Analgesic

Buprenorphine

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Buprenorphine, Subutex, Suboxone, Zubsolv, Butrans, Belbuca, Probuphine, Sublocade

  • Background
  1. Buprenorphine (with and without Naloxone) is a growing concern for misuse, abuse and diversion
  • Indications
  1. Chronic Pain Management (intravenous Buprenorphine)
  2. Opioid Addiction (e.g. Heroin addiction)
    1. Alternative to low dose Methadone
    2. Prescribing requires FDA 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
    2. Muscle relaxants (e.g. carisprodol, Cyclobenzaprine)
    3. Other Sedative-Hypnotics, other Opioids, 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. 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
  5. Opioid Withdrawal
  6. Nausea
  7. Headache
  • Toxicity
  1. Overdose has occured when taken with Benzodiazepines
  • 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
    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 other withdrawal scale)
      1. Avoid starting Buprenorphine in patients without active withdrawal symptoms
  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. Monitor at 60 min interval after first dose, titrating to dose that reduces withdrawal symptoms
      1. Re-evaluation in 24 hours (no more than 7 days)
    4. Adjusted based on physician evaluation, withdrawal
      1. Day 1: 2 mg every 1-2 hours to max 8-12 mg/day
      2. By day 7: Maximum of 32 mg/day (no benefit above 24-32 mg daily)
  3. Stabilization Phase (1-2 months)
    1. Identify minimum effective dose
    2. Typical: Buprenorphine 12-24 mg/day divided
  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
    1. Acetaminophen
    2. NSAIDs
    3. Topical agents (e.g. Lidocare or Lidocaine Patch)
  2. Opioids
    1. Divide Buprenorphine dosing every 6-8 hours (maximum daily dosing up to 32 mg)
    2. May add short acting Opioids (e.g. Morphine), but risk of relpase
    3. (2017) Presc Lett 24(1): 2-3
  • Resources
  1. SAMHSA Buprenorphine information
    1. http://buprenorphine.samhsa.gov/