Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hepatic events: Hepatitis has been reported; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic impairment. Monitor liver function tests in patients at increased risk for hepatotoxicity (eg, history of alcohol or IV drug abuse, preexisting hepatic dysfunction) prior to and during therapy.
• Hypersensitivity reactions: Hypersensitivity, including bronchospasm, angioneurotic edema, and anaphylactic shock, have been reported.
• Hypotension: May cause severe hypotension, including orthostatic hypotension and syncope; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Use with caution in patients with circulatory shock.
• Respiratory depression: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Misuse by self-injection of buprenorphine or the concomitant use of buprenorphine and benzodiazepines (or other CNS depressants, including alcohol) may result in coma or death. Use with caution in patients with compromised respiratory function (eg, chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression). Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Bowel obstruction: Use with caution in patients with a history of ileus or bowel obstruction.
• CNS depression/coma: Use with caution in patients with impaired consciousness or coma because these patients are susceptible to intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.
• Hepatic impairment: Use is not recommended in patients with moderate hepatic impairment for induction therapy (Suboxone) or in patients with severe hepatic impairment. Use with caution in patients with moderate hepatic impairment for maintenance treatment; due to reduced clearance of naloxone and potential for reduced buprenorphine efficacy, use may not be appropriate.
• Obesity: Use with caution in patients who are morbidly obese (DeVido 2015).
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease, cor pulmonale, or kyphoscoliosis, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages.
• Seizure: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Benzodiazepines and other CNS depressants: Concomitant use of benzodiazepines or other CNS depressants, including alcohol and opioids, may result in profound sedation, respiratory depression, coma, and death. Prohibiting medication-assisted treatment of opioid use disorder may increase the risk of morbidity and mortality, therefore patients should be educated on the risks of concomitant use with benzodiazepines, sedatives, opioid analgesics, and alcohol. Strategies should be developed to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of or during treatment with buprenorphine; adjustments to induction procedures and additional monitoring may be required. If appropriate, delay or omit buprenorphine dose if a patient is sedated at time of buprenorphine dosing. Discontinuation of benzodiazepines or other CNS depressants is preferred; gradual tapering of benzodiazepine or other CNS depressant, decreasing to lowest effective dose, or monitoring in a higher level of care for taper may be appropriate. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids. Benzodiazepines are not the treatment of choice for anxiety or insomnia for patients in buprenorphine treatment; make sure patients are appropriately diagnosed and consider alternative medications for anxiety and insomnia prior to coadministration of benzodiazepines and buprenorphine.
Special populations:
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for life-threatening respiratory depression, even at therapeutic dosages.
• Elderly: Use with caution in elderly patients; may be more sensitive to adverse effects (eg, life-threatening respiratory depression).
• Neonates: Neonatal withdrawal syndrome: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
Special handling:
• Disposal: Dispose of unused buccal and sublingual films (if they are no longer needed) by removing from foil patch and flushing down the toilet. If multiple films are no longer needed, flush each film individually.
Other warnings/precautions:
• Accidental ingestion: Accidental ingestion in children can result in severe respiratory depression (may be fatal); store buprenorphine-containing medications out of reach of children and dispose of unused medication appropriately.
• Acute pain: When using buprenorphine for treatment of opioid use disorder, treat acute pain with nonopioid analgesics whenever possible. If treatment with a high-affinity full opioid analgesic is required, monitor closely for respiratory depression because high doses may be necessary to achieve pain relief.
• Addiction/abuse/misuse: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of substance use disorder; potential for opioid use disorder exists. Other factors associated with an increased risk for misuse include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).
• Appropriate use: Buprenorphine/naloxone is not appropriate for pain management; deaths have been reported in opioid-naive patients receiving oral buprenorphine for analgesia.
• Discontinuation of therapy: There is no maximum recommended duration for maintenance treatment of opioid use disorder; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-assisted treatment.
• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.
• Partial opioid agonist and mixed opioid agonist/antagonist overdose: Reversal of partial opioid agonists or mixed opioid agonist/antagonists (eg, buprenorphine, pentazocine) may be incomplete and higher than normal doses and repeated administration of naloxone may be required.
• Withdrawal: Concurrent use of opioid agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms and is not recommended; taper dose gradually when discontinuing. Treatment of opioid use disorder with buprenorphine/naloxone should not be started until effects of withdrawal are evident.
Monitoring Parameters
Liver function tests (prior to initiation and periodically during therapy); pregnancy test (prior to initiation); hepatitis and HIV tests (prior to initiation), particularly for patients with opioid use disorder (SAMHSA 2018); respiratory and mental status; CNS depression; blood pressure; symptoms of withdrawal; signs of dependence, abuse, or misuse; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).
Reproductive Considerations
Pregnancy testing is recommended prior to initiating therapy for opioid use disorders (SAMHSA 2018). Long-term opioid use may cause infertility in males and females of reproductive potential. Amenorrhea may develop secondary to substance abuse. Initiation of buprenorphine maintenance treatment may improve fertility resulting in unplanned pregnancy. Contraception counseling is recommended (Dow 2012).
