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Alzheimer’s & Dementia

(2014) 1-9

Research Article

Frequent use of opioids in patients with dementia and nursing home

residents—A study of the entire elderly population of Denmark

Christina Jensen-Dahm

Christiane Gasse

, Aske Astrup

, Preben Bo Mortensen

b,c,d

Gunhild Waldemar

Department of Neurology, Danish Dementia Research Centre (DDRC), Rigshospitalet–University of Copenhagen, Copenhagen, Denmark

National Centre for Register-based Research, Aarhus University, School of Business and Social Sciences, Aarhus, Denmark

Centre for Integrated Register-Based Research, CIRRAU, Aarhus University, Aarhus, Denmark

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

Abstract

Background:

Pain is believed to be undertreated in patients with dementia; however, no larger

studies have been conducted. The aim was to investigate prevalent use of opioids in elderly with

and without dementia in the entire elderly population of Denmark.

Method:

A register-based cross-sectional study in the entire elderly (65 years) population in 2010

was conducted. Opioid use among elderly with dementia (N

35,455) was compared with elderly

without (N

870,645), taking age, sex, comorbidity, and living status into account.

Results:

Nursing home residents (NHRs) used opioids most frequently (41%), followed by

home-living patients with dementia (27.5%) and home-living patients without dementia (16.9%). Bu-

prenorphine and fentanyl (primarily patches) were commonly used among NHRs (18.7%) and home-

living patients with dementia (10.7%) but less often by home-living patients without dementia

(2.4%).

Conclusions:

Opioid use in the elderly Danish population was frequent but particularly in patients

with dementia and NHR, which may challenge patient safety and needs further investigation.

2014 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This

is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/

by-nc-nd/3.0/).

Dementia; Opioids; Elderly; Buprenorphine; Fentanyl; Pain

Keywords:

1. Introduction

Elderly patients with dementia often suffer from multi-

morbidity, and pain-causing conditions are frequent

[1].

Thus, appropriate use of drugs and treating comorbidity

represent an important public health issue. Currently, pain

is believed to be undertreated in the elderly and especially

in people with dementia

[2,3],

an assumption corroborated

by a number of small case-control studies

[4–9].

Reasons

for undertreatment are not well understood. Assessment of

pain in patients with dementia is challenging, which may

*Corresponding author. Tel.:

145-35458759;

Fax:

145-35452446.

E-mail address:

[email protected]

lead to undertreatment. On one hand, careful prescribing

may be appropriate as elderly have an increased risk of

side effects and severe adverse drug reactions

[10].

Opioids

may be particularly problematic in patients with dementia

because of sedation and their association with a reduction

in mental health functioning

[11].

On the other hand,

pain is associated with lower quality of life

[12]

and impair-

ment of working memory

[13]

and should be treated efﬁ-

ciently. Furthermore, results have indicated that treatment

of pain can improve behavioral symptoms in patients with

dementia

[14].

Studies examining data collected before 2000 have

consistently reported that patients with dementia were less

likely to receive analgesics

[5,7,8].

However, more recent

reports have shown a more varied picture, with some

1552-5260/$ - see front matter

2014 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the

CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

http://dx.doi.org/10.1016/j.jalz.2014.06.013

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C. Jensen-Dahm et al. / Alzheimer’ & Dementia

(2014) 1-9

studies reporting that patients with dementia are more likely

to receive paracetamol

[15,16]

and opioids, although the

association of opioid use in dementia was not signiﬁcant in

a multivariate analysis

[15].

Over the past 10 to 15 years,

however, several countries have reported increasing opioid

use in the general population

[17–19],

and recent results

could indicate that prescription patterns in patients with

dementia may have changed. Consequently, we conducted

a nationwide register-based study in the entire elderly popu-

lation of Denmark, comparing 2010 opioid prescription pat-

terns in home-dwelling and nursing home elderly with and

without dementia. Our hypothesis was that frail elderly

such as patients with dementia and/or nursing home resi-

dents were less likely to receive opioids and particularly

strong opioids.

2. Methods

2.1. Registry data sources

Denmark has a tax-ﬁnanced health care system that pro-

vides equal access to all residents. Because individuals are

given a permanent personal civil registration number at the

time of birth or immigration, nationwide registries allow

data retrieval at individual level

[20].

This study linked

individual-level data from national registries using the civil

registration number. The National Patient Registry contains

all hospitalizations and invasive procedures registered since

1978, and since 1995, data from hospital-based outpatient

clinics and emergency departments have been registered

[21,22].

The Psychiatric Central Research Registry

includes data on all psychiatric inpatient admissions in

Denmark since April 1, 1969, and outpatient contacts since

1995

[23].

Information comprises dates and discharge diag-

nosis, registered using WHO

International Classiﬁcation of

Diseases

(ICD) codes. ICD-8 was used from 1970 to 1993

[24]

and ICD-10 from 1994 and onward

[25].

ICD-9 was

never used. The Danish National Prescription Registry

[26]

has registered dispensed prescriptions consecutively since

1995 according to the Anatomical Therapeutic Chemical

(ATC) classiﬁcation system

[27],

including data on amount

and strength of dispensed tablets and dispensing dates

[22].

The study was approved by the Danish Data Protection

Agency (ID no: 2007-58-0015/30-0667), Statistics

Denmark, and the Danish Health and Medicine Authority

(ID no: 6-8011-907/1). Danish law did not require ethic

committee approval or informed patient consent.

