Butrans - Drug Monograph

Introduction

Butrans (buprenorphine) is a transdermal system indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Butrans belongs to the partial opioid agonist class and is formulated as a transdermal delivery system that provides continuous drug delivery for 7 days.

Mechanism of Action

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. As a partial agonist, it binds to mu-opioid receptors with high affinity but produces less maximal effect than full agonists like morphine. This partial agonist activity results in a ceiling effect for respiratory depression, making it potentially safer than full opioid agonists in overdose situations. Its antagonist activity at kappa receptors may contribute to its analgesic effects and potentially reduce dysphoric effects.

Indications

FDA-approved for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Dosage and Administration

• Initial dosing: Butrans 5 mcg/hour applied once weekly
• Titration: Increase dose in increments of 5 mcg/hour no more frequently than every 72 hours
• Maximum dose: 20 mcg/hour due to QT prolongation risk at higher doses
• Application: Apply to intact, non-irritated skin on upper outer arm, upper chest, upper back, or side of chest
• Rotation sites: Apply to a different skin site each week
• Special populations: Reduce dose in hepatic impairment; use caution in renal impairment; not recommended in severe hepatic impairment

Pharmacokinetics

• Absorption: Steady-state concentrations reached within 72 hours of initial application
• Distribution: Volume of distribution ~97-187 L; 96% protein bound
• Metabolism: Primarily hepatic via CYP3A4 to norbuprenorphine (active metabolite)
• Elimination: Terminal half-life ~26 hours; primarily fecal elimination (70%) with some renal excretion (30%)

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma in unmonitored settings
• Known or suspected gastrointestinal obstruction
• Hypersensitivity to buprenorphine
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOIs

Warnings and Precautions

• Addiction, abuse, and misuse: Risk of opioid addiction, abuse, and misuse
• Life-threatening respiratory depression: Monitor closely, especially during initiation
• Neonatal opioid withdrawal syndrome: Prolonged use during pregnancy can result in withdrawal
• QTc prolongation: Avoid doses >40 mcg/hour due to QT prolongation risk
• CNS depression: Avoid alcohol and other CNS depressants
• Application site reactions: Rotate sites and monitor for skin reactions
• Temperature effects: Avoid external heat sources which may increase drug release

Drug Interactions

• CNS depressants: Enhanced sedation with benzodiazepines, alcohol, other opioids
• CYP3A4 inhibitors: Ketoconazole, ritonavir may increase buprenorphine levels
• CYP3A4 inducers: Rifampin, carbamazepine may decrease buprenorphine levels
• Serotonergic drugs: Risk of serotonin syndrome with SSRIs, SNRIs, TCAs
• Anticholinergics: May increase risk of urinary retention and constipation

Adverse Effects

• Nausea (21%)
• Headache (15%)
• Application site reactions (13%)
• Constipation (13%)
• Somnolence (10%)
• Dizziness (9%)

• Respiratory depression
• Hypotension
• Adrenal insufficiency
• Androgen deficiency
• Anaphylaxis
• Application site burns (if heated)

Monitoring Parameters

• Pain intensity and functional assessment
• Respiratory rate and oxygen saturation
• Signs of misuse or addiction
• Bowel function (constipation management)
• Application site reactions
• QT interval monitoring (if doses >20 mcg/hour)
• Hepatic and renal function
• Signs of hypogonadism with long-term use

Patient Education

• Apply to clean, dry, intact skin without hair
• Do not cut or damage the patch
• Avoid heating pads, hot baths, or sun exposure to application site
• Proper disposal of used patches (fold adhesive sides together)
• Recognize signs of overdose: extreme sleepiness, confusion, shallow breathing
• Do not suddenly stop medication due to withdrawal risk
• Avoid alcohol and other sedating medications
• Report severe constipation, nausea, or dizziness
• Keep patches away from children and pets

References

1. Butrans [package insert]. Stamford, CT: Purdue Pharma L.P.; 2021. 2. Daitch J, Daitch D, Novinson D, et al. Effect of buprenorphine transdermal delivery system in opioid-experienced patients with chronic low back pain. Pain Med. 2012;13(9):1175-1186. 3. Webster L, Brewer R, Wang C, et al. Long-term safety and efficacy of buprenorphine transdermal system in patients with moderate to severe chronic low back pain. J Opioid Manag. 2010;6(4):261-272. 4. US Food and Drug Administration. Butrans risk evaluation and mitigation strategy (REMS). 2020. 5. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. J Pain. 2009;10(2):113-130. 6. Strain EC, Walsh SL, Bigelow GE. Blockade of opioid effects in human volunteers. Psychopharmacology (Berl). 2002;159(3):220-228.