Visual Abstract
Abstract
Background
Gabapentinoids, commonly used for treating neuropathic pain, may be misused and coprescribed with opioid and benzodiazepine, increasing the risk of mortality and dependency among kidney transplant recipients.
Methods
We identified adult kidney transplant recipients who enrolled in Medicare Part D in 2006–2017 using the United States Renal Data System/Medicare claims database. We characterized recipients' post-transplant concomitant prescription of gabapentinoids, opioids, and benzodiazepine stratified by transplant year and recipient factors (age, sex, race, and diabetes). We investigated whether concomitant prescriptions were associated with postkidney transplant mortality using Cox regression. Models incorporated inverse probability weighting to adjust for confounders.
Results
Among 63,359 eligible recipients, 13% of recipients filled at least one gabapentinoid prescription within 1 year after kidney transplant. The prevalence of gabapentinoid prescriptions increased by 70% over the study period (16% in 2017 versus 10% in 2006). Compared with nonusers, gabapentinoids users were more likely to have diabetes (55% versus 37%) and obesity (46% versus 34%). Of the 8509 recipients with gabapentinoid prescriptions, 45% were coprescribed opioids, 7% were coprescribed benzodiazepines, and 3% were coprescribed both opioids and benzodiazepines. Compared with no study prescriptions, gabapentinoid monotherapy (adjusted hazard ratio [aHR]=1.25; 95% confidence interval [CI], 1.16 to 1.32) and combination therapy (gabapentinoids and opioids [aHR=1.49; 95% CI, 1.39 to 1.60], gabapentinoids and benzodiazepines [aHR=1.46; 95% CI, 1.03 to 2.08], and coprescribing all three [aHR=1.88; 95% CI, 1.18 to 2.98]) were all associated with a higher risk of postkidney transplant mortality.
Conclusions
Gabapentinoid coprescription with both benzodiazepines and opioids among kidney transplant recipients increased over time. Kidney transplant recipients prescribed gabapentinoids had a higher risk of post-transplant mortality, and the risk was higher with opioids or benzodiazepine coprescription.
Introduction
Neurologic complications, which may be categorized into stroke, peripheral neuropathies, infection, and malignancies, can involve both the central nervous system and peripheral nervous system and are common causes of significant morbidity and mortality after solid-organ transplant.1,2 Transplant recipients with neurologic complications often experience neuropathic pain, which is an important symptom that affects a recipient's quality of life.1 For the past several decades, opioids were one of the most commonly prescribed drug classes in kidney transplant recipients.3 While opioids are effective analgesics, use for the treatment of neuropathic pain is appropriately limited because of the risks associated with opioids.4 Studies have found that high-level opioid use in the first year after transplant was associated with a two-fold elevated risk of mortality and 68% higher risk of all-cause graft failure risk over the subsequent year.5 Furthermore, chronic opioid use leads to a higher risk of mortality and dependency.6
Gabapentinoids (gabapentin and pregabalin), first approved by the US Food and Drug Administration for the treatment of epilepsy, have shown effectiveness and presumed negligible abuse potential and have become an anticonvulsant commonly used for the treatment of neuropathic pain.7,8 Both gabapentinoids and opioids were within the top 15 drug classes covered by Medicare Part D that were most commonly prescribed to patients with kidney failure in 2018.3 However, increased prescribing has raised concerns for possible misuse. A UK study conducted using primary care medical records showed that off-label gabapentinoid prescription use accounted for 52% of prescriptions in 2017. Non-neuropathic pain accounted for 80% of the off-label gabapentin use.9 Gabapentinoids may have been prescribed with a lower threshold by clinicians who were seeking an alternative to opioids and felt more comfortable prescribing gabapentinoids in treating various chronic pain other than neuropathic pain specifically.10 Notably, gabapentinoids were likely to be coprescribed with opioids and benzodiazepines, both known to decrease respiratory rates and have sedative effects. The National Institute on Drug Abuse found that more than 30% of opioid overdoses deaths also involve benzodiazepines.11 Although it is clear that concomitant prescriptions are associated with a substantially higher risk of opioid-related death,12 examining the trends of gabapentinoids and concomitant prescription of opioids and benzodiazepines is of critical importance in kidney transplant recipients given the high burden of neurologic complications in the particular population.