2.2. Study population

All permanent residents aged

years alive on January

1, 2010, were identiﬁed using the Central Population Regis-

try

[28].

Individuals with dementia were identiﬁed as those

who had been registered in the National Patient Registry

or Psychiatric Central Research Registry before January 1,

2010, with a dementia diagnosis as the main or secondary

diagnosis during admission or at an outpatient visit

(Supplementary

Table A1

for diagnostic codes) and/or

who had ﬁlled an antidementia prescription (ATC: N06D).

The individuals had to be

years at the time of diagnosis

and/or ﬁrst prescription, as prior research has shown low val-

idity of the dementia diagnosis in those

,60

years

[29].

The remaining individuals formed the group without

dementia.

2.3. Opioid treatment

In Denmark, opioids are only available by prescription

from a physician and can only be dispensed once per pre-

scription. Opioid users were deﬁned as individuals who

had redeemed at least one opioid prescription (ATC:

N02A) in 2010. We grouped morphine analogues

(N02AA01-04), oxycodone (N02AA05-55), pethidine

(N02AB02),

fentanyl

(N02AB03),

buprenorphine

(N02AE01), and ketobemidone (N02AG02) as strong opi-

oids, whereas codeine (N02AA59), dextropropoxyphene

(N02AC04), and tramadol (N02AX02) were grouped as

weak opioids.

2.4. Comorbidity and demographic information

Comorbidity was evaluated at baseline (January 1, 2010).

We evaluated potentially pain-causing diseases (cancer,

osteoporosis, arthritis, and recent fracture) and comorbidity

(diabetes, vascular, pulmonary, renal and liver disease) that

may affect opioid use (Supplementary

Table A2).

Statistics

Denmark provided information about living status (home

living and nursing home).

2.5. Statistical analysis

Our descriptive analysis showed that opioid use patterns

differed depending on living status, and the two groups

were evaluated separately. Frequency of comorbidity and

percentage of opioid users were compared using Pearson’s

chi-squared test. A logistic regression analysis was per-

formed initially to evaluate the effect of covariates indepen-

dently (crude analysis) and then in a multivariate logistic

regression analysis (adjusted analysis), where age, sex,

pain-causing disorders, and comorbidity were included as

these covariates have been shown to be potential con-

founders

[4,15].

To evaluate treatment intensity, we computed the num-

ber of prescriptions and equivalent doses of oral morphine

and total dose for each user. Equivalent doses of oral

morphine were calculated as the number of deﬁned daily

dosages redeemed in 2010 multiplied by a factor, which

was based on content of one deﬁned daily dosage and equi-

analgesic effects (Appendix

Table A3).

To calculate dura-

tion of use, a daily dose of 30 mg was assumed.

Differences were evaluated using a nonparametric test

(Wilcoxon).

Data analysis was performed using SAS statistical soft-

ware, version 9.3 (SAS Institute Inc., Cary, NC, USA).

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3. Results

3.1. Study population

On January 1, 2010, Denmark had 908,418 residents aged

years, representing 16.36% of the Danish population.

We excluded 2318 people (0.26%) who had received a de-

mentia diagnosis before the age of 60 years, leaving

906,100 individuals, 35,455 (3.91%) of whom were diag-

nosed with dementia before January 1, 2010. This left a pop-

ulation without dementia of N

870,645 (Fig.

1). Table 1

lists the characteristics of the study population stratiﬁed by

dementia diagnosis and living status. Home-living patients

with dementia were older and suffered from more comorbid-

ity than the population without dementia, whereas the

nursing home residents without dementia suffered from

more comorbidity than the patients with dementia, with

the exception of fractures.

3.2. Opioid use in 2010

Fig. 2

shows the 2010 frequency of opioid use stratiﬁed

by dementia, age, and living status. Home-living patients

with dementia received more opioids than the reference pop-

ulation (patients vs. reference: 27.5%, 95% conﬁdence inter-

val [CI], 26.8%–28.1% vs. 16.9%, 95% CI, 16.8%–17.0%;

.001 for all age groups except for 951 years, where

.007). Nursing home residents used opioids even more

frequent, but patients with dementia received fewer opioids

than those without (37.8% [37.0%–38.5%] vs. 43.0%

[42.4%–43.6%],

.001 for all age groups except for age

90–94 years, where

.12, and 951 years, where

.22).

Table 2

lists the results of the logistic regression analysis

for those receiving “any opioid” in 2010 according to living

status. Home-living patients with dementia had a crude odds

ratio (OR; 95% CI) of 1.86 (1.80–1.92) for receiving an

opioid, which after adjustment for age and sex decreased

to 1.43 (1.38–1.47), and further decreased to 1.27 (1.22–

1.31) after additional adjustment for comorbidity. In

contrast, nursing home residents with dementia were 20%

less likely to receive an opioid (crude OR, 0.80 [0.77–

0.84]), and there was minimal effect from adjustment for

age, sex, and comorbidity (adjusted OR, 0.83 [0.80–0.87]).

Use of opioids increased with age, but this was especially

pronounced for the home living. Comorbidity was associ-

ated with increased ORs, which was also the case for poten-

tial contraindications such as pulmonary or renal disease.

When we excluded those who died in 2010, the overall

pattern did not change, but the frequency decreased by

1.2% to 6.7% (Supplementary

Figure A1).

