Calvo, Andrea

Chio', Adriano

D'Errico, Angelo

D'Ovidio, Fabrizio

Scarinzi, Cecilia

English

Institutional Research Information System University of Turin

18 October 2023AperTO - Archivio Istituzionale Open Access dell'Università di TorinoOriginal Citation:The association between nervous system drugs and incidence of Amyotrophic Lateral SclerosisTerms of use:Open Access(Article begins on next page)Anyone can freely access the full text of works made available as "Open Access". Works made availableunder a Creative Commons license can be used according to the terms and conditions of said license. Useof all other works requires consent of the right holder (author or publisher) if not exempted from copyrightprotection by the applicable law.Availability:This is the author's manuscriptThis version is available http://hdl.handle.net/2318/1566302 since 2016-06-14T11:01:03ZThe association between nervous system drugs and incidence of Amyotrophic Lateral SclerosisD’Ovidio F.1, d’Errico A.2, Calvo A.1, Scarinzi C.3, Chiò A.11 Department of Neuroscience, University of Turin, Italy 2 Department of Epidemiology, ASL TO3, Piedmont Region, Italy3 Department of Environmental and Health, ARPA Piedmont Region, ItalyIntroductionThe risk of Amyotrophic Lateral Sclerosis (ALS)has been found reduced among subjects withprevious consumption of non-steroidal anti-inflammatory drugs (NSAID)1,2,3, although withmixed results, of Angiotensin-Converting Enzyme(ACE) inhibitors drugs4. Antipsychotics andantidepressants have been also hypothesized asprotective agents from ALS onset5, even thoughno longitudinal studies have been conducted onthe association between ALS and previousnervous system drugs consumption. Therefore,aim of the present study was to analyze theassociation between prescription of this class ofdrugs and subsequent risk of developingAmyotrophic Lateral Sclerosis in a large Italianurban population.Materials and methodsThe study population was composed of allpeople present at 2001 Italian census, alreadyresident in Turin (Italy) in 1996 (n=737,979).Census data were linked at the individual levelwith those of the Municipality Registry, of theATC Drug Registry (available from 1997) and ofthe ALS Piedmont Regional Registry (availablefrom 1996).Subjects were followed-up from January 1st 2002to October 8th 2014 (last ALS Registry update),while exposure to nervous system drugs wasmeasured from 1997 until December 31st 2012or until 1 year before the ALS onset. During thefollow-up period, each subject contributed toperson-years from start of follow-up until emi-gration out of town, death or end of follow-up.Not all the families of nervous systems drugswere considered, on one hand because thePiedmont Registry includes only drugs pre-scribed through the National Health Service(NHS), on the other hand because of the smallnumbers of subjects who were prescribed drugsbelonging to some families. Therefore, theassociation between ALS and drug prescriptionswas explored for the following ATC families ofnervous system drugs: opioids (N02A); anti-epileptic drugs (N03A); antiparkinson drugs(N04), including anticholinergic (N04A) anddopaminergic agents (N04B); antipsychotics(N05A); antidepressants (N06A).Antiparkinson drugs were evaluated as a singlecategory, because of the small number ofexposed ALS cases for anticholinergic (n=1) anddopaminergic agents (n=6);The association of ALS with nervous systemdrugs was estimated for ever exposure (at leastone prescription of the corresponding drugfamily), as well as cumulative exposure intertiles, using as the reference category subjectswithout prescriptions of the same drug family.The outcome variable was represented by ALSonset, ascertained from the Regional ALS Regi-stry.The association between nervous system drugsconsumption and ALS onset was estimated by.multivariate Poisson regression models, adjustedfor age (as continuous), sex, education level (pri-mary, secondary, higher and graduate edu-cation), marital status (married, unmarried andpreviously married, which included separatedand divorced people) and prescription of othernervous system drug families.ResultsThe study population was composed of 737,979subjects (46.9% males), of which 296 were dia-gnosed with ALS during the follow-up period,after exclusion of subjects diagnosed with ALSbefore start of follow-up. Annual incidence ofALS was 37.0 per million inhabitants.In the