Opioid Exposure and the Risk of Dementia: A National Cohort Study



      To examine the association between prescription opioid use and the risk of dementia in old-age, since existing studies of the association are few, and the evidence is inconsistent.


      Prospective national cohort study (N = 91,307, aged 60 years and over), without a dementia diagnosis for ten years, followed-up for incident dementia from January 2013 to October 2017.


      Opioid exposure was based on opioid purchases classified from Anatomical Therapeutic Chemical Classification system codes (N02A), and classified as exposed if the purchase period covered at least 60 days within a 120-day interval; otherwise, unexposed.


      Healthcare maintenance organization in Israel.


      During follow-up, 2,849 (3.1%) persons were opioid exposed (mean age 73.94 ± 6.71 years), and 5,298 (5.8 %) persons developed dementia (mean age 78.07 ± 6.54 years). Cox regression models were fitted to quantify the risk of incident dementia with Hazard Ratios (HR) and their associated 95% Confidence Intervals (CI). The opioid exposed group aged 75+ to 80 years were at an increased risk of incident dementia (Adjusted HR = 1.39, 95% CI = 1.01, 1.92, Z-statistic = 2.02, p <0.05) compared to the unexposed. The point-precision estimates were generally similar to the primary analysis across fourteen sensitivity analyses.


      : Policymakers, caregivers, patients, and clinicians may wish to consider that opioid exposure aged 75–80 is linked with an increased dementia risk to balance the potential benefits and adverse side effects of opioid use in old age.

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        • World Health Organization
        Risk reduction of cognitive decline and dementia: WHO guidelines.
        Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. World Health Organization, Geneva2019
        • Livingston G
        • Sommerlad A
        • Orgeta V
        • et al.
        Dementia prevention, intervention, and care.
        Lancet. 2017; 390: 2673-2734
        • Alzheimer's Association Report
        2021 Alzheimer's disease facts and figures.
        Alzheimers Dement. 2021; 17: 327-406
        • Livingston G
        • Huntley J
        • Sommerlad A
        • et al.
        Dementia prevention, intervention, and care: 2020 report of the Lancet commission.
        Lancet. 2020; 396: 413-446
        • Jalal H
        • Buchanich JM
        • Sinclair DR
        • et al.
        Age and generational patterns of overdose death risk from opioids and other drugs.
        Nat Med. 2020; 26: 699-704
        • Schieber LZ
        • Guy Jr., GP
        • Seth P
        • et al.
        Variation in adult outpatient opioid prescription dispensing by age and sex - United States, 2008-2018.
        MMWR Morb Mortal Wkly Rep. 2020; 69: 298-302
        • Taipale H
        • Hamina A
        • Lampela P
        • et al.
        Is Alzheimer's disease associated with previous opioid use?.
        Pain Med. 2017; 19: 2115-2121
        • Dublin S
        • Walker RL
        • Gray SL
        • et al.
        Use of analgesics (opioids and nonsteroidal anti-inflammatory drugs) and dementia-related neuropathology in a community-based autopsy cohort.
        J Alzheimers Dis. 2017; 58: 435-448
        • Dublin S
        • Walker RL
        • Gray SL
        • et al.
        Prescription opioids and risk of dementia or cognitive decline: a prospective cohort study.
        J Am Geriatr Soc. 2015; 63: 1519-1526
        • Li K
        • Luo S.
        Dynamic predictions in Bayesian functional joint models for longitudinal and time-to-event data: an application to Alzheimer's disease.
        Stat Methods Med Res. 2019; 28: 327-342
        • Chinitz D
        • Shalev C
        • Galai N
        • et al.
        The second phase of priority setting. Israel's basic basket of health services: the importance of being explicitly implicit.
        BMJ (Clin Res ed). 1998; 317: 1005-1007
        • World Health Organization
        International Statistical Classification of Diseases and Related Health Problems. - 10th revision.
        World Health Organization, Geneva, Switzerland2016
        • World Health Organization
        International Classification of Diseases,Ninth Revision, Clinical Modification (ICD-9-CM).
        Medicode, Salt Lake City, UT2000
        • Kodesh A.
        Prevalence and comorbidities of dementia in Israel: a nationally representative cohort study.
        Int Psychogeriatr. 2018; 31: 1-5
        • Kodesh A
        • Goldberg Y
        • Rotstein A
        • et al.
        Risk of dementia and death in very-late-onset schizophrenia-like psychosis: a national cohort study.
        Schizophr Res. 2020; 223: 220-226
        • Prince M
        • Bryce R
        • Albanese E
        • et al.
        The global prevalence of dementia: a systematic review and metaanalysis.
        Alzheimers Dement. 2013; 9: 63-75e62
        • World Health Organization
        The anatomical Therapeutic Chemical Classification System With Defined Daily Doses (ATC/DDD).
        World Health Association, Oslo2006
        • Dowell D
        • Haegerich TM
        • Chou R.
        CDC guideline for prescribing opioids for chronic pain - United States, 2016.
        MMWR Recomm Rep. 2016; 65: 1-49
        • Mojtabai R.
        National trends in long-term use of prescription opioids.
        Pharmacoepidemiol Drug Saf. 2018; 27: 526-534
        • Boudreau D
        • Von Korff M
        • Rutter CM
        • et al.
        Trends in long-term opioid therapy for chronic non-cancer pain.
        Pharmacoepidemiol Drug Saf. 2009; 18: 1166-1175
        • Shapira B
        • Rosca P.
        Mountain or molehill? A scoping review of evidence on an opioid use problem in Israel.
        Drugs: Educ Preven Policy. 2021; : 1-9
      1. Central Bureau of Statistics of Israel. Statistical abstract of Israel Jerusalem, Israel 2013.