In this study, we characterized the trends of gabapentinoid prescribing and coprescribing with opioids and benzodiazepines among kidney transplant recipients. We also quantified the effect of gabapentin coprescribing on postkidney transplant mortality.
Methods
Data Source
The study used national registry data from the United States Renal Data System (USRDS). The USRDS database includes information on donor, recipient, and transplant characteristics for all patients with kidney failure. We used the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) records collected in the USRDS dataset to ascertain baseline characteristics and postkidney transplant mortality, with Medicare billing claims to ascertain recipients' prescription histories.3 We also used the data from the 2014 American Community Survey to obtain recipients' neighborhood characteristics by linking the ZIP code of each recipient from the USRDS dataset.13,14
The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.
Study Population
Using USRDS data, we identified all recipients 18 years or older who had a first-time kidney transplant between January 1, 2006, and December 31, 2017. Recipients were included if their first service date was before June 1, 2017, enrolled in Medicare Part D, and had Medicare as the primary insurer at time of transplant. In the secondary analysis, we further restricted recipients to those who survived with a functioning graft at 1 year after transplant to study the association of gabapentinoid coprescribing with mortality risk.
Prescription Ascertainment
Pharmacy fill records were obtained using Medicare Part D data from 2006 to 2018. Recipients were classified as having been prescribed gabapentin if they had at least one incident gabapentinoid (gabapentin and pregabalin) prescription claim during the first year after kidney transplantation. We defined concomitant prescriptions for gabapentinoids with opioids and/or benzodiazepine as having any opioid drugs and/or benzodiazepines dispensed within 7 days of any gabapentinoid prescription with overlapping days supply, including an allowance for multiple prescribers.15 To examine the effect of concomitant prescription, kidney transplant recipients were classified into five time-fixed cohorts: (1) did not receive gabapentinoids, opioids, or benzodiazepines; (2) received gabapentinoids only; (3) received gabapentinoids and opioids; (4) received gabapentinoids and benzodiazepines; and (5) received all three drugs.
Statistical Analysis
We summarized and compared the population characteristics of recipients by gabapentin use within 1 year after kidney transplantation. Record-level patient claims were aggregated into the prevalence of concomitant prescription of gabapentinoids, opioids, and benzodiazepines on a national level by calendar year starting from 2006. We evaluated the proportion of concomitant prescription of opioids, benzodiazepines, or both among recipients who were gabapentin users. We also visually depicted the trends of gabapentinoid prescription by transplant year, stratified by recipient sex, age, race, and history of diabetes.
We used survival analysis to evaluate concomitant prescription of gabapentinoids, opioids, and benzodiazepines as time-fixed exposure for all-cause mortality among recipients with a functioning graft at 1 year after transplant. Recipients were excluded if they had graft failure or died within the first year time window to avoid survival bias associated with the time to initiation of gabapentinoid prescription.16,17 We defined survival time (in years) as the period starting from 1 year after transplant to the date of death or administrative censoring (December 31, 2019), which allowed for at least 1 year of follow-up time for those who had kidney transplant at the end of 2017. Cox proportional hazard models were used to compare the hazards of all-cause mortality by concomitant prescription status. The models were adjusted for recipient age, sex, race, body mass index, education, history of diabetes, years on dialysis, panel reactive antibodies (PRA), preemptive transplant, and neighborhood characteristics using the inverse probability weighting (IPTW) method. Using this model, we also estimated the cumulative incidence of postkidney transplant mortality by concomitant prescription (none, gabapentinoids only, gabapentinoids and opioids, gabapentinoids and benzodiazepines, or gabapentinoids with both opioids and benzodiazepines).
