Buprenorphine, Subutex, Suboxone, Zubsolv, Butrans, Belbuca, Probuphine, Sublocade, Acute Pain Management in patients on Chronic Buprenorphine

  • Background
  1. Buprenorphine (with and without Naloxone) is a growing concern for misuse, abuse and diversion
  2. Buprenorphine requires prescribing providers to complete 8 hour course and obtain X-Waiver DEA License
    1. However, Emergency Providers may administer Buprenorphine doses in the ED without an X-Waiver
  • Indications
  1. Chronic Pain Management
  2. Opioid Addiction (e.g. Heroin addiction)
    1. Preferred first line agent alternative to low dose Methadone
    2. Prescribing requires FDA X-waiver
  • Contraindications
  1. Use caution and liver function monitoring in hepatitis
  • Mechanism
  1. Partial mu-Opioid receptor agonist
    1. Semisynthetic derivative of Thebaine
  2. Mu-receptor activation increases with dose to ceiling
    1. No further activation once max dose effect is reached
    2. Hence, unlike Heroin or Methadone, lower risk of abuse
    3. May also have less risk of respiratory depression and Overdose potential
    4. Decreases withdrawal and craving symptoms (as long as no recent Opioid use)
  3. Slowly dissociates from mu-receptors (high affinity, but lower activity)
    1. May block other Opioid binding (e.g. Heroin)
    2. May displace recently taken Opioids (e.g. Morphine, Methadone)
      1. May result in Opioid Withdrawal symptoms
  4. Adding Naloxone to Buprenorphine intended to block the "high" if Buprenorphine is crushed and injected
    1. However still with abuse risk (e.g. Zubsolv snorting, Suboxone injection)
  • Pharmacokinetics
  1. Metabolism: Liver via P450
  2. Plasma half-life: up to 28-37 hours (sublingual), and 3 hours (IV)
  3. Routes
    1. Oral bioavailability is too low to be useful
    2. Intravenous route used for pain management
    3. Sublingual is preferred route
      1. Bioavailability: Up to 50% of IV dose
      2. Peak concentration reached 1 hour post-dose
  • Drug Interactions
  1. P450 3A4 Inducers may decrease Buprenorphine effect
    1. Carbamazepine
    2. Phenytoin
    3. Phenobarbital
    4. Reverse Transcriptase Inhibitors
    5. Rifampin
  2. P450 3A4 Inhibitors may increase Buprenorphine effect
    1. Azole Antifungals (e.g. Ketoconazole, Fluconazole)
    2. Macrolides (e.g. Erythromycin, Azithromycin)
  3. Respiratory depressants (risk of death with combined use)
    1. Benzodiazepines or other Sedative-Hypnotics
    2. Muscle relaxants (e.g. carisprodol, Cyclobenzaprine)
    3. Opioids
    4. Alcohol
  4. Other adverse effects in combination
    1. Anticholinergics (Urinary Retention, Constipation)
  • Efficacy
  • Buprenorphine compared with Methadone
  1. Low dose Methadone (<40 mg): Buprenorphine as effective
  2. High dose Methadone (>60 mg): Not as effective
  3. References
    1. Barnett (2001) Addiction 96:683-90 [PubMed]
  • Safety
  1. Pregnancy
    1. FDA Category C
    2. Risk of Neonatal Opioid Withdrawal Syndrome (NOWS)
      1. Occurs in newborns born to mothers on Opioids
      2. Buprenorphine-related NOWS is preferable to the high risks of Opioid Abuse or Methadone
  2. Lactation
    1. Naloxone excretion into milk is unknown (and should only be used with caution)
  • Adverse Effects
  1. Constipation
  2. Urinary Retention
  3. Sedation
  4. Mild respiratory depression (unless taken with other Sedatives)
  5. Opioid Withdrawal
  6. Nausea
  7. Headache
  • Toxicity
  1. Significant Respiratory Depression has occured when taken with Benzodiazepines or Alcohol
  • Preparations
  1. Pain management
    1. Buprenorphine intravenous
    2. Buprenorphine Patch (Butrans)
      1. Patch applied once weekly
    3. Buprenorphine Buccal Film (Belbuca)
      1. Buccal film used twice daily
      2. On switching from other Opioid, wean to no more than equivalant to Morphine 30 mg/day
  2. Opioid Addiction
    1. Buprenorphine sublingual
      1. Same dosing as with Buprenorphine with Naloxone
    2. Buprenorphine with Naloxone (Suboxone, Zubsolv)
      1. Sublingual
        1. Abused despite combination with Naloxone
        2. Drug Abusers crush and snort the sublingual tabs
        3. May not appear on routine Urine Drug Screen
      2. Film (2, 4, 8 and 12 mg)
        1. Prevents snorting (but has still been misused via injection)
      3. Dosing
        1. Start: 4 mg Buprenorphine and 1mg Naloxone
        2. Titrate: Over 2 days (see dosing protocol for Buprenorphine below)
        3. Goal: 16 mg Buprenorphine and 4mg Naloxone
        4. Maximum effective dose: 32 mg Buprenorphine (no benefit above 24-32 mg daily)
    3. Buprenorphine implant (Probuphine)
      1. Implanted subdermal rods with duration of 6 months (may be replaced once in opposite arm)
