Buprenorphine, Subutex, Suboxone, Zubsolv, Butrans, Belbuca, Probuphine, Sublocade, Brixadi, 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 is a DEA Schedule 3 substance
  3. Buprenorphine previously required prescribing providers to complete 8 hour course and obtain X-Waiver DEA License
    1. Prescribing requirements have been significantly reduced
      1. X-Waiver is no longer required and no limit on number of patients being treated
    2. X-Waiver (DEA license add-on) was previously required
      1. Providers applied for X-Waiver online with training exemption (allowed treatment up to 30 patients at one time)
      2. X-Waiver application is free addition to DEA license and online application is brief (5 minutes)
      3. X-Waiver is typically activated 1-2 months after application
    3. However, Emergency Providers may administer Buprenorphine doses in the ED without an X-Waiver
  • Indications
  1. Chronic Pain Management
    1. Opioid use with comorbidity at risk of respiratory depression (e.g. COPD)
    2. Opioid Use Disorder AND Chronic Pain
  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. Less euphoria, and 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)
    5. Less Constipation risk than other Opioids
  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
      3. Bypasses liver first pass metabolism
  • 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
  1. Medication for Opioid Use Disorder
    1. Decreases Overdose risk and overall mortality
    2. Decreases hospitalization, return ED visits, criminality
  2. 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. Buprenorphine has minimal excretion into Breast Milk and is recommended to be continued during Lactation
    2. 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
    1. Consider prescribing an Antiemetic (e.g. Ondansetron)
  7. Headache
  8. Dental Decay with oral formulations (Dental Cavities, dental abscess, tooth loss)
    1. FDA issued warning in 2022 after 300 reported cases (out of 2 million patients on Buprenorphine)
    2. Dissolve medication completely in mouth to fully absorb medication
      1. Follow with a large drink of water, and swish and swallow
      2. Wait at least 1 hour after taking medication to brush teeth
    3. May be related to acidic environment while on sublingual or buccal Buprenorphine
      1. Twice yearly dental care recommended
      2. Consider other formulations (e.g. monthly injection Buprenorphine) if significant dental complications
        1. See Chronic Pain Management
        2. See Opioid Addiction
    4. References
      1. (2022) Presc Lett 29(3): 16-7
  • Toxicity
  1. Significant Respiratory Depression has occured when taken with Benzodiazepines or Alcohol
  • Medications
  1. Precautions
    1. Buprenorphine doses in Chronic Pain are considerably lower than doses for Opioid Addiction
    2. Some Buprenorphine products are dosed in micrograms (e.g. Belbuca buccal, Butrans patches)
    3. Some Buprenorphine products are dosed in milligrams (e.g. Suboxone SL)
  2. Pain management
    1. Background
      1. Intended for lower chronic doses or in Opioid naive patients
      2. Switching to Butrans or Belbuca from other Opioid
        1. Taper current Opioid before switching OR
        2. Stop other Opioid in evening, and start Butrans or Belbuca the next morning
    2. Buprenorphine Patch (Butrans)
      1. Patch applied once every 7 days (dosed 5 to 20 mcg/h)
      2. Dosing if Opioid naive
        1. Start 5 mcg/hour transdermal patch
        2. Titrate dose at no more often than every 72 hours
      3. Dosing non-Opioid naive
        1. On switching from other Opioid, taper to no more than equivalant to Morphine 30 mg/day for 7 days
        2. Pre-Taper Morphine Equivalent Dose <30 mg/day: 5 mcg/hour transdermal patch
        3. Pre-Taper Morphine Equivalent Dose 30 to 80 mg/day: 10 mcg/hour transdermal patch
        4. Pre-Taper Morphine Equivalent Dose >80 mg/day: Consider other medication
        5. Titrate dose at no more often than every 72 hours
    3. Buprenorphine Buccal Film (Belbuca)
      1. Buccal film sublingual, allowed to dissolve fully under Tongue and not swallowed, used twice daily (dosed in mcg)
      2. Take nothing by mouth for 15 minutes after dose
      3. Dosing if Opioid naive
        1. Start: 75 mcg film once daily (up to twice daily if tolerated) for at least 4 days
        2. Next: 150 mcg film every 12 hours
        3. May titrate dose in increments of 150 mcg
        4. Maximum: 450 mcg every 12 hours
      4. Dosing non-Opioid naive
        1. On switching from other Opioid, taper to no more than equivalant to Morphine 30 mg/day
        2. Pre-Taper Morphine Equivalent Dose <30 mg/day: 75 mcg film once daily (up to twice daily if tolerated)
        3. Pre-Taper Morphine Equivalent Dose 30 to 89 mg/day: 150 mcg film every 12 hours
        4. Pre-Taper Morphine Equivalent Dose 90 to 160 mg/day: 300 mcg film every 12 hours
        5. Pre-Taper Morphine Equivalent Dose >160 mg/day: Consider other medication
    4. Buprenorphine IV or IM (e.g. Emergency Department use)
      1. Adult: 0.3 to 0.6 mg IM or slow IV every 6 hours as needed for moderate to severe pain
      2. Child (2 to 12 years old): 2 to 6 mcg/kg/dose (up to 0.6 mg) IM or slow IV every 6 hours as needed
  3. Opioid Addiction
    1. See Opioid Withdrawal
    2. Buprenorphine sublingual
