Work

Reply to Cataldo (2016): Arrhythmia associated with buprenorphine and methadone reported to the Food and Drug Administration

Year: 2016

Type: letter

Abstract: We reviewed the letter from Dr Cataldo of Purdue Pharma and appreciate his thoughtful and insightful comments related to Butrans®, a transdermal formulation of the synthetic opioid buprenorphine, included in our recent pharmacovigilance study 1. We acknowledge the observation that, although transdermal buprenorphine initially carried a Food and Drug Administration (FDA) boxed warning with respect to QTc prolongation, on a subsequent labeling revision this boxed warning was removed. Of note, this caution continues to appear in the ‘Warnings & precautions’ section of the label 2. We also thank Dr Cataldo for highlighting the exact point estimate and standard deviation for the 6-month change in QTc interval reported by Martell and colleagues associated with methadone induction 3. Nonetheless, our statement, that the magnitude of the QTc interval change [9.2 ms, 90% confidence interval (CI) = 5.2–13.3] from baseline with Butrans® 2 was modest and occurred at twice the maximum approved dose, remains accurate. We contend that the overlap in QTc interval—the upper bound of the 90% CI for Butrans® of 13.3 ms exceeded the point estimate of the impact of methadone of 12.3 ms as noted by Martell 3—was indeed relevant, as both buprenorphine and methadone block the delayed rectifier potassium ion channel, the predominant mechanism for QTc-prolongation, at similar micromolar concentrations [4]. That said, given typical maximal serum concentration (Cmax) for the two opioids, we expected a substantially greater cardiac safety margin for buprenorphine compared with methadone, which was borne out in our study 1. Dr Cataldo correctly points out important differences in design between the Butrans® thorough QT study and the study by Martell 3, most notably a lack of a placebo control in the prospective cohort study of methadone induction. Beyond involving different drugs, the Butrans® study was submitted for regulatory approval of a new formulation of buprenorphine, while the Martell study was an observational evaluation conducted with an approved drug formulation and represented the first prospective signal of a cardiac safety liability for methadone. Moreover, the methadone study was performed over a 12-month period in opioid-dependent patients as part of maintenance treatment for addiction. By contrast, the placebo-controlled study of Butrans® was performed only in healthy subjects over the course of just 13 days. Dr Cataldo makes a cogent argument that QTc prolongation might not be expected based on the pharmacokinetics and Cmax for Butrans®. We do not dispute this supposition. However, he is incorrect that we assumed a higher arrhythmia liability for transdermal buprenorphine. Rather, this was simply a hypothesis-generating response to the existing FDA warning regarding Butrans®. Regardless, the number of adverse event cases involving transdermal buprenorphine in the present study was statistically insufficient to either support or refute the existing warning regarding QTc prolongation, which is not present in FDA labeling for oral and sublingual forms of buprenorphine, with or without naloxone. Therefore, we believe our statements, ‘The present study does not exclude the possibility that a transdermal formulation of buprenorphine might manifest a higher arrhythmia liability relative to oral or sublingual delivery systems’ and ‘The transdermal preparation of buprenorphine was only approved in the United States in 2010, and there are currently insufficient pharmacovigilance data to adequately assess disproportionate reporting for QTc prolongation or ventricular arrhythmia with this specific formulation’, are accurate and presented with appropriate equipoise. It seemed necessary to state this methodological limitation explicitly, although we agree that the pharmacokinetic data furnished by Dr Cataldo ameliorates this concern. In conclusion, there remain insufficient pharmacovigilance data to assess disproportionate reporting of QTc-prolongation or torsade de pointes associated with transdermal buprenorphine. That minor limitation, however, should not be construed to obscure the primary findings of our study: that observational data provides convincing evidence that buprenorphine, regardless of formulation, appears potentially safer from a cardiac arrhythmia perspective relative to methadone. None.

Source: Addiction

DOI: 10.1111/add.13425

Authors: David Kao, Mark C. P. Haigney, Philip S. Mehler, Mori Krantz

Institution: University of Colorado Anschutz

Language: English

Topic: Opioid Use Disorder Treatment

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funder: National Heart, Lung, and Blood Institute