PAIN MANAGEMENT AND SEDATION/EXPERT CLINICAL MANAGEMENT

Managing Opioid Withdrawal in the Emergency

Department With Buprenorphine
Andrew A. Herring, MD; Jeanmarie Perrone, MD; Lewis S. Nelson, MD*
*Corresponding Author. E-mail: [email protected], Twitter: @LNelsonMD.

0196-0644/$-see front matter

Copyright © 2018 by the American College of Emergency Physicians.
https://doi.org/10.1016/j.annemergmed.2018.11.032

A podcast for this article is available at www.annemergmed.com. and frequency of administration.7 Use of short-acting
Continuing Medical Education exam for this article is available at opioids such as heroin or oxycodone several times daily for
http://www.acep.org/ACEPeCME/. at least 2 weeks is needed before opioid dependence
[Ann Emerg Med. 2019;73:481-487.] develops. Furthermore, the degree of dependence, and thus
the severity of opioid withdrawal, is directly related to the
OVERVIEW intensity (eg, dose, duration, continuity) of exposure. After
Emergency departments (EDs) provide acute treatment sustained exposure, m-opioid receptors adapt to the
for patients with opioid use disorder, including opioid presence of opioid agonists, which tonically suppress
overdose and opioid withdrawal, and serve as access portals neuronal excitability. When the m-opioid receptors are
for the initiation of medication-assisted therapy (also unbound, neuronal disinhibition and hyperexcitability
called medication for addiction treatment, or medication result in the clinical findings of opioid withdrawal.
for opioid use disorder).1 To combat the public health crisis
associated with opioid use disorder, the surgeon general, OPIOID WITHDRAWAL SYNDROMES
the Centers for Disease Control and Prevention, state Opioid withdrawal manifests as 2 distinct yet reinforcing
governments, and many others have called on EDs to subsyndromes, psychological and physiologic. The
improve the quality of care offered to this patient physiologic findings include restlessness, nausea, vomiting,
population, particularly through the expanded use of diarrhea, piloerection, diaphoresis, yawning, mydriasis, and
buprenorphine.1 mild autonomic hyperactivity. The psychological effects,
Although much attention has focused on treatment of including pain, anxiety, stress intolerance, irritability, and
patients with opioid overdose, opioid withdrawal is a high- drug craving, coincide with the physiologic signs but may
risk period that is associated with elevated mortality after persist for weeks to months after physiologic
discharge.2–4 More than half of patients who died from an normalization.8
opioid overdose were noted to have had a medical visit in Abstinence-related opioid withdrawal results from the
the year before their death.5 Abstinence without medical discontinuation of opioid use in a patient with opioid
intervention, whether voluntary (eg, “cold turkey,” dependence and is generally not life threatening. The onset
abstinence-based treatment) or involuntary (eg, varies according to the opioid (Table 1). Clinicians should
incarceration), further increases the risk for overdose.6 explore the underlying reason for abstinence (eg, medical
Because treatment of opioid withdrawal is a starting illness, desire for abstinence).
point for induction into medication-assisted therapy, the Precipitated opioid withdrawal develops abruptly after
two are difficult to disentangle. In fact, they do not need to administration of an opioid antagonist, partial agonist, or
be separated, and they are discussed here together. agonist-antagonist (Table 2). Depending on the specific
precipitant and the dose and rate of administration, the
PATHOPHYSIOLOGY: WHO IS AT RISK FOR clinical effects of precipitated opioid withdrawal range from
OPIOID WITHDRAWAL? mild, self-limited discomfort to more concerning findings
Opioid dependence must be present, by definition, for such as vomiting and agitation. Among the most severe
an individual to develop opioid withdrawal. The time manifestations are delirium and autonomic instability. The
course for the development of opioid dependence is latter effect, caused by massive catecholamine release, may
variable, generally from days to weeks, contingent on lead to cardiovascular complications such as pulmonary
factors such as the specific opioid formulation and routes edema.9

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Managing Opioid Withdrawal With Buprenorphine Herring, Perrone & Nelson

