buprenorphine

Buprenorphine is an opioid medication used to treat moderate-to-severe pain that doesn’t respond to other pain management therapies, and to treat opioid dependence and withdrawal symptoms while weaning off opioids.

Opioid analgesics prevent pain by stimulating opioid receptors, which block the release of chemicals (neurotransmitters) that transmit pain signals.

Opioid receptors are protein molecules on nerve cell (neuron) membranes in the central and peripheral nervous systems. Opioid receptors mediate the body’s response to most hormones and some of their functions include modulating pain, stress response, respiration, digestion, mood and emotion. The five different opioid receptors discovered in humans are mu, delta, kappa, nociceptin, and zeta receptors.

Opioid agonist drugs bind to one or more of the opioid receptors and inhibit the release of neurotransmitters and pain transmission by the neurons. Opioid antagonists block opioid receptors without a functional response but prevent agonists from stimulating the receptors and are used to reverse opioid effects.

Buprenorphine works as a partial agonist at mu and delta receptors and a weak antagonist at kappa receptors. Partial opioid agonists elicit a partial functional response at the opioid receptors and consequently, produce fewer adverse effects, while being effective for pain relief (analgesia). Buprenorphine has a slow onset and long duration of effects, hence, it provides pain relief for a longer period with milder withdrawal symptoms than those from full opioid agonists, and hence is useful in weaning off opioid dependence.

Patients who develop tolerance to opioid agonists may be able to find pain relief with lower and less frequent doses of buprenorphine, reducing the risk of dose-related adverse effects such as respiratory depression, sedation, and intoxication. Opioid-dependent patients do not experience sedation or euphoria to the same degree with buprenorphine that they might experience with more potent opioids, because it is a partial opioid agonist.

• Do not use buprenorphine in the following conditions:
  • Hypersensitivity to buprenorphine or any of its components
  • Significant respiratory depression
  • Known or suspected gastrointestinal obstruction, including paralysis of the intestinal muscles (paralytic ileus)
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Buprenorphine should be used only in patients who cannot have alternate therapy or do not have effective pain relief from other therapies, because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses.
• Buprenorphine addiction, abuse, and misuse can lead to overdose and death. Prescribe after carefully assessing the patient’s risk, and monitor regularly.
• Concurrent use with alcohol or other drugs of abuse that depress the central nervous system increases the risk for serious respiratory depression, coma and death.
• Tolerance to and physical dependence on buprenorphine can develop with need for increased doses for pain relief.
• Serious life-threatening or fatal respiratory depression can occur and the risk is greatest during initiation of therapy and increase of dosage. Monitor the patient closely.
• Advise patients and caregivers on how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
• Respiratory depressant effects of opioids may include carbon dioxide retention and lead to elevated cerebrospinal fluid (CSF) pressure.
• Do not administer buprenorphine within 2 weeks of monoamine oxidase inhibitor (MAOI) antidepressant therapy; MAOIs can enhance opioid effects.
• Do not use buprenorphine concurrently with drugs that can increase serotonin levels. It can lead to serotonin syndrome, a potentially life-threatening condition.
• Do not administer buprenorphine simultaneously with other central nervous system (CNS) depressants such as benzodiazepines. If no alternate drug is effective, limit dosages and durations to minimum required, and monitor the patient closely.
• There is a risk of breathing cessation (apnea) in patients with chronic obstructive pulmonary disease (COPD) or other conditions that compromise lung function. Use with extreme caution and monitor when initiating and titrating therapy or consider non-opioid therapy if possible.
• Use with caution in patients with irregular heart rhythm (cardiac arrhythmia). Avoid in patients with a history of long QT syndrome and coadministration with class IA and III antiarrhythmic medications.
• Buprenorphine can cause severe hypotension. Use with caution in patients with depleted blood volume (hypovolemia) or when coadministering with drugs that affect vasomotor tone (e.g., phenothiazines), vasodilators, or antihypertensives.
• Opioids (dose-dependent) can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; taper and reduce if required.
• Use with caution in patients with moderate or severe liver impairment, the risk for overdose is higher.
• Use with caution in patients with renal impairment.
• Use with caution in patients with a history of ileus or bowel obstruction. May cause sphincter of Oddi spasm and aggravate abdominal conditions, including ileus.
• Use with caution in patients with hypothyroidism, myxedema, kyphoscoliosis with respiratory compromise, prostatic hypertrophy, urethral stricture, or biliary tract dysfunction.
• Buprenorphine can cause adrenal insufficiency, more often after one month of use; monitor the patient and treat appropriately.
• Use with caution in patients with alcohol intoxication, alcohol withdrawal syndrome, delirium tremens, or toxic psychoses.
• Use with caution in patients with central nervous system (CNS) depression, head injury, intracranial lesions, intracranial hypertension or conditions in which intracranial pressure may be increased.
• Avoid use in patients with impaired consciousness or coma. Patients are susceptible to intracranial effects of carbon dioxide retention.
• All opioids may aggravate convulsions in patients with seizure disorders. Use with caution.
• Use with caution in morbidly obese patients.
• There have been reports of anaphylactic reactions.
• Sublingual buprenorphine tablets carry the risk of potential dental problems. Evaluate the patient and use with caution in patients with pre-existing dental issues.
• Consider discontinuing buprenorphine 24-36 hours prior to anticipated need for surgical anesthesia to undergo elective surgery, and use short-acting opioids during and after surgery.
• Accidental exposure of even one dose, especially in children, can result in a fatal overdose.
• Prolonged opioid use during pregnancy can cause opioid withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated. If prolonged opioid treatment is required during pregnancy, advise the patient of the risks to the fetus and ensure appropriate treatment is available.
• Even therapeutic doses of buprenorphine can cause serious, life-threatening, or fatal respiratory depression in elderly and debilitated patients. Use with extreme caution.
• When discontinuing buprenorphine in physically-dependent patients, do not abruptly discontinue. Taper dosage gradually to avoid severe withdrawal symptoms.
• Discuss the availability of the opioid antagonist naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers. Consider prescribing it to patients who are at increased risk of opioid overdose.
• Healthcare workers are strongly encouraged to complete opioid analgesic risk evaluation and mitigation strategy (REMS) education program to be able to counsel patients and caregivers appropriately on safe use and disposal of opioid analgesics.