        • Kleinbaum DG
        • Klein M.
        Survival Analysis. 3. Springer, New York2010
        • Bohnert AS
        • Valenstein M
        • Bair MJ
        • et al.
        Association between opioid prescribing patterns and opioid overdose-related deaths.
        JAMA. 2011; 305: 1315-1321
        • Commenges D
        • Letenneur L
        • Joly P
        • et al.
        Modelling age-specific risk: application to dementia.
        Stat Med. 1998; 17: 1973-1988
        • Grambsch PM
        • Therneau TM.
        Proportional hazards tests and diagnostics based on weighted residuals.
        Biometrika. 1994; 81: 515-526
        • Therneau TM
        • Grambsch PM.
        Modeling Survival Data: Extending the Cox Model.
        Springer, London2000
      2. R: a language and environment for statistical computing R foundation for statistical computing; 2021. Available at: Accessed August 21, 2021

        • van der Wal WM
        • Geskus RB.
        ipw: An R package for inverse probability weighting.
        J Statistl Soft. 2011; 43: 1-23
        • Kivimaki M
        • Luukkonen R
        • Batty GD
        • et al.
        Body mass index and risk of dementia: analysis of individual-level data from 1.3 million individuals.
        Alzheimers Dement. 2018; 14: 601-609
        • Anstey KJ
        • von Sanden C
        • Salim A
        • et al.
        Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies.
        Am J Epidemiol. 2007; 166: 367-378
        • Clayton D
        • Hills M.
        Statistical Models in Epidemiology.
        Oxford University Press, United Kingdom2013
        • Ferreira P
        • Ferreira AR
        • Barreto B
        • et al.
        Is there a link between the use of benzodiazepines and related drugs and dementia? A systematic review of reviews.
        Eur Geriatr Med. 2022; 13: 19-32
        • Lang L
        • Clifford A
        • Wei L
        • et al.
        Prevalence and determinants of undetected dementia in the community: a systematic literature review and a meta-analysis.
        BMJ Open. 2017; 7e011146
        • VanderWeele TJ.
        Can sophisticated study designs with regression analyses of observational data provide causal inferences?.
        JAMA Psychiatry. 2020; 78: 244-246
        • Griffioen C
        • Willems EG
        • Husebo BS
        • et al.
        Prevalence of the use of opioids for treatment of pain in persons with a cognitive impairment compared with cognitively intact persons: a systematic review.
        Curr Alzheimer Res. 2017; 14: 512-522

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