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Adjunctive treatments for opioid withdrawal symptoms

Symptoms	Medication	Usual effective dose range (adult)	Notes
Anxiety
Anxiety, irritability, restlessness	Diphenhydramine*	50 to 100 mg orally every 4 to 6 hours as needed (maximum 300 mg daily)	May also treat nausea Use reduced dose in hepatic impairment IV and IM administration available
	Hydroxyzine	25 to 100 mg orally every 6 to 8 hours as needed (maximum 400 mg daily)	May also treat lacrimation and rhinorrhea Use reduced dose (50%) in renal or hepatic impairment IM administration available
	Clonazepam^¶	0.5 to 1.5 mg orally every 6 to 8 hours as needed (maximum 6 mg daily)	Use with caution and reduce dose in mild hepatic or renal impairment; active metabolites can accumulate Avoid in moderate to severe hepatic impairment or hepatic encephalopathy
	Lorazepam^¶	1 mg orally every 4 to 6 hours as needed (maximum 6 mg daily)	Relatively safe in mild to moderate hepatic impairment; use of reduced dose may be needed Avoid in severe hepatic impairment or hepatic encephalopathy IV and IM administration available; use caution in renal impairment due to propylene glycol diluent
	Oxazepam^¶	15 to 30 mg orally every 6 to 8 hours as needed (maximum 120 mg daily)	Relatively safe in mild to moderate hepatic or renal impairment Use with caution in severe renal impairment Avoid in severe hepatic impairment or hepatic encephalopathy
Gastrointestinal
Abdominal cramping	Dicyclomine*	10 to 20 mg orally every 6 to 8 hours as needed (maximum 160 mg daily)	IM administration available (lower doses are used) Use with caution and reduce dose in renal or hepatic impairment
Diarrhea	Bismuth*	~524 mg orally every 30 to 60 minutes as needed (up to 4200 mg daily)	Monitor for dehydration and maintain fluid levels with oral and/or IV hydration
Diarrhea	Loperamide	4 mg orally followed by 2 mg after each loose stool (maximum 16 mg daily)
Nausea/vomiting	Ondansetron*^Δ	4 to 8 mg orally or IV every 12 hours as needed (maximum 16 mg/day)	Monitor for dehydration and maintain fluid levels with oral and/or IV hydration Dose-dependent QT interval prolongation; risk of rare, potentially fatal, ventricular arrhythmia; use with caution (eg, monitor baseline and post-dose electrocardiogram) or avoid in patients with features of elevated risk^Δ Use caution and reduced dose (50%) in severe hepatic impairment
	Prochlorperazine	5 to 10 mg orally three times daily before meals or every six hours as needed (maximum 40 mg/day)	Monitor for dehydration and maintain fluid levels with oral and/or IV hydration Use with caution in mild to moderate hepatic impairment; avoid in severe hepatic impairment IV and rectal administration available
	Promethazine	12.5 to 25 mg orally every 4 to 6 hours as needed (maximum 50 mg/day)	Monitor for dehydration and maintain fluid levels with oral and/or IV hydration Use with caution in mild to moderate hepatic impairment; avoid in severe hepatic impairment IM and rectal administration available (IV use not recommended)
Insomnia, pain, muscle spasm, and restless legs
Insomnia	Trazodone*	25 to 100 mg orally at bedtime	May titrate nightly up to 300 mg at bedtime if needed Use with caution in severe hepatic or renal impairment
	Doxepin	6 to 50 mg orally at bedtime	Use with caution and reduce dose in severe hepatic impairment
	Mirtazapine	7.5 to 15 mg orally at bedtime	May need to use lower dose in moderate to severe hepatic or renal impairment
	Quetiapine	50 to 100 mg orally at bedtime	Use lower initial dose (25 mg) in hepatic impairment and adjust based on response
	Zolpidem^¶	5 to 10 mg orally at bedtime	A dose of 5 mg is usually appropriate for female patients and those with mild or moderate hepatic impairment Avoid in severe hepatic impairment or hepatic encephalopathy
Muscle aches^◊, joint pain, headache	Ibuprofen*^§	400 mg orally every 4 to 6 hours as needed (maximum 2400 mg daily)	Patient should be well hydrated and without significant kidney disease Use with caution in mild to moderate hepatic or renal impairment Avoid all NSAIDs in severe renal or hepatic impairment or cirrhosis
	Acetaminophen	650 to 1000 mg orally every 4 to 6 hours as needed (maximum 4000 mg daily)	Appropriate analgesic for most patients Use reduced dose (ie, 2000 mg daily) or avoid in hepatic impairment or if malnourished
	Ketorolac^§	15 to 30 mg IV or IM every 6 hours as needed (maximum 120 mg daily)	Patient should be well hydrated and without significant kidney disease Limit use to 5 days or less Use with caution and reduce dose (50%) in older adults (ie, ≥65 years), patients <50 kg, and patients with mild to moderate renal impairment Use with caution in mild to moderate hepatic impairment Contraindicated in severe renal or hepatic impairment or volume depletion
	Naproxen^§	500 mg orally twice daily with meals	Patient should be well hydrated and without significant kidney disease Use with caution in mild to moderate hepatic or renal impairment Avoid all NSAIDs in severe renal or hepatic impairment or cirrhosis
Muscle spasm^◊, restless legs	Cyclobenzaprine*	5 to 10 mg orally every 8 hours as needed (maximum 30 mg daily)	Use reduced dose in mild hepatic impairment Avoid in moderate to severe haptic impairment
	Baclofen	5 to 10 mg orally every 8 hours as needed (maximum 60 mg daily)	Use reduced dose in renal impairment
	Diazepam^¶	5 to 10 mg orally every 6 to 12 hours as needed (maximum 40 mg daily)	Use with caution in hepatic or renal impairment Avoid in severe hepatic impairment or hepatic encephalopathy IM and IV administration available
	Methocarbamol	750 to 1500 mg orally every 8 hours as needed (maximum 6 g daily)	Use with caution in hepatic or renal impairment IM and IV administration available (lower doses are used); avoid parenteral formulation in renal impairment (propylene glycol additive)