No consensus exists for the treatment of neuropathic pain in kidney transplant recipients.1 As such, there is a concern for confounding by indication, a common challenge in pharmacoepidemiology, which might occur when an indication for use of gabapentinoids is also associated with outcomes of interest.18 To minimize confounding by indication and the possibility of imbalanced baseline characteristics, we used IPTW to formulate kidney transplant recipients into comparable groups on the basis of whether they had been prescribed gabapentinoids, opioids, and benzodiazepines. We first fit a multinomial logistic regression model to estimate propensities of being prescribed (1) none; (2) gabapentinoids only; (3) gabapentinoids and opioids; (4) gabapentinoids and benzodiazepines; or (5) all three agents. The covariates in the multinomial logistic regression model included recipient age, sex, race, body mass index, education level, history of diabetes, years on dialysis, PRA, preemptive transplant, percentage of neighborhood population below poverty level, and percentage of population in an urban county. Missing data for any covariates in the analyses were reported as separate categories.
We conducted three sensitivity analyses. First, for recipients restricted with 3 months after transplant follow-up of gabapentinoid prescriptions, exposure status was ascertained within the first 3 months instead of 1 year. Recipients were excluded if they had a graft failure or died within the first 3 months after transplant. Second, to test whether gabapentinoid-associated mortality risk was affected by GFR, we adjusted for eGFR as a continuous variable in the propensity score model described above. eGFR was calculated based on hospital discharge creatinine using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation.19 Finally, we treated the total sum of the gabapentinoid days of supply during the study period as a categorical exposure and studied the association with post-transplant mortality. Days of supply was ascertained by linking with Medicare claims. All analyses were performed using Stata version 16.0/MP for Linux (College Station, TX) and R version 4.0.2.
Results
Recipient Characteristics
Between 2006 and 2017, 13% of the total 63,359 kidney transplant recipients who met our inclusion criteria received at least one gabapentinoid prescription within 1 year after kidney transplant (n=8509). Among the recipients who were gabapentinoid users, the median age at transplant was 56 (interquartile range [IQR], 46–64) years, 43% were women recipients, 62% were White, and 31% were Black. Recipient baseline characteristics were similar for users and nonusers except for body mass index, history of diabetes, and cause of kidney failure. Kidney transplant recipients prescribed gabapentinoids were more likely to be obese (gabapentinoids versus no gabapentinoids: 46% versus 34%) and diabetic (gabapentinoids versus no gabapentinoids: 55% versus 37%). The primary cause of kidney failure was diabetes in recipients prescribed gabapentinoids (44%), whereas in those who were not prescribed these agents, the primary cause was hypertension (29%) (Table 1). Among the 8509 recipients who had at least one gabapentinoid prescription within 1 year after kidney transplant, 45% were coprescribed opioids, 7% were coprescribed benzodiazepines, and 3% were coprescribed with both opioids and benzodiazepines (Supplemental Table 1).
Table 1.
