II. Background
- Buprenorphine (with and without Naloxone) is a growing concern for misuse, abuse and diversion
- Buprenorphine requires prescribing providers to complete 8 hour course and obtain X-Waiver DEA License
- However, Emergency Providers may administer Buprenorphine doses in the ED without an X-Waiver
- https://www.samhsa.gov/medication-assisted-treatment/training-materials-resources/apply-for-practitioner-waiver
III. Indications
-
Chronic Pain Management
- Opioid use with comorbidity at risk of respiratory depression (e.g. COPD)
- Opioid Use Disorder AND Chronic Pain
-
Opioid Addiction (e.g. Heroin addiction)
- Preferred first line agent alternative to low dose Methadone
- Prescribing requires FDA X-waiver
IV. Contraindications
- Use caution and liver function monitoring in hepatitis
V. Mechanism
- Partial mu-Opioid receptor agonist
- Semisynthetic derivative of Thebaine
- Mu-receptor activation increases with dose to ceiling
- Slowly dissociates from mu-receptors (high affinity, but lower activity)
- Adding Naloxone to Buprenorphine intended to block the "high" if Buprenorphine is crushed and injected
- However still with abuse risk (e.g. Zubsolv snorting, Suboxone injection)
VI. Pharmacokinetics
- Metabolism: Liver via P450
- Plasma half-life: up to 28-37 hours (sublingual), and 3 hours (IV)
- Routes
- Oral bioavailability is too low to be useful
- Intravenous route used for pain management
- Sublingual is preferred route
- Bioavailability: Up to 50% of IV dose
- Peak concentration reached 1 hour post-dose
VII. Drug Interactions
- P450 3A4 Inducers may decrease Buprenorphine effect
- Carbamazepine
- Phenytoin
- Phenobarbital
- Reverse Transcriptase Inhibitors
- Rifampin
- P450 3A4 Inhibitors may increase Buprenorphine effect
- Azole Antifungals (e.g. Ketoconazole, Fluconazole)
- Macrolides (e.g. Erythromycin, Azithromycin)
- Respiratory depressants (risk of death with combined use)
- Benzodiazepines or other Sedative-Hypnotics
- Muscle relaxants (e.g. carisprodol, Cyclobenzaprine)
- Opioids
- Alcohol
- Other adverse effects in combination
VIII. Efficacy: Buprenorphine compared with Methadone
IX. Safety
- Pregnancy
- FDA Category C
- Risk of Neonatal Opioid Withdrawal Syndrome (NOWS)
- Occurs in newborns born to mothers on Opioids
- Buprenorphine-related NOWS is preferable to the high risks of Opioid Abuse or Methadone
-
Lactation
- Naloxone excretion into milk is unknown (and should only be used with caution)
X. Adverse Effects
- Constipation
- Urinary Retention
- Sedation
- Mild respiratory depression (unless taken with other Sedatives)
- Opioid Withdrawal
- Nausea
- Headache
- Dental Decay with oral formulations (Dental Cavities, dental abscess, tooth loss)
- FDA issued warning in 2022 after 300 reported cases (out of 2 million patients on Buprenorphine)
- Dissolve medication completely in mouth to fully absorb medication
- Follow with a large drink of water, and swish and swallow
- Wait at least 1 hour after taking medication to brush teeth
- May be related to acidic environment while on sublingual or buccal Buprenorphine
- Twice yearly dental care recommended
- Consider other formulations (e.g. monthly injection Buprenorphine) if significant dental complications
- References
- (2022) Presc Lett 29(3): 16-7
XI. Toxicity
- Significant Respiratory Depression has occured when taken with Benzodiazepines or Alcohol
XII. Preparations
- Pain management
-
Opioid Addiction
- Buprenorphine sublingual
- Same dosing as with Buprenorphine with Naloxone
- Buprenorphine with Naloxone (Suboxone, Zubsolv, generic)
- Sublingual
- Abused despite combination with Naloxone
- Drug Abusers crush and snort the sublingual tabs
- May not appear on routine Urine Drug Screen
- Film (2, 4, 8 and 12 mg)
- Prevents snorting (but has still been misused via injection)
- Dosing
- Sublingual
- Buprenorphine implant (Probuphine)
- Implanted subdermal rods with duration of 6 months (may be replaced once in opposite arm)
