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Clinical Interventions in Aging 2018:13 935–946
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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/CIA.S161052
Tolerability of buprenorphine transdermal
system in nursing home patients with advanced
dementia: a randomized, placebo-controlled trial
(DEP.PAIN.DEM)
Ane Erdal1
Elisabeth Flo2
Dag Aarsland3,4
Geir Selbaek5–7
Clive Ballard8
Dagrun D Slettebo1
Bettina S Husebo1,9
1Department of Global Public
Hea lth an d P rim ary Care, Centre for
Elderly and Nursing Home Medicine,
University of Bergen, Bergen, Norway;
2Department of Clinical Psychology,
University of Bergen, Bergen, Norway;
3Department of Old Age Psychiatry,
Institute of Psychiatry, Psychology and
Neuroscience, King’s College London,
London, UK; 4Centre for Age-Related
Medicine, Stavanger University
Hospital, Stavanger, Norway; 5Centre
for Old Age Psychiatric Research,
Innlandet Hospital Trust, Ottestad,
Norway; 6National Advisory Uni t o n
Aging and Health, Tønsberg, Norway;
7Institute of Health and Society,
Faculty of Medicine, University
of Oslo, Oslo, Norway; 8Exeter
Medical School, University of Exeter,
Exeter, UK; 9Municipality of Bergen,
Bergen, Norway
Purpose: Buprenorphine transdermal system is increasingly prescribed in people with advanced
dementia, but no clinical trial has investigated the safety and factors associated with discontinu-
ation due to adverse events in this population.
Patients and methods: One hundred sixty-two people with advanced dementia and significant
depression from 47 nursing homes were included and randomized to active analgesic treatment
(acetaminophen/buprenorphine) or identical placebo for 13 weeks. In this secondary analysis,
the main outcomes were time to and reasons for discontinuation of buprenorphine due to adverse
events. Change in daytime activity as measured by actigraphy was a secondary outcome.
Results: Of the 44 patients who received active buprenorphine 5 µg/hour, 52.3% (n=23) dis-
continued treatment due to adverse events compared to 13.3% (6 of 45) in the placebo group
(p,0.001). Psychiatric and neurological adverse events were the most frequently reported
causes of discontinuation (69.6%, n=16). Concomitant use of antidepressants significantly
increased the risk of discontinuation (HR 23.2, 95% CI: 2.95–182, p=0.003). Adjusted for age,
sex, cognitive function, pain and depression at baseline, active buprenorphine was associated
with 24.0 times increased risk of discontinuation (Cox model, 95% CI: 2.45–235, p=0.006).
Daytime activity dropped significantly during the second day of active treatment (−21.4%,
p=0.005) and decreased by 12.9% during the first week (p=0.053).
Conclusion: Active buprenorphine had significantly higher risk of discontinuation compared
with placebo in people with advanced dementia and depression, mainly due to psychiatric and
neurological adverse events. Daytime activity dropped significantly during the first week of treat-
ment. Concomitant use of antidepressants further reduced the tolerability of buprenorphine.
Keywords: opioids, analgesics, dementia, drug safety, adverse drug reactions
Introduction
More than 80% of elderly people in long-term residential care have dementia.1
Approximately 50% of these individuals suffer from pain of clinically significant
intensity.2 Cognitive impairment leads to difficulty in verbally expressing painful
symptoms and complicates the assessment and treatment of pain.3 This may increase
the risk of untreated chronic pain in people with dementia compared with cognitively
intact patients.4 In the past few decades, systematic reviews have expressed concern
that nursing home patients with dementia receive less analgesic treatment than those
without dementia, despite comparable diagnoses of pain.5,6
Correspondence: Ane Erdal
Department of Global Public Health and
Primary Care, Centre for Elderly and
Nursing Home Medicine, University of
Bergen, Kalfarveien 31, PO Box 7804,
Bergen N-5018, Norway
Tel +47 55 58 6036
Fax +47 55 58 6130
Email ane.erdal@uib.no
Journal name: Clinical Interventions in Aging
Article Designation: Original Research
Year: 2018
Volume: 13
Running head verso: Erdal et al
Running head recto: DEP.PAIN.DEM
DOI: 161052
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Clinical Interventions in Aging
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Erdal et al
Data from the entire population of Denmark in 2010
showed that 41% of the country’s 42,291 nursing home
patients used opioids, and that patients without dementia
received significantly more opioid analgesics compared with
those with dementia (43% and 38%, respectively).7 A study
including 425 patients from 12 nursing homes in Austria
in 2011–2012 found that despite having more pain, fewer
cognitively impaired patients received scheduled analgesic
prescriptions compared with patients without cognitive
impairment (36% and 58%, respectively).8 Several studies