Study population characteristics by gabapentinoid prescription within 1 year after kidney transplant among recipients between 2006 and 2017 (n=63,359)
| Recipient Characteristics | No Gabapentinoids (n=54,850) | Gabapentinoids (n=8509) |
|---|---|---|
| Recipient age, yr | 53 (41–64) | 56 (46–64) |
| Recipient female, n (%) | 21,505 (39) | 3688 (43) |
| Recipient race/ethnicity, n (%) | ||
| White | 31,353 (57) | 5300 (62) |
| Black | 19,044 (35) | 2671 (31) |
| Others | 4438 (8) | 536 (6) |
| Attended college, n (%) | 20,742 (40) | 3269 (41) |
| Body mass index, kg/m2 | ||
| 0–24.9 | 17,410 (32) | 1982 (23) |
| 25–29.9 | 18,584 (34) | 2623 (31) |
| 30+ | 18,722 (34) | 3894 (46) |
| Hypertension, n (%) | 44,166 (91) | 7029 (91) |
| History of diabetes, n (%) | 20,160 (37) | 4677 (55) |
| Cardiovascular disease, n (%) | 1651 (3) | 342 (4) |
| Cancer, n (%) | 1012 (2) | 208 (3) |
| Alcohol dependence, n (%) | 490 (1) | 77 (1) |
| Tobacco use, n (%) | 2410 (5) | 507 (7) |
| Cause of kidney failure, n (%) | ||
| Glomerulonephritis | 11,060 (20) | 1336 (16) |
| Diabetes | 15,542 (28) | 3781 (44) |
| Hypertension | 15,791 (29) | 1776 (21) |
| Others | 12,457 (23) | 1616 (19) |
| Panel reactive antibodies, n (%) | ||
| 0–9 | 37,898 (71) | 5703 (69) |
| 10–79 | 10,875 (20) | 1713 (21) |
| 80+ | 4645 (9) | 832 (10) |
| Preemptive transplant, n (%) | 4079 (7) | 583 (7) |
| Years on dialysis, median (IQR) | 3.6 (1.7–5.8) | 3.7 (1.8–5.9) |
| Cold ischemic time, median (IQR) | 14.3 (7.1–21.0) | 14.0 (7.0–21.0) |
| ABO incompatibility, n (%) | 361 (0.7) | 67 (0.8) |
| Induction agent, n (%) | ||
| T-cell depleting | 32,414 (59) | 5238 (62) |
| IL2RA | 10,800 (20) | 1613 (19) |
| Other/multiple | 2659 (5) | 389 (5) |
| None | 8977 (16) | 1269 (15) |
| Estimated GFR (ml/min per 1.73 m2) | 39 (20–61) | 38 (19–61) |
| Donor age at time of recovery (yr) | 41 (28–52) | 41 (29–52) |
| Donor female, n (%) | 24,592 (45) | 3802 (45) |
| Donor race, n (%) | ||
| White | 44,558 (81) | 6979 (82) |
| Black | 8171 (15) | 1222 (14) |
| Others | 2119 (4) | 308 (4) |
| Donor type: living, n (%) | 11,611 (21) | 1798 (21) |
| Donor after cardiac death, n (%) | 7303 (13) | 1116 (13) |
Continuous variables are shown in median (interquartile range [IQR]) including recipient age, cold ischemic time, years on dialysis, eGFR, and donor age at the time of recovery. IL2RA, IL-2 receptor antagonists.
Trends of Concomitant Prescription of Gabapentin, Opioid, and Benzodiazepine
Among kidney transplant recipients, the prevalence of gabapentinoid prescriptions increased from 10% in 2006 to 16% in 2017. In gabapentinoid users, the median cumulative days of supply were 180 (IQR, 60–300) days and the median quantity dispensed was 330 (IQR, 120–660) (capsules/tablets). The prevalence of opioid prescriptions increased 1.1-fold from 76% in 2006 to 85% in 2013, followed by a slight drop in 2014 to 80% and then stayed constant at 84% from 2015 to 2017 (Figure 1). When stratified by recipient characteristics, we observed that the prevalence of gabapentinoid prescribing was constantly higher in recipients who were women, were White, and had diabetes (Figure 2).
Figure 1.
Secular trends of gabapentinoids and opioids prescription by transplant year from 2006 to 2017.
Figure 2.
Trends in gabapentinoids use by patient baseline characteristics among adult kidney-only transplant recipients between 2006 and 2017 (n=98,902). Plots present the percentage of gabapentinoid prescriptions stratified by (A) age (18–39, 40–64, and ≥65 years), (B) sex, (C) race (White, Black, and others), and (D) history of diabetes.