Table 1. Typical time course following last use of physiologic pressure to make medication-assisted therapy a standard
opioid withdrawal for common opioids. practice; Massachusetts recently mandated ED treatment of
Drug Onset, Hours Peak Resolution, Days opioid use disorder.14 Nevertheless, despite the strong
Buprenorphine 4–48 96 h 14–21 evidence supporting the benefit of medication-assisted
Fentanyl (intravenous) 2–5 8–12 h 4–5 therapy, there remains substantial variation in personal,
Heroin 6–12 24–72 h 7–10 institutional, and regional culture in opioid use disorder
Short-acting prescription 6–12 24–72 h 7–10 treatment approaches.11
opioids
Long-acting prescription 12–36 2–5 days 10–14
opioids
Nonopioid Treatments
Methadone 24–72 4–6 days 14–21
Self-treatment of opioid withdrawal (eg, kratom) and
nonopioid pharmacologic treatment are described in
The psychological effects (ie, postacute withdrawal syndrome) may last for several Table 3.15,16
months.

Opioid Agonist Treatment

DIAGNOSIS AND ASSESSMENT OF OPIOID The evidence-based approach and growing consensus in
WITHDRAWAL the ED is to use an opioid agonist (a form of medication-
Opioid withdrawal is a clinical diagnosis based on the assisted therapy) to both treat opioid withdrawal and
physical examination and patient history. There are several bridge to long-term treatment. Buprenorphine and
tools that may be used to assist in evaluation of opioid methadone are both widely used and highly effective in
withdrawal severity. The most widely used tool is the safely stemming the physiologic and psychological effects
Clinical Opiate Withdrawal Scale. The scale grades severity of opioid withdrawal.17 Although hospital logistics often
from 0 to 36 points in accordance with the evaluation of dictate the decision, buprenorphine is the preferred option
typical effects, including pulse, pupillary size, restlessness, in the ED.
and yawning. Although the scale was not developed for use Methadone is a full agonist at the m-opioid receptor and
as a guideline for buprenorphine initiation, its long- commonly used through opioid treatment programs for
standing use in this role has been valuable.10 Unobserved or maintenance treatment, with daily oral doses ranging from
“home” induction, which is finding increasing use from the 10 mg to greater than 100 mg. A methadone dose of 10 mg
ED, is often guided by the Subjective Opioid Withdrawal intramuscularly or 20 mg orally significantly reduces the
Scale.11 Clinical Opiate Withdrawal Scale score in ED patients with
opioid withdrawal.18 At this recommended dose,
methadone will not lead to consequential sedation or
TREATMENT OF OPIOID WITHDRAWAL respiratory depression in awake patients.
Although very uncomfortable, opioid withdrawal is Buprenorphine is a unique m-opioid receptor partial
rarely life threatening. However, untreated opioid agonist with minimal euphoric reward and a ceiling effect
withdrawal commonly results in return to high- on both sedation and respiratory depression. It is generally
consequence opioid use, with a high risk of overdose death administered as a sublingual (not swallowed) tablet or strip
after discharge from the ED.6,12,13 There is increasing and is available for intravenous use as an analgesic.

Table 2. The pharmacology of precipitated opioid withdrawal.

Onset of Opioid Duration of Opioid
Precipitant Class Typical Route* Withdrawal, Minutes Withdrawal Treatment
Butorphanol or nalbuphine Agonist-antagonist Parenteral (intramuscular) 15 90 min Supportive
Naloxone Antagonist Parenteral 1–3 30–60 min Supportive†
Naltrexone Antagonist Oral 15–30 12–24 h Buprenorphine or
high-dose opioids‡
Buprenorphine Partial agonist Sublingual 10–15 12–24 h Buprenorphine

*All of these agents can be administered by multiple routes, affecting the pharmacokinetics, clinical effects, and necessary treatment approaches.
†
The potential benefit of buprenorphine in patients with naloxone-precipitated opioid withdrawal is being investigated.
‡
High-dose opioids: fentanyl is frequently used because of titratability; start with 50 mg (adult) intravenously and increase.

482 Annals of Emergency Medicine Volume 73, no. 5 : May 2019

Herring, Perrone & Nelson Managing Opioid Withdrawal With Buprenorphine

Table 3. Pharmacologic and dietary supplement options to treat opioid withdrawal.

