What is the recommended medication-assisted treatment regimen for opioid withdrawal in an adult without severe hepatic impairment?

Opioid Withdrawal Treatment

Buprenorphine is the first-line medication for opioid withdrawal in adults without severe hepatic impairment, with an initial dose of 4–8 mg sublingual when the Clinical Opiate Withdrawal Scale (COWS) score is ≥8, followed by maintenance at 16 mg daily. 1

Pre-Induction Assessment

Before administering buprenorphine, verify the timing since last opioid use to prevent precipitated withdrawal: 1

• >12 hours for short-acting opioids (heroin, immediate-release oxycodone, hydrocodone, fentanyl) 1
• >24 hours for extended-release formulations (OxyContin, MS Contin) 1
• >72 hours for methadone maintenance patients 1

Use the COWS to objectively confirm withdrawal severity before initiating buprenorphine. 1 The scale assesses 11 clinical signs including pulse rate, sweating, restlessness, pupil size, bone/joint aches, runny nose/tearing, GI upset, tremor, yawning, anxiety, and piloerection. 1 COWS interpretation: 1

• 5–12: mild withdrawal
• 13–24: moderate withdrawal
• 25–36: moderately severe withdrawal

• 36: severe withdrawal

Only administer buprenorphine when COWS ≥8 (moderate to severe withdrawal). 1 If COWS <8, defer buprenorphine and reassess in 1–2 hours. 1

Day 1 Induction Protocol

Give an initial dose of 4–8 mg sublingual buprenorphine based on withdrawal severity when COWS ≥8. 1 Reassess after 30–60 minutes. 1 If withdrawal persists, provide additional 2–4 mg doses every 2 hours as needed, targeting a total Day 1 dose of approximately 8 mg (range 4–8 mg). 1

Maintenance Dosing

The standard maintenance dose is 16 mg sublingual daily for most patients. 1 This dose occupies approximately 95% of mu-opioid receptors and creates a ceiling effect for both therapeutic benefit and respiratory depression. 1 The acceptable dose range is 4–24 mg daily. 1 Once-daily dosing is preferred; twice-daily dosing (e.g., 8 mg BID) increases respiratory risk when combined with benzodiazepines. 1

Why Buprenorphine Is Superior

Buprenorphine demonstrates clear superiority over alpha-2 adrenergic agonists (clonidine/lofexidine) with lower average withdrawal scores and significantly higher treatment completion rates. 1, 2 For every 4 patients treated with buprenorphine versus clonidine/lofexidine, 1 additional patient will complete treatment (NNT = 4). 1, 2 Buprenorphine has an 85% probability of being the most effective treatment, compared to 12.1% for methadone, 2.6% for lofexidine, and 0.01% for clonidine. 1

Compared to methadone, buprenorphine has similar efficacy for withdrawal management but offers advantages including a ceiling effect on respiratory depression, lower overdose risk, and no requirement for specialized clinic attendance. 1, 2 However, methadone should be considered for patients already on methadone maintenance, as switching to buprenorphine requires a >72-hour waiting period and risks precipitated withdrawal. 1

Management of Precipitated Withdrawal

If precipitated withdrawal occurs, administer additional buprenorphine (not less) as the primary treatment. 1, 3 This approach is supported by pharmacologic rationale and case reports demonstrating that rapid increases in buprenorphine dose can effectively treat buprenorphine-induced precipitated withdrawal. 1, 3

Adjunctive symptomatic management includes: 1

• Clonidine 0.1–0.2 mg every 6–8 hours for autonomic symptoms (sweating, tachycardia, hypertension, anxiety)
• Antiemetics (promethazine or ondansetron) for nausea and vomiting
• Benzodiazepines for anxiety and muscle cramps
• Loperamide for diarrhea

Second-Line Options: Alpha-2 Adrenergic Agonists

Use clonidine or lofexidine only when buprenorphine is contraindicated, unavailable, or the patient declines opioid-based therapy. 1, 4 These agents reduce autonomic symptoms by binding to alpha-2 receptors but are less effective than buprenorphine for overall symptom reduction and treatment completion. 1, 4, 2

Lofexidine is preferred over clonidine in outpatient settings because it causes less hypotension. 4, 5 Lofexidine is FDA-approved specifically for opioid withdrawal at a dose of 2.16–2.88 mg total daily (0.54–0.72 mg four times daily). 5 In clinical trials, 49% of lofexidine patients completed 5 days of treatment versus 33% of placebo patients. 5

Start alpha-2 agonists at low doses and titrate based on withdrawal symptoms and blood pressure monitoring. 4 Combine with symptom-specific medications such as antiemetics for nausea and loperamide for diarrhea. 4

Prescribing Authority and Discharge Planning

As of 2023, the X-waiver requirement has been eliminated, allowing any DEA-licensed provider to prescribe buprenorphine. 1 Prescribe buprenorphine/naloxone 16 mg sublingual daily for 3–7 days or until follow-up. 1 Non-waivered providers can administer (but not prescribe) buprenorphine for up to 72 hours while arranging referral. 1

Provide a take-home naloxone kit and overdose prevention education at discharge. 1 Offer hepatitis C and HIV screening and consider reproductive health counseling. 1

Critical Safety Considerations

Avoid concurrent benzodiazepines whenever possible due to FDA black-box warning for increased risk of respiratory depression and death. 1 If the combination is unavoidable, use the lowest effective doses, obtain informed consent documenting the respiratory depression risk, and schedule frequent follow-up visits (initially weekly). 1

Screen for QT-prolonging medications before initiating buprenorphine, as concomitant use is contraindicated. 1

Maintenance Versus Detoxification

Buprenorphine maintenance therapy is more effective than detoxification alone in preventing relapse among patients with opioid use disorder. 1, 6 The CDC explicitly recommends offering medication-assisted treatment with buprenorphine in combination with behavioral therapies, emphasizing maintenance therapy over detoxification. 1 There is no maximum recommended duration of maintenance treatment—patients may require treatment indefinitely. 1

Never discontinue buprenorphine once started, as discontinuation precipitates withdrawal and dramatically increases relapse risk to more dangerous illicit opioids. 1, 6

Common Pitfalls to Avoid

• Initiating buprenorphine when COWS <8 precipitates severe withdrawal. 1
• Providing buprenorphine to methadone patients earlier than 72 hours after the last dose leads to prolonged precipitated withdrawal. 1
• Prescribing discharge doses below 16 mg daily often results in persistent withdrawal symptoms and treatment failure. 1
• Using alpha-2 agonists as first-line therapy when buprenorphine is available represents suboptimal care. 1, 4