The prevalence of opioid prescribing among individuals who were prescribed gabapentinoids (n=8509) increased from 45% in 2006 to 51% in 2011 and decreased after 2012. In 2017, coprescribing of gabapentinoids and opioids was 41%, which was the lowest throughout the 11-year study period. Overall, the prevalence of concomitant prescribing of both opioids and benzodiazepines with gabapentinoids rose rapidly from 0.2% in 2010–2011 to 5% starting in 2012, largely because of the sharp increase of concomitant prescription of benzodiazepines among patients receiving gabapentinoids around the same year. Before 2012, the prevalence of concomitant prescriptions of benzodiazepines stayed relatively steady at around 1%. However, the number increased to 11% in 2012–2013 and subsequently remained above 11% (Table 2). In the propensity score model, younger White female recipients with obesity and diabetes were the prime risk group for gabapentinoid concomitant use with opioids and/or benzodiazepines compared with not using gabapentinoids at all (Supplemental Table 2).
Table 2.
Gabapentinoids, concomitant prescription of opioids, benzodiazepines, or both by calendar year among kidney transplant recipients between 2006 and 2017 (n=8509)
| Concomitant | 2006–2007 | 2008–2009 | 2010–2011 | 2012–2013 | 2014–2015 | 2016–2017 |
|---|---|---|---|---|---|---|
| Gabapentinoids | 1063 | 1170 | 1287 | 1458 | 1837 | 2134 |
| Opioids, n (%) | 461 (43) | 573 (49) | 646 (50) | 654 (45) | 786 (43) | 862 (40) |
| Benzodiazepines, n (%) | <11 (<1) | >12 (>1) | <11 (<0.9) | 151 (10) | 234 (13) | 239 (11) |
| Both, n (%) | <11 (<1) | <11 (<0.9) | <11 (<0.9) | 62 (4) | 119 (7) | 93 (4) |
Percentage shows the prevalence of coprescription among recipients who were prescribed gabapentin within 1 year after kidney transplant (n=8509).
Association between Postkidney Transplant Mortality and Concomitant Prescription
At 1 year after transplant, 92% recipients survived with a functioning graft and were included in the survival analysis to study the association between coprescribing and subsequent mortality (n=58,196). The 5-year all-cause mortality after kidney transplant was 10% for recipients not prescribed gabapentinoids, 14% for those who were only prescribed gabapentinoids, and 17% for those with coprescribing. Among recipients with concomitant prescribing, the 5-year all-cause mortality after kidney transplant was 17% for gabapentinoid coprescribing with opioids, 16% for gabapentinoid coprescribing with benzodiazepines, and 21% for gabapentinoid coprescribing with both agents (Figure 3).
Figure 3.
Gabapentinoids, concomitant prescription, and all-cause mortality among kidney transplant recipients who survived with functioning graft at 1 year after kidney transplant (n=58,196).
Compared with no prescriptions, gabapentinoid use alone was associated with a 1.25-fold (95% confidence interval [CI], 1.16 to 1.32) higher risk of mortality after adjusting for recipient characteristics and transplant factors. Recipients coprescribed gabapentinoids with opioids (adjusted hazard ratio [aHR]=1.49; 95% CI, 1.39 to 1.60) and benzodiazepines (aHR=1.46; 95% CI, 1.03 to 2.08) were equally (P=0.91) associated with a higher risk of mortality. The postkidney transplant mortality risk observed when gabapentin was coprescribed with both opioid and benzodiazepine was 1.88-fold higher compared to no prescriptions (aHR=1.88; 95% CI, 1.18 to 2.98). However, recipients with gabapentinoid coprescribed with opioids were at a significantly higher risk of mortality than recipients with gabapentinoid prescription only (aHR=1.49; 95% CI, 1.39 to 1.60 versus aHR=1.25; 95% CI, 1.16 to 1.32, P<0.05) (Table 3).
Table 3.
