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Sedative Load of Drugs and Adverse Outcomes Faculty of Health Sciences Is in Kuopio

Sedative Load of Drugs and Adverse Outcomes Faculty of Health Sciences Is in Kuopio

Sirpa Hartikainen Professor of Geriatric Pharmacotherapy, MD Kuopio Research Center of Geriatric Care School of Pharmacy, University of Eastern Finland

Sedative load of and adverse outcomes Faculty of Health Sciences is in Kuopio

- 2400 undergraduate students 1 - 60 doctoral degrees every year 5 . 4 UEF - 100 professors 2 . 2 0 1 3 The city of Kuopio with about 120 000 inhabitants

Esityksen nimi / Tekijä 15.4.2013 3 Esityksen nimi / Tekijä 15.4.2013 4 Kuopio Research Centre of Geriatric Care (GerHo) http://www.uef.fi/gerho

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•objectively measured decrease in psychomotor functioning including memory and attention

•subjective feelings of drowsiness and sleepiness

•subjective and objective do not necessarily correlate with each other.

•The sedative effects of drugs may be pronounced among older people due to age- related changes in body, in CNS and in pharmacokinetics and - dynamics

Esityksen nimi / Tekijä 15.4.2013 6 Pharmacological mechanisms

•GABA-A complex ( and ) Subtypes of GABA-A receptor also mediate other effects like muscle relaxation.

•Histamine H1 receptors in the CNS () Sedative effects of histamine antagonism may be explained with the fact that histamine regulates the -wake cycle •: μ- receptors which also mediate sedation •A potential source of sedative effect is antagonism or agonism of α1- and α2-adrenergic receptors in the CNS

Esityksen nimi / Tekijä 15.4.2013 7 Several models of assessing sedative load of drugs

•Sedative Load Model •Sloan Model • Burden Index •CNS Drug Model

15.4.2013 8 Comparison of the different methods to calculate cumulative effect of taking multiple drugs with sedative properties and ratings proposed to drug classes. Sedative Load Sloane Drug Burden CNS Drug Model Model Index Model

Conventional rating: 2 rating: 3 included included Atypical rating: 1 rating: 3 included included antipsychotics TCAs, non-selective rating: 2 rating: 3 included included MAO inhibitors

SSRIs rating: 1 rating: 3 included included Second generation rating: 1 rating: 3 included included ( rating 2) Benzodiazepines rating: 2 rating: 6 included included

Other rating: 2 rating: 3 included not included and Esityksen nimi / Tekijä 15.4.2013 9 Reference : Taipale H 2012 Comparison of the different methods to calculate cumulative effect of taking multiple drugs with sedative properties and ratings proposed to drug classes. Sedative Load Sloane Drug Burden CNS Drug Drug class Model Model Index Model Opioids rating: 1 rating: 3 included included Antiepileptics rating: 1 rating: 3 included not included rating: 1 rating: 3 included not included (metoclopramide, ) Antispasmodics rating: 1 no included not included with psychotropics Centrally acting rating: 1 no included not included muscle relaxants Anticholinergic rating: 1 rating: 3 included not included anti-parkinson drugs Indomethacin (with rating: 1 rating: 3 not included not included ethylmorphine) Esityksen nimi / Tekijä 15.4.2013 10 Sedative load model •reviewing the summary of product characteristics for all drugs available in Finland from 1998 to 2001 and updated 2008. •a comprehensive classification of all drugs on market and to include also drugs for somatic disorders. • All drugs were classified into 1 of 4 groups – (1) primary sedatives (score 2) – (2) drugs with sedation as a prominent side effect or preparations with a sedating component (score 1) – (3) drugs with sedation as a potential (score 0) – (4) drugs with no known sedation. (score 0) Esityksen nimi / Tekijä 15.4.2013 11 The classification was based on consensus between a psychogeriatrician, a geriatrician, and a physician specialized in pharmacoepidemiology.