Common side effects of buprenorphine include:

• Headache
• Pain
• Withdrawal syndrome
• Insomnia
• Infection
• Weakness (asthenia)
• Back pain
• Sweating
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Diarrhea
• Chills
• Nasal inflammation (rhinitis)
• Flu syndrome
• Runny eyes
• Dizziness
• Vertigo
• Nervousness

Less common side effects of buprenorphine include:

• Low blood pressure (hypotension)
• Respiratory depression (hypoventilation)
• Dilation of blood vessels (vasodilation)
• Constriction of pupils (miosis)
• Indigestion (dyspepsia)
• Gas (flatulence)
• Fever
• Accidental injury
• Abscess

Rare side effects of buprenorphine include:

• Confusion
• Euphoria
• Nervousness
• Depression
• Abnormal dreams
• Hallucinations
• Depersonalization
• Psychosis
• Coma
• Blurred vision
• Double vision (diplopia)
• Visual abnormalities
• Lazy eye (amblyopia)
• Inflammation of the conjunctiva, the membrane over the eye whites and inner eyelid surfaces (conjunctivitis)
• Fatigue
• Feeling unwell (malaise)
• Dry mouth
• Slurred speech
• Ringing in the ears (tinnitus)
• Abnormal skin sensations (paresthesia)
• Tremor
• High blood pressure (hypertension)
• Rapid or slow heart rate (tachycardia or bradycardia)
• Shortness of breath (dyspnea)
• Pause in breathing (apnea)
• Bluish discoloration of skin (cyanosis)
• Rash
• Itching (pruritus)
• Injection site reactions
• Urinary retention
• Flushing/warmth
• Chills/cold
• Pallor
• Wenckebach block, a type of abnormal cardiac rhythm
• Serotonin syndrome, a serious drug reaction that leads to high serotonin levels
• Adrenal insufficiency
• Severe allergic reaction (anaphylaxis)
• Male hormone (androgen) deficiency
• Tongue pain and inflammation (glossodynia/glossitis)
• Oral inflammation (stomatitis)
• Redness of the insides of the mouth (oral mucosal erythema)
• Reduced sensation in the mouth (oral hypoesthesia)

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug.

Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injectable solution: Schedule III (Buprenex)

• 0.3 mg/mL

Tablet, sublingual: Schedule III (generic)

• 2 mg
• 8 mg

Adult:

Moderate-to-Severe Pain

• 0.3 mg intravenous/intramuscular (IV/IM) every 6 hours; may be repeated once (up to 0.3 mg) if required 30-60 minutes after initial dose

Opioid Dependence

Induction (sublingual tablet)

• 8 mg sublingual (SL) on day 1, then 16 mg SL on day 2; continued over 3-4 days

Maintenance (buprenorphine-naloxone combination)

• Switch to buprenorphine/naloxone combination for unsupervised maintenance

Dosage Modifications

Renal impairment

• No differences in pharmacokinetics observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine
• Renal failure: Pharmacokinetics are unknown

Hepatic impairment

• SL use
  • Mild: No dose adjustment is needed
  • Moderate: No dose adjustment is necessary, closely monitor for signs and symptoms of toxicity or overdose
  • Severe: Reducing starting and titration incremental dose by half, and monitor for signs and symptoms of toxicity or overdose

IV/IM use

• Mild-to-moderate: No dosage adjustments provided
• Severe: No dosage adjustment provided; use with caution

