Visual Overview
Abstract
Background Gabapentin and pregabalin are used to manage neuropathic pain, pruritus, and restless legs syndrome in patients on hemodialysis. These patients may be especially predisposed to complications related to these agents, which are renally cleared, but data regarding the risk thereof are lacking.
Methods From the US Renal Data System, we identified 140,899 Medicare-covered adults receiving hemodialysis with Part D coverage in 2011. Using Cox regression models in which we adjusted for demographics, comorbidities, duration of exposure, number of medications, and use of potentially confounding concomitant medications, we investigated the association between gabapentin and pregabalin, modeled as separate time-varying exposures, and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture. We evaluated risk according to daily dose categories: gabapentin (>0–100, >100–200, >200–300, and >300 mg) and pregabalin (>0–100 and >100 mg).
Results In 2011, 19% and 4% of patients received gabapentin and pregabalin, respectively. Sixty-eight percent of gabapentin or pregabalin users had a diagnosis of neuropathic pain, pruritus, or restless legs syndrome. Gabapentin was associated with 50%, 55%, and 38% higher hazards of altered mental status, fall, and fracture, respectively, in the highest dose category, but even lower dosing was associated with a higher hazard of altered mental status (31%–41%) and fall (26%–30%). Pregabalin was associated with up to 51% and 68% higher hazards of altered mental status and fall, respectively.
Conclusions Gabapentin and pregabalin should be used judiciously in patients on hemodialysis, and research to identify the most optimal dosing is warranted.
Neuropathic pain, pruritus, and restless legs syndrome are commonly experienced symptoms among patients receiving hemodialysis1,2 and have been associated with poor quality of life.3–5 The anticonvulsant medications gabapentin and pregabalin have been shown to be efficacious treatments for these symptoms in several small, short-term randomized trials conducted in patients on hemodialysis,6–15 and they are recommended as first-line agents for the treatment of neuropathic pain in ESRD.16,17
However, patients on hemodialysis may be particularly vulnerable to complications from the use of gabapentin and pregabalin due to reduced clearance of these agents, which are dependent on renal excretion for their elimination. In the general population, gabapentin and pregabalin have been associated with sedation18,19 and decreased bone mineral density,20,21 which may predispose to risk for falls22,23 and fractures.24 The literature regarding the adverse effects of gabapentin and pregabalin in patients on hemodialysis is limited to case reports or series highlighting the risk of altered mental status25–28 and a cohort study, in which anticonvulsants, including gabapentin, were not independently associated with fracture.29 However, the prevalence, reasons for use, and risks of gabapentin and pregabalin have not been examined in the United States hemodialysis population.
We aimed to describe the prevalence and diagnoses associated with gabapentin and pregabalin use and investigate the association of gabapentin and pregabalin dose with risk of major adverse outcomes (i.e., altered mental status, fall, and fracture) in patients on hemodialysis in the United States. We hypothesized that gabapentin and pregabalin would be associated with risk of these outcomes in a dose-dependent manner.
Methods
Study Design, Data Sources, and Population
We conducted a cohort study using the 2013 standard analytic and Medicare payment files in the US Renal Data System (USRDS), which includes clinical and prescription drug data from 2011.30 This study was not considered human subjects research by the University of California, San Francisco Committee on Human Research.
Diagnoses Associated with Gabapentin and Pregabalin Use
Gabapentin is Food and Drug Administration (FDA)-approved for the treatment of epilepsy and postherpetic neuralgia,31 but it is commonly used off-label for other conditions, such as neuropathic pain, diabetic neuropathy, trigeminal neuralgia, and restless legs syndrome.32 Pregabalin is FDA-approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, adjunctive therapy for partial-onset seizures, and fibromyalgia, and it is also approved for the treatment of generalized anxiety disorder in Europe.33,34 We were interested in capturing the prevalence of both on-label and off-label diagnoses associated with gabapentin and pregabalin use, including specific diagnoses that have been evaluated in patients on hemodialysis (e.g., neuropathic pain, pruritus, and restless legs syndrome).6–15 Diagnoses of interest were captured using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (Supplemental Table 1).
Gabapentin and Pregabalin Exposure Variables
Ascertainment of gabapentin and pregabalin exposure was started in January 2011, and we delayed ascertainment of the outcomes until February 2011 to allow for determination of prior exposure. Gabapentin exposure and pregabalin exposure were modeled as separate time-varying predictors. Our database was structured such that there was a record for every person for each day of observation. With this database structure, we defined periods of medication possession as the period starting from the date of service of a prescription and continuing until the days supply of the prescription was completed.35 The time at risk began on the first day of the prescription claim. Gaps between prescriptions were considered as periods of nonexposure. For each period of medication possession, we calculated a daily dose averaged over the duration of the prescription, and we classified periods of exposure into the following dose categories for gabapentin (0, >0–100, >100–200, >200–300, and >300 mg) and pregabalin (0, >0–100, and >100 mg).
