BUPRENORPHINE

for Opioid Use Disorder

Module 2: Pharmacology and Administration

 Buprenorphine for Opioid Use Disorder
MODULE 2 Pharmacology and Administration

• Buprenorphine is a partial agonist at the mu-opioid receptor, (among other

pharmacologic actions).1
• Buprenorphine binds with high affinity and activates opioid receptors,
but not to the same extent as full agonists.2,3
• Buprenorphine relieves drug cravings without producing the euphoric
effects of full opioid agonists4 and with a lower risk of overdose
compared to full agonists.5,6
• Partial agonist properties give buprenorphine a “ceiling effect”. Increasing the dose
of buprenorphine does not produce the same subjective or physiologic effect as
increasing the dose of a full agonist.7,8
• In spite of the “ceiling effect”, exposure to buprenorphine in pediatric
patients may result in fatal respiratory depression.9 Appropriate storage
should be ensured to avoid unintentional exposure to children.10
• Individuals who are not opioid dependent may experience euphoric effects
with buprenorphine use.11,12

Exhibit 3A.4. Intrinsic Activity of OUD Medications

100

90
Full Agonist (Methadone)
80

70
Intrinsic Activity

60

50
Partial Agonist (Buprenorphine)
40

30

20

10
Antagonist (Naltrexone)
0
-10 -9 -8 -7 -6 -5 -4

Log Dose of Opioid

SAMSHA 13

2
 Buprenorphine for Opioid Use Disorder
MODULE 2 Pharmacology and Administration

Potential for Misuse and Diversion

of Buprenorphine Products
Buprenorphine products for sublingual (SL) or buccal administration containing naloxone (an
opioid antagonist) have been developed to decrease potential for misuse via injection or
intranasal routes of administration14, 15, 16
• Naloxone will attenuate the pharmacologic action of buprenorphine when
administered by injection or intranasally, but has limited bioavailability when taken
transmucosally (SL or buccally) and thus has little-to-no pharmacologic action when
these products are administered as directed.17

Buprenorphine products are diverted18 for purposes of self-medication of opioid dependence,

self-medication of withdrawal, to decrease use of other opioids, to decrease injection use,
and to relieve pain and to produce euphoria.19
• Naloxone lowers the desirability of buprenorphine/naloxone combination
products for misuse.4
• Data have shown a significant decrease in heroin overdoses once buprenorphine
has been implemented into specific treatment systems in the US.20

Buprenorphine Method of Administration

SL or buccal administration of buprenorphine is used due to poor oral bioavailability.21
Patients should be instructed to leave the medication on the inside of the cheek or under
their tongue until dissolved.
An implantable intramuscular depot formulation of buprenorphine lasting 6 months is also
available. This product is recommended for use in patients needing 8 mg or less of
buprenorphine per day, a low to moderate dose.22
Care must be taken when switching between buprenorphine products as dosage can
vary based on different bioavailability between products.
Patient preference, insurance coverage of formulations and out-of-pocket expenses for the
patient are considerations in selection of formulation.
An extended release injection is available for subcutaneous administration. It is given
monthly and started only after initiation of a transmucosal buprenorphine product.24

3
2
 Buprenorphine for Opioid Use Disorder
MODULE 2 Pharmacology and Administration

Buprenorphine Drug Interactions

Buprenorphine should be used cautiously with other Central Nervous System (CNS)
depressants, including benzodiazepines, alcohol and other sedative drugs.24,25
• Excessive sedation, respiratory depression, impaired cognition, and death
can occur.26, 27, 28, 29, 30, 31, 32
• Buprenorphine’s “ceiling effect” may be overcome when administered with
other CNS depressants, particularly benzodiazepines; this can potentially
increase the risk of overdose and fatalities.37
• Concomitant treatment with benzodiazepines and buprenorphine can be
accomplished with careful monitoring. If deemed medically necessary,
treatment with benzodiazepines or other CNS depressants is not a reason
to withhold buprenorphine treatment.34

Buprenorphine is metabolized to norbuprenorphine and other metabolites by CYP 450 3A4

and has the potential to interact with other inhibitors, or inducers of this pathway.35,36
These include azole antifungals such as ketoconazole, macrolide antibiotics such as
erythromycin, and protease inhibitors.

Opioid antagonists can block the effects of buprenorphine, and buprenorphine has the
potential to displace and block other opioids from the opioid receptor due to its high
affinity for and slow dissociation from the opioid receptor.37,38,39 At higher doses,
buprenorphine can precipitate withdrawal in individuals dependent on full opioid agonists.
• Opioid antagonists, such as naltrexone, can block the effects of buprenorphine.
• Use of naltrexone in a patient with buprenorphine in their system will
precipitate withdrawal.40
• If emergency treatment with full opioid agonists is required, careful titration of
dose and close monitoring for safety and effectiveness is required (see Module 4:
Special Populations - Patients with Pain).