According to the model, sedative load was calculated by summing the sedative rating for each drug in a person’s regimen according to the following formula:

Esityksen nimi / Tekijä 15.4.2013 12 GeMS-study

•Population is 1000 randomly sampled inhabitants of Kuopio, aged 75 years or older. •Randomization into intervention (500 persons) and control group (500 persons) •Intervention group: Comprehensive Geriatric Assessment (CGA) by a geriatrician, a nurse and a physiotherapist •Interventions: physical exercise counselling and gym, examination by dentist, nutritional counselling if needed, new diagnoses, assessment of medication …

Esityksen nimi / Tekijä 15.4.2013 13 Population People aged ≥75 years living in Kuopio N=5615 (1 January, 2004)

Random sample n=1000 (1 November, 2003) Intervention group, n=500 Comparison group, n=500 Not examined Refused n=162 Died n=55 Moved n=2

Baseline 2004 Intervention group, n=404 Comparison group, n=377 Loss to follow-up Refused n=11 Died n=52 No contact n=1

1. Follow-up 2005 Intervention group, n=371 Comparison group, n=346 Loss to follow-up Refused n=4 Died n=55 Moved n=1

2. Follow-up 2006 Intervention group, n=339 Comparison group, n=318 Loss to follow-up Refused n=2 Died n=46

3. Follow-up 2007 Intervention group, n=315 Comparison group, n=294 Esityksen nimi / Tekijä 15.4.2013 14 Characteristics of the study participants according to sedative load groups in the baseline of the GeMS Study. All Sedative Sedative Sedative p- % (n) load 0 load 1-2 load ≥3 valuea % (n) % (n) % (n) Women 69 (486) 66 (324) 80 (118) 76 (44) 0.002

Education ≤6 y 51 (346) 50 (240) 50 (72) 63 (34) 0.173

Loneliness <0.001

Often 4 (32) 3 (13) 8 (11) 14 (8)

Sometimes 32 (225) 28 (138) 41 (60) 47 (27)

Never 63 (441) 69 (343) 52 (76) 39 (22)

Esityksen nimi / Tekijä 15.4.2013 15 Age, comorbidity and number drugs in the study participants according to sedative load groups in the baseline of the GeMS Study. All Sedative Sedative Sedative p- a load 0 load 1-2 load ≥3 value Mean value Mean value Mean value Mean value ±SD ±SD ±SD ±SD Mean age 81.3 (4.6) 80.8 (4.4) 82.4 (4.7) 82.5 (5.6) <0.001

FCI mean 2.6 (1.7) 2.5 (1.7) 2.9 (1.8) 3.4 (1.7) <0.001

Mean number of 4.9 (3.2) 4.1 (2.7) 6.4 (3.1) 8.6 (3.6) <0.001 drugs a Continuous variables were tested with analysis of variance, and are presented Esityksen nimi / Tekijä 15.4.2013 16 as means (±SD), comparison between sedative load groups 0, 1-2 and ≥3. FCI=Functional Comorbidity Index score. Cognitive functioning, an self-rated health of the study participants according to sedative load groups in the baseline of the GeMS Study. All Sedative Sedative Sedative p- valuea % (n) load 0 load 1-2 load ≥3 % (n) % (n) % (n) Poor self-rated 15 (103) 10 (51) 24 (35) 30 (17) <0.001 health MMSE <25 25 (170) 20 (99) 30 (44) 47 (27) <0.001

Dementia 16 (109) 12 (61) 20 (30) 31 (18) <0.001 diagnosis GDS ≥5 8 (55) 5 (25) 12 (18) 21 (12) <0.001 Geriatric depression scale Esityksen nimi / Tekijä 15.4.2013 17 Physical functioning of the study participants according to sedative load groups in the baseline of the GeMS Study. Physical All Sedative Sedative Sedative p- valuea functioning % (n) load 0 load 1-2 load ≥3 % (n) % (n) % (n) Poor IADL, 36 (252) 30 (146) 46 (67) 67 (39) <0.001 score ≤6 Physical <0.001 activity Inactive 36 (245) 31 (150) 44 (62) 60 (33) Moderate or 64 (429) 69 (328) 56 (79) 40 (22) active Unable to walk 46 (324) 46 (229) 47 (69) 45 (26) 0.963 independently 400m Esityksen nimi / Tekijä 15.4.2013 18 Sedative load and associations with phycical performance, balance, muscle strenght and mobility

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Timed up and go Muscle strenght (TUG) Balance ASSOCIATION WITH MUSCLE STRENGHT Grip strenght (kg) Knee extension (Newtons)

Esityksen nimi / Tekijä 15.4.2013 20 Taipale HT. J Gerontol A Biol Sci Med Sci 66: 1384-1392, 2011. ASSOCIATIONS WITH MUSCLE STRENGHT Five time chair stand 10 m walking speed (m/s) (time in seconds)

Taipale HT. J Gerontol A Biol Sci Med Sci 66: 1384-1392, Esityksen nimi / Tekijä 15.4.2013 21 2011 ASSOCIATIONS WITH BALANCE AND MOBILITY TUG (Timed Up and Go) Berg’s Balance Test (time in seconds) max 56 points

The present study population consisted of 158 community-dwelling, dentate, non-smoking older people who participated in an oral clinical examination (110 women and 48 men, with a mean age of 79.3 and SD being 3.7 years).