Outcome Variables
We examined first episodes of altered mental status, fall, and fracture requiring an emergency room visit or hospitalization during 2011 in separate models. Using our continuous database structure, we were able to assign event dates to the outcomes of interest, and we stopped classifying days as time at risk after the occurrence of the first events. Outcomes were ascertained from the revenue, physician/supplier, and institutional claims files using ICD-9-CM diagnosis and Current Procedural Terminology codes (Supplemental Table 2). Fractures of interest included those of the hip, femur, pelvis, leg, foot, arm, hand, or axial skeleton. We included emergency room visits in which there was a code for the outcomes and hospitalizations in which the outcomes were identified as the primary diagnosis according to standard USRDS methodology.36
Statistical Analyses
We calculated the prevalence of at least one prescription for gabapentin and pregabalin during 2011, and among those with at least one prescription for these agents, we calculated the prevalence of at least one high-dose prescription (defined as >300 mg for gabapentin and >100 mg for pregabalin). In Table 1, patients were categorized into two groups: receipt of at least one prescription for gabapentin or pregabalin in 2011 or no use of these agents in 2011. Baseline characteristics are presented as means and SDs or medians with interquartile ranges for continuous variables and percentages for categorical variables. We compared characteristics of those who received gabapentin or pregabalin with those who did not using Mann–Whitney and chi-squared tests. We calculated outcome rates, expressed as the number of events per 100 person-years, with follow-up time partitioned according to gabapentin dose category (0, >0–100, >100–200, >200–300, and >300 mg) and pregabalin dose category (0, >0–100, and >100 mg). Among individuals with at least one prescription for gabapentin and pregabalin in 2011, we ascertained diagnoses associated with use of gabapentin and pregabalin according to whether a relevant ICD-9-CM code was present within 60 days before the date of service of each prescription in the Medicare Part D prescription drug file.
Baseline characteristics by receipt of gabapentin or pregabalin
For each predictor and outcome analysis, we constructed a Cox model using a time-varying definition of gabapentin and pregabalin exposure to compare the hazard of each outcome during each dose category with no use. We controlled for the following potential confounders: baseline demographic characteristics (i.e., age, duration on dialysis, sex, race, geographic location of ESRD network as defined by US Census geographic divisions, body mass index, and comorbidities [i.e., alcohol dependence, coronary artery disease, cancer, other cardiac disease, dysrhythmia, congestive heart failure, cerebrovascular disease, diabetes, drug dependence, opioid dependence, hypertension, inability to ambulate, inability to transfer, chronic obstructive pulmonary disease, peripheral vascular disease, tobacco dependence, liver disease, dementia, depression, and seizures/epilepsy]), and medication burden (i.e., total number of unique medications prescribed at baseline). We also adjusted for duration of gabapentin and pregabalin exposure to account for the possibility of differential associations according to shorter duration of exposure (<30 days) compared with longer duration of exposure (≥30 days). Comorbidities were ascertained using the USRDS Medical Evidence Report and ICD-9-CM diagnosis and procedure codes. Specifically, we included diagnoses indicated at the time of dialysis initiation on the USRDS Medical Evidence Report or present on two outpatient claims or one inpatient claim during 2010 in the institutional claims or physician/supplier files (Supplemental Table 3).37–40 We adjusted for use of concomitant medications that could affect risk of the outcomes (e.g., benzodiazepines and antidepressants with anticholinergic properties) as a time-varying covariate. We included anticholinergic antidepressants in particular, because their side effects (e.g., sedation and orthostatic hypotension) could predispose to fall and fracture.41,42
Patients were censored from the study cohort at the time of death, kidney transplantation, change in modality, uncertain or recovered function, withdrawal from dialysis, loss to follow-up, discontinuation of Part D coverage, or end of the study period. We also performed a sensitivity analysis to account for potential misclassification of the exposure related to the Medicare Part D coverage gap (i.e., “donut hole”) that occurs every calendar year, beginning when the initial coverage limit has been exceeded and ending when catastrophic coverage begins.36 The Part D program offers a low-income subsidy that provides full or partial coverage during the coverage gap. Thus, we performed an analysis restricting to patients with the low-income subsidy.43 We considered a two-tailed P value <0.05 to be statistically significant. We used SAS version 9.4 (SAS Institute, Inc., Cary, NC) for all analyses.
