Gabapentin utilization among older adults with different cognitive statuses enrolled in the National Alzheimer’s Coordinating Center (2006–2019)

Abstract

This study aimed to examine gabapentin utilization trends among older adults with different cognitive statuses and investigate concurrent medication use of potentially inappropriate medications. Data were extracted from National Alzheimer’s Coordinating Center Uniform Data Set (2006–2019). We estimated the yearly prevalence of gabapentin use, both overall and within subgroups defined by cognitive status [normal, mild cognitive impairment, and dementia] and demographics [age and sex] for participants aged 65+. Additionally, we assessed the prevalence of concurrent use of gabapentin with opioids, combined opioids and benzodiazepine, antidepressant, and antipsychotic. From 35,205 eligible older adults (mean age [SD]: 75.7 [7.0]; male: 43.1%), gabapentin use increased from 2006 to 2019 in both overall and every participant subgroup. About 10–30% of gabapentin users reported to concurrently use of opioids, and the concurrent use of gabapentin, opioid, and benzodiazepine was up to 7.5% throughout the study period. The frequency of concurrent use with antipsychotics or antidepressants was higher in participants with dementia than those with normal cognition or mildly cognitively impaired. Given increasing use among older adults, rigorous studies are needed to examine the safety of gabapentin in this population.

Introduction

Gabapentin was approved by the United States (US) Food and Drug Administration (FDA) to treat partial seizures (1993) and postherpetic neuralgia (2004)¹. Additionally, gabapentin was approved for epilepsy and neuropathic pain by the European Medicine Agency² and the United Kingdom (UK)³. However, by 2018 up to 95% of gabapentin prescriptions were for off-label indications (e.g., neuropathic pain, migraines, substance use disorder, and psychiatric symptoms)^4–6. The mechanisms of gabapentin are not understood; however, the predominant pharmacological mechanism of gabapentin is known to be through the voltage-gated calcium channels⁷. Gabapentin has been described as relatively safer than opioids or antipsychotics⁴, and its use has been increasing in recent years. For example, a study using Medical Expenditure Panel Survey (MEPS) data reported that gabapentin use tripled among adults age 18 and older from 2002 to 2015, and this trend was also observed among adults age 65 and older⁸.

While off-label use of gabapentin allows clinicians to have more options for treating pain and psychological symptoms, there are important gaps in reliable evidence of efficacy⁴ and safety related to misuse and adverse events^9–14. Previous studies have reported that gabapentin use is associated with abuse, respiratory depression, sedation, depression, and suicidality^9–11. Moreover, concurrent use of gabapentin with opioids or benzodiazepines has been reported to be associated with adverse outcomes, including falls, opioid-related overdose, substance-related overdose, and respiratory depressions^12–14. Due to the concerns about increasing reports of gabapentin misuse and side effects, policymakers have also started to regulate prescribing of gabapentin in the US. Kentucky was the first state that reclassified gabapentin as a Scheduled-V controlled substance medication in July 2017¹⁵, followed by several states, including Alabama, Michigan, Tennessee, West Virginia, and Virginia. Also, gabapentin was reclassified as class C controlled substance, which requires physically signed prescriptions instead of electronic copies, in the UK in April 2019¹⁶. In 2019, FDA announced a safety concern of severe breathing difficulties in gabapentin users when concurrently used with opioid medications and other CNS depressants¹⁷. In addition, the American Geriatrics Society (AGS) Beers Criteria (2019) added gabapentin to the list of drugs to avoid using concurrently with opioids due to the risks of excessive sedation and respiratory depression¹⁸. The adverse events from gabapentin could be higher in older adults who have more polypharmacy, higher comorbidities, and decreased renal functions. Since gabapentin is also prescribed to treat behavioral and psychological symptoms of dementia (BPSD)¹⁹, gabapentin could be widely prescribed in patients with dementia. However, a recent paper addressed that there is a possibility of an association between gabapentin and cognitive decline²⁰. Thus, it is important to understand the pattern of gabapentin use in older adults with different cognitive statuses.