Table 3

lists the distribution of opioid subtypes and over-

all results of logistic regression analysis (for detailed results,

see

Supplementary Table

A1A–G). The crude analysis

showed that home-living patients with dementia received

all subtypes of opioid more frequent, but after adjusting

for age, sex, and comorbidity, they were less likely to receive

weak opioids. The crude analysis showed that home-living

patients with dementia had a ﬁvefold increased OR for bu-

prenorphine and a fourfold OR for fentanyl, which after

adjustment decreased to 2.57 (2.41–2.74) and 2.32 (2.15–

2.50), respectively. Use of buprenorphine and fentanyl was

highly dependent on age, and the 951 group had, compared

with the 65- to 69-year-old group, a crude OR of 17.24

(15.41–19.30) for buprenorphine use (Supplementary

Table

A4D). The pattern was similar for fentanyl, although

the OR was lower (951: crude OR, 10.46 [9.17–11.93]).

For both buprenorphine and fentanyl, the estimates dimin-

ished with adjustment for age, sex, and comorbidity but re-

mained high at 11.18 (9.95–12.55) and 7.10 (6.20–8.13),

respectively (Supplementary

Table

A4C).

Comparing nursing home residents and home living,

27.9% (27.5%–28.4%) of nursing home residents used

strong opioids in contrast with 7.1% (7.1%–7.2%) of the

home living without dementia and 17.4% (16.9%–17.9%)

of the home living with dementia, but the difference was

especially pronounced for buprenorphine and fentanyl.

The age dependency in the home-living population for bu-

prenorphine (951: crude OR, 2.58 [2.06–3.23]) and fentanyl

(951: crude OR, 1.74 [1.38–2.19]) was less pronounced in

nursing home residents (Supplementary

Table 4AC–D).

The pattern differed for nursing home residents with no sig-

niﬁcant difference between groups for strong opioids but less

frequent use of weak opioids in those with dementia. Fenta-

nyl and buprenorphine were mainly used as transdermal for-

mulations, that is, patches.

3.3. Treatment intensity

Home-living patients with dementia were more likely to

receive more than one opioid prescription than those without

(75.6% [74.5%–76.8%] vs. 70.8% [70.6%–71.0%],

Fig. 1. Population selection.

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Table 1

Characteristics of the study population stratiﬁed by living status and dementia diagnosis

Home living (N

863,809)

Characteristic

Female

Age groups (y)

65–69

70–74

75–79

80–84

85–89

91–94

951

Time since diagnosis, y

Antidementia treatment

Living alone

Comorbidity

Cancer

Osteoporosis

Arthritis

Recent fracture

Diabetes

Vascular

Pulmonary

Renal

Liver

Reference (N

844,402)

463,414 (54.9)

296,622 (35.1)

211,647 (25.1)

150,591 (17.8)

103,524 (12.3)

57,972 (6.9)

19,358 (2.3)

4688 (0.6)

326,929 (39.0)

118,575 (14.0)

90,407 (10.7)

134,254 (15.9)

22,357 (2.7)

79,166 (9.4)

169,001 (20.0)

75,533 (9.0)

17,443 (2.1)

8426 (1.0)

Dementia (N

19,407)

11,782 (60.7)*

1547 (8.0)*

2647 (13.6)

3974 (20.5)

5035 (25.9)

4094 (21.1)

1676 (8.6)

434 (2.2)

2.3 (0.9–4.5)

8060 (41.5)

11,058 (57.0)

2992 (15.4)*

3330 (17.2)*

3973 (20.5)*

1303 (6.7)*

2249 (11.6)*

7443 (38.4)*

2315 (11.9)*

663 (3.4)*

323 (1.7)*

Nursing home (N

42,291)

Reference (N

26,243)

18,110 (69.0)

1490 (5.7)

2232 (8.5)

3311 (12.6)

5265 (20.1)

6633 (25.3)

4913 (18.7)

2399 (9.1)

4418 (16.8)

5234 (19.9)

5921 (22.6)

2234 (8.5)

3381 (12.9)

11,760 (44.8)

3664 (14.0)

1202 (4.6)

434 (1.7)

Dementia (N

16,048)

11,452 (71.4)*

528 (3.3)*

1192 (7.4)

2283 (14.2)

4091 (25.5)

24,696 (29.3)

2533 (15.8)

725 (4.5)

3.3 (1.5–5.6)

6333 (39.5)

2275 (14.2)*

2864 (17.9)*

2996 (18.7)*

1557 (9.7)*

1691 (10.5)*

6210 (38.7)*

1639 (10.2)*

470 (2.9)*

223 (1.4)*

Abbreviation: NA, not applicable.

NOTE. Numbers are given as n (%) or median (25% quartile to 75% quartile) as appropriate.

.001.

respectively,

.0001). Half of the home-living patients

with dementia had a duration of use exceeding 93 days

(25%–75% interquartile range, 27–288 days), compared

with 70 days (19–272 days;

.0001) for those without.

Among nursing home residents, approximately 80%

received more than one opioid prescription, but patients

with dementia were less likely to receive more than

one prescription than those without dementia (78.8%

[77.8%–79.9%] vs. 82.7% [82.0%–83.4%], respectively,

.0001). Likewise, patients with dementia at nursing

homes were treated for a shorter period, as half of patients

with dementia had a duration of use exceeding 112 days

(32–331 days), compared with 153 days (40–454 days;

.0001) for those without.

