What is the recommended treatment regimen for opioid withdrawal, including symptom‑directed therapy based on the Clinical Opiate Withdrawal Scale?

Opioid Withdrawal Management

For opioid withdrawal, initiate buprenorphine when the Clinical Opiate Withdrawal Scale (COWS) score reaches >8 (moderate to severe withdrawal), starting with 4-8 mg sublingual, and use symptom-directed adjunctive medications including clonidine for autonomic symptoms, antiemetics for nausea, benzodiazepines for anxiety, and loperamide for diarrhea. 1, 2

COWS Assessment and Scoring

The Clinical Opiate Withdrawal Scale is an 11-item clinician-administered tool that objectively quantifies withdrawal severity through assessment of:

• Vital signs: Resting pulse rate (0-4 points based on heart rate ranges) 1
• Autonomic symptoms: Sweating, pupil size, rhinorrhea/lacrimation (0-5 points each) 1
• Neuromuscular signs: Restlessness, tremor, bone/joint aches (0-5 points each) 1
• Psychological symptoms: Anxiety, yawning (0-5 points each) 1
• Physical signs: Piloerection, gastrointestinal upset (0-5 points each) 1

Score interpretation: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe; >36 = severe withdrawal 3

Serial COWS assessments every 1-2 hours during treatment allow real-time dose adjustments and early detection of complications. 1 Nurses can reliably perform COWS scoring with substantial agreement (82.5% concordance, weighted kappa 0.65) compared to physicians, which expedites treatment initiation. 4

Buprenorphine Induction Protocol

Timing Requirements Before Buprenorphine Administration

Critical waiting periods to prevent precipitated withdrawal:

• Short-acting opioids (heroin, oxycodone, hydrocodone): Wait >12 hours since last use 2
• Extended-release formulations: Wait >24 hours since last dose 2
• Methadone maintenance: Wait >72 hours since last dose 2
• Fentanyl: Minimum 12 hours, though longer may be needed due to lipophilic properties 2

Dosing Algorithm

Day 1 Induction (only when COWS >8):

• Initial dose: 4-8 mg sublingual buprenorphine based on withdrawal severity 1, 2
• Reassess after 30-60 minutes 2
• Additional 2-4 mg doses at 2-hour intervals if withdrawal persists 2
• Target Day 1 total: 8 mg (range 4-8 mg) 2

Day 2 and Maintenance:

• Standard dose: 16 mg daily (becomes maintenance dose for most patients) 2
• Dosing range: 4-24 mg daily 2
• Buprenorphine occupies approximately 95% of mu-opioid receptors at doses ≥16 mg, creating a ceiling effect for both therapeutic benefit and respiratory depression 2

Management of Precipitated Withdrawal

If precipitated withdrawal occurs despite proper timing:

• Primary treatment: Give more buprenorphine (has pharmacological basis and proven effective in case reports) 2, 5
• Adjunctive symptomatic management: 2
  • Clonidine or lofexidine for autonomic symptoms (sweating, tachycardia, hypertension)
  • Antiemetics (promethazine, ondansetron) for nausea/vomiting
  • Benzodiazepines for anxiety and muscle cramps
  • Loperamide for diarrhea

Symptom-Directed Adjunctive Therapy

Alpha-2 Adrenergic Agonists (Second-Line When Buprenorphine Unavailable)

Clonidine:

• Mechanism: Reduces autonomic symptoms (sweating, tachycardia, hypertension, anxiety) by binding alpha-2 receptors 6
• Dosing: 0.1-0.2 mg every 6-8 hours, start low and titrate based on symptoms and blood pressure 6, 2
• Limitation: Causes hypotension, requires blood pressure monitoring 6

Lofexidine:

• FDA-approved specifically for opioid withdrawal 6
• Similar efficacy to clonidine but causes less hypotension, making it more suitable for outpatient settings 6
• Preferred over clonidine when available for outpatient management 6

Comparative effectiveness: Buprenorphine demonstrates clear superiority over alpha-2 agonists with lower average withdrawal scores and significantly higher treatment completion rates (number needed to treat = 4). 3, 6 For every 4 patients treated with buprenorphine versus clonidine/lofexidine, 1 additional patient will complete treatment. 6