The association of concomitant prescription with postkidney transplant mortality in first-time recipients between 2006 and 2017 who survived with a functioning graft at 1 year after kidney transplant (n=58,196)
| Concomitant Prescription | Adjusted HR (95% CI) |
|---|---|
| No prescription (n=50,151) | Reference |
| Gabapentinoids only (n=4205) | 1.25 (1.16 to 1.32) |
| Gabapentinoids and opioids (n=3237) | 1.49 (1.39 to 1.60) |
| Gabapentinoids and benzodiazepines (n=338) | 1.46 (1.03 to 2.08) |
| Gabapentinoids, opioids, and benzodiazepines (n=265) | 1.88 (1.18 to 2.98) |
The adjusted model accounted for age, sex, race/ethnicity, body mass index, education level, history of diabetes, years on dialysis, peak panel reactive antibodies, preemptive transplant, percentage of neighborhood population below poverty level, and percentage of population in an urban county using the propensity score method. HR, hazard ratio; 95% CI, 95% confidence interval.
Sensitivity Analysis
When we conditioned the population at 3 months after transplant and defined those exposed as having at least one gabapentinoid prescription within the first 3 months (N=60,386), the magnitude of mortality risk associated with gabapentinoids and concomitant prescriptions were similar (Supplemental Table 3). When eGFR was adjusted as a confounder, similar results were noted (Supplemental Table 4). Gabapentinoid use alone and concomitant prescriptions were all associated with higher post-transplant mortality risk (gabapentinoids only: aHR=1.25; 95% CI, 1.16 to 1.34; gabapentinoids and opioids: aHR=1.51; 95% CI, 1.40 to 1.62; gabapentinoids and benzodiazepines: aHR=1.42; 95% CI, 1.00 to 1.98; all three agents: aHR=1.84; 95% CI, 1.17 to 2.90). Higher mortality risk was observed with increasing days of supply of gabapentinoids compared with no prescription (Supplemental Table 5).
Discussion
In this cohort study of real-world medication use among 63,359 adult kidney transplant recipients, we found that the percentage of recipients with gabapentinoid prescribing during the first year after kidney transplant increased from 10% in 2006 to 16% in 2017. This national study suggested a rising trend of gabapentinoid prescribing and concomitant prescribing with opioids and benzodiazepines among kidney transplant recipients. Recipients who were women, were White, had diabetes, or were aged 40–64 years were more likely to be prescribed gabapentinoids. Of the 8509 recipients with a gabapentinoid prescription, 45% were coprescribed with opioids, 7% were coprescribed with benzodiazepines, and 3% were coprescribed with both opioids and benzodiazepines. Recipients who were coprescribed gabapentinoids with both opioids and benzodiazepines had an 88% higher risk of death (aHR=1.88; 95% CI, 1.18 to 2.98) after kidney transplant compared with no prescription. The magnitude of mortality risk was higher than that among recipients coprescribed gabapentinoids with either opioids (aHR=1.49; 95% CI, 1.39 to 1.60) or benzodiazepines (aHR=1.46; 95% CI, 1.03 to 2.08), and those with gabapentinoid prescription only (aHR=1.25; 95% CI, 1.16 to 1.32). Our findings added to the growing evidence of a life-threatening drug interaction between gabapentinoids, opioids, and benzodiazepines.
Increasing rates of gabapentinoid prescribing and coprescribing have been documented internationally.9,20,21 A retrospective study conducted among US patients aged 18–64 years who were enrolled in a commercial insurance plan found that the prevalence of gabapentin prescribing nearly doubled from 2009 to 2016, and the increase was observed in every state (range, 44%–179%). Individuals prescribed gabapentin were also more likely to fill opioid prescriptions (61% versus 17%).21 A UK database consisting of primary care patients also showed that from 2007 to 2017, the rate of patients newly treated increased from 230 to 679 per 100,000 person-years for gabapentin and from 128 to 379 per 100,000 person-years for pregabalin. The coprescription rate of opioids and/or benzodiazepines also increased from 56.4 to 148.1 per 100,000 person-years for gabapentin.9 Other research found a rate of coprescribing of gabapentinoids and opioids at 50% of patients who received gabapentinoids in Scotland and with 27% coprescribed a benzodiazepine.22 These findings in general population samples showed consistency in increased prevalence to our study focused on kidney transplant recipients.