4. Discussion

This is the ﬁrst study to investigate an entire elderly pop-

ulation’s use of opioids. Contrary to our hypothesis, the

frequency of opioid use rose steadily with age and was

Fig. 2. Percentage receiving an opioid in 2010 stratiﬁed by dementia, age group, and living status.

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Table 2

Opioid drug use in 2010

Home living

Characteristic

Dementia

Sex (females)

Age groups (y)

65–69

70–75

75–80

80–85

85–90

90–95

951

Comorbidity

Cancer

Osteoporosis

Arthritis

Recent fracture

Diabetes

Vascular

Pulmonary

Renal

Liver

Crude OR (95% CI)

1.86 (1.80–1.92)

1.51 (1.49–1.53)

1.0

1.30 (1.28–1.32)

1.60 (1.57–1.63)

1.94 (1.90–1.97)

2.36 (2.31–2.41)

2.77 (2.68–2.86)

3.33 (3.14–3.54)

1.73 (1.71–1.76)

2.59 (2.55–2.63)

2.86 (2.82–2.90)

2.44 (2.37–2.50)

1.54 (1.51–1.57)

1.89 (1.86–1.91)

2.20 (2.17–2.24)

2.26 (2.19–2.33)

2.11 (2.02–2.21)

Adjusted OR (95% CI)

1.27 (1.22–1.31)

1.39 (1.38–1.41)

1.0

1.18 (1.16–1.20)

1.31 (1.29–1.34)

1.48 (1.46–1.51)

1.73 (1.70–1.77)

2.06 (1.99–2.13)

2.58 (2.42–2.74)

1.56 (1.53–1.58)

1.84 (1.81–1.87)

2.35 (2.32–2.39)

1.81 (1.76–1.87)

1.40 (1.38–1.43)

1.55 (1.53–1.57)

1.74 (1.71–1.77)

1.44 (1.39–1.49)

1.74 (1.66–1.82)

Nursing home

Crude OR (95% CI)

0.80 (0.77–0.84)

1.41 (1.35–1.47)

1.0

1.11 (0.99–1.25)

1.28 (1.15–1.42)

1.36 (1.23–1.51)

1.43 (1.29–1.58)

1.46 (1.32–1.62)

1.42 (1.26–1.59)

1.39 (1.32–1.47)

2.14 (2.04–2.25)

1.76 (1.68–1.84)

1.73 (1.62–1.85)

1.03 (0.97–1.10)

1.15 (1.11–1.20)

1.37 (1.29–1.45)

1.33 (1.20–1.47)

1.26 (1.08–1.47)

Adjusted OR (95% CI)

0.83 (0.80–0.87)

1.27 (1.21–1.32)

1.0

1.11 (0.99–1.25)

1.22 (1.09–1.36)

1.27 (1.15–1.41)

1.31 (1.18–1.45)

1.34 (1.20–1.49)

1.34 (1.18–1.51)

1.35 (1.28–1.42)

1.83 (1.74–1.93)

1.59 (1.51–1.67)

1.60 (1.50–1.72)

1.04 (0.98–1.11)

1.14 (1.09–1.19)

1.23 (1.16–1.31)

1.22 (1.10–1.35)

1.27 (1.09–1.50)

Abbreviations: OR, odds ratio; CI, conﬁdence interval.

NOTE. This table shows the logistic regression analysis comparing opioid users and nonopioid users according to living status. The results are given as OR

(95% CI). The crude ORs for comorbidity and demographic variables are modeled for any opioids. The adjusted ORs include adjustment for age, sex, and co-

morbidity.

particularly pronounced among the most vulnerable pa-

tients, that is, patients with dementia (32%) and nursing

home residents (41%). Home-living patients with dementia

were more likely to receive multiple prescriptions and higher

dosages than those without dementia. However, the highest

percentage of use was found among nursing home residents.

Our results also show that there are clear differences in treat-

ment of patients with dementia in relation to living status, as

nursing home residents without dementia were the most

frequent users. This is surprising for two reasons. First, our

ﬁndings are in opposition to the current belief that pain is un-

dertreated in the elderly, especially those with dementia

[2,3].

Second, frail elderly patients, and particularly

patients with dementia, are much more prone to adverse

events associated with opioids, leading us to believe

physicians would be reluctant to prescribe them.

Previous studies, which had limited sample size and

generalizability, have found that among elderly, increasing

age was associated with lower likelihood of receiving anal-

gesics

[30,31],

which is opposite to our results, which

showed that use of opioids rose steadily with age.

Likewise, our results contrast with most studies on home-

living patients with dementia, which have found that patients

with dementia receive fewer analgesics

[5–8].

Second, all

the studies were published in 2004 or prior, and over the

past 15 years, several countries have reported an increase

in opioid prescriptions

[17–19].

