What medications are used to treat opioid withdrawal in a patient?

Medications for Opioid Withdrawal

First-Line Treatment: Buprenorphine

Buprenorphine is the definitive first-line medication for managing opioid withdrawal, demonstrating superior efficacy to all alternatives with an 85% probability of being the most effective treatment. 1

Critical Pre-Administration Requirements

Before initiating buprenorphine, you must confirm the patient is in active withdrawal to avoid precipitating a more severe withdrawal syndrome:

• Wait at least 12 hours since last short-acting opioid use (heroin, oxycodone, hydrocodone) 1
• Wait at least 24 hours for extended-release opioid formulations 1
• Wait at least 72 hours for patients on methadone maintenance 1
• Confirm COWS score >8 (moderate to severe withdrawal) before administering the first dose 1, 2

Dosing Protocol

Day 1:

• Administer 4-8 mg sublingual buprenorphine initially based on withdrawal severity 1, 2
• Reassess after 30-60 minutes 1
• Give additional 2-4 mg doses at 2-hour intervals if withdrawal persists 1
• Target total Day 1 dose: 8-16 mg 1, 2

Day 2 and Maintenance:

• Standard maintenance dose is 16 mg daily for most patients 1, 2
• Dose range: 4-24 mg daily 1
• Can be given once daily or divided 2

Evidence Supporting Buprenorphine Superiority

Compared to alpha-2 agonists (clonidine/lofexidine), buprenorphine demonstrates:

• Lower average withdrawal scores with small-to-moderate effect size (SMD -0.43) 3
• Significantly longer treatment duration with large effect size (SMD 0.92) 3
• Higher completion rates (RR 1.59), meaning for every 4 patients treated with buprenorphine versus clonidine, 1 additional patient completes treatment 1, 3

Second-Line Treatment: Alpha-2 Adrenergic Agonists

When buprenorphine is contraindicated or unavailable, use alpha-2 agonists as second-line agents, recognizing they are significantly less effective. 4, 2

Lofexidine (Preferred in Outpatient Settings)

Lofexidine is FDA-approved specifically for opioid withdrawal and causes less hypotension than clonidine, making it more suitable for outpatient management. 4, 5

• FDA trials showed 40-49% treatment completion versus 28-33% with placebo 5
• Mean withdrawal scores reduced by 2.3-2.7 points on SOWS-Gossop scale 5
• Dosing: 2.16-2.88 mg/day divided into 4 doses 5
• Start at low doses and titrate based on withdrawal symptoms and blood pressure 4

Clonidine (Off-Label Alternative)

• Used off-label for opioid withdrawal; lacks FDA approval for this indication 4, 2
• Similar efficacy to lofexidine but causes more hypotension 4
• More appropriate for inpatient settings where blood pressure can be closely monitored 4
• Directly attenuates autonomic symptoms: sweating, tachycardia, hypertension, anxiety 4

Comparative Effectiveness Data

Buprenorphine has an 85% probability of being most effective, compared to 12.1% for methadone, 2.6% for lofexidine, and 0.01% for clonidine. 4

Third-Line Alternative: Methadone

Methadone has similar efficacy to buprenorphine but is less commonly used in acute settings due to regulatory restrictions and potential interference with ongoing treatment programs. 1, 2

• Initial dose: 30-40 mg daily in inpatient settings 2
• Similar withdrawal severity and completion rates as buprenorphine (RR 1.04) 3
• Withdrawal symptoms may resolve more quickly with buprenorphine 3, 6
• Consider methadone for patients already on methadone maintenance to avoid the 72-hour waiting period required for buprenorphine 1

Essential Adjunctive Medications

Regardless of primary agent, always add symptom-specific medications to improve comfort and treatment retention: 2

Gastrointestinal Symptoms

• Loperamide for diarrhea and abdominal cramping 1, 4, 2
• Antiemetics (promethazine, ondansetron) for nausea and vomiting 1, 2

Autonomic Symptoms

• Clonidine or lofexidine (if not primary agent) for sweating, tachycardia, hypertension 1, 4

Psychological Symptoms

• Benzodiazepines (lorazepam) for anxiety and muscle cramps—monitor closely for respiratory depression when combined with opioids 1, 2
• Gabapentin for anxiety and restlessness (short-term use) 4
• Trazodone for insomnia and anxiety (short-term use) 4
• Mirtazapine for insomnia, anxiety, and appetite stimulation (short-term use) 4

Critical Management of Precipitated Withdrawal

If buprenorphine precipitates withdrawal (most common when transitioning from methadone or fentanyl):

Give more buprenorphine as the primary treatment—this is pharmacologically sound and proven effective. 1

Simultaneously provide aggressive symptomatic management:

• Clonidine or lofexidine for autonomic symptoms 1
• Antiemetics for nausea 1
• Benzodiazepines for anxiety 1
• Loperamide for diarrhea 1

Discharge Planning and Harm Reduction

For patients with prescribing authority (X-waiver eliminated as of 2023): 1

• Prescribe buprenorphine/naloxone 16 mg sublingual daily for 3-7 days or until follow-up 1
• Provide take-home naloxone kit and overdose prevention education—patients become more sensitive to opioid effects after withdrawal, increasing overdose risk 2

For non-prescribing providers: 1

• Can administer (but not prescribe) buprenorphine for up to 72 hours while arranging referral 1

Additional discharge considerations: 1

• Offer hepatitis C and HIV screening 1
• Consider reproductive health counseling 1

Critical Safety Considerations

Never abruptly discontinue buprenorphine once started—this precipitates withdrawal and dramatically increases relapse risk to more dangerous opioids. 1

• Buprenorphine should not be tapered to comply with opioid dose guidelines due to its ceiling effect on respiratory depression 1
• There is no maximum recommended duration of maintenance treatment; patients may require treatment indefinitely 1
• Abrupt withdrawal or major dose reduction constitutes unacceptable medical care except in extreme cases like confirmed diversion 4