Medication Class Clinical Use Dose Comments*
Clonidine a-2 agonist Autonomic 0.1 mg PO; can repeat Hypotension and bradycardia common but
hyperactivity generally inconsequential
Kratom (Mitragyna Opioid agonist mitragynine Opioid agonist Undefined Can reduce craving because of its opioid
speciosa) and 7-hydroxymitragynine (unregulated) agonism. Significant abuse potential.
Lofexidine a-2 agonist Autonomic 0.54 mg PO FDA approved, $1,700. Less hypotension than
hyperactivity with clonidine.
Loperamide Nonabsorbed opioid Diarrhea 2–4 mg PO Abuse potential at high doses
agonist†
Metoclopramide Dopamine antagonist Vomiting 10 mg PO; can repeat QT prolongation
Ondansetron Serotonin antagonist Vomiting 4 mg PO; can repeat QT prolongation

PO, Orally; FDA, Food and Drug Administration.

*None of the nonopioid pharmacologic options reduce craving.
†
Can be absorbed at high doses, leading to its popular use as self-treatment for opioid withdrawal.

There is currently no definitive approach to the ED several factors, including the relative plasma concentrations
dosing strategies for buprenorphine. Office-based clinical and receptor affinities of the agonist and partial
guidelines for induction are not practical for ED use agonist.25–27 For example, the relative antagonism after
because of their low dosing and slow titration.19 administration of a large dose of buprenorphine (partial
There are few formal studies of buprenorphine for the agonist/high binding affinity) to a patient receiving
treatment of opioid withdrawal. In 2 small studies, patients methadone (full agonist/low binding affinity) will likely
with a history of heroin use who presented in withdrawal result in precipitated opioid withdrawal, whereas patients
(Clinical Opiate Withdrawal Scale score 13) and were receiving buprenorphine can receive full-agonist opioids
receiving 8 mg SL and had a mean reduction in Clinical for analgesia without concern for precipitated opioid
Opiate Withdrawal Scale score of 7 points (from 15 to 8),20 withdrawal.28–30
whereas those treated with 24 mg SL buprenorphine The relief provided by buprenorphine increases with
experienced a larger mean reduction in Clinical Opiate worsening opioid withdrawal severity and increased dose of
Withdrawal Scale score (from 17 to 2).21 Given the paucity buprenorphine. Although a Clinical Opiate Withdrawal
of approaches that are ED specific, there is variation in Scale score of 8 is a suggested minimum for initiation by
current practice.22–24 In general, patients in the ED can be some guidelines, at least one objective sign of opioid
expected to require buprenorphine at at least 8 mg SL to withdrawal indicates readiness to initiate buprenorphine.
achieve substantive relief, and the majority of patients More conservative guidelines suggest withholding
markedly improve with a 16-mg SL total dose; the buprenorphine until the Clinical Opiate Withdrawal Scale
maximum is 32 mg SL. score is 13. Particular caution should be taken with patients
Excessive buprenorphine dosing causes mild sedation, receiving methadone; most guidelines recommend waiting
but the use of insufficient buprenorphine risks the at least 48 hours since last use and until objective signs of
premature return of opioid withdrawal and craving during withdrawal are present.
the high-risk period immediately after discharge from the There is no consensus for the optimal initial
ED. For this reason, certain guidelines recommend up to buprenorphine dose. Some guidelines recommend a lower
32 mg SL as an induction dose to prolong the duration of initial dose of buprenorphine (eg, 2 to 4 mg SL). However,
opioid withdrawal suppression after discharge.24 because the treatment for buprenorphine-precipitated
Reasonable caution, particularly in regard to the elderly, opioid withdrawal is administration of additional
patients with decreased respiratory function, or those with buprenorphine, a larger initial dose may carry less risk of
co-occurring sedative use, should be exercised when higher precipitated opioid withdrawal. This seemingly paradoxic
doses are used. effect occurs because of optimization of partial agonist
An immediate concern with initiating buprenorphine is stimulation as the buprenorphine dose increases before
the displacement of a full agonist by a partial agonist reaching its ceiling dose.31
that can result in precipitated opioid withdrawal. The Although no single algorithm can account for the
development of precipitated opioid withdrawal depends on clinical complexity encountered in emergency practice, a

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Managing Opioid Withdrawal With Buprenorphine Herring, Perrone & Nelson

reasonable approach is shown in Figures 1 and 2. A A recently available injectable depot formulation
common induction target dose before ED discharge is 16 provides several weeks of opioid withdrawal suppression,
mg SL, which may be comfortably increased as provider but it is costly and has not yet been studied for use in
experience and judgment increase.22,32,33 the ED.34,35

Figure 1. Algorithm for treatment of opioid withdrawal. BID, Twice a day.