In Denmark, use of

opioids in the entire population has increased by 34%

Table 3

Percentage of individuals receiving prescriptions for different kinds of opioids in 2010

Home living (N

863,809)

Opioid

All opioids

Strong opioids

Morphine

Oxycodone

Fentanyl

Buprenorphine

Weak opioids

Tramadol

Dementia

27.5

17.4

5.0

5.2

4.4

6.3

14.9

13.6

Reference

16.9

7.1

2.6

3.5

1.1

1.3

12.4

11.1

Crude OR

1.86 (1.80–1.92)

2.74 (2.64–2.85)

1.98 (1.85–2.12)

1.53 (1.43–1.63)

4.07 (3.78–4.37)

5.15 (4.84–5.47)

1.23 (1.18–1.28)

1.27 (1.21–1.32)

Adjusted OR

1.27 (1.22–1.31)

1.79 (1.72–1.86)

1.35 (1.26–1.44)

1.07 (1.01–1.15)

2.28 (2.12–2.46)

2.57 (2.41–2.74)

0.88 (0.85–0.92)

0.91 (0.87–0.95)

Nursing home (N

42,291)

Dementia

37.8

27.8

6.8

6.0

7.9

12.3

16.6

15.1

Reference

43.0

28.1

8.6

9.4

8.4

9.5

24.1

22.2

Crude OR

0.80 (0.77–0.84)

0.99 (0.94–1.03)

0.77 (0.72–0.84)

0.61 (0.57–0.66)

0.94 (0.88–1.01)

1.34 (1.26–1.42)

0.63 (0.59–0.66)

Adjusted OR

0.83 (0.80–0.87)

1.04 (0.99–1.08)

0.82 (0.76–0.88)

0.63 (0.58–0.68)

0.99 (0.92–1.07)

1.38 (1.29–1.47)

0.64 (0.61–0.67)

Abbreviation: OR, odds ratio.

NOTE. The cumulative percentage is higher than “all opioids” as a user may have used more than one opioid. This table also shows the OR (95% conﬁdence

interval) of the logistic regression analysis comparing those with dementia with those without dementia according to living status. The adjusted ORs include

adjustment for age, sex, and comorbidity.

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from 1999 to 2010

[32],

which the high percentage of users

in our study may reﬂect. More recent publications have re-

ported results that were closer to our ﬁndings. In accordance

with our study, a smaller Swedish study found that home-

living patients with dementia used opioids more frequently

(8.0% without dementia [N

2199] and 14.3% with

119])

[15].

A Finnish register-based study examining

2005 data found that home-living patients with Alzheimer’s

disease received opioids less frequently than those without

(3.6% vs. 4.6%) but were more likely to receive strong opi-

oids. However, the percentage of users is much lower than

what we found (3.6% vs. 27.5% for home-living dementia

patients), but the study has limited generalizability as they

excluded nursing home residents and those with dementia

due to other causes than Alzheimer’s disease.

In our study, the highest percentage of use was found

among the most fragile patients living at nursing homes.

Forty-one percent of nursing home residents had used an

opioid in comparison with 17% of the home living without

dementia. To our knowledge, only one other study has

compared home-living and nursing home residents and like-

wise found that a higher percentage of nursing home resi-

dents received analgesics

[15].

In our study, nursing home

residents with dementia received opioids less frequently

than residents without dementia (38% vs. 43%), but this

was due to fewer receiving weak opioids. This ﬁnding is in

accordance with a number of smaller studies, with limited

generalizability, which have found that nursing home resi-

dents with dementia were less likely to receive pain medica-

tion compared with the cognitively intact

[5,6,33,34].

Denmark, dementia is the primary reason for nursing

home placement, and most residents without dementia

have severe physical disability

[35],

which could also

explain the differences between the two groups. Our results

also show that there are different treatment patterns of pa-

tients with dementia depending on living situation as nursing

home residents with dementia received opioids less

frequently than those without dementia. Nevertheless,

opioid use was very common in nursing home residents

and much more common than among home-living elderly.

This study raises an important question, whether the

frequent opioid use in the elderly, and especially in patients

with dementia and nursing home residents, is appropriate.

On one hand, frailty and comorbidity have been associated

with pain

[36],

and pain is frequent among nursing home res-

idents

[37,38].

On the other hand, the main limitations of

opioid use are adverse reactions, which increase with age,

frailty, dementia, and higher dosages

[2,39].

The frequent

opioid use is in sharp contrast to the fact that very few

elderly of age

.65

years have been included in analgesic

trials and no trials have included patients with dementia or

elderly of age

.85

years

[40]

among which we found the

most frequent use. At present, little data exist supporting

evidence-based prescribing of opioids in dementia and frail

elderly. Furthermore, most patients received multiple pre-

scriptions, but the evidence for long-term use is limited

[41].

A recent Cochrane review concluded that the effect

of strong opioids in osteoarthritis is outweighed by large in-

creases in risk of adverse events and strong opioids should

not be used routinely

[42].

Guidelines for pain treatment in

the elderly are few, but an expert consensus statement on

opioids for treatment of chronic severe pain states that “in

properly selected and monitored patients, opioid analgesics

constitute a potentially effective treatment as part of a multi-

modal strategy, but should only be prescribed on a trial basis

with clearly deﬁned therapeutic goals”

[43].

One may ques-

tion if 41% of nursing home residents constitute a properly

selected group of patients.

Our analysis revealed that fentanyl and buprenorphine were

used by 20% of nursing home residents with dementia, in

contrast to 10% of home-living patients with dementia and

2% of the home-living reference population. Among the

home living, those aged

years had, compared with the

age group 65 to 69 years, a risk of receiving buprenorphine

and fentanyl, which were 17 and 11 times higher, respectively.