4
 Buprenorphine for Opioid Use Disorder
MODULE 2 Pharmacology and Administration

References
1. Buprenorphine and naloxone tablet [package insert]. Parsippany, NJ:
Actavis Pharma, Inc.; 2016.
2. Buprenorphine and naloxone tablet [package insert]. Parsippany, NJ: Actavis Pharma, Inc.
3. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63, Full Document.
HHS Publication No. (SMA) 18-5063FULLDOC. Rockville, MD: Substance Abuse and
Mental Health Services Administration, 2018.
4. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice
guideline for the use of medications in the treatment of addiction involving opioid use. J
Addict Med. 2015;9(5):358-367.
5. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
6. HIV Clinical Resource. Treatment Modalities Guideline – AIDS Institute Guideline.
Appendix: Use of Buprenorphine in HIV-Infected Patients. February 2009. Available
at https://www.hivguidelines.org/substance-use/treatment-modalities/#tab_7. Accessed
December 28, 2017.
7. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
8. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical Pharmacology of
buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55(5):569-580.
9. Kim HK, Smiddy M, Hoffman RS, Nelson LS. Buprenorphine may not be as safe as you
think: a pediatric fatality from unintentional exposure. Pediatrics. 2012;130(6):
e1700–e1703.
10. Lofwall MR and Walsh SL. A review of buprenorphine diversion and misuse: the current
evidence base and experiences from around the world. J Addict Med. 2014;8(5):315-326.
11. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
12. Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus
buprenorphine/naloxone tablets in non-dependent opioid abusers.
Psycho-pharmacology (Berl). 2000;148(4):374–383.
13. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
14. Stoller KB, Bigelow GE, Walsh SL, Strain EC. Effects of buprenorphine/naloxone in
opioid-dependent humans. Psychopharmacology (Berl). 2001;154(3):230-242.
15. Substance Abuse and Mental Health Services Administration. Medications To Treat Opioid
Use Disorder.
16. Stoller KB, Bigelow GE, Walsh SL, Strain EC. Effects of buprenorphine/naloxone in
opioid-dependent humans. Psychopharmacology (Berl). 2001;154(3):230-242.
17. Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenous
buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained
intravenous heroin abusers. Addiction. 2010;105(4):709-718.
18. Schwartz RP, Grycznski J, O’Grady KE, et al. Opioid agonist treatments and heroin
overdose deaths in Baltimore, Maryland, 1995-2009. Am J Public Health.
2013;103(5):917-922.

5
 Buprenorphine for Opioid Use Disorder
MODULE 2 Pharmacology and Administration

References (continued)
19. Bullingham RES, McQuay HJ, Moore A, Bennett MRD. Buprenorphine kinetics. Clin
Pharmacol Ther. 1980;28(5):667-672.
20. Mendelson J, Upton RA, Everhart ET, Jacob P 3rd, Jones RT. Bioavailability of sublingual
buprenorphine. J Clin Pharmacol. 1997;37(1):31-37.
21. Probuphine® [package insert]. Princeton, NJ: Braeburn Pharmaceuticals; 2/2018.
22. Buprenorphine and naloxone tablet [package insert]. Parsippany, NJ: Actavis Pharma, Inc.
23. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
24. Selden T, Ahlner J, Druid H, Kronstrand. Toxicological and pathological findings in a
series of buprenorphine related deaths. Possible risk factors for fatal outcome. Forensic
Sci Internat. 2012;220:284-290.
25. Killcarslan T, Sellers EM. Lack of Interaction of buprenorphine with flunitrazepam
metabolism. Am J Psychiatry. 2000;157(7):1164-1166.
26. Ibrahim RB, Wilson JG, Thorsby ME, Edwards DJ. Effect of buprenorphine on CYP3A
activity in rat and human liver microsomes. Life Sci. 2000;66(14):1293-1298.
27. Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I. A critical review of the
causes of death among post-mortem toxicological investigations: analysis of 34
buprenorphine-associated and 35 methadone-associated deaths. Addiction.
2004;99(8):978-988.
28. Kay B. Buprenorphine, benzodiazepines, and respiratory depression. Anaesthesia.
1984;39(5):491-492.
29. Gaulier JM, Marquet P, Lacassie E, Dupuv JL, Lachatre G. Fatal intoxication following
self-administration of a massive dose of buprenorphine. J Forensic Sci.
2000;45(1):226-228.
30. Reynaud M, Petit G, Potard D, Courty P. Six deaths linked to concomitant use of
buprenorphine and benzodiazepines. Addiction. 1998;35:1385-1392.
31. Lintzeris N, Mitchell T, Bond A et al. Pharmacodynamics of diazepam co-administered
with methadone or buprenorphine under high dose conditions in opioid-dependent
patients. Drug Alcohol Depend. 2007;91:187-194.
32. Lintzeris N, Mitchell T, Bond A, Nestor L, Strang J. Interactions on mixing diazepam with
methadone or buprenorphine in maintenance patients. J Clin Psychopharmacol.
2006;26:274-283.
33. Nielsen S, Taylor DA. The effect of buprenorphine and benzodiazepines on respiration in
the rat. Drug Alcohol Depend. 2005;79(1):95-101.
34. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
35. FDA Drug Safety Communication: FDA urges caution about withholding opioid addiction
medications from patients taking benzodiazepines or CNS depressants: careful
medication management can reduce risks. Available at https://www.fda.gov:80/FDAgov/
Drugs/DrugSafety/ucm575307.htm. Accessed September 30, 2017.
36. Buprenorphine and naloxone tablet [package insert]. Parsippany, NJ: Actavis Pharma, Inc.
37. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder.
38. Substance Abuse and Mental Health Services Administration. Medications To Treat
Opioid Use Disorder. Kampman & Jarvis, 358-367

6
 Buprenorphine for Opioid Use Disorder
MODULE 2 Pharmacology and Administration

References (continued)
39. FDA Drug Safety Communication: FDA urges caution about withholding opioid addiction
medications from patients taking benzodiazepines or CNS depressants: careful
medication management can reduce risks.
40. Vivitrol® [package insert]. Waltham, MA: Alkermes, Inc.; 2015.

This project is supported by 1 NU17CE002742 (Prescription Drug Overdose Prevention), funded by the Centers for
Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent
the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services.

7
0111 6/21