have reported similar rates of analgesic use in nursing home
patients with and without dementia,9,10 with an overall
increase in total analgesic use irrespective of cognitive
state and a shift toward increased use of opioid analgesics.9
In Norway, the use of opioid analgesics in nursing home
patients increased from 11% in 2000 to 24% in 2011, with a
substantial increase in the use of strong opioids from 1.9%
to 17.9%.9 In 2011, the odds ratio for the use of strong opioids
in nursing home patients with dementia did not differ signifi-
cantly compared with those without dementia.9
Buprenorphine transdermal system (TDS) has been
recommended for elderly patients because of its favorable
pharmacodynamic and pharmacokinetic profile, with low
risk of serious adverse events.11 Buprenorphine, a strong
opioid, is a partial mu receptor agonist and a kappa receptor
antagonist. This pattern of activity gives a ceiling effect for
respiratory depression, without a clinically relevant ceiling
effect on analgesia.12 As one of few opioids, it does not
require dose adjustment in renal insufficiency due to hepatic
clearance.13 Buprenorphine TDS is prescribed to over 10%
of nursing home patients in countries where it is marketed,
with estimated use in people with dementia ranging from
10.5% to 14.8%.7,9,10 While buprenorphine TDS has shown
high persistence rates in the general population, the rate of
common adverse events such as nausea, dizziness, or sedation
is higher than that of comparator opioids.14,15 Dementia, age-
related physiological changes, multimorbidity, frailty, and
interactions with psychotropic drugs may impact the safety
and tolerability of buprenorphine TDS.16
There is a well-documented association between pain and
increased depressive symptoms in people with dementia,17
and antidepressants have questionable efficacy for depression
in these patients.18 In a recent study, we investigated whether
analgesic treatment with acetaminophen or buprenorphine
TDS could improve depression in people with dementia.
Contrary to our hypothesis, we found that active treatment
was associated with more persistent depressive symptoms,
and 52% of patients who received active buprenorphine
were withdrawn from the study due to adverse events dur-
ing treatment.39 Few studies have assessed the tolerability
and adverse effects of buprenorphine TDS in nursing home
patients with dementia, and none with a placebo-controlled
design. Furthermore, buprenorphine may have additive or
synergistic interaction effects with other drugs that have seda-
tive effects. Elderly patients and people with dementia are
particularly vulnerable to adverse effects such as sedation, but
interactions between opioids and other commonly prescribed
psychotropic drugs such as antidepressants have not been
studied in this population. Similarly, anticholinergic drugs
may negatively impact cognition in people with dementia, but
we do not know whether high anticholinergic drug burden is
associated with poorer tolerability of buprenorphine. There
is a need to investigate clinically significant interactions
between opioids and anticholinergic and psychotropic drugs
in people with dementia.
In these secondary analyses of our study, the primary
aim was to assess the tolerability of buprenorphine TDS in
nursing home patients with moderate to severe dementia,
controlling for pain intensity, depressive symptoms, cogni-
tive state, and concomitant use of psychotropic and anti-
cholinergic drugs. Secondary aims were to assess which
adverse effects most frequently caused discontinuation and
to determine how daytime activity changed during the first
week of treatment.
Patients and methods
Study design and population
The current study comprises secondary analyses of data
collected in the randomized, placebo-controlled trial
“Efficacy of analgesic treatment for depression in nursing
home patients with dementia (DEP.PAIN.DEM),” which
was conducted in 47 nursing homes in 10 municipalities of
Norway, including people with dementia (Mini-Mental State
Examination [MMSE] #20) and depression (Cornell Scale
for Depression in Dementia [CSDD] $8; full inclusion and
exclusion criteria are presented in Table 1). The intervention
consisted of a stepwise increase in analgesic treatment, and
patients who did not use scheduled analgesics at baseline or
used acetaminophen #1 g/day were prescribed acetamino-
phen in a total dose of 1 g three times daily. Patients who
already used acetaminophen .1 g daily, nonsteroidal antiin-
flammatory drugs (except low-dose acetylsalicylic acid), or
buprenorphine 5 µg/hour, or who had difficulty swallowing
tablets, were prescribed buprenorphine TDS 5 µg/hour in
addition to their regular treatment and randomized to receive
active treatment or placebo for 13 weeks with no further dose
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DEP.PAIN.DEM
adjustment.39 Patients who received buprenorphine/placebo
TDS are included in the current analyses.
