Retrospective Cohort Study of the Prevalence of Off-label Gabapentinoid Prescriptions in Hospitalized Medical Patients

A total of 4,103 unique patients were admitted from December 2013 to July 2017, of whom 550 (13.4%) were receiving a gabapentinoid before admission. Two preadmission users were coprescribed gabapentin and pregabalin for a total of 552 prescriptions. The prevalence of preadmission gabapentinoid use remained steady during the period of interest (Appendix 1; P = .29 for temporal trend). There were no significant differences between gabapentinoid users and nonusers with regard to age or sex, but users had a higher prevalence of chronic disease (Table 1). In addition, compared with nonusers, gabapentinoid users were more likely to be coprescribed opioids (28.2% vs 12%; P < .01), benzodiazepines (24.5% vs 14.3%; P < .01), and nonbenzodiazepine sedative hypnotics (7.5% vs 3.6%; P < .01). Of note, 10.2% of gabapentinoid users were simultaneously coprescribed both opioids and benzodiazepines versus. 3.6% of nonusers (P < .01; Table 1). Nonetheless, there was no statistically significant difference between users and nonusers with regard to inpatient mortality (10% vs 12%; P = .17).

The indications for gabapentinoid use are presented in Table 2. Only a minority (17% or 94/552) had an approved indication. Among these 94 patients, 38 (40%) received FDA-recommended doses, 47 (50%) received doses below those demonstrated to be effective, and 9 (10%) received higher-than-recommended doses. New prescriptions at discharge were observed in 1.5% of patients, with the majority given for off-label indications (Appendix 2).

In this large cohort study of hospitalized medical patients, preadmission gabapentinoid use was present in one in every eight admitted patients. Most patients had off-label indications, including the small number of patients who had the drug started in hospital. Even for approved indications, the doses were often lower than what trials have suggested to be effective. Finally, although we have demonstrated that deprescribing occurred, it was uncommon and either precipitated by an adverse event or the justification was poorly documented.

To our knowledge, our study is one of the first to examine what happens to gabapentinoids in hospitalized patients and we present important new data with respect to dosing and prescribing patterns. The low rates of discontinuation, intent to taper, or dose decreases in our cohort represent a potential area of improvement in deprescribing.

Deprescribing should be considered for patients with serious adverse events, for whom less serious adverse effects preclude achieving clinically effective doses, and for those who do not perceive benefit. Given the magnitude of the problems presented by polypharmacy, we propose that stopping priority be given to off-label use (especially when clinically ineffective) and for patients coprescribed opioids or sedatives. Up to a third of users in our cohort were coprescribed opioids or benzodiazepines, which is particularly concerning given the association with increased opioid-related mortality.^12,15 Although we did not observe a difference in inpatient mortality, such a study is underpowered for this outcome especially when considering the competing risks of death in hospital. Importantly, when deprescribing, the drug should be tapered over several weeks to limit symptoms of withdrawal and to prevent seizure.¹¹

Presumed off-label use and subtherapeutic doses were common in our cohort, with only 17% of users having a clearly documented FDA-approved indication, in agreement with a previous study that reported only 5% on-label use.⁴ High doses of gabapentinoids required for efficacy in clinical trials may be difficult to achieve because of dose-limiting side effects, which may explain the relatively low median doses recorded in our real-world cohort. Another possibility is that frail, older patients with renal dysfunction experience effectiveness at lower median doses than those quoted from study populations. In our study, patients on lower doses of gabapentinoids had a higher prevalence of stage IV or V chronic kidney disease (CKD). Stage IV/V CKD was identified in 16/47 (34.0%) patients on lower doses of gabapentinoids, compared to 4/38 (10.5%) on doses within the FDA-recommended range.

Our study has limitations; findings from a single Canadian tertiary care hospital may not be generalizable to other hospitals or countries, particularly given the differences between the Canadian and US health systems. Indications were extracted from the patient chart and even with the best possible medication history and thorough review, sometimes they had to be inferred. Caution should also be exercised when interpreting the omission of an indication as equating to a lack of justifiable medication use; however, the rate of off-label use in our cohort is in agreement with prior research.⁴ Moreover, with a retrospective design, the effectiveness of the drug on an individual basis could not be assessed, which would have allowed a more precise estimate of the proportion of patients for whom deprescribing might have been appropriate. The strengths of this study include a large sample of real-world, heterogeneous, general medical patients spanning several years and our use of trained pharmacists and physicians to determine the drug indication as opposed to reliance on administrative data.