buprenorphine (Rx)

>10% (SL)

Headache (29.1-30%)

Pain (18.4-24%)

Withdrawal syndrome (18.4-22%)

Insomnia (21.4%)

Infection (20%)

Asthenia (14%)

Back pain (7.8-14%)

Nausea (10-13.6%)

Sweating (12-12.6%)

Abdominal pain (11.7%)

Infection (11.7%)

Constipation (7.8-11%)

1-10% (IV/IM)

5-10%

• Nausea
• Dizziness/vertigo

1-5%

• Sweating
• Headache
• Hypotension
• Nausea/vomiting
• Hypoventilation
• Miosis

1-10% (SL)

Rhinitis (9.7%)

Chills (6-7.8%)

Vomiting (5-7.8%)

Flu syndrome (6%)

Nervousness (6%)

Runny eyes (5%)

Diarrhea (4.9-5%)

Asthenia (4.9%)

Vasodilation (3.9%)

Fever (3%)

Dyspepsia (3%)

Accidental injury (2-3%)

Abscess (2%)

<1%

Confusion, blurred vision, euphoria, weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia

Hypertension, tachycardia, bradycardia

Constipation

Dyspnea, cyanosis

Pruritus

Diplopia, visual abnormalities

Injection site reaction, urinary retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis, Wenckebach block, and psychosis

Other effects observed infrequently include malaise, hallucinations, depersonalization, coma, dyspepsia, flatulence, apnea, rash, amblyopia, tremor, and pallor

Postmarketing Reports

Serotonin syndrome

Adrenal insufficiency

Anaphylaxis

Androgen deficiency

Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis

Contraindications

Hypersensitivity

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Cautions

Partial agonist at the mu opioid receptor and a schedule III controlled opioid exposes users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids owing to the larger amount of active opioid present (see Black Box Warnings)

Serious, life-threatening, or fatal respiratory depression reported; may occur more frequently in elderly or debilitated patients, or in conditions associated with hypoxia or hypercapnia (even moderate therapeutic doses) (see Black Box Warnings)

Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black Box Warnings)

Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

Accidental exposure reported, including fatalities (see Black Box Warnings)

May impair mental or physical abilities needed to perform potentially hazardous activities (eg, driving a car, operating machinery)

Risk of apnea in patients with chronic pulmonary disease; closely monitor these patients, when initiating and titrating therapy; alternatively, consider the use of alternative non-opioid analgesics in these patients (see Black Box Warnings and Contraindications)

QTc prolongation observed in healthy individuals at 40 mcg/hr; avoid in patients with history of long QT syndrome or coadministration with class IA (eg, quinidine, procainamide, disopyramide) or class III (eg, sotalol, amiodarone, dofetilide) antiarrhythmics

Respiratory depressant effects of opioids may include carbon dioxide retention and lead to elevated CSF pressure

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper

Can cause severe hypotension; caution with depleted blood volume or coadministration of drugs that that affect vasomotor tone (eg, phenothiazines), vasodilators, or antihypertensives

Hypothyroidism, myxedema, adrenocortical insufficiency, alcohol intoxication, alcohol withdrawal syndrome, coma, geriatric or debilitated patients, delirium tremens, toxic psychoses, kyphoscoliosis, prostatic hypertrophy, urethral stricture, central nervous system (CNS) depression, biliary tract dysfunction, head injury, intracranial lesions, intracranial hypertension or conditions in which intracranial pressure may be increased

Cases of cytolytic hepatitis and hepatitis with jaundice observed in individuals receiving buprenorphine SL for opioid dependence treatment; increased risk for overdose with moderate or severe hepatic impairment (see Dosage Modifications)

Anaphylactic reactions reported

May cause sphincter of Oddi spasm and aggravate abdominal conditions, including ileus (see Contraindications)

Similar to other opioids, may aggravate seizure disorders by lowering seizure threshold

Special risk groups may experience increased adverse reactions; caution with alcoholism, delirium tremens, adrenocortical insufficiency, CNS depression, debilitation, kyphoscoliosis associated with respiratory compromise, myxedema or hypothyroidism, prostatic hypertrophy or urethral stricture, severe impairment of hepatic, pulmonary or renal function, and toxic psychosis

Prescribers should discuss with patients importance and benefits of management of opioid addiction throughout pregnancy

Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

Consider discontinuing therapy 24-36 hr prior anticipated need for surgical anesthesia to undergo elective surgery; may administer short-acting opioids during and/or after surgery; in patients unable to abruptly discontinue therapy may add full opioid to buprenorphine to maintain proper anesthesia; increased doses may be required to overcome buprenorphine receptor blockade; continuously monitor if opioid therapy required as part of anesthesia in an anesthesia care setting

Abrupt discontinuation following prolonged therapy may lead to withdrawal symptoms; not recommended; taper gradually

Use caution in patients who are morbidly obese

Avoid use in patients with impaired consciousness or coma; patients are susceptible to intracranial effects of CO2 retention

Use caution in patients with a history of ileus or bowel obstruction; contraindicated in patients with known or suspected GI obstruction including paralytic ileus

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential; unknown whether effects on fertility are reversible (see Pregnancy)

Drug interactions overview

• Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose and death (See Black Box Warnings)
• Opioids may reduce efficacy of diuretics by inducing release of antidiuretic hormone
• Anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus; monitor for signs of urinary retention or reduced gastric motility when buprenorphine is concomitantly used with anticholinergics

• Serotonergic drugs

  • Opioids may enhance serotonergic effect of drugs (eg, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors) that affect the serotonergic neurotransmitter system; which increases the risk of serotonin syndrome; if concomitant use is warranted, monitor; discontinue if serotonin syndrome is suspected
  • Use of MAOIs with buprenorphine is not recommended during or within 14 days of discontinuing treatment

• CYP3A4 inhibitors

  • Concomitant use of buprenorphine and CYP3A4 inhibitor may increase the plasma concentration of buprenorphine, resulting increased or prolonged opioid effects; specifically when adding a CYP3A4 inhibitor after achieving a stable buprenorphine dose

• CYP3A4 inducers

  • Concomitant use of buprenorphine and CYP3A4 inducers may decrease plasma concentration of buprenorphine, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine

Pregnancy

Data in pregnancy are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure; observational studies reported on congenital malformations among exposed pregnancies, but were also not designed appropriately to assess risk of congenital malformations specifically due to drug exposure

Dosage adjustments of buprenorphine may be required during pregnancy, even if patient was maintained on stable dose prior to pregnancy; withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary

Fetal/neonatal adverse reactions

• Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment

Lactation

Data on two studies in 13 lactating women receiving therapy where the drug and it metabolite were present in low levels in human milk did not show adverse reactions in breastfed infants; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Advise breastfeeding women taking buprenorphine products to monitor infant for increased drowsiness and breathing difficulties

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Semisynthetic narcotic mixed agonist-antagonist analgesic; exerts agonistic effects at mu and delta opioid receptors in CNS and antagonistic effects at kappa opioid receptor

Absorption

Onset: 15 min (IM); ~1 hr (IV)

Duration: >6 hr (IM)

Peak plasma time: 1.84 hr (2-mg SL dose); 1.28 hr (8-mg SL dose); 1.42 hr (16-mg SL dose)

Peak plasma concentration: 1.25 ng/mL (2-mg SL dose); 2.88 ng/mL (8-mg SL dose); 4.7 ng/mL (16-mg SL dose)

AUC: 10.93 hr·ng/mL (2-mg SL dose); 28.39 hr·ng/mL (8-mg SL dose); 47.09 hr·ng/mL (16-mg SL dose)

Distribution

Protein bound: 96%, primarily to alpha and beta globulin

Metabolism

Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation

N-dealkylation pathway is mediated primarily by CYP3A4

Metabolites: Norbuprenorphine (N-dealkylbuprenorphine)

Elimination

Mean half-life: 2.2 hr (IV); 31-35 hr (SL)

Excretion: Urine (30%), feces (69%)

IV Incompatibilities

Additive: Floxacillin, furosemide

Y-site: Amphotericin B cholesteryl sulfate, doxorubicin liposomal

IV Compatibilities

Additive: Bupivacaine

Syringe: Heparin, midazolam

Y-site: Allopurinol, amifostine, aztreonam, cefepime, cisatracurium, cladribine, docetaxel, etoposide phosphate, filgrastim, gatifloxacin, gemcitabine, granisetron, linezolid, melphalan, piperacillin-tazobactam, propofol, remifentanil, teniposide, thiotepa, vinorelbine

IV Preparation

Solution: Dilute to final concentration of 15 mcg/mL in D5W, D5/NS, NS, or LR

Administer via controlled infusion device

IV/IM Administration

Administer by deep IM injection or by slow IV injection over ≥2 minutes

Storage

Injection: Store at 20-25°C (68-77°F)

SL tablets: Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

Protect from prolonged exposure to light