Although adjustment for age, sex, and comorbidity diminished

the effect estimates, home living

.95

years had an 11 and 7

times increased risk for receiving buprenorphine or fentanyl,

respectively. The prevalent use of fentanyl and buprenorphine

(i.e., patches) in nursing home residents, patients with demen-

tia, and very old individuals is potentially problematic as it

may pose a risk to patient safety. First, in 2005, the US Food

and Drug Administration released a black box warning against

using fentanyl patches in nonopioid–tolerant patients because

of serious adverse events and deaths

[44].

The elderly and

those with cognitive impairment are the most susceptible to

serious adverse events or death, and a recent study showed

that initiation of transdermal fentanyl in opioid na€ persons

ıve

was more frequent among those with advanced age and/or

cognitive impairment

[45].

Second, even palliation guidelines

from the National Institute for Clinical Excellence in the

United Kingdom do not recommend use of transdermal patch

formulations as ﬁrst-line maintenance treatment in patients for

whom oral opioids are suitable

[46].

Last, but not least, using

drugs with potentially serious side effects in patients with de-

mentia poses an ethical challenge as patients with dementia

eventually lose the ability to consent to treatment.

One of the strengths of this study is that it investigates

“real-life prescription patterns” in an entire elderly population

eliminating problems of selection bias. The validity of regis-

tered dementia diagnoses at hospitals has previously been

shown to be high

[47],

but most cases are registered as unspec-

iﬁed dementia. However, dementia is generally underdiag-

nosed, and previous research has shown that estimated 50%

to 70% of cases are diagnosed and therefore captured by the

Danish hospital registries

[48].

Potential undiagnosed cases

among the reference group could lead to an underestimation

of differences. An additional strength is that we are able to

distinguish between home-living and institutionalized indi-

viduals, which is not possible in several countries

[4,49].

However, in some cases, patients or their caregivers may

not report moving to a nursing home, and it has been

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C. Jensen-Dahm et al. / Alzheimer’ & Dementia

(2014) 1-9

estimated that this leads to an underestimation of the number

of nursing home residents by approximately 10%

(information provided by Statistics Denmark). The Danish

National Prescription Registry registers all prescriptions

ﬁlled at pharmacies, and the information has proven to be

accurate

[22],

but we cannot be certain that the patients

consumed the drugs. However, between 73.8% and 82.7%

of patients redeemed multiple prescriptions indicating that

the majority did consume the medication. Furthermore, the

exact indication for the prescriptions is unknown. In our anal-

ysis, we adjusted for a number of potential confounders (both

indications and contraindications for opioid use), but not all

pain-causing comorbidity can be accounted for in hospital

registries, in particular disease states such as back pain, which

are mainly treated by general practitioners. Our logistic

regression analysis showed that the crude estimates for de-

mentia were confounded by age, sex, and comorbidity, but

age was the most important confounder. It is noteworthy

that even conditions that must be considered relative contrain-

dications for opioids (i.e., pulmonary, renal and liver disease)

were associated with use of opioids, which was contrary to ex-

pected. However, we cannot rule out that unmeasured con-

founding could explain part of the remaining association

between dementia and opioids. An alternative explanation

could be that patients with dementia are more likely to receive

opioids for other indications such as end-of-life treatment. We

explored this by excluding those who died in 2010, which

decreased the frequency of use to 1.2% to 6.7%, but the over-

all pattern remained unchanged, indicating that end-of-life

treatment was not the explanation. An alternative explanation

may be found in a recent study that showed that a systematic

approach to pain treatment (though mainly paracetamol) leads

to reduced agitation in people with moderate-to-severe de-

mentia

[14],

and one may speculate if opioids in our popula-

tion were used to treat behavioral symptoms and not pain.

5. Conclusions

In the entire elderly population of Denmark, we surpris-

ingly found that use of opioids rose steadily with age and

was particularly high for patients with dementia and nursing

home residents. This study raises a number of questions, the

ﬁrst being if the frequent opioid use with increasing age,

dementia, and/or nursing home residency may challenge pa-

tient safety? Future studies should explore potential conse-

quences of opioid use in these groups to further assess

this. As opioid use has been increasing in several countries,

there are reasons to suspect that our ﬁndings apply outside

Denmark. Our study also highlights the urgent need

for more evidence to guide analgesic prescribing in the elderly

and especially those who are frail and/or suffer from dementia.

Acknowledgments

The Danish Dementia Research Centre is supported by

grants from the Danish Health Foundation (j.nr.

2007B0004) and the Danish Ministry of Health (j.nr. 2007-

12143-112/59506 and j.nr. 0901110/34501). All researchers

were independent of the funders. All authors declare no sup-

port from any organization for the submitted work.

Contributors: C.J.D. drafted the manuscript and conducted

the analysis. C.J.D., C.G., A.A., and G.W. outlined the sta-

tistical analysis. All authors participated in the design of

the study, edited the manuscript, and approved the ﬁnal

version.

Supplementary data

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.jalz.2014.06.013.

RESEARCH IN CONTEXT

1. Systematic review: We searched PubMed using the

keywords: “dementia,” “opioid,” “pain,” “analge-

sics,” and “nursing home.” Articles published in En-

glish and from peer-reviewed journals were collected

and reviewed. We speciﬁcally reviewed studies that

had assessed use of analgesics in the elderly, de-

mentia, and nursing home residents.

2. Interpretation: This study is the ﬁrst to study

opioid use in an entire elderly population, elimi-

nating problems of selection bias. Contrary to ex-

pected, patients with dementia and nursing home

residents were the most frequent users of opioids.

