Conclusions This study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Results During the study period, 10 026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17 144 (8.9%) experienced an unintentional overdose, 12 070 (6.3%) had a road traffic incident or offence, 70 522 (36.7%) presented with head/body injuries, and 7984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behaviour and deaths from suicide (age adjusted hazard ratio 1.26, 95% confidence interval 1.20 to 1.32), unintentional overdoses (1.24, 1.19 to 1.28), head/body injuries (1.22, 1.19 to 1.25), and road traffic incidents and offences (1.13, 1.06 to 1.20). Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was associated with increased hazards of all outcomes, whereas gabapentin was associated with decreased or no statistically significant hazards. When stratifying on age, increased hazards of all outcomes were associated with participants aged 15 to 24 years.

Main outcome measures Primary outcomes were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidents and offences, and arrests for violent crime. Stratified Cox proportional hazards regression was conducted comparing treatment periods with non-treatment periods within an individual. Participants served as their own control, thus accounting for time invariant factors (eg, genetic and historical factors), and reducing confounding by indication. Additional adjustments were made by age, sex, comorbidities, substance use, and use of other antiepileptics.

Gabapentinoids have been linked to overdoses and related deaths. 22 In a nested case-control study of opioid users, concomitant gabapentin use was associated with a 60% increase in opioid related death compared with no concomitant use. 23 In the United Kingdom, gabapentinoids are being reclassified as a class C controlled substance. 24 25 Evidence is, however, limited and is based on a small number of reported deaths. 26 Little data exist on the association between gabapentinoids and other psychosocial adverse outcomes. Isolated cases of aggression have been reported for gabapentin in children with psychiatric morbidity. 27 28 29 Most of this research is based on case reports, limiting conclusions about causality. Thus, evidence about adverse outcomes associated with gabapentinoids is limited, despite broadening clinical indications and increasing use. 6 Furthermore, gabapentinoids are widely used off-label, which could account for up to 90% of prescriptions for pregabalin. 9 Reliable information about adverse outcomes is required to test whether these concerns are valid, as inaccurate findings may influence prescribing practices. 13 16

Gabapentinoids have anticonvulsant, analgesic, and anxiolytic properties. The two main gabapentinoids, gabapentin and pregabalin, are currently approved for the treatment of epilepsy and neuropathic pain disorders in Europe (including Sweden). Pregabalin is also approved for treating generalised anxiety disorder in Europe, and has received approval for treating fibromyalgia in the United States. 1 Prescriptions have risen steeply in recent years, 2 and gabapentinoids are among the top 15 drugs globally in terms of revenue. 3 4 5 Concerns have, however, been expressed about overprescription, particularly for pain relief, 2 3 as well as adverse effects, 6 7 including dizziness, somnolence, balance problems, blurred vision, 1 6 8 9 10 11 12 coordination problems, and impairments in cognitive performance. 6 13 Although a 2008 Food and Drug Administration study of antiepileptic drugs reported an increased suicidal risk, separate analyses for pregabalin and gabapentin did not show clear effects. 14 However, suicidal ideation accounted for most reported events; suicidal behaviour was rare. 14 Since the FDA investigation, pharmacoepidemiological studies have used administrative data with larger sample sizes to examine suicidal outcomes for gabapentin. 15 16 Results have been inconsistent, with increased, 17 decreased, 18 and no changes in suicide risk. 19 20 21 Furthermore, conclusions have been limited owing to confounding by indication 16 (ie, the reason for prescribing the drug is also associated with the adverse outcome studied).

Methods

Design We carried out a population based cohort study using Swedish registers with national coverage, linked through unique identification numbers.30 A within-individual design was used, where participants acted as their own control, thus more fully accounting for confounding by indication and time invariant factors such as individual vulnerability or psychiatric history. Furthermore, we examined associations for specific subgroups based on sex, age, substance use disorders, use of other antiepileptic drugs, and pre-existing comorbidities to further clarify risks and benefits of gabapentinoids.

Participants and setting In the total population of Sweden aged 15 and older during the study period (n=8 945 712), we identified all those who had collected at least two consecutive prescriptions for gabapentinoids. Follow-up started on 1 January 2006 (or on the date of immigration to Sweden) and ended on 31 December 2013. Single prescriptions were not included in the main analyses owing to uncertainty over drug adherence or tolerance. We also collected demographic data (see Methods section in supplementary file). Our cohort included both prevalent users (ie, participants who used gabapentinoids before follow-up started) and new users.