Procedures
Clinicians were advised to keep doses of psychotropic
and analgesic drugs unchanged during the study period, if
possible. If lasting changes were made to regular analgesic
treatment or antidepressants, the patient was withdrawn
from the study. The study treatment was prescribed in
addition to any regular or as-needed analgesics. In mild to
moderate acute pain, patients were given as-needed analge-
sics in addition to study treatment, and the number of doses
given during the study period was recorded. Patients with
severe pain at baseline were excluded because it would be
unethical to risk treating them with a placebo. We there-
fore ensured that the included patients would not suffer
from prolonged or unnecessary untreated pain because of
the study protocol. Furthermore, the physician who was
responsible for the patient had full authority to discontinue
study treatment promptly if clinical changes necessitated
treatment with a known dose of active analgesic. Written
informed consent was obtained from patients with medical
decision-making capacity, or written presumed consent
was obtained from a legally authorized representative in
those with reduced capacity to consent in accordance with
ethics committee requirements and current Norwegian
legislation. The trial was approved by the Regional Com-
mittee for Medical and Health Research Ethics (REC-
West 2013/1474) and the Norwegian Medicines Agency
(EudraCT 2013-002226-23), and registered at ClinicalTri-
als.gov (NCT02267057).
Randomization and masking
The trial was double blinded, and participants were ran-
domly allocated to each arm in a 1:1 ratio according to
computer-generated random numbers in blocks of 12 with
no stratification factors. Buprenorphine TDS and identical,
inert placebo (Mundipharma Research Limited, Cambridge,
UK) were packed and marked indiscernibly, identifiable only
by pack number. Patients, nursing home staff, physicians,
pharmacy, researchers, and statisticians were all masked to
group identity until completion of the analyses.
Assessments
Assessments were made by the researchers in collabora-
tion with the nursing home staff and included scheduled
assessments at baseline, 6 and 13 weeks in addition to any
spontaneous reports during the whole 13-week period. The
tolerability of buprenorphine TDS was operationalized by
assessing how many patients discontinued treatment due to
adverse events (defined as suspected adverse event, clinical
deterioration, or death) and how long treatment lasted before
such discontinuation. Discontinuation for other reasons, such
as protocol violation, was not included in the analysis, and
in the following, “discontinuation” refers only to those cases
defined here as caused by adverse events. To ensure that
all suspected adverse events were reported, the proxy rater
received standardized detailed verbal and written information
Table 1 Inclusion and exclusion criteria
Type of criterion Patient characteristics
Inclusion criteria Age $60 years
Long-term nursing home placement with .4 weeks’ stay
Dementia (MMSE #20)
Depression (CSDD $8, .3 weeks’ duration)
Exclusion criteria Life expectancy ,6 months
Severe medical disease that could interfere with study participation
Impaired liver function, assessed by elevated serum alanine aminotransferase
Severe renal impairment with serum creatinine indicative of eGFR #30 (Cockcroft–Gault equation)
Anemia (Hb ,8.5 mmol/L for men, ,7.5 mmol/L for women) or electrolyte imbalance (Na+, K+)
History of severe psychiatric disease prior to dementia onset
Suicide risk (any attempts during the last year)
Severe aggression (NPI-NH aggression item score $8, with aggression as the predominant symptom)
Severe pain (MOBID-2 $8)
Uncontrolled epilepsy
Contraindication or clinically signicant drug interaction to the assigned study treatment
Regular use of any opioid analgesic other than or exceeding buprenorphine 5 µg/hour
Cognitive impairment related to diagnoses other than Alzheimer’s disease, frontotemporal dementia,
vascular dementia, dementia with Lewy bodies, or mixed dementia
Abbreviations: CSDD, Cornell Scale for Depression in Dementia; eGFR, estimated glomerular ltration rate; MMSE, Mini-Mental State Examination; MOBID-2, Mobilization-
Observation-Behavior-Intensity-Dementia-2 Pain Scale; NPI-NH, Neuropsychiatric Inventory-Nursing Home Version.
