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Gabapentinoids linked to suicide, overdoses and injuries in young people
- 1. Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden
- 2. Yasmina Molero Henrik Larsson Brian M D Onfrio David J Sharp Seena Fazel 12 June 2019 Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden
- 3. 12/June/2019 Department of Psychiatry, Warneford Hospital, UK Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden School of Medical Sciences, Örebro University, Örebro, Sweden Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA Division of Brain Sciences, Imperial College London, London, UK
- 5. Introduction Gabapentinoids - anticonvulsant, analgesic, and anxiolytic Gabapentin and Pregabalin Epilepsy and Neuropathic pain Pregabalin----- GAD(Europe) Fibromyalgia (US)
- 6. Cont…… over prescription Adverse effects d. Blurred vision e. Coordination problems f. Impairments in cognitive performance a. Dizziness b. Somnolence c. Balance problems
- 7. Cont….. Statistical review and evaluation, antiepileptic drugs and suicidality 2008 FDA study Increased suicidal risk Suicidal ideation accounted for most reported events
- 8. Cont….. Increased/decreased/no changes in suicide risk Suicidal outcome ----Gabapentin Larger sample sizes FDA - Pharmacoepidemiologic studies
- 9. Cont…. Gabapentinoids - Overdoses and Related deaths Nested case control study Gabapentin ----Concomitant use 60 % Opioid related death
- 10. Cont….. U.S-----Reclassified Gabapentinoids Class C controlled substance Little data ---Psychosocial outcomes Wide off label use ---Pregabalin
- 11. Objective • To examine associations between gabapentinoids and adverse outcomes related to 1.Coordination disturbances (head or body injuries, or both and road traffic incidents or offences) 2. Mental health (suicidal behaviour, unintentional overdoses) 3.Criminality.(violent crime)
- 13. Design Population based cohort study Swedish registers - unique identification numbers Within-individual design Associations for specific subgroups
- 14. Participants and setting Age >15 yrs. Those who collected at least two consecutive prescriptions Follow-up : 1 Jan 2006 -31 Dec 2013. Cohort study - Prevalent users and New users
- 15. Ethical approval Sponsor Regional ethics review board Stockholm,Sweden Declaration of Helsinki Welcome trust Swedish research council Karolinska institutet funds Swedish research council for health working life and welfare
- 16. Drugs Data - Dispensed drugs ---- Swedish pharmacies Pregabalin (Anatomical Therapeutic Chemical code N03AX16) Gabapentin (N03AX12) Swedish Prescribed Drug Register
- 17. Outcome Suicidal behavior Unintentional overdoses Head or body injuries Road traffic incidents Swedish Patient Register
- 18. Cont…….. Information on death------- Cause of Death Register Suspected offences ----- Register of People Suspected of Offences Convicted offences ---- National crime register
- 19. Definitions Emergency hospital visit/Death Suicidal Behaviour Self injurious behavior ,suicide attempt, death Unintentional overdoses Poisoning - illicit drugs, medications, biological substances Accidental poisoning - noxious substances A/C intoxications and overdoses –alcohol and illicit drugs Head /body injuries Superficial, open/crushing injuries,dislocations,fractures& amputations Road traffic incidents and offences Road traffic accidents/arrest /convictions of traffic offences Violent crime Murder,manslaughter,unlawful threats,harassment,robbery,assault ,assault on an official,kidnapping,sexual offences etc.
- 20. Statistical analyses Within-individual design Stratified cox proportional hazards regression Adverse outcomes: Treatment periods vs non-treatment period
- 21. Sensitivity Analysis Preexisting comorbidity Exclusion of comorbidity Long term effect Head or neck injury/body injury
- 22. Defined daily dose (DDD) Estimation of the dose of Gabapentinoid used Sum of the dispensed drugs Number of days in Rx period Low use - <1 DDD Moderate use – 1-2 DDD High use - >2 DDD
- 23. Cont…… Confidence interval: 95% SAS version 9.4 and STATA version 14.1 STROBE guidelines
- 24. RESULTS
- 28. In within-individual analyses Gabapentinoids • Suicidal behavior • Deaths from suicide • Unintentional overdoses • Head/body injuries • Road traffic incidents and offences Stratification Pregabalin >> Gabapentin
- 30. Within-individual associations between gabapentinoid treatment and adverse outcomes by age
- 31. Cont…..