Dosing Considerations

Also given in combination with naloxone

Induction with SL tablets

• Patients dependent on heroin or other short-acting opioids
  • At initiation, administer first dose of buprenorphine SL tablets only when signs/symptoms of moderate opioid withdrawal appear, and at least 4 hours after patient last used an opioid
  • Titrate to clinical effectiveness achieved as rapidly as possible; dosing on the initial day of treatment may be given in 2-4 mg increments if preferred
• Patients dependent on methadone or other long-acting opioids
  • Administer first dose of buprenorphine sublingual tablets only when clear signs/symptoms of moderate opioid withdrawal appear, and generally 24 hours or longer after the patient last used a long-acting opioids

Access to naloxone for opioid overdose

• Assess need for naloxone upon initiating and renewing treatment
• Consider prescribing naloxone
  • Based on patient’s risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, prior opioid overdose); presence of risk factors should not prevent proper pain management
  • Household members (including children) or other close contacts at risk for accidental ingestion or overdose
• Consult patients and caregivers on the following:
  • Availability of naloxone for emergency treatment of opioid overdose
  • Ways differ on how to obtain naloxone as permitted by individual state dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, as part of a community-based program)

Pediatric:

Moderate-to-Severe Pain

• Children younger than 2 years: Safety and efficacy not established
• Children 2-12 years: 2-6 mcg/kg IV/IM every 4-6 hours as needed  
• Children older than 12 years: 0.3 mg IV/IM every 6 hours; may be repeated once (up to 0.3 mg) if required 30-60 minutes after initial dose

Geriatric:

Moderate-to-Severe Pain

• 0.15 mg IV/IM every 6 hours; titrate slowly due to increased risk of respiratory depression

• Buprenorphine has a high potential for addiction, abuse, and misuse, and can lead to overdose and death.
• Buprenorphine overdose can cause respiratory depression, drowsiness that can progress to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pulmonary edema, bradycardia, hypotension, airway obstruction, and death.
• Buprenorphine overdose treatment includes:
  • Supportive care to maintain respiration with assisted ventilation, oxygen, intravenous fluids, and medication to increase arterial pressure.
  • Severe overdose may require respiratory resuscitation, cardiac defibrillation, and other advanced life-support measures.
  • Administration of an opioid antagonist, naloxone or nalmefene, specific antidotes for opioid overdose, if there is significant respiratory and circulatory depression.
• Buprenorphine is a long-acting depressant while opioid antagonist effects last for far less duration. The patient must be carefully monitored until spontaneous respiration is established, and additional doses, if required, may be administered.
• Patients with opioid physical dependence may develop severe withdrawal symptoms from opioid antagonist and the dosage should be initiated and titrated carefully.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of buprenorphine include:
  • alvimopan
  • lefamulin
• Buprenorphine has serious interactions with at least 103 different drugs.
• Buprenorphine has moderate interactions with at least 213 different drugs.
• Mild Interactions of buprenorphine include:
  • brimonidine
  • dextroamphetamine
  • elvitegravir
  • eucalyptus
  • lidocaine
  • sage
  • ziconotide

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Animal studies indicate that buprenorphine use during pregnancy may cause fetal harm. Use only if clearly needed and no other alternative drug is effective.
• Safety of buprenorphine use during labor and delivery is not established. It may produce respiratory depression and other adverse effects in the newborn. Monitor the newborn closely, and keep an opioid antagonist, such as naloxone, available for reversal of opioid-induced respiratory depression in the newborn.
• Animal reproduction studies show buprenorphine may affect milk production.
• Buprenorphine is excreted in breastmilk. If a breastfeeding mother requires opioid treatment for post-surgical pain, the lowest effective dose of buprenorphine for the shortest possible duration may be administered. The infant must be carefully monitored, and the drug or nursing must be discontinued if the infant develops adverse effects.
• Chronic use of opioids may reduce fertility in both men and women of reproductive potential; it is not known whether these effects are reversible.
• Chronic opioid use by the mother during pregnancy can result in physical dependence and opioid withdrawal syndrome in the newborn, and increase the risk of sudden infant death syndrome.

• Buprenorphine has a high risk for addiction, abuse, and misuse that can lead to a fatal overdose. Exercise caution.
• Take buprenorphine exactly as prescribed; do not take a higher or more frequent dosage.
• Buprenorphine can cause life threatening respiratory depression. Seek medical help immediately if you develop breathing difficulties.
• Do not drink alcohol or take alcohol-containing drugs while taking buprenorphine; it increases the risk for sedation and respiratory depression.
• Store buprenorphine well out of reach of children; accidental consumption, especially in children, can result in a fatal overdose.
• In case of known or suspected overdose, seek medical help immediately.
• Buprenorphine can impair mental and physical ability; avoid driving, operating heavy machinery or performing other potentially hazardous tasks while on buprenorphine therapy.