be able to reassure patients that they will be adequately treated should they have severe withdrawal.…”

Hospitalist perspectives on buprenorphine treatment for inpatients with opioid use disorder

“…Ketamine has been observed to potentiate opioid analgesia and to act as a rapid antidepressant. Subdissociative doses of the drug could help treat precipitated withdrawal and facilitate buprenorphine induction, titration, and stabilization among patients who use fentanyl ( Hailozian et al., 2022 ).…”