Results
Demographics, Gabapentin and Pregabalin Use, and Indications
We identified 159,467 adult patients receiving chronic in-center hemodialysis with Medicare coverage in 2010 (required to capture claims data for determining comorbidities and potential indications for gabapentin and pregabalin treatment) and Part D coverage as of January 2011. To optimize accuracy of exposure and outcome ascertainment, we then eliminated patients with intermittent Part D coverage, patients with Veterans Affairs coverage, and those with no institutional, dialysis, or Part D medication claims in 2011 (n=9042). We also eliminated patients with a missing body mass index to have complete data for this possible confounding variable (n=7412). Patients who died, received a kidney transplant, changed dialysis modality away from in-center hemodialysis, had uncertain or recovered kidney function, were lost to follow-up, withdrew from dialysis, or lost Part D coverage (which precluded subsequent ascertainment of exposure) during January 2011 were also excluded (n=2114). The final study cohort consisted of 140,899 adult Medicare-covered patients on chronic hemodialysis with continuous Part D coverage beginning in January 2011 (Figure 1).
Flow diagram demonstrating selection of study cohort. BMI, body mass index; VA, Veterans Affairs. aPatients were also excluded if the following occurred in January 2011: death, kidney transplantation, change in modality away from in-center hemodialysis (e.g., home hemodialysis or peritoneal dialysis), uncertain/recovered function, loss to follow-up, withdrawal from dialysis, or loss of Part D coverage, which precluded ascertainment of exposure status as of February 2011.
The median age was 61 years old (interquartile range, 51–72 years old), 52% were men, and 50% were white. Nineteen percent of the cohort was censored for the following reasons: death (13%), transplant (2%), change in modality (1.5%), dialysis withdrawal (1.7%), and loss of Part D (0.6%). Younger patients, women, white patients, and those with higher body mass index and comorbid conditions (cerebrovascular disease, depression, hypertension, coronary artery disease, congestive heart failure, other cardiac disease, dysrhythmia, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes mellitus, liver disease, tobacco dependence, opioid dependence, and inability to ambulate) were more likely to be prescribed gabapentin or pregabalin (Table 1). The number of total prescriptions and percentage of patients prescribed benzodiazepines and anticholinergic antidepressants at baseline were higher among those who were prescribed gabapentin or pregabalin than those who were not.
Nineteen percent (n=26,916) of the cohort received gabapentin in 2011, of whom 43% (n=11,638) had at least one high-dose (>300 mg) prescription. Four percent (n=5829) received pregabalin in 2011, of whom 45% (n=2634) had at least one high-dose (>100 mg) prescription. The median dose of gabapentin prescribed for most indications was 300 mg, and the median dose of pregabalin prescribed for most indications was 100 mg (Supplemental Table 4). The median duration of exposure to gabapentin was 117 days (25th to 75th percentiles, 38 to 229), and the median duration of exposure to pregabalin was 93 days (25th to 75th percentiles, 31 to 211) (Supplemental Table 5). Usage of gabapentin and usage of pregabalin were similar among those who received the low-income subsidy (n=108,901), with 20% (n=21,761) and 5% (n=4983) receiving gabapentin and pregabalin in 2011, respectively.
Among those with at least one prescription for gabapentin during 2011, the most common diagnoses associated with use were as follows: neuropathic pain (65%), anxiety (14%), insomnia (8%), fibromyalgia (6%), pruritus (5%), restless legs syndrome (4%), and bipolar disorder (2%) (Table 2). A similar pattern was observed for pregabalin: neuropathic pain (69%), anxiety (15%), insomnia (8%), fibromyalgia (8%), pruritus (5%), restless legs syndrome (4%), and bipolar disorder (2%). Diagnoses of migraine, seizures/epilepsy, withdrawal seizures, periodic limb movement of sleep, and attention deficit hyperactivity disorder were uncommon, and 29% of gabapentin users and 26% of pregabalin users did not have any of the diagnoses of interest during the 60 days preceding the prescription. There were relatively few patients taking gabapentin (n=96) and pregabalin (n=27) for seizures/epilepsy, of whom 75% and 78%, respectively, had a diagnosis for another indication of interest. The most common overlapping diagnosis was neuropathic pain, which was present in 69% and 70% of patients taking gabapentin and pregabalin for seizures/epilepsy, respectively.
