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Letters to the Editor: Letter to the Editor

Lack of Evidence for Ceiling Effect for Buprenorphine Analgesia in Humans

Richardson, Michael G. MD; Raymond, Britany L. MD

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doi: 10.1213/ANE.0000000000003368
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To the Editor

Buprenorphine is increasingly supplanting methadone in medication-assisted pharmacotherapy in pregnant women with opioid use disorder, owing to its safety profile, administration convenience, and favorable maternal and neonatal outcomes. Chronic buprenorphine exposure renders common opioid analgesic modalities less effective, due to drug-induced cross-tolerance and buprenorphine’s unique pharmacologic properties. The report by Leighton and Crock1 is a valuable addition to the evidence base regarding the care of parturients who take buprenorphine chronically, as it highlights elements of effective management of postcesarean pain in this growing population.1

Buprenorphine’s safety is conferred by ceiling effects (flattening of the dose/effect curve) for respiratory depression, sedation, and subjective measures (ratings of euphoria/liking the drug), effects that distinguish it from methadone and other full opioid agonists.2 However, buprenorphine does not appear to exhibit a ceiling effect for analgesia3,4 as is commonly asserted. The detailed human pharmacologic studies conducted by Walsh et al,5 including the study cited by Leighton and Crock1 as evidence of an analgesic ceiling effect, did not actually examine any analgesic effects. A 2006 study of respiratory and analgesic effects of 2 incremental doses of buprenorphine in 20 healthy young volunteers confirmed a ceiling effect for respiration, but not for analgesia.3 Raffa et al4 reviewed 24 controlled clinical trials that compared the analgesic effect of buprenorphine with that of other opioid agonists (morphine, fentanyl, sufentanil, oxycodone). In 23 trials, buprenorphine produced equivalent or superior analgesia. The bell-shaped analgesia dose–response curve reported in some early rodent studies has thus far not been observed in subsequent animal studies nor in humans.4

The notion of a ceiling effect for buprenorphine analgesia may persist for several reasons. These include its ceiling effect for nonanalgesic effects, its long half-life and high receptor affinity, its ability to both precipitate and suppress withdrawal in the presence of chronic opioid use (depending on the particular opioid, dose, and duration since last administration), and the common use of the term “opioid-blocking” to describe one of its greatest therapeutic benefits, namely cross-tolerance and attenuation of responses to other opioids (which is distinct from a particular mechanism, such as pharmacologic antagonism).2 We think that clarity and precision regarding buprenorphine’s analgesic effects are vital, given the perioperative management implications for those taking the drug.

Michael G. Richardson, MD
Britany L. Raymond, MD
Department of Anesthesiology
Vanderbilt University Medical Center
Nashville, Tennessee
[email protected]


1. Leighton BL, Crock LWCase series of successful postoperative pain management in buprenorphine maintenance therapy patients. Anesth Analg. 2017;125:1779–1783.
2. Walsh SL, Eissenberg TThe clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic. Drug Alcohol Depend. 2003;70:S13–S27.
3. Dahan A, Yassen A, Romberg R, et al.Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth. 2006;96:627–632.
4. Raffa RB, Haidery M, Huang HM, et al.The clinical analgesic efficacy of buprenorphine. J Clin Pharm Ther. 2014;39:577–583.
5. Walsh SL, Preston KL, Bigelow GE, Stitzer MLAcute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther. 1995;274:361–372.
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