Abstinence-related, or spontaneous, withdrawal occurs gradually over hours to days, whereas precipitated withdrawal, caused by the administration of a receptor antagonist, occurs suddenly and with immediate peak intensity. Precipitated withdrawal is therefore often much more severe and distressing and more likely to be dangerous. In the case of opioid dependence, precipitated withdrawal is best known to occur after the administration of naloxone, a mu receptor antagonist. Though opioid withdrawal syndrome (OWS) is classically thought to be unpleasant but benign, precipitated withdrawal causes an autonomic surge, which may be hazardous, especially in patients without generous cardiorespiratory reserve, in addition to physiological derangements that are often extremely unpleasant (total body pain, vomiting, diarrhea) and, perhaps most important, intense psychological dysphoria that may be unbearable and lead to desperate acts in search of relief. The prospect of OWS can lead opioid use disorder (OUD) patients to fear entering the health care system and is postulated to sometimes delay the summoning of emergency services to treat overdose.

Treatment Options

Naloxone is a lifesaving overdose rescue medication, but it can be overutilized and used at too high a dose. Health care professionals should differentiate between the patient who is dangerously opioid toxic, with physiologically consequential respiratory depression, and the patient who is somnolent, even poorly arousable, but ventilating adequately. The latter patient should usually not be treated with naloxone but rather allowed to recover through natural metabolism under close observation. Opioid-toxic patients who have dangerous respiratory depression but are not at imminent risk of decompensation should receive small doses of intravenous naloxone (eg, 0.04 mg) titrated every few minutes to adequate ventilation, not titrated to arousal.

Buprenorphine, a partial agonist with a mu receptor affinity higher than almost any other opioid, can similarly precipitate withdrawal in opioid-dependent patients by replacing the full agonist on the receptor, leading to a loss of agonism and subsequent buprenorphine-precipitated withdrawal (BPW).

Traditionally, buprenorphine treatment of OUD has been initiated using small doses (2–4 mg sublingually) only after a period of abstinence and the development of spontaneous withdrawal (often determined by satisfying a Clinical Opiate Withdrawal Scale score of greater than 8). These “test doses” are used to determine whether the patient is in sufficient withdrawal to avoid BPW. If the patient’s symptoms are improved (or at least do not worsen), increased doses are given. But if these smaller doses cause BPW, the process is halted, and symptoms are treated with non-agonist medications (eg, clonidine, ondansetron). Several hours later, if the patient is willing, buprenorphine initiation can be reattempted.

An Alternative Approach

A growing body of experience supports an alternative approach: the treatment of BPW with higher doses of buprenorphine. Early experience demonstrates this strategy to be significantly more effective in treating withdrawal symptoms than non-agonists. This pathway demonstrates buprenorphine’s ability to abolish OWS and cravings while simultaneously transitioning the patient to medication-assisted therapy–based recovery. Future initiation pathways will likely skip the test doses and proceed to a single big dose (≥16 mg sublingually), which appears less likely to precipitate withdrawal and provides long-lasting protection from spontaneous withdrawal, cravings, and overdose. Protocols around high-dose initiation that account for appropriate patient selection and the possibility of provoking both protracted withdrawal and buprenorphine toxicity are being developed.

ILLUSTRATION: Chris Whissen & shutterstock.com

In Camden, New Jersey, our institution sits in an area with a high prevalence of opioid overdose and medical complications related to OUD. Our emergency department, recognizing its pivotal frontline role, waivered all of our physicians to prescribe buprenorphine and opened a multidisciplinary bridge clinic where emergency patients could be immediately referred to facilitate ongoing buprenorphine therapy while outpatient comprehensive addiction care is arranged. We currently have the ability to bridge 22 patients weekly.

As our program developed, we found that traditional buprenorphine titration was poorly suited to the demands of our emergency department. As a result, many patients—even those in moderate withdrawal—were discharged with a buprenorphine prescription for home initiation. When we examined our resources in the prehospital arena, we were alarmed to discover that, in 2019, more than one-third of patients treated in the field for overdose refused transport to the emergency department. This resulted in a significant health care gap as well as provider frustration and compassion fatigue with patients who required rescue repeatedly, in some cases with multiple overdoses in a single day. Our only opportunity to engage this population was during the brief EMS encounter; we therefore started a program aimed at administering buprenorphine after naloxone reversal and directly linking these patients to care, all within the constraints of a busy EMS system.

Though published evidence is scant, through experience we have learned that high doses of buprenorphine are less likely to precipitate withdrawal and can rapidly and effectively treat naloxone-precipitated withdrawal (NPW). We created an EMS protocol where we treat NPW with 16–24 mg of sublingual buprenorphine.

In the first months of this program, results have been overwhelmingly positive: Patients have done well, NPW symptoms have been relieved, BPW has not occurred, and scene times and unit availability have not been affected. Remarkably, we have found no difference in bridge clinic follow-up rates between patients who refuse versus allow ED transport. To date, almost 70 percent of patients with OUD rescued in the field have attended their first clinic appointment. This program also fundamentally changed the relationship of EMS providers to this underserved, vulnerable, and challenging population. “Just another overdose” is now an opportunity to make a difference.

Treatments That Work for Patients

OUD patients presenting to the emergency department and to EMS, whether after an overdose or due to medical complications related to opioid use, are at extraordinary risk for short-term mortality. Emergency providers can have a significant impact on outcomes by initiating buprenorphine treatment and referring patients for ongoing medication-based addiction care. However, traditional time-intensive initiation models are discordant with emergency care, where we often have only a brief window to engage these patients, especially patients in withdrawal, who are very likely to decline further care and leave.

Most patients find withdrawal symptoms intolerable, and despite being given a buprenorphine prescription at discharge, many are unable to bear the development of severe enough OWS to initiate buprenorphine at home using a conventional gradual dosing strategy. Treating precipitated withdrawal with high-dose buprenorphine has the potential to close this treatment gap by quickly relieving withdrawal symptoms without the fear of precipitated withdrawal. Administration of 16–24 mg of buprenorphine binds a high fraction of the patient’s opioid receptors, which decreases cravings, prevents withdrawal, and protects the patient from opioid overdose for 24 hours or longer. Initiating high-dose buprenorphine to ED and EMS patients with low Clinical Opiate Withdrawal Scale scores may therefore allow successful transition to buprenorphine recovery among a group of patients who would otherwise fail to establish therapy.

Though these strategies are in their infancy, they have thus far been demonstrated to be safe and effective. While more experience and outcome data are needed, treatment of precipitated withdrawal with high-dose buprenorphine has the potential to significantly expand the reach of emergency providers at the front lines of addiction care. 

Dr. Haroz is assistant professor of emergency medicine at Cooper Medical School of Rowan University and division head, toxicology and addiction medicine, in the department of emergency medicine at Cooper University Health Care in Camden, New Jersey.

Dr. Carroll is assistant professor of emergency medicine and EMS fellowship director at Cooper Medical School of Rowan University and medical director, division of EMS and disaster medicine, in the department of emergency medicine at Cooper University Health Care.

Dr. Strayer is associate medical director of emergency medicine at Maimonides Medical Center in Brooklyn, New York.