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Erdal et al
about known possible adverse effects of buprenorphine. They
were instructed to pay attention to and report changes in any
of the symptoms listed as potential adverse events, as well
as any other clinical changes that occurred during treatment.
If any clinical changes were observed during treatment, the
raters were instructed to contact the researchers by phone
immediately to report the symptoms. This information was
distributed to other staff members, along with instructions
to contact the researchers by phone immediately upon
suspicion of any adverse event. In addition, the research-
ers asked specifically whether any adverse events were
suspected at other contacts with the nursing home staff and
during scheduled follow-up at 6 and 13 weeks of treatment.
All suspected adverse events, irrespective of whether the
patient discontinued treatment, were recorded verbatim as
reported by nursing home staff, in as much detail as possible,
including information about time from initiation to presenting
symptoms and discontinuation of treatment.
Demographic information and a complete list of sched-
uled drug prescriptions (excluding prescriptions given pro re
nata, ie, “as needed”) were extracted from the patients’
medical records at baseline. The total number of scheduled
drug prescriptions was counted. Analgesic use was assessed
by counting the number of prescriptions for drugs classified as
systemic analgesics (Anatomical Therapeutic Chemical
[ATC] code N02 or M01A). In addition, the individual
and total numbers of scheduled psychotropic drugs were
counted (antidepressants [N06A], anti-dementia [N06D],
antipsychotic [N05A], anxiolytic [N05B], hypnotic and
sedative [N05C], and antiepileptic [N03A] drugs). The total
anticholinergic cognitive burden (ACB) was calculated by
assigning 1 point for each prescribed drug with mild anti-
cholinergic properties, 2 points for each drug with moderate
anticholinergic effects, and 3 points for each drug with strong
anticholinergic properties.19,20 Between-group differences
in drug use and morbidity at baseline were assessed by
counting the number of prescriptions for drugs within each
ATC group (A–V).
Activity was assessed by actigraphy registration using
the Philips Actiwatch Spectrum, which was worn on the
patients’ dominant or mobile wrist continuously for 14 days
(7 days before and 7 days after treatment was started).21,22
Total activity counts per day (Total AC) and mean intensity
of activity per minute (AC/minute) for daily 12-hour intervals
(09:00–21:00) were extracted from the Respironics Actiware
6.0.9 software. Mean activity counts for Total AC and
AC/minute were calculated for both 7-day periods in all patients
with at least 5 valid days of actigraphy recording per week.
Cognitive function was assessed using the MMSE, a
30-item questionnaire administered directly to the patient cov-
ering 11 domains (registration, orientation to time and place,
short-term recall, attention, calculation, long-term recall,
naming, repetition, comprehension [verbal and written],
writing, and visuospatial construction) to yield a sum score
from 0 (most severe impairment) to 30 (no impairment).23,24
Pain was assessed using the Mobilization-Observation-
Behavior-Intensity-Dementia-2 Pain Scale (MOBID-2),
a two-part staff-administered instrument to assess pain in
people with advanced dementia.25 The proxy evaluation of
inferred pain intensity is based on the patient’s pain behaviors
during standardized, guided movements of different body
parts (Part 1), and pain behaviors that might be related to
internal organs, head, and skin are recorded on an anatomical
figure along with the inferred pain intensity for each region to
allow monitoring over time (Part 2). The scale yields a final
score from 0 (no pain) to 10 (worst pain imaginable). Good
interrater and test–retest reliability, internal consistency, and
validity have been shown, and the MOBID-2 scale has also
demonstrated responsiveness to change.25
Depressive symptoms were assessed using the CSDD,
which is a validated and widely used screening tool for depres-
sion in people with dementia.26 It is administered by an inter-
view with a proxy rater who is familiar with the patient, and
it contains 19 items in five domains (mood-related signs,
behavioral disturbance, physical signs, cyclic functions, and
ideational disturbance). Each item is rated from 0 (no symp-
tom) to 2 (severe symptoms) to yield a sum score of between
0 (no depression) and 38 (most severe depression).26
The main outcome measure was time to discontinuation
of treatment due to adverse events. Secondary outcome
measures were reasons for discontinuation, and change in
total daytime activity and mean intensity of daily activity as
measured by actigraphy recording.
Sample size calculation
The DEP.PAIN.DEM trial was designed to obtain 90% power
to detect a 2-point CSDD difference between active treatment
(acetaminophen or buprenorphine) and identical placebo,
with an SD of 5, a standardized effect size of 0.4, p,0.05.
