(62) Buprenorphine for Naltrexone-XR-Precipitated Opioid Withdrawal

Background & Introduction: Naltrexone is a μ-opioid antagonist which is FDA-approved to treat both alcohol use disorder (AUD) and opioid use disorder (OUD). It can precipitate opioid withdrawal syndrome (OWS) in patients with opioid dependence if administered too soon after the administration of a full opioid agonist. In this case, we describe a patient who was maintained on methadone for the treatment of OUD, and was unfortunately administered injectable extended-release naltrexone (naltrexone-XR) for the treatment of AUD. The optimal treatment of naltrexone-XR-precipitated OWS is not well-established. While some case reports suggest that buprenorphine can improve symptoms in cases of naltrexone- or naloxone-precipitated OWS, data is even more limited for cases involving the naltrexone-XR formulation as well as tolerance maintained by a long-acting full opioid agonist such as methadone. Our patient was treated with buprenorphine with notable improvement in his symptoms. Given its pharmacologic properties, buprenorphine may be a reasonable treatment strategy for patients who experience precipitated OWS due to naltrexone-XR.

Case Description: A 61-year-old male with a past medical history of chronic obstructive pulmonary disease, depression, tobacco use disorder, OUD (three bags daily, never injects), type II diabetes, and AUD presented to the emergency department (ED) for chills and rhinorrhea that began the day before. He went to his primary care doctor the day prior, where he received an influenza vaccination and naltrexone-XR for AUD. Approximately one hour after his appointment, he developed subjective fever, chills, rhinorrhea, and diarrhea. He reported taking his last dose of 100 milligrams (mg) of methadone the day prior to admission. He denied chest pain, emesis, abdominal pain, or sick contacts.

On exam, the patient was uncomfortable with rhinorrhea and chills, keeping himself covered with blankets. He had diarrhea in the ED. Vital signs included blood pressure 137/84 mm Hg, temperature 99.7 degrees Fahrenheit, pulse 112, respiratory rate 22, 100% oxygen saturation on room air.
ED workup was remarkable for elevated high-sensitivity troponin of 52.3 ng/L, negative COVID, Influenza, and RSV testing, hemoglobin 12.4 g/dL, potassium 3.3 mmol/L, sodium 132 mmol/L, chloride 91 mmol/L, alkaline phosphatase 201 U/L, aspartate aminotransferase 68 U/L. Chest Xray and electrocardiogram were unremarkable.

While in the ED he was offered buprenorphine for its high binding affinity, but he declined. He was instead given 30 mg methadone PO, hydromorphone 6 mg IV, ondansetron 4 mg IV, loperamide 4 mg PO, oxycodone IR 30 mg PO, oxycodone ER 60 mg PO, hydromorphone 10 mg IV, one liter of lactated ringers, and diazepam 10 mg IV. He was admitted to medicine for further care.

Addiction medicine was consulted on hospital day two. At the time of the initial consult, he showed persistent signs of opioid withdrawal, most notably diaphoresis and piloerection, though he was overall improved from initial ED presentation. With guidance from the addiction medicine team, the patient started buprenorphine-naloxone 8-2 mg three times daily. The following day, hospital day three, he was noted to be feeling much improved. He was amenable to continuing buprenorphine-naloxone treatment for at least a month, with the goal of overcoming the effects of naltrexone with buprenorphine-naloxone until he metabolized the naltrexone depot. His long-term plan was to return to methadone treatment after that time. He was discharged on hospital day four in good condition, with no symptoms of opioid withdrawal. He filled an outpatient buprenorphine-naloxone prescription at the time of hospital discharge.

Conclusion & Discussion: This case describes a patient with precipitated OWS after receiving naltrexone-XR while on methadone. Naltrexone is a full competitive antagonist of the μ-opioid receptor with a high binding affinity (Ki=0.29), which allows it to displace full agonists already occupying the μ-opioid receptors and to outcompete additional full agonists administered. In this case, administration of naltrexone displaced methadone molecules (with a relatively higher Ki of 3.378) occupying the μ-opioid receptors, causing sudden and severe onset of OWS. The patient had incomplete relief of symptoms with subsequent doses of methadone, oxycodone (Ki=25.87), and hydromorphone (Ki=0.3654). As our case illustrates, effective treatment of naltrexone-associated OWS is challenging and can require hospitalization, particularly if precipitated by naltrexone-XR.

Buprenorphine is a partial μ-opioid agonist with a very high binding affinity (Ki=0.2157). As such, it can displace both full antagonists and agonists at the μ-opioid receptor. Our patient had complete relief of OWS symptoms when treated with buprenorphine-naloxone. There are increasing reports of buprenorphine being used to manage naloxone-precipitated OWS, and we suggest that its pharmacologic properties make it a particularly good option for managing naltrexone-precipitated OWS as well.

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