Esityksen nimi / Tekijä 15.4.2013 22 Taipale HT et al. J Clin Psychopharmacol 32: 218-224, 2012. LONGITUDINAL STUDY ON SEDATIVE LOAD

•Baseline 2004 to the final examination in 2007, the sample decreased from 700 persons to 581 persons. •Among survivors the prevalence of sedative load at least 1 increased during the study years, from 29% to 36%.

Esityksen nimi / Tekijä 15.4.2013 23 Sedative use during years 2004 to 2007 in the GeMS Study population, home-dwelling (n=700) at the baseline. 2004 2005 2006 2007 n=700 n=656 n=621 n=581 % n % n % n % n Users with sedative 29.3 205 30.0 197 33.7 209 36.1 210 load >1 1-2 21.0 147 22.1 145 24.3 151 24.4 142 ≥3 8.3 58 7.9 52 9.3 58 11.7 68 Women users 33.3 162 33.7 155 37.4 162 38.8 158

Men users 20.1 43 21.4 42 25.0 47 29.9 52 Age groups with sedative load >1 75-79 22.8 79 21.6 72 26.5 86 29.7 92 80-84 34.0 73 36.4 72 39.5 73 39.9 69

≥85 38.1 53 42.4 53 44.6 50 50.0 49 15. Esityksen nimi / 4.2 Tekijä 013 24 Drug classes contributing to sedative load at the baseline of the GeMS Study. Cross-sectional point prevalence of sedative drug use in 2004 (n=700) and in 2007 (n=581).

Drug group Users 2004 Users 2007 Change in % % (n) % (n) Conventional antipsychotics 3.4 (24) 0.9 (5) -68 antidepressants 1.7 (12) 1.2 (7) -29 Anxiolytics 3.3 (23) 3.4 (20) +3 Hypnotics 14.6 (102) 14.1 (82) -3 Atypical antipsychotics 2.6 (18) 4.7 (27) +80 SSRIs 4.6 (32) 4.1 (24) -11 Other antidepressants 3.4 (24) 6.9 (40) +103

Antiepileptics 2.1 (15) 2.1 (12) 0

Opioids 1.9 (13) 3.3 (19) +7415.4.2013 25 Esityksen nimi / Tekijä Longitudinal study : Sedative load and mortality

•From the baseline examination (2004) to the end year 2008 159 (22.7%) participants died •The unadjusted HR for risk of associated with time-dependent sedative load were – 1.40 (CI 0.98-2.01) for sedative load 1-2 – 1.88 (CI 1.20-2.95) for sedative load ≥3. •In the fully adjusted model, sedative load was not associated with risk of death – sedative load 1-2 HR 1.12 [CI 0.76-1.64], – sedative load ≥3 HR 0.92 [CI 0.55-1.56]).

26 Conclusion •Persons with sedative load are more often – persons with poor self rated health physical functioning – Persons with declined cognition

• Sedative load is associated with decline in mobility, muscle strenght, balance

• Sedative load is associated with poor oral health, dental caries

Esityksen nimi / Tekijä 15.4.2013 27 Other researchers in these studies Muscle strenght, balance and mobility •PhD Heidi Taipale, University of Eastern Finland, Finland •PhD Danijela Gnidic, University of Sydney, Australia •Professor J Simon Bell, University of Eastern Finland, Finland

Oral health PhD-student Antti Tiisanoja, University of Oulu, Finland PhD Heidi Taipale, University of Eastern Finland, Finland Professor Pekka Ylöstalo, University of Eastern Finland, Finland Docent Anna-Maija Syrjälä, University of Oulu, Finland PhD-student Kaija Komulainen, University of Eastern Finland, Finland

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Thank you for your attentionEsityksen nimi / Tekijä 15.4.2013 29