484 Annals of Emergency Medicine Volume 73, no. 5 : May 2019

Herring, Perrone & Nelson Managing Opioid Withdrawal With Buprenorphine

Initial clinical assessment

• Is the patient experiencing moderate opioid withdrawal (OW)? The clinical opioid withdrawal scale
(COWS) may be used if unsure,
• Is the time since last use of opioid consistent with OW?
• Is there a complicating factor to be addressed prior to administration of buprenorphine?
• Mild withdrawal—is it too early for buprenorphine administration?
• Altered mental status—co-intoxicant, decompensated psychiatric disease
• Methadone use—methadone is usually a better option
• No laboratory testing is required, pregnancy testing, Hepatitis C and HIV, and urine drug screening
may be offered.
• No initial counseling or psychosocial intervention is required.
• Interest in long-term treatment is not required.

First dose
• Typically, 4-8 mg sublingual (SL) buprenorphine or buprenorphine/naloxone
• Initial doses ranging from 2-32 mg SL may be considered depending on the clinical situation

Clinical Reassessment at 30-60 minutes

• Marked and unequivocal improvement in signs and symptoms confirms clinical diagnosis of OW
and that buprenorphine is well tolerated.
• Lack of improvement should provoke reassessment of the clinical situation and treatment.
• Is there a primary medical issue such as sepsis from an injection-related infection?
• Is there persistent or worsening (precipitated) withdrawal suggesting insufficient partial
agonism (higher buprenorphine dose needed, up to 16 mg)?
• Is there worsening withdrawal suggesting antagonist effects (POW?)

Completion of treatment and discharge

• If the patient is comfortable after the first dose no additional treatment is required.
• Additional doses can be administered in the ED to prolong duration and magnitude of effect; typical
daily doses of SL buprenorphine range from 8-32 mg.
• X-waivered
• Prescribe for patients wishing to continue buprenorphine treatment or as a harm reduction
rescue measure
• Prescribe sufficient days of buprenorphine for patients awaiting entry into a treatment
program
• In general, the prescribing X-waiver provider must have a face-to-face visit with the
patient. Under emergency circumstances a two-way audio-visual encounter (Telehealth)
can be used to provide up to a 5-day prescription.
• Non-X-waivered
• Provide a patient awaiting entry to a treatment program with once-daily direct
administrations of buprenorphine for up to three consecutive days from the ED.
• Care navigation will increase rates of engagement in long-term treatment for OUD and should be
provided if local resources allow.

Complicating factors
• Is there a viable pregnancy? If so, fetal monitoring during treatment may be considered. Pregnancy
is not a contraindication to the use of buprenorphine with our without naloxone.
• Is the patient under full agonist treatment for either pain or OUD? If so, methadone may be the
more appropriate treatment.
• Will the patient require surgery or full agonist opioids for acute pain? If so, full agonist opioid may
be the more appropriate treatment. Alternatively, buprenorphine can be started and continued as a
lower dose, more frequently dosed regimen, such as 2-4mg Q 4-8 hours, with additional high-
affinity full agonist opioids as needed.
• Opioid withdrawal co-occurring with sedative intoxication (alcohol, benzodiazepines) may require
complex management not easily protocolized. The PDMP may include information about other
controlled substance prescriptions that may contribute to substantive withdrawal.
• Expert opinion varies on the optimal timing for buprenorphine administration after naloxone-POW.
Better understanding of both the complex pharmacokinetic interactions involved and clinical study
is required before evidence-based clinical recommendations are possible. Buprenorphine should be
strongly considered in a patient with naltrexone-POW.

Figure 2. Guideline for treatment of opioid withdrawal. OUD, Opioid use disorder; PDMP, prescription drug monitoring program.