Our central finding that concomitant prescriptions of gabapentinoids with opioids or benzodiazepines were associated with a higher mortality risk is consistent with a nested case-control study of data for Ontario residents enrolled in the Ontario Public Drug Programs (1997–2013), where coprescription of opioids and gabapentinoids was associated with a 45% higher odds of opioid-related death.12 As government restrictions decrease the number of opioid prescriptions, medical providers may turn to alternative medications for pain control. In this context, off-label use of gabapentinoids is increasing despite the absence of strong evidence of safety.23,24 Although initially presumed to have no abuse potential, a systematic review estimated the prevalence of gabapentin misuse in the general population to be 1%, 40%–65% among individuals with prescriptions, and 15%–25% in people abusing opioids.23 This is even more concerning in kidney transplant recipients because of the neurotoxicity of gabapentinoids in the setting of kidney failure and nephrotoxicity, and in combination with opioids and benzodiazepines, gabapentinoid use further increases the risk of serious side effects and overdose.22,25–28
To our knowledge, this is the first to evaluate a nationally representative sample of kidney transplant recipients to isolate the independent effect of coprescribed gabapentinoids with opioids and benzodiazepines on postkidney transplant mortality risk. The comparison of mortality risks among different combinations of concomitant prescription (gabapentinoids, opioids, and/or benzodiazepines) has not been evaluated among kidney transplant recipients although a prior study also using USRDS dataset and Medicare claims compared the associations between concomitant use of gabapentin and opioids and concomitant use of pregabalin with opioids among prekidney transplant dialysis patients.29 In this prior analysis, compared with not filling a prescription for either of the drugs, concomitant prescription of opioids and pregabalin was associated with a higher hazard of death (aHR=1.22; 95% CI, 1.16 to 1.28) and hospitalization (aHR=1.37; 95% CI, 1.33 to 1.41). Concomitant prescription of opioids and gabapentin was further associated with 14% higher risk of dialysis discontinuation (aHR=1.14; 95% CI, 1.03 to 1.27) in addition to death (aHR=1.16; 95% CI, 1.12 to 1.19) and hospitalizations (aHR=1.33; 95% CI, 1.31 to 1.36).29
Our study has limitations. As in any observational studies, particularly in pharmacoepidemiology research, we were not able to rule out the possibility of unmeasured confounding by indication. To address this, we applied the IPTW approach and, after which, the difference in the distribution of recipients' covariates among recipients who were on various gabapentinoid therapy has been well balanced in the weighted pseudopopulation (Supplemental Table 1), although we recognize the potential of residual confounding such as recipient age, which was modeled as a categorical variable (18–39 versus 40–64 versus ≥65). In addition, we were not able to ascertain from the Medicare claims data whether the drugs were prescribed for treating pain or other indications or off-label use such as anxiety or depression, nor could we verify that a prescribed medication was actually taken, like in any pharmacoepidemiology studies built upon administrative database. This could lead to bias regarding the magnitude of mortality risk; however, this bias is likely toward the null. Finally, we limited the population to Medicare Part D coverage–eligible recipients to capture medication prescriptions. The association may differ in patients with other forms of insurance, although the population is relevant as Medicare is the primary insurer for kidney transplant services.30–33
In conclusion, along with the observation of rising prevalence of gabapentinoid prescription among kidney transplant recipients in recent years, we found that recipients with concomitant prescription of gabapentinoids with opioids and benzodiazepines experienced higher mortality risk compared with recipients prescribed none of those. Although the prescription of gabapentinoids in kidney transplant recipients was relatively uncommon, the elevated mortality suggested that prescribing gabapentinoids as an alternative to opioids for pain treatment should be carefully considered, particularly when the possibility of coprescribed gabapentinoids with opioids and benzodiazepines is high in certain groups of kidney transplant recipients, especially among those with respiratory syndromes.
Supplementary Material
Acknowledgments
The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government.
Footnotes
See related editorial, “Balancing Risk and Uncertain Benefit in Pharmacotherapy for Pain in Kidney Transplant Recipientsis,” on pages 3–4.