A calm, quiet environment with supportive and reassuring staff can be instrumental for helping patients overcome most symptoms of acute opioid withdrawal and decreases the need for pharmacologic interventions.
Patients who have diarrhea, vomiting, or sweating should be monitored for dehydration and fluid levels maintained with oral and/or intravenous fluids.
The role of opioid replacement therapies and alpha-2 agonists (eg, clonidine) in management of acute opioid withdrawal and maintenance pharmacotherapy in opioid use disorder is discussed separately; refer to accompanying text.
This is not a complete list of cautionary information or dose adjustments in organ impairment. For additional information refer to the Lexicomp drug monographs included within UpToDate.

IV: intravenous; IM: intramuscular; NSAID: nonsteroidal anti-inflammatory drug.
* Author's first choice.
¶ Use of benzodiazepines and benzodiazepine agonists (eg, zolpidem) is NOT recommended in patients receiving methadone or buprenorphine therapy unless under close medical supervision. Patients who resume heroin (diamorphine) use after a period of abstinence are at high risk of fatally overdosing, particularly if heroin use is resumed in combination with benzodiazepines, alcohol, or other drugs with sedative characteristics (eg, quetiapine). The use of benzodiazepines should be limited to 5 to 10 days in total and tapered. They are not recommended for use in supervised outpatient withdrawal and should be reserved for inpatient settings where frequent clinical monitoring is provided.
Δ Risk of QTc prolongation or torsades de pointes is also elevated with advanced age, female sex, heart disease, congenital long QT syndrome, hypokalemia or hypomagnesemia, overly rapid IV administration, and combination of drugs with QTc prolonging effects (eg, methadone). Refer to topic on acquired long QT syndrome.
◊ Warm baths, rehydration, and gentle stretching are also helpful for relieving muscle aches and cramps.
§ Safety concerns of NSAID use in older adults and patients with, or at elevated risk for, cardiovascular disease, gastrointestinal bleeding, organ dysfunction, or thrombotic events are addressed separately in UpToDate.

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