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Managing Opioid Withdrawal With Buprenorphine Herring, Perrone & Nelson

REGULATORY AND LEGAL ISSUES the fragmented system of care return visits to the ED
It is a common misconception that the administration of should be not discouraged.
buprenorphine requires a Drug Addiction Treatment Act of For admitted patients, buprenorphine or methadone will
2000 X-waiver. In fact, short-term treatment with direct reduce craving and the risk of leaving against medical
administration of any opioid approved for use in advice because of untreated opioid withdrawal.39 As with
maintenance or detoxification treatment (typically many ED therapies, those started in the ED are often
buprenorphine or methadone) is permitted under the “3- continued in the hospital; ED partnership with hospital-
day rule” (Title 21, Code of Federal Regulations, Part based care teams will promote continuity of treatment and
1306.07). Under this rule, discharged patients may return to engagement in long-term treatment after discharge.
the ED daily to receive the medication for up to 72 hours.36
An X-waiver is required to prescribe buprenorphine for the SUMMARY
treatment of opioid use disorder. Any provider who holds a Because EDs have the opportunity to influence opioid-
Drug Enforcement Administration registration may apply for related morbidity and mortality, developing a systematic
an X-waiver after an 8-hour training program and approach is increasingly important to optimize patient
examination.37 Although abbreviated training programs outcomes. The best-practice approach supports the
designed for emergency physicians may provide the needed administration of buprenorphine in the ED, with adequate
tools for ED buprenorphine use, they currently do not suffice titration to both quell withdrawal and mitigate the risk of
to gain prescribing privileges. Prescribing methadone for opioid opioid use after discharge. This initial dosing serves as
use disorder is not covered by an X-waiver and is not allowed induction into medication-assisted therapy, and rapid
outside of an opioid treatment program. However, admitted referral, preferably directly to a treatment program, is
patients with opioid use disorder may receive buprenorphine or optimal. Return visits for buprenorphine dosing for up to 3
methadone indefinitely to permit the ongoing treatment of a days or prescribing buprenorphine for a duration needed to
concomitant medical issue.38 ensure treatment access is an alternative.
Buprenorphine diversion may occur, but its abuse
potential and risk profile remain substantially better than Supervising editor: Steven M. Green, MD. Specific detailed
that of full-agonist opioids. State prescription drug information about possible conflict of interest for individual editors
monitoring programs typically collect buprenorphine is available at https://www.annemergmed.com/editors.
dispensing data and specifically omit data on opioid Author affiliations: From the Department of Emergency Medicine,
treatment program dispensing of methadone (by law). Substance Use Disorder Program, Highland Hospital–Alameda
State law and insurance providers vary in their requirements Health System, University of California, San Francisco, San
Francisco, CA (Herring); the Department of Emergency Medicine,
for previous authorization and other administrative Division of Medical Toxicology, University of Pennsylvania Perelman
expectations. These sometimes impede the ability to readily School of Medicine, Philadelphia, PA (Perrone); and the Department
obtain prescribed buprenorphine, although an ED pharmacist of Emergency Medicine, Division of Medical Toxicology, Rutgers New
or care coordinator may provide assistance. Jersey Medical School, Newark, NJ (Nelson).
Authorship: All authors attest to meeting the four ICMJE.org
DISPOSITION authorship criteria: (1) Substantial contributions to the conception
Local resources determine the available options for or design of the work; or the acquisition, analysis, or interpretation
patients who would like to continue buprenorphine of data for the work; AND (2) Drafting the work or revising it
treatment. As noted, providers with an X-waivercan critically for important intellectual content; AND (3) Final approval
of the version to be published; AND (4) Agreement to be
prescribe buprenorphine until the next available treatment accountable for all aspects of the work in ensuring that questions
appointment. If no waivered provider is available, a related to the accuracy or integrity of any part of the work are
systematic plan for next-day or at least rapid follow-up appropriately investigated and resolved.
should be developed. This may include a warm handoff to a Funding and support: By Annals policy, all authors are required to
treatment provider (eg, face-to-face interaction), which disclose any and all commercial, financial, and other relationships
results in better treatment engagement than an in any way related to the subject of this article as per ICMJE conflict
appointment or a referral.11 More advanced programs of interest guidelines (see www.icmje.org). The authors have stated
include care coordinators, a “bridge clinic” (perhaps as part that no such relationships exist.
of the ED) for immediate treatment access, or a recovery
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