analysis for ever exposure, opioids(IRR=0.17) and antiparkinson drugs (IRR=0.42)were significantly inversely associated with ALSrisk, while for antidepressants the associationwas only marginally significant (IRR=0.79).Examining cumulative exposure, the protectiverole of opiods was confirmed for all exposurecategories (test for trend: p<0.001), whereas forantiparkinson drugs only a non-significant pro-tective effect was present in the highestexposure category (IRR=0.23).ALS was also significantly associated withcumulative exposure to antidepressants in theintermediate cumulative category (IRR=0.54),with a significant test for trend across dosecategories (p=0.03).ConclusionIn conclusion, the present study revealed aprotective effect of opioids and antidepressantson ALS onset, which is a novel finding, to ourknowledge. The dose-response effect observedbetween ALS risk and cumulative exposure tothese drug families indicates that these asso-ciations may reflect a causal relationship. Thesignificant association found with ever exposureto antiparkinsons is also suggestive of a pro-tective role of this drug family on ALS risk, al-though the number of exposed ALS cases wastoo small to draw any sound conclusion.References1 Popat RA, Tanner CM, van den Eeden SK, Bernstein AL, BlochDA, Leimpeter A, McGuire V, Nelson LM. Effect of non-steroidalanti-inflammatory medications on the risk of amyotrophiclateral sclerosis. Amyotroph Lateral Scler. 2007; 8(3): 157-63.2 Fondell E, O’Reilly EJ, Fitzgerald KC, Falcone GJ, McCulloughML, Thun MJ, Park Y, Kolonel LN, Ascherio A. Non-steroidalanti-inflammatory drugs and Amyotrophical Lateral Slerossis:Results from 5 prospective cohort studies. Amyotroph LateralScler. 2012; 13(6): 573-579.3 Tsai CP, Lin FC, Lee JK, Lee CT. Aspirin use associated withamyotrophic lateral sclerosis: a total population-based case-control study. J Epidemiol. 2015; 25(2): 172-7.4 Lin FC, Tsai CP, Kuang-Wu Lee J, Wu MT, Tzu-Chi Lee C.Angiotensin-Converting Enzyme Inhibitors and AmyotrophicLateral Sclerosis Risk. A total population-based case-controlstudy. JAMA Neurol. 2015; 72(1): 40-48.5 Stommel EW, Graber D, Montanye J, Cohen JA, Harris BT.Does treating schizophrenia reduce the chances of developingamyotrophic lateral sclerosis? Medical Hypotheses. 2007; 69:1021–1028.Table. Incidence Rate Ratio (IRR) of ALS onset associated with nervous system drugs prescriptions distinguishedby family (ATC), ever exposure (model 1) and categorical cumulative dose (model 2) – Poisson regressionmodels adjusted for age, sex, education and marital status.Total pop. (%) ALS pop. (%) IRR 95% CIModel 1 prescription of:                     opioids (N02A) 127,978 (17.3) 16 (5.4) 0.17 0.10-0.28antiepileptics (N03A) 77,840 (10.5) 32 (10.8) 1.09 0.75-1.59antiparkinsons (N04) 25,759 (3.5) 6 (2.0) 0.42 0.19-0.95antipsychotics (N05A) 63,210 (8.6) 23 (7.8) 0.82 0.53-1.28antidepressants (N06A) 196,150 (26.6) 74 (25.0) 0.79 0.60-1.04Model 2 opioids (N02A) no prescription 610,001 (82.7) 280 (94.6) 1 -I tertile (up to 3) 47,656 (6.5) 9 (3.0) 0.25 0.13-0.49II tertile (4 - 13) 37,855 (5.1) 3 (1.0) 0.10 0.03-0.35III tertile (over 14) 42,467 (5.7) 4 (1.4) 0.14 0.05-0.39antiepileptics (N03A) no prescription 660,139 (89.5) 264 (89.2) 1 -I tertile (up to 6) 26,208 (3.5) 16 (5.4) 1.15 0.69-1.91II tertile (7 - 34) 25,546 (3.5) 8 (2.7) 1.19 0.57-2.51III tertile (over 35) 26,086 (3.5) 8 (2.7) 1.25 0.58-2.67antiparkinsons (N04) no prescription 712,220 (96.5) 290 (98.0) 1 -I tertile (up to 14) 8,792 (1.2) 2 (0.7) 0.38 0.09-1.55II tertile (15 - 63) 8,213 (1.1) 3 (1.0) 0.73 0.22-2.41III tertile (over 64) 8,754 (1.2) 1 (0.3) 0.23 0.03-1.60antipsychotics (N05A) no prescription 674,769 (91.4) 273 (92.2) 1 -I tertile (up to 7) 20,993 (2.9) 9 (3.0) 0.77 0.40-1.50II tertile (8 - 39) 20,776 (2.8) 7 (2.4) 0.99 0.43-2.26III tertile (over 40) 21,441 (2.9) 7 (2.4) 1.24 0.51-3.00antidepressants (N06A) no prescription 541,829 (73.4) 222 (75.0) 1 -I tertile (up to 4) 70,129 (9.5) 40 (13.5) 1.06 0.76-1.49II tertile (5 - 20) 60,474 (8.2) 15 (5.1) 0.54 0.31-0.92III tertile (over 21) 65,547 (8.9) 19 (6.4) 0.58 0.32-1.05

The association between nervous system drugs and incidence of Amyotrophic Lateral Sclerosis

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The association between nervous system drugs and incidence of Amyotrophic Lateral Sclerosis

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