To our knowledge, the utilization of gabapentin in older adults with different cognitive statuses has not been studied yet. Therefore, this study aimed to examine trends of gabapentin use among older adults with different levels of cognitive status and to assess concurrent use of gabapentin with CNS-depressant medications.

Methods

A longitudinal dataset from the National Alzheimer’s Coordinating Center’s (NACC) Uniform Data Set (UDS) (years 2006 to 2019) was used for this participant-visit level time series analysis. The dataset was pulled from the March 2021 freeze, but due to changes in data collection and study visits caused by the COVID-19 pandemic, we truncated the data after December 31, 2019 for the current study. The NACC data, established in 1999 and funded by National Institute on Aging, includes participants with a range of normal to dementia²¹. The participants are followed-up approximately annually until they are deceased or decline to participate, and trained clinicians and other Alzheimer’s Disease Research Centers (ADRC) research personnel collected data from the participants and their care givers²². We included participant-visits from 41 unique ADRCs meeting the following inclusion criteria: (1) participant was 65 years or older at study visit; and (2) medication data recorded at study visit. Participant-visit data were analyzed within calendar years. Participants typically visit NACC annually; however, some participants can have more than one visit in a single calendar year because they can visit NACC earlier. Therefore, for participants with multiple visits in a single calendar year, we included only the first visit in that same year to exclude any duplicate individuals in a single calendar year (2,070 visits were excluded). Cognitive status at each visit was determined based on clinician assessments as normal, mild cognitive impairment (MCI) (including impaired other), and dementia²².

Medication ascertainment

Determination of gabapentin use at each participant-visit was based on the reported medications, which include all prescription and over-the-counter medications taken by the participant in the two weeks prior to the study visit²². The reported medications were reviewed through the ‘brown bag’ review process²³, in which the participants and caregivers were asked to bring all current medications to the visit²². Data regarding doses and duration of use are not consistently collected in the NACC data. Among gabapentin users, concurrent use of potentially inappropriate medications was assessed at each visit. We determined opioid (excluding antitussives) and benzodiazepine use by examining the participant’s reported medication use at each study visit. Use of antidepressants and antipsychotics was determined by NACC-derived variables based on the reported medications²⁴.

Outcomes

The prevalence of gabapentin use was measured each year (2006 to 2019) across different levels of cognitive status. In addition, we examined the prevalence of gabapentin use stratified by age groups (65 to 74 years; 75 to 84 years; and 85+ years) and sex across different categories of cognitive status.

All participants in the NACC database provided written informed consent under Institutional Review Board-approved protocols at their local ADRC. Because the NACC database is limited to de-identified participant data, no additional IRB review and approval was necessary for this secondary data analysis.

Results

The study sample included 35,205 older adults [at the first study visit, mean age (SD): 75.7 (7.0); male: 43.1%; normal cognition: 39.1%, mild cognitive impairment: 26.8%, dementia: 34.0%] with 123,423 total visits during the 2006 to 2019 study period. Gabapentin use increased both overall (3.8% change from 2006 to 2019) and across levels of cognitive status [normal: 1.9% (57/3,001) (95% confidence interval: 1.4, 2.4) to 5.6% (267/4,760) (4.9, 6.3); MCI: 3.0% (58/1,909) (2.3, 3.8) to 8.0% (161/2,014) (6.8, 9.2); dementia: 2.0% (60/2,970) (1.5, 2.5) to 5.2% (102/1,970) (4.2, 6.2)]. Furthermore, the prevalence of gabapentin use increased throughout the study period in all groups defined by age and sex (Figure 1).

Figure 1. Time trends for reported gabapentin use among research participants in the Uniform Data Set (2006–2019), overall and by subgroups defined by cognitive status, age, and sex.

Among all gabapentin users, reported concurrent use of opioids by the final year of follow-up (2019) was 16.1%, 14.3%, and 10.8% in participants with normal cognition, MCI, and dementia, respectively. Up to 7.5% of gabapentin users reported concurrent use of both opioids and benzodiazepines. Throughout the study period, participants with dementia more often reported concurrent use of gabapentin with antidepressants or antipsychotics than those with normal cognition or who were mildly cognitively impaired (Table 1).

Table 1.