Disclosures
G.P. Hess reports employment with SomaLogic; consultancy agreements with Flexion Therapeutics; ownership interest in SomaLogic; research funding from Vertex, Inc.; serving as an American Society of Clinical Oncology Physician Advisory Board Member and Chair of Precision Medicine Advisory Council SomaLogic; and serving in advisory or leadership role for Millennium Health Clinical Excellence Committee and Neogenomics Scientific Advisory Board. C. Joseph reports consultancy agreements with and ownership interest in Takeda Pharmaceuticals. K.L. Lentine reports consultancy agreements with CareDx, Inc., ownership interest in CareDx, Inc., and speaker honoraria from Sanofi. B.E. Lonze reports research funding from AbbVie, CareDx, and Hansa; honoraria from Physicians' Education Resource, LLC (PER); and advisory or leadership roles for AlloVir, Argenx, and Hansa. M. McAdams-DeMarco reports honoraria from UpToDate. M. Schnitzler reports consultancy agreements with CareDx and honoraria from OPTUM. D.L. Segev reports consultancy agreements with AstraZeneca, Bridge to Life, CareDx, CSL Behring, Jazz Pharmaceuticals, Kamada, Mallinckrodt, MediGO, Novartis, Novavax, Regeneron, Sanofi, Takeda, Thermo Fisher Scientific, Transmedics, and Veloxis; honoraria from AstraZeneca, CareDx, and Sanofi; speaking honoraria from CSL Behring, Novartis, and Sanofi; and serving as Editor-in-Chief of Current Transplant Reports. The remaining authors have nothing to disclose.
Funding
This study was funded by the National Institute of Diabetes and Digestive and Kidney Disease (R01DK120518) and the National Institute on Aging (R01AG077888). Study investigators were funded by the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Disease, and the National Institute of Allergy and Infectious Diseases: K24AI144954 (PI: D.L. Segev), R01AG055781 (PI: M. McAdams-DeMarco), R01DK114074 (PI: M. McAdams-DeMarco).
Author Contributions
J.B. Ahn, S. Bae, Y. Chen, G.P. Hess, K.L. Lentine, B.E. Lonze, M. McAdams-DeMarco, M. Schnitzler, and D.L. Segev conceptualized the study; J.B. Ahn and M. McAdams-DeMarco were responsible for investigation; S. Bae, Y. Chen, C. Joseph, and M. McAdams-DeMarco were responsible for methodology; Y. Chen was responsible for formal analysis; M. McAdams-DeMarco provided funding acquisition; Y. Chen and M. McAdams-DeMarco wrote the original draft; and J.B. Ahn, S. Bae, Y. Chen, G.P. Hess, C. Joseph, K.L. Lentine, B.E. Lonze, M. McAdams-DeMarco, M. Schnitzler, and D.L. Segev reviewed and edited the manuscript.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/CJN/B79.
Supplemental Table 1. Weighted baseline characteristics by gabapentinoid concomitant prescription with opioids and/or benzodiazepines among recipients with combination therapy and who survived with a functioning graft at 1 year after kidney transplant between 2006 and 2017 (n=4205).
Supplemental Table 2. The association of gabapentinoid concomitant prescription with baseline characteristics among kidney transplant recipients between 2006 and 2017 in the propensity score model.
Supplemental Table 3. The association of concomitant prescription with postkidney transplant mortality in first-time recipients between 2006 and 2017 who survived with a functioning graft at 3 months after kidney transplant (n=60,386).
Supplemental Table 4. The association of concomitant prescription with postkidney transplant mortality in first-time recipients between 2006 and 2017 who survived with a functioning graft at 1 year after kidney transplant (n=58,196).
Supplemental Table 5. The association of gabapentinoid days of supply with postkidney transplant mortality in first-time recipients between 2006 and 2017 who survived with a functioning graft at 1 year after kidney transplant (n=58,196).
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