Drugs All citizens in Sweden are insured through a common non-claims healthcare insurance, and drugs are subsidised. Our data consisted of dispensed drugs (filled prescriptions) from Swedish pharmacies, obtained from the Swedish Prescribed Drug Register. This register includes information on all prescriptions dispensed by pharmacies in Sweden since July 2005, with less than 0.3% missing information.31 We extracted information on prescriptions for pregabalin (Anatomical Therapeutic Chemical code N03AX16) and gabapentin (N03AX12) from the Swedish Prescribed Drug Register. The Swedish Pharmaceutical Benefits allows for a maximum of three months’ supply for each prescription.32 To ensure treatment continuity, we defined treatment periods as at least two consecutively collected prescriptions no more than three months apart. Participants were considered to have used the drugs from the date of the first prescription to the date of the last prescription within that treatment period (which could last from a few weeks to up to eight years). We considered prescriptions if they were dispensed more than three months apart to be the start of a new treatment period, and we investigated each treatment period in the analyses.33

Outcomes Information on suicidal behaviour, unintentional overdoses, head or body injuries, and road traffic incidents was collected from the Swedish Patient Register,34 which includes all admissions to hospitals in Sweden, as well as outpatient contacts with specialised secondary care. This register includes the primary diagnoses listed in 99% of all hospital discharges. In validation studies, the positive predictive value of diagnoses in this register is between 85% and 95%.34 Only diagnoses received during unplanned (emergency) visits were used in our analyses, and diagnoses received during planned visits (follow-ups and referrals) were excluded. Although this is a more conservative approach, we used this measure to avoid overestimation of the diagnoses, as the diagnosis that is the reason for treatment initiation could also be coded during follow-ups and referrals regardless of current symptoms. Information on death by suicide, unintentional overdoses, head or body injuries, and road traffic incidents was collected from the Cause of Death Register—a register of all deaths in Sweden; the underlying cause is specified in 96% of the cases.35 For violent crime, we used arrests as the primary outcome because some investigations may be dropped by the prosecution.36 Furthermore, the decision to discontinue criminal proceedings might or might not be influenced by the charged person taking psychotropic medication. In sensitivity analyses we used convictions (rather than arrests) as an outcome. We extracted information on suspected offences from the Register of People Suspected of Offences, including all those arrested of a crime after a completed investigation by police, customs authority, or prosecution service.37 Information on convicted offences came from the National Crime Register, including all convictions in Swedish district courts.37 Suicidal behaviour—suicidal behaviour was defined as emergency hospital visits due to self injurious behaviour or suicide attempt, or death by suicide (international classification of diseases, 10th revision (ICD-10) codes X60-X84). Unintentional overdoses—unintentional overdoses were defined as emergency hospital visits or death due to poisoning by illicit drugs, medications, and biological substances (ICD-10: T36-T50), accidental poisoning by noxious substances (X40-X49), and acute intoxications and overdoses by alcohol and illicit drugs (F10.0, F11.0, F12.0, F13.0, F14.0), excluding intentional self poisoning (ICD-10: X60-X69). Head/body injuries—head/body injuries were defined as emergency hospital visits or death due to superficial, open, or crushing injuries, dislocations, fractures, and amputations (ICD-10: S00-T14), with intentional self injuries (ICD-10: X70-X84) excluded. In sensitivity analyses, we stratified injuries into two separate categories; injuries to the head or neck (ICD-10: S00-S19) and injuries to the body (ICD-10: S20-T14). Road traffic incidents and offences—road traffic incidents and offences were defined as emergency hospital visits or death due to road traffic accidents (ICD-10: V00-V99), or arrests or convictions of traffic offences (including reckless driving, hit and run offences, causing death or injury by driving, and moving violations, as in previous work38). In sensitivity analyses, we investigated hospital treatment for road traffic incidents and arrests or convictions for road traffic offences separately. Violent crime—violent crime was defined as crimes against people, as in previous work,39 and included attempted, completed, and aggravated forms of murder, manslaughter, unlawful threats, harassment, robbery, arson, assault, assault on an official, kidnapping, stalking, coercion, and all sexual offences.