- 32. Pregabalin treatment Increases in all outcomes----- 15-34 years Suicidal behavior, unintentional overdoses, and head/body injuries - 35 to 44 Age 55 and older - No or decreased associations with outcomes Gabapentin treatment increased hazards of unintentional overdoses in participants < 25 head/body injuries in participants aged 15-54 Reduced or no associations - participants aged >=55
- 33. Adverse outcomes by excluded participants
- 34. Within-individual associations between gabapentinoid treatment and adverse outcomes
- 36. Gabapentinoids stratified by defined daily dose (DDD)
- 37. Discussion
- 38. Gabapentinoid treatment Suicidal behavior Unintentional overdoses Head/body injuries Age > 55 year ---- HR Road traffic incidents or offences 15-24 years ---- HR Arrests for violent crime
- 39. Strengths and limitations of this study Large population based cohort Wide range of outcomes Clinical outcomes from high quality nationwide registers Comprehensive information on gabapentinoid treatment Within-individual design
- 40. • Indications for gabapentinoids • Differences in prescription practices & outcome rate • Sweden & UK Lowest report rates Pregabalin –M/c prescribed
- 41. Relation to previous studies Pregabalin ----increased hazard of suicidal behavior Higher potency Greater bioavailability Quicker absorption Prevalence of gabapentinoid misuse is higher among people who misuse opioid
- 42. Road traffic incidents and offences and violent crime Pregabalin >>>> gabapentin Motor coordination Off-label prescription Concomitant alcohol or drug use
- 43. Cont……. 15 to 24 years Suicidal behavior Unintentional overdoses Head/body injuries Faster metabolism Impulsivity and risk taking Alcohol or illicit drugs
- 44. Conclusions Gabapentinoids - & Risks of adverse outcomes Increased risks ----Adolescents & Young adults (ages 15-24 years) Pregabalin shows higher hazards of these outcomes than gabapentin Guidelines - Gabapentinoid treatment in young people may need review
- 45. Critical appraisal • Abstract • Methodology • Results • Discussion
- 46. THANK YOU
Hinweis der Redaktion
- Pregabalin is also approved for treating generalised anxiety disorder in Europe, and has received approval for treating fibromyalgia in the United States
- suicidal behaviour was rare
- Results have been inconsistent
- Evidence about gabapentinoid adverse effect is limited despite broadening clinical indications and increasing use
- population based cohort study using Swedish registers with national coverage, inked through unique identification numbers 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
- Single prescriptions were not included in the main analyses owing to uncertainty over drug adherence or tolerance
- All citizens in Sweden are insured through a common non-claims healthcare insurance, and drugs are subsidised. This register includes information on all prescriptions dispensed by pharmacies since July 2005,with less than 0.3% missing information.
- This register includes the primary diagnoses listed in 99% of all hospital discharges In validation studies the positive predictive value of diagnosis in this register is between 85% and 95%. Only diagnoses received during unplanned visits were used in the analysis
- a register of all deaths in Sweden Death,suicides ,RTA
- Reckless driving, hit and run offences, causing death or injury by driving and moving violations as in previous work
- The strengthening of the observational studies in epidemiology Reporting guidelines
- Pregabalin users were younger and associated with a higher prevalence of all outcomes compared with gabapentin users
- Association for arrest and violent crime less clear
- gabapentin treatment was associated with reductions in road traffic incidents and offences and arrests for violent crime
- highest hazards were in the age group 15-24 years (1.67, 1.52 to 1.84). Patterns were similar for other outcomes; younger participants (15-34 years) showed increased hazards, whereas older participants (≥55 years) showed reduced or no associations
- Within-individual associations between gabapentinoid treatment and adverse outcomes, excluding participants who used other antiepileptics or with substance use disorders during follow-up Within-individual associations between gabapentinoid treatment and adverse outcomes, excluding participants who used other antiepileptics or with substance use disorders during follow
- ithin-individual associations between gabapentinoid treatment and adverse outcomes in individuals treated with gabapentinoids stratified by defined daily dose (DDD)
- Participants in the other age bands showed heterogeneous associations, with increased hazards of suicidal behaviour, unintentional overdoses, and head/body injuries, and no associations with road traffic incidents or offences and arrests for violent crimes
- , as each collected prescription is registered
- Swedish Prescribed Drug Registe Although we excluded treatment periods from July 2005 to 1 January 2006 (start of follow-up), participants could have been treated with gabapentinoids before that time
- Notably, when excluding participants with substance use disorders from our analyses, associations with suicidal behaviour were attenuated, and no associations remained for overdoses
- Pregabalin and gabapentin also showed contrasting associations with road traffic incidents and offences and violent crime; gabapentin was associated with decreased hazards of these outcomes, whereas pregabalin was associated with increases
- he reduced hazards in older people could reflect pharmacodynamic differences related to age,6162 less concurrent use of alcohol or drugs, different indications for treatment, or reduced symptom severity of underlying condition
- Abstract included background,methods,results ,conclusion Trial design , trial population,randomization, trial protocol,trial endpoint,follow up ,statistical analysis Consort diagram Baseline characteristics ,graphs .