The sample size was calculated using a sample size formula
for longitudinal continuous response, adjusted for within-
subject correlation between repeated measurements which
was estimated to be 0.25 using data from the first 113 patients.
One hundred thirty-two participants (66 in each group) were
required, and adjusting for 20% dropouts, our final aim was
to include 165 participants in total.39
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DEP.PAIN.DEM
Statistical analysis
Baseline characteristics were described as mean and standard
deviation for continuous variables, and with the number of
patients and percentages of the sample size for categorical
variables. Between-group differences were tested using
independent-samples t-test for continuous variables with
normal distribution; Mann-Whitney U-test for continuous
variables with non-normal distribution; and Pearson’s χ2 test
for categorical variables. We used a Kaplan–Meier survival
plot and Cox regression models to determine whether patients
who were randomized to receive active buprenorphine had a
higher risk of discontinuation compared to those who received
placebo. Cox regression analyses were repeated with age, sex,
and MOBID-2, CSDD, and MMSE as covariates to determine
which variables should be included in the adjusted analyses.
To further assess whether the risk of discontinuation of active
buprenorphine was modified by drug use, we tested the interac-
tion between the treatment effect and each of the drug variables
(total number of prescribed drugs, ACB score, total number of
psychotropic drugs, and use of each class of psychotropic drugs
[N06A, N06D, N05A, N05B, N05C, N03A]) on discontinua-
tion, both unadjusted and adjusted for age, sex, and MOBID-2,
CSDD, and/or MMSE at baseline if these covariates impacted
discontinuation risk. We used cluster-robust variance estimates
to account for dependence within nursing homes. To assess
immediate changes in daytime activity during the early days
of treatment, we used linear mixed-effects models for Total
AC and AC/minute/day using the mean recording from the
7 days before treatment was initiated as baseline. Time was
included as a categorical variable, with fixed effects for time,
intervention, and their interaction in the models. The models
were fitted with random intercepts for patients to account for
correlation between longitudinal measurements, random slope
for time, and residual error structure specified as independent
by day. We regarded p,0.05 as significant. All statistical
analyses were conducted with STATA/IC 15 (Stata Corp LP,
College Station, TX, USA).
Results
In total, 162 patients were included in the DEP.PAIN.DEM
trial: 73 were prescribed acetaminophen/placebo tablets, and
89 patients were prescribed buprenorphine/placebo TDS and
included in the current study. In the latter group, 44 were
allocated to active treatment (hereafter, “active group”), and
45 to placebo (hereafter, “placebo group”; see Figure 1).
Characteristics of the included patients at baseline are shown in
Table 2. The groups were comparable at baseline on all tested
variables except that the active group received more drugs
in ATC group M (seven patients in active treatment and one
patient in placebo; p=0.025), and the placebo group received
more drugs in ATC group N (mean number of prescriptions
2.2 [SD 1.6] in the active group and 3.2 [SD 1.7] in the placebo
group; p=0.001). From the latter ATC group, use of antidepres-
sants and total number of psychotropic drugs were significantly
higher in the placebo group; we also found significantly higher
ACB in the placebo group (Table 2). Fifteen patients used
buprenorphine TDS 5 µg/hour prior to inclusion, eight of
whom were allocated to receive active treatment.
Frequency and types of adverse events
All adverse events recorded are presented in Table 3. Because
each patient may have had more than one adverse event of
each type, the number of adverse events may not correspond
to the number of patients affected unless specified. Psychiatric
adverse events were reported most frequently, with 17 sepa-
rate adverse effects recorded in the active treatment group
and none in the placebo group (p=0.003). Of psychiatric
symptoms, personality changes (ie, changed emotional labil-
ity or other behavioral changes described as such) were the
most frequent, reported in eight patients (18.2%), followed
by confusion reported in five patients (11.4%). Neurological
adverse events were the second most commonly reported,
with 11 adverse effects recorded in the active treatment group
and 2 in the placebo group (p=0.039). The most frequent neu-
rological adverse event and the single most frequent adverse
symptom was sedation/somnolence, which was reported in
nine patients (20.5%) receiving active treatment and two
patients receiving placebo (4.4%, p=0.022).
Rates and causes of discontinuation
Buprenorphine TDS active treatment was discontinued in
23 patients (52.3%) due to adverse events, compared with
6 patients (13.3%) in the placebo group (p,0.001). Mean
time to discontinuation was 61 days (SD 36) in the active
treatment group and 82 days (SD 24) in the placebo group.
