Synthetic opioids and arrhythmia risk: a new paradigm?

Abstract

The most commonly prescribed class of medications in the United States for chronic severe pain is opioid analgesics. Due to their low cost and widespread availability, the synthetic opioids are popular choices among clinicians and patients. However, there is an increasingly recognized risk of QT prolongation with several drugs in this class, and recently propoxyphene (Darvon) was withdrawn from the market by the Food and Drug Administration (FDA) due to, in part, the risk of QT prolongation and ventricular arrhythmias Updated Epidemiological Review of Propoxyphene Safety. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; 2010. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234383.pdf on 5 May 2012.

Keywords::

• Darvon
• QTc
• arrhythmia
• synthetic opioid

In a recent issue of Expert Opinion on Pharmacotherapy, Raffa, et al. review the data associated with the mechanism of QT prolongation of the drug propoxyphene and then perform a systemic review of the literature on the QT effects of 50 opioid and non-opioid analgesic drugs [2]. The authors conclude that there is a paucity of experimental and clinical data for most of the available analgesics with regard to effects on cardiac conduction and repolarization. They also note that for the synthetic opioids methadone, oxycodone, and LAAM (levo-α-acetylmethadol) both experimental and clinical data exists, thus allowing for better characterization of the risk of QT prolongation and for patient safety monitoring.

Propoxyphene was introduced in the market in 1957 and had been widely available as a sole product (Darvon) or in combination with acetaminophen (Darvocet). It has long been recognized that the analgesic effect of propoxyphene was minimal, and has been demonstrated to be no better than non-opioid alternatives [3]. With the expanding body of data demonstrating the excess mortality in the setting of propoxyphene overdose compared to other similar drugs as well as a link between propoxyphene dose and QT prolongation [4], the drug was withdrawn from European markets starting in 2005 and was withdrawn from the US market in 2009 [5]. The modest benefit of LAAM, given its thrice weekly dosing versus daily oral methadone, was felt not justify the perceived greater cardiac arrhythmia risk associated with its use.

The fate of propoxyphene prompts the consideration of the potential cardiac toxicities of other synthetic opioids with similar chemical properties. Methadone has perhaps the best characterized risk of QT prolongation and potential pro-arrhythmic cardiac effects. If fact, in 2006 the FDA added a black box warning about the risk of serious cardiac arrhythmias [6]. Methadone is a potent analgesic with a low cost and long terminal elimination half-life, making it a good choice for chronic pain or addiction treatment. However, this drug is also a potent blocker of the human Ether-à-go-go (hERG) potassium ion channel (Ikr), thereby prolonging the repolarization of the cardiac myocyte, which leads to the risk of torsade de pointes [7]. LAAM, a synthetic opioid removed from the marked due to fatal arrhythmia events, shares a very similar chemical structure to both methadone and propoxyphene. LAAM, however, demonstrated slightly greater potency blocking Ikr than methadone [7]. Buprenorphine is another synthetic opioid used both in chronic pain and in addiction medicine, but its chemical structure differs from the three previous drugs as there is not a bi-phenyl ring structure in the molecule, and appears to have less in vitro repolarization liability [7]. Wedam et al. meticulously demonstrated less potent QT prolonging effect of this drug compared to LAAM and methadone using cardiologist manual electrocardiography interpretation [8]. Dextromethorphan, a weak opioid and commonly used cough suppressant, is another synthetic opioid that has been weakly associated with QT prolonging effects at toxic doses [9]. Lacking the bi-phenyl ring, this drug has a somewhat different chemical structure and appears to be a less potent blocker of Ikr [10].

The clinical use and potential for abuse of these drugs creates a challenging assessment of animal model and pre-clinical data. Isolated myocyte study of potassium channels, studies of hERG effect and animal model QT monitoring are vital to drug development but are insufficient endpoints for patient safety. Similarly, pre-approval human studies cannot account for the variety of patient conditions, drug interactions, and changes in electrolyte balance that contribute to adverse events. In a clinical setting of drug addiction or chronic pain there is even greater potential for treatment abuse or concomitant drug and alcohol abuse. Often QT prolongation is a combination of factors such as serum potassium or magnesium derangement, or drug interactions leading to increased drug effect. This combination of effects with the underlying QT prolonging effect of the drug likely yields the adverse events.

There are a number of important points to take from the analgesic review. First, among analgesics only the synthetic opioids have a theoretic potential to prolong the QT interval and increase the risk of cardiac arrhythmias. This risk varies by drug, and it is important to recognize and monitor those patients. Presently, the only synthetic opioid where QT interval monitoring is guideline-based is methadone hydrochloride [11]. The authors of the current systematic review [2] suggest that there do not appear to be analgesics within the limited available dataset that have hERG current inhibitory activity (at least based on IC50/Cmax ratio) indicative of a problem greater than that perceived clinically. We agree with this assertion, but reiterate that the clinical arena always trumps in-vitro evidence. In the case of drug-induced torsade de pointes, the absolute potency of the medication with regard to hERG blockade is often less important than the clinical population in which is being utilized. For example, in patients with structural heart disease and in particular coronary artery disease, a greater prevalence of QTc prolongation and arrhythmia-related will be seen at baseline [12,13]. In the addiction and chronic pain arena high doses of methadone coupled with concomitant hERG blocking drugs (both prescription and illicit) may dramatically magnify arrhythmia risk. Finally, these novel findings that opioids may be proarrhythmic highlight the critical importance of post market surveillance and continued pharmacovigilance, especially in the chronic pain and addiction medicine arenas where patients may be uniquely vulnerable to life-threatening arrhythmia.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.