      1. Same dosing as with Buprenorphine with Naloxone
    3. Buprenorphine with Naloxone (Suboxone, Zubsolv, generic)
      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)
        2. Allowed to dissolve fully under Tongue and not swallowed (and nothing by mouth for 15 minutes)
      3. Dosing
        1. See Induction Protocol below
        2. Start: 4 mg Buprenorphine and 1mg Naloxone
        3. Titrate: Over 2 days (see dosing protocol for Buprenorphine below)
        4. Goal: 16 mg Buprenorphine and 4mg Naloxone
        5. Maximum effective dose: 32 mg Buprenorphine (no benefit above 24-32 mg daily)
    4. 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)
    5. Buprenorphine monthly injection (Sublocade)
      1. Once monthly Subcutaneous Injection
      2. Very expensive ($1900 per month in 2023)
      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)
    6. Buprenorphine extended release injection (Brixadi)
      1. Indicated in patients at higher risk for diversion, misuse and poor adherence
      2. Cost in 2023 is $1600/month
      3. Two formulations that are NOT Interchangeable
        1. Weekly ER Buprenorphine slow Subcutaneous Injection
          1. Requires at least one test dose of transmucosal Buprenorphine (exclude Opioid Withdrawal risk)
            1. Observe for Yawning, Vomiting, Tremor after test dose
          2. Unlike monthly formulations, does not require stabilization on transmucosal dose first
        2. Monthly ER Buprenorphine slow Subcutaneous Injection
          1. Must be transitioning from another Buprenorphine product after induction and stabilization
          2. Similar to Sublocade (see above)
      4. References
        1. (2023) Presc Lett 30(10): 58
  1. X DEA waiver is no longer required
  2. 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. No lab testing is required before Buprenorphine initiation
    6. Clinical Opiate Withdrawal Scale or COWS >8-12 (or other withdrawal scale)
      1. Avoid starting Buprenorphine in patients without active withdrawal symptoms
      2. Buprenorphine will precipitate withdrawal if not already present
  3. 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. High Dose Protocol: Start with Buprenorphine 8 mg SL (preferred protocol)
        1. Repeat every 1-2 hours as needed (up to maximum of 32 mg)
        2. If symptoms improved after single dose, second 8 mg SL dose may be given to complete loading dose
        3. Lower dosing protocols may precipitate withdrawal
      3. Standard Dose Protocol: Start with Buprenorphine 4 mg SL
        1. May repeat dose based on COWS>=6, 4 mg every 1-2 hours until adequate effect (up to 16 mg)
      4. Lower Dose Protocol: Start with Buprenorphine 2 mg SL
        1. May repeat 2-4 mg every 1-2 hours up to 8 mg/day maximum on Day 1, and 16 mg/day max thereafter
    4. Disposition
      1. Bridge therapy discharge dosing to get to outpatient management: Buprenorphine 8 mg SL twice daily
      2. Re-evaluation in 24 hours (no more than 7 days)
    5. Adjusted based on physician evaluation, withdrawal
      1. By day 7: Maximum of 32 mg/day (no benefit above 24-32 mg daily)
    6. Home Buprenorphine Induction Dosing
      1. Consider for those not currently in Opioid Withdrawal
      2. Day 1: Start 4 mg SL every 2 hours as needed for withdrawal symptoms up to 24 mg total
      3. Day 2: Start bridge therapy to outpatient management with Buprenorphine 8 mg SL twice daily
      4. 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)
      5. Iphone Application (BUP Home) created by Yale Clinicians
    7. 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
    8. 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]
  4. Stabilization Phase (1-2 months)
    1. Identify minimum effective dose
    2. Typical: Buprenorphine 12-24 mg/day divided (typically 16 mg/day)
  5. 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
  6. 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)
    5. Central Alpha 2 Adrenergic Agonists (e.g. Clonidine)
    6. Gabapentin (Neurontin)
  2. Opioids
    1. Maintain Buprenorphine dosing during the emergency department visit, hospitalization and perioperative period
    2. Alert Buprenorphine/Naloxone prescriber of acute Pain Evaluation and acute Opioid prescription
      1. May otherwise void Controlled Substance Contract with the prescriber
    3. 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)
    4. May add short acting Opioids, but risk of relapse
      1. Limit to 3 day supply and continue with Buprenorphine/Naloxone (Suboxone)
      2. Decrease Suboxone dose while using short acting Opioid
      3. Hydromorphone (Dilaudid) may be preferred short-term Opioid due to stronger Opioid receptor binding
      4. Avoid Tramadol (unlikely to overcome Suboxone's tight binding)
    5. References
      1. (2019) Presc Lett 26(11): 65
      2. (2017) Presc Lett 24(1): 2-3
  • References
  1. (2023) Presc Lett 30(4): 23-4
  2. (2021) Presc Lett 28(11): 64
  3. (2015) Presc Lett 22(8)
  4. (2012) Presc Lett 19(10): 60
  5. Long, katona, Kolb and dos Santos (2022) Crit Dec Emerg Med 36(9): 4-11
  6. LoVecchio (2023) Crit Dec Emerg Med 37(3): 32
  7. Strayer in Herbert (2020) EM:Rap 20(6):10-2
  8. Donaher (2006) Am Fam Physician 73(9):1573-8 [PubMed]
  9. Fudala (2003) N Engl J Med 349:949-58 [PubMed]
  10. Zoorob (2018) Am Fam Physician 97(5): 313-20 [PubMed]