Buprenorphine

Introduction

• Buprenorphine is a Schedule III opioid analgesic commonly used for maintenance therapy in opioid use disorder (OUD) but can also be used for both chronic and acute pain management.^1-3
• The United States Food and Drug Administration has approved two formulations of buprenorphine for the management of chronic pain: buccal and transdermal.
• Buprenorphine may be a safer option when compared to other opioids due to less respiratory depression, physical dependence, and opioid induced hyperalgesia.^1,3,6
• Further investigation is required to assess its efficacy and safety profile compared to other long-acting opioids in chronic pain management.¹

Mechanism of Action

• Buprenorphine is a partial agonist at the mu opioid receptor and an antagonist at the delta and kappa opioid receptors.³
• It demonstrates high receptor affinity, low intrinsic activity, and slow dissociation kinetics.³
• It has an average half-life of 38 hours, with a range of 25 to 70 hours after sublingual administration.²
• Buprenorphine is metabolized by cytochrome CYP3A4 enzymes, in which substances that alter the enzyme may affect buprenorphine levels.²
• Unlike full opioid receptors, buprenorphine may mediate analgesic signaling at spinal opioid receptors while having less effect on brain receptors.³
• Due to its high affinity to the mu receptor, it can displace other opioids from the receptor.
• Due to its poor bioavailability, administration routes are typically sublingual, buccal film, or transdermal mediums.

Dosing Recommendations

• Buprenorphine has several routes of administration. Oral administration includes buccal films and sublingual tablets, which are widely used to treat OUD and can be combined with a 4:1 buprenorphine-to-naloxone ratio. The transdermal patch is used for chronic pain relief. Parenteral routes are available in subdermal/subcutaneous implants, IV, or intramuscular injections.²
• Opioid use disorder: General initiation should occur at least 6-12 hours after the last use of heroin or other short-acting opioids, and 24-72 hours after the last use of long-acting opioids.⁴ Opioid dependent patients should experience mild to moderate opioid withdrawal before initiating buprenorphine to decrease the risk of precipitated withdrawal.⁴
  • Sublingual tablet: Initial 2-4 mg; if there are no signs of precipitated withdrawal within 1 to 2 hours, may increase dose by increments of 2 to 4 mg until clinically effective, with 24 hours of stabilization. The maximum dose for day 1 is up to 32mg in emergency department settings.⁵
    • Maintenance: Maintain clinically effective dose from day 1 and adjust dose in increments of 4 mg to a level that maintains suppression of opioid withdrawal symptoms⁵
• Chronic pain (moderate to severe):
  • Buccal film – max dose: 900mcg every 12 hours
    • Opioid-naïve: Initial 75mcg once daily or if tolerated, every 12 hours for ≥4 days, then increase to 150mcg every 12 hours⁵
    • Opioid-experienced: Discontinue all other scheduled opioids when buprenorphine is initiated. Taper the current opioid to no more than 30mg oral morphine sulfate equivalents (MME) daily before initiating buprenorphine⁵
• <30mg oral MME: 75mcg once daily or every 12 hours
• 30-89mg oral MME: 150mcg every 12 hours
• 90-160mg oral MME: 300mcg every 12 hours
• >160mg: consider alternate analgesic
  • Transdermal patch – maximum dose: 20mcg/hour every 7 days
    • Opioid-naïve: Initial 5mcg/hour once every 7 days
    • Opioid-experienced: All other scheduled opioids should be discontinued when buprenorphine is initiated. Short-acting analgesics may be continued, as needed, until optimal analgesia is achieved with a patch.⁵
• <30mg of oral MME: 5mcg/hour once every 7 days
• 30-80mg of oral MME: 10mcg/hour once every 7 days
• >80mg oral MME: 20mcg/hour once every 7 days
• Acute pain (moderate to severe): IM or slow IV injection: Initial 0.3mg every 6 to 8 hours as needed, may be repeated once 30-60 minutes after initial dose⁵

Common Side Effects/Considerations

• Tooth decay, tooth loss, and oral infections have been reported with sublingual/buccal use.⁹
• Opioid-induced constipation is seen in a lower incidence than morphine.⁵
• Opioid induced respiratory depression (related to the ceiling effect)
  • Reversal may require a higher naloxone bolus dose (IV 2-3mg), followed by continuous infusion (4 mg/hour) due to high mu-opioid receptor affinity and slow receptor dissociation kinetics.⁵
• Withdrawal: nausea, vomiting, diarrhea, abdominal cramps, tachycardia, chills, muscle aches, bone pain, agitation, anxiety, insomnia, psychosis

Chronic Pain Management with Buprenorphine

• Although buprenorphine is commonly used for maintenance therapy in OUD, it can provide similar analgesia compared to other opioids for chronic noncancer pain.¹
• Transdermal and buccal routes of administration produce significant pain reduction in patients with chronic pain, with more evidence for the use of chronic low back pain.^1,7
• Buprenorphine can potentially have a milder adverse effect profile of euphoria, addiction, or respiratory depression compared to other opioids due to its partial mu receptor agonistic mechanism and ability to signal spinal opioid receptors while having less effect on brain receptors.³
• Although buprenorphine is a partial mu agonist, its analgesic effects have been shown to be noninferior to opioids like oxycodone and morphine. Some authors opine that buprenorphine should not be classified as having partial analgesic efficacy.⁶
• Continuation of buprenorphine-naloxone may be beneficial in patients with OUD in a perioperative setting, as the unoccupied mu receptor availability may achieve adequate pain relief with the addition of full opioid agonists at lower dosages.⁸