BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE
Clinical safety rating: safe
No significant drug interactions Can precipitate acute withdrawal in patients dependent on opioids.
Partial mu-opioid receptor agonist (buprenorphine) and mu-opioid receptor antagonist (naloxone). Buprenorphine has high affinity but low intrinsic activity at mu receptors, producing ceiling effects on respiratory depression and euphoria. Naloxone antagonizes opioid effects and is poorly absorbed sublingually, added to discourage parenteral abuse.
| Metabolism | Primarily via N-dealkylation by CYP3A4 to norbuprenorphine (active metabolite); also glucuronidation by UGT1A1, UGT2B7, UGT1A3. Naloxone is extensively metabolized in the liver, primarily by glucuronidation. |
| Excretion | Buprenorphine: primarily fecal (69-70%) via biliary excretion; renal (10-30%) as unchanged drug and metabolites. Naloxone: extensively metabolized in liver, primarily conjugated; renal excretion of metabolites (70%), minimal unchanged (<1%). |
| Half-life | Buprenorphine: terminal half-life 24-60 hours (mean ~37 h) due to slow dissociation from opioid receptors; clinically relevant for once-daily or alternate-day dosing. Naloxone: terminal half-life 1-2 hours; rapid elimination limits oral systemic availability. |
| Protein binding | Buprenorphine: ~96% bound primarily to alpha- and beta-globulins, also to albumin. Naloxone: ~45% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | Buprenorphine: Vd ~3-5 L/kg; high due to lipophilicity and extensive tissue distribution. Naloxone: Vd ~2 L/kg; moderate distribution. |
| Bioavailability | Sublingual buprenorphine: ~30-50% (range 15-70%). Oral buprenorphine: <10% due to first-pass metabolism. Sublingual naloxone: <2% due to extensive first-pass; negligible under normal conditions, but sufficient to precipitate withdrawal if injected. |
| Onset of Action | Sublingual: 30-60 minutes (buprenorphine); peak analgesic effect 1-2 hours. Intravenous: 5-15 minutes. Naloxone IV: 2-5 minutes. |
| Duration of Action | Buprenorphine: analgesia 6-12 hours; opioid blockade 24-72 hours due to high receptor affinity and slow dissociation. Sublingual maintenance dosing every 1-2 days. Naloxone: reversal of opioid effects lasts 30-60 minutes; may require repeat dosing due to shorter half-life than buprenorphine. |
Sublingual: 2/0.5 mg to 4/1 mg once daily initially; titrate up to 8/2 mg, 12/3 mg, or 16/4 mg once daily; maximum 24/6 mg once daily. Buccal: 2.1/0.3 mg once daily initially; titrate up to 4.2/0.7 mg, 8.4/1.4 mg, or 12.6/2.1 mg once daily; maximum 12.6/2.1 mg once daily.
| Dosage form | FILM |
| Renal impairment | No dose adjustment required for mild-moderate renal impairment (GFR >=30 mL/min). For severe renal impairment (GFR <30 mL/min), initiate with low doses and titrate cautiously; buprenorphine is highly protein bound but naloxone may accumulate. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: use lower initial doses (e.g., 2/0.5 mg sublingual) and titrate slowly. Child-Pugh C: contraindicated due to risk of accumulation and prolonged effects. |
| Pediatric use | Approved for ages >=16 years: dosing same as adults, but start at lowest possible dose (e.g., 2/0.5 mg sublingual) and titrate based on response. For <16 years: safety and efficacy not established. |
| Geriatric use | Use with caution; start at low end of dosing range (e.g., 2/0.5 mg sublingual) and titrate slowly due to increased sensitivity, risk of respiratory depression, falls, and cognitive impairment. Monitor renal and hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
No significant drug interactions Can precipitate acute withdrawal in patients dependent on opioids.
| FDA category | Animal |
| Breastfeeding | Buprenorphine is excreted in breast milk with an estimated average infant dose of 1-2% of maternal weight-adjusted dose. Naloxone has poor oral bioavailability. M/P ratio: buprenorphine ~0.6-1.0. Generally considered compatible with breastfeeding, but monitor infant for drowsiness, respiratory depression, and feeding difficulties. |
| Teratogenic Risk |
■ FDA Black Box Warning
Risk of serious respiratory depression, especially during initiation or dose escalation. Concomitant use with CNS depressants (e.g., benzodiazepines, alcohol) may lead to profound sedation, respiratory depression, coma, and death. Neonatal opioid withdrawal syndrome may occur if used during pregnancy. Accidental ingestion, especially by children, can cause fatal respiratory depression.
| Common Effects | Precipitated withdrawal |
| Serious Effects |
Hypersensitivity to buprenorphine or naloxone. Significant respiratory depression. Acute or severe bronchial asthma. Known or suspected gastrointestinal obstruction. Concomitant use with MAOIs or within 14 days of MAOI use (relative).
| Precautions | Risk of respiratory depression, misuse/abuse, dependence, and withdrawal if abruptly discontinued. Adrenal insufficiency, hepatotoxicity (rare), QTc prolongation (buprenorphine high doses), and precipitation of withdrawal if given too soon after full agonist opioids. Use caution in patients with hepatic impairment, biliary tract disease, or head injury. |
Loading safety data…
| Pregnancy Category C. First trimester: Limited human data; animal studies show reduced fetal growth and increased fetal loss at high doses. Second and third trimesters: Chronic exposure may cause neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at delivery. Not associated with major malformations. |
| Fetal Monitoring | Maternal: Assess for sedation, respiratory rate, use of other CNS depressants. Fetal: Ultrasound for growth restriction in third trimester; electronic fetal monitoring during labor for signs of withdrawal or toxicity. Neonatal: Observe for NOWS for at least 4-7 days after delivery. |
| Fertility Effects | Buprenorphine may cause menstrual cycle irregularities and reduced fertility due to hyperprolactinemia. Animal studies show decreased fertility at high doses. No human data on naloxone. Reversible upon discontinuation. |
| Food/Dietary | No specific food interactions. Grapefruit juice may increase buprenorphine levels via CYP3A4 inhibition; avoid excessive consumption. Avoid alcohol-containing foods or beverages due to additive CNS depression. |
| Clinical Pearls | Buprenorphine/naloxone is a partial mu-opioid agonist with a ceiling effect on respiratory depression, reducing abuse potential but requiring careful induction in opioid-dependent patients to avoid precipitated withdrawal. Sublingual administration bypasses first-pass metabolism; naloxone has poor sublingual bioavailability but precipitates withdrawal if injected parenterally. Monitor hepatic function due to rare hepatotoxicity. Avoid use in severe hepatic impairment. The combination is preferred over buprenorphine alone to deter diversion. Dose adjustments may be needed in renal impairment. Pregnancy: not recommended unless benefit outweighs risk; can cause neonatal opioid withdrawal syndrome. |
| Patient Advice | Take this medication exactly as prescribed under the tongue; do not chew or swallow it. · Do not inject or snort the medication; this can cause severe withdrawal or overdose. · Avoid alcohol and other central nervous system depressants (e.g., benzodiazepines) as they increase risk of respiratory depression. · Store the medication securely and out of reach of children; properly dispose of unused medication via a take-back program. · Do not stop abruptly; withdrawal symptoms may occur. Follow your provider's tapering plan. · Inform all healthcare providers that you are taking this medication. · Seek emergency care if you experience difficulty breathing, severe drowsiness, or signs of allergic reaction. · This medication is part of a comprehensive treatment plan including counseling and behavioral therapy. |