Statistical analyses All observable follow-up time was split into periods of treatment and non-treatment. We censored observations at the end of follow-up, or in the event of death or permanent emigration from Sweden. When a treatment period ended, the participant crossed over to a non-treatment period. If adverse outcomes were experienced during a period, this period was further split into the period before the first outcome, period between outcomes, and period after the last outcome. We measured time at risk from the start of all periods. To account for unobserved time—that is, periods where gabapentinoid use or adverse outcomes, or both might not have been captured in the registers—we removed (truncated) periods of intermittent emigration, prison stay, stay in secure residential homes for juveniles, and hospital admission. Time after immigration, hospital discharge, and release from prison or secure residential homes was added to the observed time again, and we measured time at risk from the start of this period. We used a within-individual design, which was analysed by stratified Cox proportional hazards regression. This design is a variant of self controlled cases series, where participants serve as their own control.4041 In this design, the rate of adverse outcomes during all treatment periods is compared with the rate of adverse outcomes during all non-treatment periods within each participant. This reduces the potential for unmeasured confounding that is time invariant during the study period, such as due to genetics and historical factors. In the model, only those who change drug status contribute directly to the estimate. All others contribute indirectly through the estimate of the association with age. To adjust for age as a categorical time varying covariate, we coded age with one category for each whole year. We used restricted cubic splines to allow for non-linear effects of age.42 In sensitivity analyses, we stratified on predetermined age bands (15-24, 25-34, 35-44, 45-54, 55-64, and ≥65 years). Because the unadjusted covariates in the stratified Cox proportional hazards regression are time varying, we did not test for the proportional hazards assumption. We initially analysed gabapentinoids as one class and examined associations for the whole sample. Then we analysed pregabalin and gabapentin separately. These samples were not mutually exclusive, as certain participants were dispensed both drugs during follow-up. Subsequent stratifications were made on sex and predetermined age bands. Several additional analyses were carried out. To account for the potential effect of other antiepileptics, we excluded participants who had been dispensed another antiepileptic (ATC codes N03AA-AG, N03AX03-11, N03AX13-15, and N03AX17-30) during follow-up. To account for the influence of alcohol and drug use, we excluded all those with diagnosed substance use disorders (ICD-10: F10-F19, not including overdoses and acute intoxications F10.0, F11.0, F12.0, F13.0, F14.0). To examine if single prescriptions (ie, not part of a treatment period) were differently associated with adverse outcomes, we examined adverse outcomes 30 days after a single prescription was dispensed. We also carried out analyses where we examined participants who had collected only one gabapentinoid prescription during follow-up. In our main analyses, we used a more conservative measure to define the end of a treatment period—that is, we considered treatment to end at the date of the last prescription. To account for the possibility that participants take gabapentinoids for up to three months after their last dispensed prescription (as the Swedish Pharmaceutical Benefits allows for a maximum of three months’ supply for each prescription), we repeated the main models with a different definition of a treatment period, by extending the end of a treatment period to three months after the last collected prescription. To account for previous use of gabapentinoids, we included a two year wash-out period to include only those who had been treatment-free for at least 24 months before starting their first treatment during our follow-up (a new user design). To examine new onsets of adverse outcomes, we excluded those who had experienced an event of the examined outcome before starting gabapentinoid treatment. To estimate dose of gabapentinoids used, we calculated the defined daily dose by summing dispensed drugs and then dividing the sum by the number of days in the treatment period. We then categorised defined daily doses into three separate treatment interval categories; low use (<1 defined daily dose), moderate use (1-2 defined daily doses), and high use (>2 defined daily doses), and we compared each treatment interval category to intervals with no use. For all analyses, 95% confidence intervals are presented. We used SAS version 9.4 and STATA version 14.1. The Methods section in the supplementary file provides more information on statistical analyses, including sensitivity analyses. The strengthening the reporting of observational studies in epidemiology (STROBE) reporting guidelines were followed (see supplementary file).

Sensitivity analyses Separately, we analysed only participants who had a pre-existing comorbidity before the start of gabapentinoid treatment,4344 including epilepsy (n=10 891), psychiatric disorders (n=61 526), or musculoskeletal disorders (n=91 932) (ie, all approved indications for gabapentinoids in Sweden). We also carried out analyses where we excluded those with any of these pre-existing comorbidities (n=60 797). We studied long term associations by comparing all time before the first collected gabapentinoid to all time after, using a conditional fixed effects Poisson regression analysis. We tested if gabapentinoids were differentially associated with hospital treatment for road traffic incidents (when it is undetermined who caused the incident) and arrests or convictions for road traffic offences (which would be caused by the individual) by examining these separately. Similarly, we examined differential associations for head or neck injuries and body injuries separately. Finally, we examined convictions (as opposed to arrests) of violent crime.