However, clinical trials of analgesics have never

included patients with dementia and nursing

home residents, representing the frailest patient

groups. Our ﬁndings highlight the urgent need

for more evidence to guide analgesic prescribing

in these groups.

3. Future directions: This study raises a number of

questions, the ﬁrst being if the frequent opioid use

with increasing age, dementia, and nursing home

residence may challenge patient safety, which

should be explored in future studies. As opioid use

has been increasing in several countries, there are

reasons to suspect that our ﬁndings apply outside

Denmark.

References

[1]

Black BS, Finucane T, Baker A, Loreck D, Blass D, Fogarty L, et al.

Health problems and correlates of pain in nursing home residents with

advanced dementia. Alzheimer Dis Assoc Disord 2006;20:283–90.

[2]

McLachlan AJ, Bath S, Naganathan V, Hilmer SN, Le Couteur DG,

Gibson SJ, et al. Clinical pharmacology of analgesic medicines in

PDF to HTML - Convert PDF files to HTML files

C. Jensen-Dahm et al. / Alzheimer’ & Dementia

(2014) 1-9

older people: impact of frailty and cognitive impairment. Br J Clin

Pharmacol 2011;71:351–64.

Scherder E, Oosterman J, Swaab D, Herr K, Ooms M, Ribbe M,

et al. Recent developments in pain in dementia. BMJ 2005;

330:461–4.

Bell JS, Laitinen ML, Lavikainen P, Lonnroos E, Uosukainen H,

Hartikainen S. Use of strong opioids among community-dwelling per-

sons with and without Alzheimer’s disease in Finland. Pain 2011;

152:543–7.

Closs SJ, Barr B, Briggs M. Cognitive status and analgesic provision in

nursing home residents. Br J Gen Pract 2004;54:919–21.

Reynolds KS, Hanson LC, DeVellis RF, Henderson M,

Steinhauser KE. Disparities in pain management between cognitively

intact and cognitively impaired nursing home residents. J Pain Symp-

tom Manage 2008;35:388–96.

Mantyselka P, Hartikainen S, Louhivuori-Laako K, Sulkava R. Effects

of dementia on perceived daily pain in home-dwelling elderly people:

a population-based study. Age Ageing 2004;33:496–9.

Schmader KE, Hanlon JT, Fillenbaum GG, Huber M, Pieper C,

Horner R. Medication use patterns among demented, cognitively

impaired and cognitively intact community-dwelling elderly people.

Age Ageing 1998;27:493–501.

Monroe TB, Misra SK, Habermann RC, Dietrich MS, Cowan RL,

Simmons SF. Pain reports and pain medication treatment in nursing

home residents with and without dementia. Geriatr Gerontol Int

2014;14:541–8.

Barber JB, Gibson SJ. Treatment of chronic non-malignant pain in the

elderly: safety considerations. Drug Saf 2009;32:457–74.

Papaleontiou M, Henderson CR Jr, Turner BJ, Moore AA,

Olkhovskaya Y, Amanfo L, et al. Outcomes associated with opioid

use in the treatment of chronic noncancer pain in older adults: a sys-

tematic review and meta-analysis. J Am Geriatr Soc 2010;58:1353–69.

Jensen-Dahm C, Vogel A, Waldorff FB, Waldemar G. Discrepancy be-

tween self- and proxy-rated pain in Alzheimer’s disease: results from

the Danish Alzheimer Intervention Study. J Am Geriatr Soc 2012;

60:1274–8.

Berryman C, Stanton TR, Jane BK, Tabor A, McFarlane A,

Lorimer MG. Evidence for working memory deﬁcits in chronic

pain: a systematic review and meta-analysis. Pain 2013;154:1181–96.

Husebo BS, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efﬁcacy of

treating pain to reduce behavioural disturbances in residents of nursing

homes with dementia: cluster randomised clinical trial. BMJ 2011;

343:d4065.

Haasum Y, Fastbom J, Fratiglioni L, Kareholt I, Johnell K. Pain treat-

ment in elderly persons with and without dementia: a population-based

study of institutionalized and home-dwelling elderly. Drugs Aging

2011;28:283–93.

Lovheim H, Karlsson S, Gustafson Y. The use of central nervous sys-

tem drugs and analgesics among very old people with and without de-

mentia. Pharmacoepidemiol Drug Saf 2008;17:912–8.

Compton WM, Volkow ND. Major increases in opioid analgesic abuse

in the United States: concerns and strategies. Drug Alcohol Depend

2006;81:103–7.

Fredheim OM, Skurtveit S, Breivik H, Borchgrevink PC. Increasing

use of opioids from 2004 to 2007 - pharmacoepidemiological data

from a complete national prescription database in Norway. Eur J

Pain 2010;14:289–94.

Schubert I, Ihle P, Sabatowski R. Increase in opiate prescription in Ger-

many between 2000 and 2010: a study based on insurance data. Dtsch

Arbztel Int 2013;110:45–51.

Thygesen LC, Daasnes C, Thaulow I, Bronnum-Hansen H. Introduc-

tion to Danish (nationwide) registers on health and social issues: struc-

ture, access, legislation, and archiving. Scand J Public Health 2011;

39:12–6.

Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The

Danish National Hospital Register. A valuable source of data for mod-

ern health sciences. Dan Med Bull 1999;46:263–8.

[22]

Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Reg-

ister. Scand J Public Health 2011;39:30–3.