- Indicated for patients on stable dose of Buprenorphine SL at 8 mg/day for at least 3 months
- Very expensive (>$800 per month)
- (2016) Presc Lett 23(8)
- Buprenorphine monthly injection (Sublocade)
- Once monthly Subcutaneous Injection
- Very expensive (>$1600 per month)
- Indicated for patients on stable dose of Buprenorphine SL at 8-24 mg/day for at least 1 week
- (2018) Presc Lett 25(3)
- Buprenorphine sublingual
XIII. Dosing: Buprenorphine For Opioid Withdrawal (prescriber must have X DEA waiver)
- Preparation
- Urine drug test
- Informed Consent
- Treatment contract
- Patient should be at least 12 hours from last short-acting or 24 hours from last long-acting Opioid
- Clinical Opiate Withdrawal Scale or COWS >8 (or other withdrawal scale)
- Avoid starting Buprenorphine in patients without active withdrawal symptoms
- Buprenorphine will precipitate withdrawal if not already present
- Induction Phase (3-7 days)
- Started >12 hours after last short acting Narcotic
- Started >24 hours after last long acting Narcotic
- Initiation Dosing on Day 1 (provider observed)
- Monitor at 60 min intervals after first dose, titrating to dose that reduces withdrawal symptoms
- Higher Dose Protocol: Start with Buprenorphine 4-8 mg SL
- May repeat 4-8 mg every 30-60 minutes until adequate effect (up to 16 mg)
- Lower Dose Protocol: Start with Buprenorphine 2 mg SL
- May repeat 2-4 mg every 1-2 hours up to 8-16 mg/day
- Re-evaluation in 24 hours (no more than 7 days)
- Adjusted based on physician evaluation, withdrawal
- By day 7: Maximum of 32 mg/day (no benefit above 24-32 mg daily)
- Home Buprenorphine Induction Dosing
- Consider for those not currently in Opioid Withdrawal
- Requires patient to withstand abstaining from Opioids long enough at home to precipitate withdrawal
- Offer Opioid Withdrawal symptomatic management (e.g. Clonidine, Zofran, Loperamide)
- Iphone Application (BUP Home) created by Yale Clinicians
- Home Microdosing Induction Dosing
- Alternative to Home Buprenorphine Induction Dosing, for those not currently in Opioid Withdrawal
- Very low doses (e.g. 0.5 mg on day 1) are gradually titrated daily until at 8 mg sublingual dose
- Requires cutting Buprenorphine film into small strips
- EMS initiated withdrawal protocol (Cooper University Hospital, Camden, NJ)
- EMS identifies Opiate withdrawal patient in field
- EMS coordinates with Emergency command physician
- Command physician authorizes "Bupe Bundle"
- Buprenorphine 16 mg SL (high dose)
- Ondansetron 4 mg SL
- Next day follow-up coordinated with addiction medicine provider
- References
- https://www.reliasmedia.com/articles/144864-paramedics-empowered-to-administer-addiction-treatment-to-patients-in-the-field
- Wasserman and Swaminathan in Herbert (2021) EM:Rap 21(4): 15-6
- Carroll (2021) Prehosp Emerg Care 25(2):289-93 [PubMed]
- Stabilization Phase (1-2 months)
- Identify minimum effective dose
- Typical: Buprenorphine 12-24 mg/day divided (typically 16 mg/day)
- Maintenance Phase (indefinite)
- Dosing based on stabilization phase
- Evaluate compliance
- Review State prescription monitoring programs
- Random urine drug tests
- Pill counts
- Discontinuation
- Slowly taper (unless discontinued for diversion)
XIV. Management: Acute Pain Control for patients on Buprenorphine
- Non-Opioids (preferred)
- Acetaminophen
- NSAIDs
- Topical agents (e.g. Lidocare or Lidocaine Patch)
- Ketamine Analgesic dosing at 0.1 to 0.3 mg/kg IV (in Emergency Department)
-
Opioids
- Alert Buprenorphine/Naloxone prescriber of acute Pain Evaluation and acute Opioid prescription
- May otherwise void Controlled Substance Contract with the prescriber
- Divide Buprenorphine/Naloxone dosing every 6-8 hours (maximum daily dosing up to 32 mg)
- May add short acting Opioids, but risk of relapse
- References
- (2019) Presc Lett 26(11): 65
- (2017) Presc Lett 24(1): 2-3