Frequency of concurrent use of gabapentin with potentially inappropriate medication classes among research participants in the Uniform Data Set (2006–2019)

	2006	2007	2008	2009	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019
Mean age (SD)	78.1 (7.9)	78.7 (7.5)	78.2 (7.1)	78.2 (7.3)	77.4 (7.3)	77.5 (7.3)	77.7 (7.7)	77.6 (7.5)	77.8 (7.5)	77.5 (7.5)	77.6 (7.7)	77.3 (7.4)	77.7 (7.5)	77.3 (7.2)
Male, N(%)	60 (34.3)	89 (42.2)	104 (40.8)	105 (36.7)	121 (39.7)	137 (43.2)	156 (41.7)	168 (41.0)	149 (38.2)	158 (38.6)	169 (39.6)	178 (39.0)	200 (39.2)	208 (39.3)
Normal
Total (N)*	57	77	95	103	133	153	173	194	189	195	204	225	252	267
Opioid	19.3	20.8	16.8	22.3	15.8	21.6	16.2	22.2	14.8	20.0	20.6	20.9	17.9	16.1
Opioid and BZD	5.3	3.9	3.2	1.0	1.5	2.6	2.9	3.1	2.7	3.1	2.0	1.3	2.0	1.9
Antidepressant	28.1	39.0	30.5	29.1	33.8	31.4	26.6	32.5	37.0	35.9	37.8	34.7	36.5	36.3
Antipsychotics	0	1.3	2.1	1.9	0.8	0.7	1.2	0	0	2.1	0.5	1.3	1.2	0.8
Mild cognitive impairment
Total (N)*	58	66	80	80	85	76	109	105	106	121	135	130	148	161
Opioid	12.1	28.8	15.0	28.8	18.8	19.7	20.2	17.1	15.1	19.0	19.3	19.2	16.9	14.3
Opioid and BZD	3.5	4.6	7.5	2.5	1.2	2.6	7.3	4.8	4.7	6.6	7.4	3.1	0.7	2.5
Antidepressant	44.8	40.9	51.3	40.0	38.8	34.2	43.1	39.1	36.8	41.3	43.0	47.7	45.3	46.6
Antipsychotics	6.9	7.6	5.0	3.8	1.2	1.3	5.5	2.9	1.9	5.8	3.7	4.6	6.1	3.1
Dementia
Total (N)*	60	68	80	103	87	88	92	111	95	93	88	102	110	102
Opioid	13.3	14.7	15.0	21.4	16.1	14.8	18.5	16.2	13.7	20.4	20.5	17.7	9.1	10.8
Opioid and BZD	0	4.4	5.0	6.8	4.6	4.6	1.1	2.7	1.1	4.3	5.7	2.9	2.7	2.0
Antidepressant	56.7	58.8	42.5	52.4	55.2	62.5	59.8	53.2	56.8	61.3	63.6	56.9	60.0	57.8
Antipsychotics	15.0	14.7	16.3	14.6	16.1	20.5	17.4	12.6	15.8	21.5	11.4	15.7	7.3	10.8

Abbreviation: BZD, benzodiazepine

All results presented are % unless otherwise noted.

^*Total number of gabapentin users

Conclusions

In this study of research participants enrolled in cohort studies at ADRCs, prevalence of gabapentin use increased from 2006 to 2019 both overall, as well as across all groups defined by cognition, age, and sex. The increasing trends of gabapentin use were consistent to the previous studies of other populations in the US. Using MEPS data (2002–2015), the prevalence of gabapentin prescriptions increased from 1.2% (2002) to 3.9% (2015) in adults aged >17 years⁸. In another study, Pauly et al. (2020) reported that the prevalence of gabapentin prescription doubled from 2009 to 2016 in a commercially insured population aged 18–64 years old²⁵.

Among gabapentin users, concurrent use of antidepressants, antipsychotics, or opioids, was common throughout the study period. In addition, up to 39%, 51%, and 64% of gabapentin users with normal cognition, MCI, and dementia concurrently used gabapentin with antidepressants, respectively. Compared to a previous study from 2011 to 2016 that reported 24.3% of adults (>17 years) who used gabapentin off-label concurrently with antidepressants²⁶, our study indicates that the concurrent use of gabapentin with antidepressants may be substantially higher in older adults. This result could be due in part to the higher prevalence of depression in older adults²⁷.

