We found that, compared with users of opiates and of alprazolam or diazepam, users of both gabapentin and pregabalin were at increased risk of initiating treatment with medicines specifically used in the management of AF within 3 months after treatment initiation. The RR estimates were consistent for the primary and secondary variables and across the age, sex, and co-medication strata, and they showed a dose–response trend.
AF associated with gabapentin or pregabalin has not been described in reports of randomized clinical trials (RCTs) or in systematic reviews of RCTs. The reason may be that participants in placebo-controlled RCTs with gabapentin [8] or pregabalin [9] had a mean age of 55 years. In contrast, in a series of patients with AF possibly induced by gabapentin [13] or pregabalin [14], > 80% were older than 60 years.
Gabapentin and pregabalin exhibit L-type calcium channel antagonism and attenuate calcium influx, which can explain unwanted electrophysiological effects. Both drugs are eliminated by renal excretion as unchanged drugs, and both Summary of Product Characteristics (SPCs) state that elderly patients may require a dose reduction [17, 18]. However, pharmacokinetic studies in subjects over the age of 65 years have not been reported [7].
Our study covered the whole population, so that representativeness of the study population is not a concern. Patients on cardiovascular medications were excluded and the analyses were restricted to incident users, so that the potential biases and confounding that would have been introduced by the inclusion of patients with high cardiovascular risk and prevalent users were avoided. Patients initiating treatment with gabapentin or with pregabalin were compared with patients initiating treatment with two different alternative therapeutic options in the most common indications of gabapentinoids. The comparison with both opiates and benzodiazepines showed increases of risk in the same direction and of similar magnitudes. The results are biologically plausible, and they were consistent for the primary and the secondary variables and across all age, sex, and NSAID co-treatment strata. A dose–effect trend was found. A material increase in risk with alprazolam or diazepam was not recorded. These features indicate that users of gabapentin and pregabalin are at increased risk of initiating antithrombotic and antiarrhythmic drugs, probably prompted by a diagnosis of AF.
Our study has several limitations. Those which merit more emphasis relate to the lack of clinical details on the participants and to the validity of the outcome variables used. The lack of clinical details precluded describing their clinical course and their prognosis and adjusting for potential clinical confounding factors such as the indication for use and co-morbidities. The outcome variables were surrogate markers of AF. A recent study performed in the French healthcare databases has suggested that the initiation of an oral anticoagulant and an antiarrhythmic drug (OAC + AA) recorded in the national pharmaceutical benefits database (SNIRAM) is the strongest predictor for confirmed AF [19]. In our study, the number of patients initiating OAC + AA was low. However, when patients exposed to either gabapentin or pregabalin were considered, the risk was significantly increased with respect to both opiate analgesics and alprazolam/diazepam. Due to lower numbers of exposed patients, our stratified age, sex, and dose–response analyses were based on the variables OAC/APA and OAC/APA + AA, which may be less specific for AF but included higher numbers of patients. For these reasons, our results should be regarded as hypothesis generating.
It is generally considered that the use of prescription claims as proxy variables for the clinical conditions under study can limit the validity of the results. However, as an outcome variable, the prescription of an oral antithrombotic and/or an antiarrhythmic agent is at least as hard as an often tentative diagnosis of AF in the medical record. The use of antiarrhythmic drugs without antithrombotic medication, which may reflect prescribing for a patient with AF with a low risk of stroke, was also significantly increased in users of gabapentin or pregabalin.
If the association between exposure to gabapentinoids and AF is a causal one, its public health impact could be higher than suggested by our data, at least for three reasons. First, although the respective SPCs warn “caution in cardiovascular patients” [17, 18], more than 80% of the new users of gabapentin or pregabalin were already on at least one cardiovascular medication, which is a marker of cardiovascular risk. In order to avoid confounding, we excluded these high-risk patients from the study. Second, in large series of cases reported to the FDA, 70–80% of patients with newly diagnosed AF attributed to gabapentin or pregabalin had developed the condition during the first 3 months of treatment [13, 14], suggesting that additional cases can appear > 3 months after treatment initiation. Third, up to 30% of cases of AF may take time to be diagnosed [20, 21] and many of those who are diagnosed do not receive full anticoagulation initially [22], so that the actual number of cases of AF is probably higher than the number of patients initiating treatment with an antithrombotic drug. Conversely, an episode of AF occurring before the prescription of gabapentin or pregabalin may have been initially overlooked or left untreated, but diagnosed and treated some weeks after the gabapentinoid was prescribed, and this would overestimate the risk.
In recent years, the consumption of gabapentin and pregabalin has increased steadily [1, 3,4,5, 23]. Pain appears to be their most common indication [2, 24]. Although their efficacy in neuropathic pain is modest at best, they are widely used for conditions in which the neuropathic component is difficult to establish. In industry-sponsored placebo-controlled RCTs in neuropathic pain, gabapentin was ineffective at doses < 1200 mg per day [8] and pregabalin at doses < 150 mg per day [9]. The best (lowest) number needed to treat for at least a 50% pain relief over baseline with pregabalin was 3.9, but only with a dose of 600 mg daily, which in turn was associated with a withdrawal rate of 19% (mainly due to dizziness and somnolence) [9]. In a recent rigorously conducted placebo-controlled trial, pregabalin at doses of 150–600 mg daily was ineffective to mitigate pain or disability in patients with painful sciatica, and it was associated with a 3-fold increase in the incidence of dizziness [6]. A recent systematic review on gabapentinoids in chronic low back pain concluded that limited evidence shows a significant risk of adverse effects without any demonstrated benefit [25]. In our study, 84% of patients on gabapentin or pregabalin had been prescribed < 1200 mg per day or 150 mg per day, respectively, and the risks of the main outcome variables were already increased with these lower doses.
Gabapentin was approved in 1993 as adjunctive therapy for partial complex seizures. Heavy promotion for unapproved indications pushed its sales in the US from US$98 million in 1995 to nearly US$3 billion in 2004 [26]. In that year gabapentin lost its patent, but Pfizer launched pregabalin, not only for epilepsy but also for the wider, softer, and better selling indications of anxiety and neuropathic pain. Gabapentin and pregabalin are being prescribed off-label for painful conditions, mainly low back pain [2], where the neuropathic component is difficult to establish. In 2016 pregabalin reached global sales of US$5435M, and it ranked 12th in the list of global top-selling pharmaceuticals [27]. Between 2012 and 2016, prescriptions of gabapentin increased from 39 to 64 million, and sales of pregabalin increased by more than 2.4-fold in the US [1]. Our results contrast with the fact that after decades of wide and rising clinical use of gabapentin and pregabalin, only a few case reports and case series of AF attributed to these drugs have been described.