[23]

Munk-Jorgensen P, Mortensen PB. The Danish Psychiatric Central

[24] Danish National Board of Health: Danish National Board of Health:

Classiﬁcation of Diseases: the Danish edition of ICD-8; Copenha-

gen, 1971.

[25]

World Health Organization. The ICD-10 classiﬁcation of mental and

behavioural disorders: diagnostic criteria for research. Geneva: World

Health Organization; 1993.

[26]

Kildemoes HW, Sorensen HT, Hallas J. The Danish National Prescrip-

tion Registry. Scand J Public Health 2011;39:38–41.

[27] World Health Organization: Introduction to drug utilization

research; 2003.

[28]

Pedersen CB. The Danish Civil Registration System. Scand J Public

Health 2011;39:22–5.

[29]

Salem LC, Andersen BB, Nielsen TR, Stokholm J, Jorgensen MB,

Rasmussen MH, et al. Overdiagnosis of dementia in young pa-

tients—a nationwide register-based study. Dement Geriatr Cogn Dis-

ord 2012;34:292–9.

[30]

Bernabei R, Gambassi G, Lapane K, Landi F, Gatsonis C, Dunlop R,

et al. Management of pain in elderly patients with cancer. SAGE Study

Group. Systematic Assessment of Geriatric Drug Use via Epidemi-

ology. JAMA 1998;279:1877–82.

[31]

Landi F, Onder G, Cesari M, Gambassi G, Steel K, Russo A, et al. Pain

management in frail, community-living elderly patients. Arch Intern

Med 2001;161:2721–4.

[32] Statens Serum Institut: Medstat.dk; Copenhagen, Denmark, 2013.

[33]

Horgas AL, Tsai PF. Analgesic drug prescription and use in cogni-

tively impaired nursing home residents. Nurs Res 1998;47:235–42.

[34]

Lapane KL, Quilliam BJ, Chow W, Kim M. The association between

pain and measures of well-being among nursing home residents. J Am

Med Dir Assoc 2012;13:344–9.

[35] The Ministry of Social Affairs and Integration: Quality of life and de-

cision making at nursing homes; 2012.

[36]

Blyth FM, Rochat S, Cumming RG, Creasey H, Handelsman DJ, Le

Couteur DG, et al. Pain, frailty and comorbidity on older men: the

CHAMP study. Pain 2008;140:224–30.

[37]

Achterberg WP, Gambassi G, Finne-Soveri H, Liperoti R, Noro A,

Frijters DH, et al. Pain in European long-term care facilities: cross-

national study in Finland, Italy and the Netherlands. Pain 2010;

148:70–4.

[38]

Takai Y, Yamamoto-Mitani N, Okamoto Y, Koyama K, Honda A.

Literature review of pain prevalence among older residents of nursing

homes. Pain Manag Nurs 2010;11:209–23.

[39]

Cepeda MS, Farrar JT, Baumgarten M, Boston R, Carr DB, Strom BL.

Side effects of opioids during short-term administration: effect of age,

gender, and race. Clin Pharmacol Ther 2003;74:102–12.

[40]

Bayer A, Tadd W. Unjustiﬁed exclusion of elderly people from studies

submitted to research ethics committee for approval: descriptive study.

BMJ 2000;321:992–3.

[41]

Freynhagen R, Geisslinger G, Schug SA. Opioids for chronic non-

cancer pain. BMJ 2013;346:f2937.

[42] N€esch E: Oral or transdermal opioids for osteoarthritis of the knee or

hip; in Rutjes AWS, Husni E, Welch V, J€ni P, (eds): Cochrane Data-

base of Systematic Reviews, 2009.

[43]

Pergolizzi J, Boger RH, Budd K, Dahan A, Erdine S, Hans G, et al.

Opioids and the management of chronic severe pain in the elderly:

consensus statement of an International Expert Panel with focus on

the six clinically most often used World Health Organization Step

III opioids (buprenorphine, fentanyl, hydromorphone, methadone,

morphine, oxycodone). Pain Pract 2008;8:287–313.

[44] FDA: A public health advisory: safety warnings regarding use of fen-

tanyl transdermal (skin) patches.; 2007.

[45]

Dosa DM, Dore DD, Mor V, Teno JM. Frequency of long-acting opioid

analgesic initiation in opioid-naive nursing home residents. J Pain

Symptom Manage 2009;38:515–21.

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

PDF to HTML - Convert PDF files to HTML files

C. Jensen-Dahm et al. / Alzheimer’ & Dementia

(2014) 1-9

[46] NHS - National Institute for Health and Clinical Excellence: Opioids

in palliative care: safe and effective prescribing of strong opioids for

pain in palliative care of adults; NICE clinical guideline 140. 2012.

[47]

Phung TK, Andersen BB, Hogh P, Kessing LV, Mortensen PB,

Waldemar G. Validity of dementia diagnoses in the Danish hospital

registers. Dement Geriatr Cogn Disord 2007;24:220–8.

[48]

Phung TK, Waltoft BL, Kessing LV, Mortensen PB, Waldemar G.

Time trend in diagnosing dementia in secondary care. Dement Geriatr

Cogn Disord 2010;29:146–53.

[49]

Mellbye A, Karlstad O, Skurtveit S, Borchgrevink PC, Fredheim OM.

Co-morbidity in persistent opioid users with chronic non-malignant

pain in Norway. Eur J Pain 2014;18:1083–93.