- Alert Buprenorphine/Naloxone prescriber of acute Pain Evaluation and acute Opioid prescription
XV. Resources
- SAMHSA Buprenorphine information
XVI. References
- (2021) Presc Lett 28(11): 64
- (2015) Presc Lett 22(8)
- (2012) Presc Lett 19(10): 60
- Strayer in Herbert (2020) EM:Rap 20(6):10-2
- Donaher (2006) Am Fam Physician 73(9):1573-8 [PubMed]
- Fudala (2003) N Engl J Med 349:949-58 [PubMed]
- Zoorob (2018) Am Fam Physician 97(5): 313-20 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
buprenorphine (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
BUPRENORPHINE 2 MG TABLET SL | Generic | $0.89 each |
BUPRENORPHINE 8 MG TABLET SL | Generic | $1.49 each |
BUPRENORPHINE-NALOXONE 2-0.5 MG SL TABLET | Generic | $3.10 each |
BUPRENORPHINE-NALOXONE 8-2 MG SL TABLET | Generic | $3.98 each |
suboxone (on 1/2/2017 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
SUBOXONE 12 MG-3 MG SL FILM | $14.98 each | |
SUBOXONE 2 MG-0.5 MG SL FILM | $4.18 each | |
SUBOXONE 4 MG-1 MG SL FILM | $7.52 each | |
SUBOXONE 8 MG-2 MG SL FILM | $7.46 each | |
zubsolv (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
ZUBSOLV 1.4-0.36 MG TABLET SL | $3.76 each | |
ZUBSOLV 2.9-0.71 MG TABLET SL | $7.56 each | |
ZUBSOLV 5.7-1.4 MG TABLET SL | $7.53 each | |
ZUBSOLV 8.6-2.1 MG TABLET SL | $11.28 each | |
butrans (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
BUTRANS 10 MCG/HR PATCH | $88.38 each | |
BUTRANS 15 MCG/HR PATCH | $127.63 each | |
BUTRANS 20 MCG/HR PATCH | $156.14 each | |
BUTRANS 5 MCG/HR PATCH | $58.83 each | |
BUTRANS 7.5 MCG/HR PATCH | $82.64 each | |
belbuca (on 3/1/2017 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
BELBUCA 150 MCG FILM | $4.52 each | |
BELBUCA 300 MCG FILM | $6.99 each | |
BELBUCA 450 MCG FILM | $9.53 each | |
BELBUCA 75 MCG FILM | $4.44 each |
Ontology: Subutex (C0006404)
Concepts | Pharmacologic Substance (T121) , Organic Chemical (T109) |
MSH | D002047 |
English | Temgesic, subutex, temgesic, Essex Brand of Buprenorphine Hydrochloride, Reckitt Benckiser Brand of Buprenorphine Hydrochloride, Reckitt Brand of Buprenorphine Hydrochloride, Schering Plough Brand of Buprenorphine Hydrochloride, Schering-Plough Brand of Buprenorphine Hydrochloride, Subutex, Buprenorphine Grünenthal Brand, Grünenthal Brand of Buprenorphine Hydrochloride, Grünenthal Brand of Buprenorphine, Temgésic, Buprex, Reckitt & Colman Brand 2 of Buprenorphine Hydrochloride |
Czech | suboxon, subutex |
Ontology: Buprenorphine (C0006405)
Definition (MSH) | A derivative of the opioid alkaloid THEBAINE that is a more potent and longer lasting analgesic than MORPHINE. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use. |
Definition (CSP) | 21-cyclopropyl-7-alpha-(2-hydroxy-3, 3-dimethyl-2-butyl)-6,14-endo-ethano -6,7,8,14-tetrahydro oripavine, a narcotic analgesic with mixed agonist-antagonist opiate properties; potential efficacy in heroin withdrawal. |
Concepts | Pharmacologic Substance (T121) , Organic Chemical (T109) |
MSH | D002047 |
SnomedCT | 370250006, 31684002, 387173000 |
LNC | LP16054-6, MTHU006723 |
English | Buprenorphine, 6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha-methyl-, (5alpha,7alpha(S))-, Buprenorphine [Chemical/Ingredient], BUPRENORPHINE, buprenorphine, Buprenorphine product, Buprenorphine product (product), Buprenorphine (product), Buprenorphine (substance) |
Swedish | Buprenorfin |
Czech | buprenorfin |
Finnish | Buprenorfiini |
Russian | BUPRENORFIN, БУПРЕНОРФИН |
Japanese | ザルバン, レペタン, 塩酸ブプレノルフィン, ブプレノルフィン |
Polish | Buprenorfina |
Spanish | producto con buprenorfina, producto con buprenorfina (producto), buprenorfina (producto), buprenorfina (sustancia), buprenorfina, Buprenorfina |
French | Buprénorphine |
German | Buprenorphin |
Italian | Buprenorfina |
Portuguese | Buprenorfina |
Ontology: Suboxone (C1170625)
Concepts | Pharmacologic Substance (T121) , Organic Chemical (T109) |
MSH | C510748 |
English | suboxone, Suboxone |