Diagnoses associated with gabapentin and pregabalin use among individuals with at least one prescription in 2011
Outcome Rates and Associations with Gabapentin
The rates of the outcomes of interest were greater when patients were receiving higher doses of gabapentin. Patients not using gabapentin experienced 14 altered mental status episodes per 100 person-years, seven falls per 100 person-years, and four fractures per 100 person-years, whereas rates during periods of use of >0–100, >100–200, >200–300, and >300 mg were higher (18, 22, 24, and 26 altered mental status episodes per 100 person-years, respectively; ten, 11, ten, and 13 falls per 100 person-years, respectively; and five, five, five, and six fractures per 100 person-years, respectively).
Compared with no gabapentin use, the hazard of altered mental status was greater with higher gabapentin dose category (Table 3). Patients were at higher risk for this outcome beginning with the >100-200 mg category (adjusted hazard ratio [HR], 1.31; 95% confidence interval [95% CI], 1.17 to 1.46), and the risk was higher for each successive dose range, with those receiving >300 mg at 50% higher risk (95% CI, 39% to 63%). The apparent gradient of hazard according to dose was also observed for falls, except that even those taking >0–100 mg were also at significantly higher risk (HR, 1.26; 95% CI, 1.07 to 1.48). Patients receiving >300 mg of gabapentin were 55% more likely to fall (95% CI, 39% to 72%). Although the hazards of fracture were higher at each dose level than for patients not receiving gabapentin, only those receiving >300 mg were at statistically significantly higher risk (HR, 1.38; 95% CI, 1.18 to 1.61). Shorter duration of drug exposure (i.e., <30 days) was associated with significantly higher hazard of altered mental status (HR, 1.15; 95% CI, 1.06 to 1.25) and fall (HR, 1.15; 95% CI, 1.03 to 1.29) for gabapentin than longer duration of exposure.
Risk of altered mental status, fall, and fracture by gabapentin and pregabalin dose category
Outcome Rates and Associations with Pregabalin
The rates of outcomes of interest were greater when patients were receiving higher doses of pregabalin (no use, >0–100 mg, and >100 mg): altered mental status (15, 26, and 25 per 100 person-years, respectively), fall (seven, ten, and 14 per 100 person-years, respectively), and fracture (four, five, and five per 100 person-years, respectively).
Compared with no pregabalin use, both low-dose (HR, 1.51; 95% CI, 1.32 to 1.74) and high-dose (HR, 1.46; 95% CI, 1.24 to 1.71) pregabalin were associated with higher hazard of altered mental status (Table 3). Only high-dose pregabalin (HR, 1.68; 95% CI, 1.36 to 2.08) but not low-dose pregabalin (HR, 1.24; 95% CI, 1.00 to 1.54) was associated with higher hazard of fall. Neither low-dose (HR, 1.20; 95% CI, 0.87 to 1.66) nor high-dose (HR, 1.38; 95% CI, 1.00 to 1.92) pregabalin was associated with statistically significantly higher hazard of fracture. Shorter duration of drug exposure (i.e., <30 days) was associated with significantly higher hazard of altered mental status (HR, 1.29; 95% CI, 1.07 to 1.54) and fall (HR, 1.32; 95% CI, 1.02 to 1.72) for pregabalin than longer duration of exposure.
The associations for gabapentin and pregabalin were similar in the sensitivity analysis restricted to patients with the low-income subsidy (Supplemental Table 6).
Discussion
Among patients receiving hemodialysis with Medicare Part D coverage, we observed that the use of gabapentin was common, whereas the use of pregabalin was relatively uncommon. Gabapentin and pregabalin were originally developed as antiepileptic medications,44,45 but the prevalence of a diagnosis for seizure or epilepsy in the 60 days before receipt of a gabapentin or pregabalin prescription was rare. Neuropathic pain was the predominant diagnosis observed among users of these agents, and other common diagnoses included anxiety, insomnia, fibromyalgia, pruritus, restless legs syndrome, and bipolar disorder. A substantial proportion of patients receiving these medications did not have any of the diagnoses of interest around the time of prescription. Gabapentin and pregabalin were associated with risk of altered mental status, fall, and fracture in a largely dose-dependent manner and in some cases, even at levels of dosing considered safe by guidelines. Shorter duration of use was associated with higher risk of altered mental status and fall for gabapentin and pregabalin, which could reflect an expected finding if these drugs are being discontinued early after adverse events occur.