Symptom-Specific Medications

Gastrointestinal symptoms:

• Loperamide 2-4 mg as needed for diarrhea 2
• Antiemetics (promethazine, ondansetron) for nausea/vomiting 2

Psychological symptoms:

• Benzodiazepines for anxiety and muscle cramps 2
• Gabapentin 300-600 mg three times daily for anxiety and restlessness 6
• Trazodone 50-100 mg at bedtime for insomnia 6

Pain symptoms:

• NSAIDs or acetaminophen for bone/joint aches 2

Special Populations and Considerations

Pediatric Patients

Risk assessment for withdrawal:

• <7 days opioid exposure: Can discontinue quickly without weaning 3
• 7-14 days exposure: May need weaning but can be weaned more quickly 3

• 14 days exposure: Usually requires weaning protocol to prevent withdrawal 3

The Sophia Observation Withdrawal Symptoms Scale is the only validated pediatric-specific scale, though COWS can be adapted for children with >7 days opioid exposure. 3, 1

Methadone-Maintained Patients

Critical timing: Wait at least 72 hours since last methadone dose before administering buprenorphine to avoid precipitating severe withdrawal. 2 Methadone's long half-life (up to 30 hours) creates higher risk for precipitated withdrawal when buprenorphine is introduced prematurely. 2

Alternative approach: Consider continuing methadone for withdrawal management, as it has similar effectiveness to buprenorphine and may be safer for methadone-maintained patients. 2

Patients on Naltrexone

Oral naltrexone: Wait 2-3 days after last dose before starting buprenorphine to allow antagonist effect to wear off. 2

Extended-release injectable naltrexone (Vivitrol): Wait 24-30 days after last injection before initiating buprenorphine due to depot release kinetics. 2

Critical Safety Warnings

Benzodiazepine Combination

FDA black-box warning: Combining opioids with benzodiazepines markedly increases risk of respiratory depression and death. 2 High-dose benzodiazepines (e.g., lorazepam 6 mg daily) with buprenorphine 16 mg daily creates overlapping peak sedative effects that further increase respiratory risk. 2

Management approach:

• Do not discontinue buprenorphine (prevents withdrawal and relapse) 2
• Initiate gradual benzodiazepine taper rather than abrupt cessation 2
• Consider switching to longer-acting benzodiazepine before tapering 2
• Substitute non-benzodiazepine anxiolytics (SSRIs, SNRIs, buspirone, gabapentin) 2
• If combination unavoidable: obtain informed consent, use lowest effective doses, schedule frequent follow-up 2

Prevention of Precipitated Withdrawal

Risk factors for precipitated withdrawal: 5

• Chronic fentanyl use
• Methadone use
• Concurrent benzodiazepine use
• Insufficient time since last opioid use
• COWS score <13 at time of buprenorphine administration

Prevention strategy: Wait for COWS >13 (moderate withdrawal) and ensure sufficient time since last full opioid agonist use before buprenorphine administration. 5 Research suggests COWS >13 provides additional safety margin, though clinical guidelines recommend COWS >8. 1, 5

Discharge Planning and Long-Term Management

Prescribing at discharge (for providers with prescribing authority):

• Buprenorphine/naloxone 16 mg sublingual daily for 3-7 days or until follow-up 2
• Provide take-home naloxone kit and overdose prevention education 2
• Consider hepatitis C and HIV screening 2

Critical principle: Buprenorphine should not be discontinued once started, as discontinuation precipitates withdrawal and dramatically increases relapse risk to more dangerous opioids. 2 There is no maximum recommended duration of maintenance treatment—patients may require treatment indefinitely. 2 The CDC explicitly recommends offering medication-assisted treatment with buprenorphine in combination with behavioral therapies for patients with opioid use disorder, emphasizing maintenance therapy over detoxification alone. 2

Non-waivered providers: Can administer (but not prescribe) buprenorphine for up to 72 hours while arranging referral. 2 As of 2023, the X-waiver requirement has been eliminated, expanding prescribing access. 2