UMEM Educational Pearls

Category: Toxicology

Title: CYP3A4 inducing agents may cause opioid withdrawal in patients on buprenorphine

Keywords: buprenorphine, CYP3A4, induction, inhibition, metabolism (PubMed Search)

Posted: 4/23/2020 by Hong Kim, MD, MPH
Click here to contact Hong Kim, MD, MPH


Buprenorphine (BUP) is increasingly prescribed/used to treat opioid use disorder (OUD) in the United State. BUP is mainly metabolized by CYP3A4 where its enzymatic activity can be either induced or inhibited by many agents. 


For example, a study showed that Rifampin administration for 15 days, a potent 3A4 inducer, resulted in (1): 

  • Reduction of plasma BUP concentration (70% reduction in area under the curve [AUC]) 
  • 50% of the study subjects (12 out of 24) experienced opioid withdrawal symptoms (OWS)
  • 4 out of 12 who experience OWS received transient increase in their BUP dose (25-100%)


On the contrary, exposure to voriconazole – strong 3A4 inhibitor - resulted in (n=12 health volunteers) (2):

  • Increased the plasma BUP AUC by 4.3 fold
  • Increased peak BUP concentration by 3.9 fold
  • Documented adverse effects were dizziness and nausea only


Cannabis use – (CBD is a CYP 3A4 inhibitor) also increased the BUP concentration by 2.7 fold. (3)


Bottom line:

  1. Be mindful of drug-drug interaction when initiating a new medication in patients with OUD on BUP
  2. Inquire about any recent medication change in patients who may be experiencing OWS while on steady dose of BUP for their OUD. 


1. Drug Alcohol Depend. 2011 Nov 1;118(2-3):326-34. doi: 10.1016/j.drugalcdep.2011.04.013. Epub 2011 May 19.

Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine-maintained patients.

McCance-Katz EF1Moody DEPrathikanti SFriedland GRainey PM.


2. Eur J Clin Pharmacol. 2018 Dec;74(12):1615-1622. doi: 10.1007/s00228-018-2548-8. Epub 2018 Aug 30.

Voriconazole greatly increases the exposure to oral buprenorphine.

Fihlman M1,2Hemmilä T2Hagelberg NM1,2Backman JT3Laitila J3Laine K4,5Neuvonen PJ3Olkkola KT6Saari TI7,8.


3. Eur Arch Psychiatry Clin Neurosci. 2020 Jan 6. doi: 10.1007/s00406-019-01091-0. [Epub ahead of print]

Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy.


Vierke C1Marxen B2Boettcher M3Hiemke C4Havemann-Reinecke U2,5.