Gabapentin is not metabolized, and it is solely eliminated by renal excretion; pregabalin is not appreciably metabolized, and it is over 90% renally eliminated.2,46,47 Accordingly, clinical practice recommendations and published reviews for the management of neuropathic pain in ESRD recommend conservative dosing of gabapentin and pregabalin, up to a maximum dose of 300 or 100 mg daily, respectively.2,16,17 However, there are limited studies about the pharmacokinetics of gabapentin and pregabalin among patients on hemodialysis,46–48 and none have compared pharmacokinetics according to dose category. Thus, these recommendations are based on expert opinion. In the context of pruritus, studied doses have actually been lower, ranging from 100 to 300 mg three times per week to 400 mg of gabapentin two times per week after dialysis7–11,49 and 25–75 mg of pregabalin daily11,50 and 75 mg three times per week postdialysis.12,51 Similarly, gabapentin doses ranging from 200 to 300 mg three times per week postdialysis have been studied for restless legs syndrome.13–15,52 In our cohort, use of high doses of gabapentin (>300 mg) and pregabalin (>100 mg) was common, suggesting that providers are prescribing these agents liberally and may not universally be aware of recommended dose limits.
Despite the recognized role of gabapentin and pregabalin in the management of symptoms in patients on hemodialysis, there are limited data about the relationship between their use and major complications in this population. In a small patient series that included nine patients on dialysis taking gabapentin, six were hospitalized with obtundation, unresponsiveness, or coma, and one was hospitalized with progressive weakness and ataxia, which led to a fall and fracture requiring surgery.28 In an international study of 12,782 patients on hemodialysis, anticonvulsants, including gabapentin, were not associated with risk of hip or other fractures.29 In contrast, we identified that gabapentin was an independent risk factor for fracture, which may reflect differences in the study population, sample size, predictor ascertainment (we examined gabapentin as a separate exposure), outcome ascertainment, and analytic approach.
There are several limitations that we acknowledge. Our study was observational, and therefore, we cannot exclude the possibility of residual confounding, although we adjusted for a large set of variables. We ascertained diagnoses associated with gabapentin and pregabalin use with ICD-9-CM codes, but we do not know with certainty that these were the indications for their use, because we lacked accompanying clinical information. We determined gabapentin and pregabalin exposure on the basis of claims data, and therefore, we were unable to verify whether patients took their medications and the exact dates over which the medications were used. We were unable to account for the timing of gabapentin and pregabalin dosing relative to a dialysis session and the potential for clearance by the dialysis treatment. However, regardless of the timing of receipt, we still observed that gabapentin and pregabalin use was associated with adverse outcomes. Ascertainment of outcomes was on the basis of ICD-9-CM codes; therefore, it is possible that outcomes may not have been fully captured. However, it is likely that misclassification of the exposure did not differ according to outcome status and that misclassification of the outcome did not differ according to exposure status, both of which would tend to bias the results to the null. Pregabalin use and fractures were relatively uncommon; therefore, our precision for this association was low, and the 95% CI included clinically important increases (up to a 92% higher risk). We evaluated associations with the events of interest, but we did not evaluate associations with mortality after the events. The large sample size and detailed medication data, which enabled determination of anticonvulsant agent and dose, were strengths of our study.
In summary, gabapentin use was common among patients receiving hemodialysis in the United States, but pregabalin use was not. Although neuropathic pain was a common diagnosis, there seemed to be a variety of indications for use of gabapentin and pregabalin, which is consistent with data from several clinical trials supporting the efficacy of these medications.6–15 We observed that these agents were associated with risk of altered mental status, fall, and fracture in a dose-dependent manner, even at lower doses that would be deemed safe according to guidelines.
Given that there is evidence of benefit and risk associated with the use of gabapentin and pregabalin in patients on hemodialysis, determining how to optimally use these agents in clinical practice is important. Ideally, the responsibility for determining the appropriate use of gabapentin and pregabalin in this population should be shared by drug manufacturers, the FDA, and physicians. However, now that their use for off-label indications is prevalent, which may, in part, reflect inappropriate marketing of these agents by the manufacturer that occurred over a decade ago,53–55 and given the inherent challenges of postmarketing safety surveillance (e.g., spontaneous reporting, which may not fully capture their adverse event profile),56 the research community may be in the best position to address questions of appropriate use. Future studies that focus on defining the minimally effective dosage that balances the risks and benefits for a given indication are warranted.
Disclosures
None.
Acknowledgments
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants K23DK103963 (to J.H.I.) and K24DK085153 (to K.L.J.), National Institute on Aging grants K24AG049057 (to M.A.S.) and P30 AG044281 (to M.A.S.), and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) through UCSF Clinical & Translational Science Institute (UCSF-CTSI) grants KL2 TR000143 and KL2 TR001870.
The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funding organizations had no role in the study design; collection, analysis, and interpretation of the data; writing of the report; and decision to submit the article for publication. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2018010096/-/DCSupplemental.
- Copyright © 2018 by the American Society of Nephrology
References
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