Concurrent use of gabapentin with antidepressants is particularly concerning given that, in 2019, the FDA announced that there is an increased risk of respiratory depression associated with concurrent use of gabapentin with antidepressants, especially among older adults¹⁷. Therefore, a high proportion of gabapentin users in our study were at risk of respiratory depression. Additionally, although the FDA and CDC recommend avoiding concurrent use of gabapentin with opioids and benzodiazepines²⁸, by the end of the study period (2019), over 10% of gabapentin users reported concurrent use gabapentin with opioids and around 2% reported use of both opioid and benzodiazepine medications with gabapentin. Recent studies have reported the risk of concurrent use of gabapentin with other medications. Shah et al. reported that older adults taking three and more combination drugs from opioids, gabapentinoids, benzodiazepines, and selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors and taking opioids concurrently with gabapentinoids were associated with increased risk of fall compared to older adults with concurrent use of opioid and benzodiazepines¹³. Also, a case-control study reported that concurrent use of gabapentin, opioid, and benzodiazepines was associated with higher odds of respiratory depression and opioid-related overdose compared to opioid only use¹². Therefore, further studies are required to understand the potential risks of gabapentin misuse in older adults.

We found that the prevalence of concurrent use of gabapentin with antidepressants and antipsychotics was higher in older adults with dementia compared to those with normal cognition. Moreover, a recent study in older adults with dementia using Medicare claims data reported that gabapentin ranked as the most common medication contributing to days of polypharmacy comprising CNS medications, and the most frequent medications comprising CNS-active polypharmacy included trazodone (antidepressant), quetiapine (antipsychotic), and gabapentin²⁹. Therefore, there is a possibility that many older adults with dementia are at risk of adverse events due to concurrent use of gabapentin with antidepressants or antipsychotics. Further studies are needed to investigate the safety of concurrent use of gabapentin with other CNS medications in this population.

This study has several limitations. First, since the use of gabapentin, opioids, and benzodiazepine were assessed on the reported medications used within two weeks of the UDS visit²², as was the use of antidepressants and antipsychotics, the assessment of concurrent medication use could include participants with medications that are not exactly overlapping. That is, it is possible that one medication was discontinued and the other initiated in the two-week period. Also, the relatively small numbers of gabapentin users in the NACC data may result in higher estimates of concurrent use prevalence in this study sample. Lastly, participants in the NACC database tend to be highly educated; thus, the study may not generalize to all older adult populations. However, these results are relevant to populations with cognitive impairment.

This study investigated prevalence of gabapentin use from 2006 to 2019 and found increasing trends among all levels of cognitive status. Of concern, a high proportion of participants with dementia seemed to be more at risk of inappropriate use of gabapentin with concurrent CNS-active medications. Additionally, a recent postmortem toxicology report from the CDC detected that gabapentin involved overdose death doubled in the second quarter of 2020 compared to the first quarter of 2019³⁰. Considering the vulnerability of older adults and the possibility of misuse of gabapentin, the results from this study call for other studies to fully evaluate the efficacy and risk of using off-label gabapentin in older adults. Policymakers and the clinicians need to be aware of the risk of gabapentin use in older adults to prevent any health burden that may increase in the future.

What is already known about this subject

• The prevalence of gabapentin use has increased in all populations.

• Due to misuse and adverse effects of gabapentin, the United Kingdom, countries in Europe, and several states in the US reclassified gabapentin as a controlled substance.

• The utilization of gabapentin in older adults, especially with cognitive impairment or dementia, has not been studied yet.

What this study adds

• The prevalence of gabapentin use increased from 2006 to 2019, both in overall population and within every subgroup (i.e., cognitive status, age group, and sex).

• About 10–30% of gabapentin users reported to concurrently use gabapentin with opioids.

• Over one-half of gabapentin users with dementia concurrently used gabapentin with antidepressants.

Data availability statement

Data was obtained from the National Alzheimer’s Coordinating Center.