      2. Indicated for patients on stable dose of Buprenorphine SL at 8 mg/day for at least 3 months
      3. Very expensive (>$800 per month)
      4. (2016) Presc Lett 23(8)
    4. Buprenorphine monthly injection (Sublocade)
      1. Once monthly Subcutaneous Injection
      2. Very expensive (>$1600 per month)
      3. Indicated for patients on stable dose of Buprenorphine SL at 8-24 mg/day for at least 1 week
      4. (2018) Presc Lett 25(3)
  • Dosing
  • Buprenorphine (prescriber must have X DEA waiver)
  1. Preparation
    1. Urine drug test
    2. Informed Consent
    3. Treatment contract
    4. Patient should be at least 12 hours from last short-acting or 24 hours from last long-acting Opioid
    5. Clinical Opiate Withdrawal Scale or COWS >8 (or other withdrawal scale)
      1. Avoid starting Buprenorphine in patients without active withdrawal symptoms
      2. Buprenorphine will precipitate withdrawal if not already present
  2. Induction Phase (3-7 days)
    1. Started >12 hours after last short acting Narcotic
    2. Started >24 hours after last long acting Narcotic
    3. Initiation Dosing on Day 1 (provider observed)
      1. Monitor at 60 min intervals after first dose, titrating to dose that reduces withdrawal symptoms
      2. Higher Dose Protocol: Start with Buprenorphine 4-8 mg SL
        1. May repeat 4-8 mg every 30-60 minutes until adequate effect (up to 16 mg)
      3. Lower Dose Protocol: Start with Buprenorphine 2 mg SL
        1. May repeat 2-4 mg every 1-2 hours up to 8-16 mg/day
      4. Re-evaluation in 24 hours (no more than 7 days)
    4. Adjusted based on physician evaluation, withdrawal
      1. By day 7: Maximum of 32 mg/day (no benefit above 24-32 mg daily)
    5. Home Buprenorphine Induction Dosing
      1. Consider for those not currently in Opioid Withdrawal
      2. Requires patient to withstand abstaining from Opioids long enough at home to precipitate withdrawal
        1. Offer Opioid Withdrawal symptomatic management (e.g. Clonidine, Zofran, Loperamide)
      3. Iphone Application (BUP Home) created by Yale Clinicians
    6. Home Microdosing Induction Dosing
      1. Alternative to Home Buprenorphine Induction Dosing, for those not currently in Opioid Withdrawal
      2. Very low doses (e.g. 0.5 mg on day 1) are gradually titrated daily until at 8 mg sublingual dose
        1. Requires cutting Buprenorphine film into small strips
    7. EMS initiated withdrawal protocol (Cooper University Hospital, Camden, NJ)
      1. EMS identifies Opiate withdrawal patient in field
      2. EMS coordinates with Emergency command physician
      3. Command physician authorizes "Bupe Bundle"
        1. Buprenorphine 16 mg SL (high dose)
        2. Ondansetron 4 mg SL
      4. Next day follow-up coordinated with addiction medicine provider
      5. References
        2. Wasserman and Swaminathan in Herbert (2021) EM:Rap 21(4): 15-6
        3. Carroll (2021) Prehosp Emerg Care 25(2):289-93 [PubMed]
  3. Stabilization Phase (1-2 months)
    1. Identify minimum effective dose
    2. Typical: Buprenorphine 12-24 mg/day divided (typically 16 mg/day)
  4. Maintenance Phase (indefinite)
    1. Dosing based on stabilization phase
    2. Evaluate compliance
      1. Review State prescription monitoring programs
      2. Random urine drug tests
      3. Pill counts
  5. Discontinuation
    1. Slowly taper (unless discontinued for diversion)
  1. Non-Opioids (preferred)
    1. Acetaminophen
    2. NSAIDs
    3. Topical agents (e.g. Lidocare or Lidocaine Patch)
    4. Ketamine Analgesic dosing at 0.1 to 0.3 mg/kg IV (in Emergency Department)
  2. Opioids
    1. Alert Buprenorphine/Naloxone prescriber of acute Pain Evaluation and acute Opioid prescription
      1. May otherwise void Controlled Substance Contract with the prescriber
    2. Divide Buprenorphine/Naloxone dosing every 6-8 hours (maximum daily dosing up to 32 mg)
      1. Buprenorphine/Naloxone tightly binds Opioid receptors, preventing withdrawal for full day
      2. However, Analgesic effect wanes more quickly, and therefore divided dosing may be needed
      3. Although tabs/films may be cut in half, may result in uneven dosing (consider new prescription)
    3. May add short acting Opioids, but risk of relapse
      1. Limit to 3 day supply and continue with Buprenorphine/Naloxone (Suboxone)
      2. Hydromorphone (Dilaudid) may be preferred short-term Opioid due to stronger Opioid receptor binding
      3. Avoid Tramadol (unlikely to overcome Suboxone's tight binding)
    4. References
      1. (2019) Presc Lett 26(11): 65
      2. (2017) Presc Lett 24(1): 2-3
  • Resources
  1. SAMHSA Buprenorphine information
  • References