Within the first 14 days, nine patients (20.5%) discontinued
active treatment, and two patients (4.4%) discontinued
placebo. Nearly half of patients who did not tolerate active
treatment reported several types of adverse events (Table 4).
Psychiatric adverse events were the most frequent cause of
discontinuation reported in 12 of 23 patients (52%). Neuro-
logical adverse events were the second most frequent cause
of discontinuation reported in nine patients (39%), five of
whom also had psychiatric symptoms.
Kaplan–Meier estimates of time to discontinuation are
shown in Figure 2. Throughout the study, patients who
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Erdal et al
2,323 patients from 47 NHs
screened for eligibility
89 prescribed
buprenorphine/placebo TDS
44 randomly allocated
to receive active buprenorphine
45 randomly allocated
to receive placebo TDS
73 prescribed
acetaminophen/placebo tablets
162 enrolled
6-Week assessments:
17 dropouts from baseline
2 died
15 adverse events
0 other
6-Week assessments:
6 dropouts from baseline
1 died
3 adverse events
2 other
13-Week assessments:
3 dropouts from 6 weeks
2 died
0 adverse events
1 other
13-Week assessments:
6 dropouts from 6 weeks
3 died
3 adverse events
0 other
2,161 excluded:
2,015 did not meet primary eligibility criteria
562 used opioid analgesics
895 did not have depression (CSDD <8)
139 did not have dementia (MMSE >20)
14 had changes in analgesic or antidepressant treatment
56 had life expectancy <6 months
14 had contraindication or allergy to study treatment
65 had psychiatric disorder which warranted exclusion
99 had blood test indicative of renal/hepatic failure and/or electrolyte imbalance/anemia
54 died prior to enrolment
87 had short-term placement or moved
30 aged <60 years
137 did not consent
9 were excluded for other reasons/reasons not recorded
Figure 1 Trial prole.
Abbreviations: CSDD, Cornell Scale for Depression in Dementia; MMSE, Mini-Mental State Examination; NH, nursing home; TDS, transdermal system.
Table 2 Background characteristics of included patients at baseline
Characteristics Total
(n=89)
Active treatment
(n=44)
Placebo
(n=45)
p-value
Agea85.8 (7.2) 85.6 (8.5) 86.0 (5.9) 0.782
Sex (female)b67 (75.3%) 33 (75.0%) 34 (75.6%) 0.952
MMSEa7.0 (6.1) 6.8 (5.6) 7.3 (6.5) 0.737
MOBID-2a3.1 (1.9) 2.7 (1.8) 3.5 (2.0) 0.095
CSDDa10.9 (3.4) 10.3 (2.4) 11.5 (4.1) 0.099
Analgesicsb (N02/M01A) 78 (87.6%) 37 (84.1%) 41 (91.1%) 0.314
Antidepressantsb (N06A) 41 (46.1%) 14 (31.8%) 27 (60.0%) 0.008
Antipsychoticsb (N05A) 20 (22.5%) 8 (18.2%) 12 (26.7%) 0.338
Anti-dementia drugsb (N06D) 17 (19.1%) 5 (11.4%) 12 (26.7%) 0.066
Anxiolyticsb (N05B) 24 (27.0%) 9 (20.5%) 15 (33.3%) 0.171
Antiepilepticsb (N03A) 9 (10.1%) 5 (11.4%) 4 (8.9%) 0.699
Sedatives/hypnoticsb (N05C) 26 (29.2%) 9 (20.5%) 17 (37.8%) 0.072
Total number of psychotropicsc1.6 (1.3) 1.2 (1.1) 1.9 (1.3) 0.007
Anticholinergic drugsc (ACB) 1.4 (1.5) 0.9 (1.3) 1.8 (2.8) 0.014
Total number of drugsa6.7 (3.0) 6.4 (3.5) 7.1 (2.5) 0.262
Notes: Numbers represent mean (SD) or number of patients (%). aIndependent samples t-test. bPearson’s χ2-test. cMann–Whitney U-test.
Abbreviations: ACB, anticholinergic cognitive burden; CSDD, Cornell Scale for Depression in Dementia; MMSE, Mini-Mental State Examination; MOBID-2, Mobilization-
Observation-Behavior-Intensity-Dementia-2 Pain Scale.
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Table 3 Adverse events that may be related to study treatment
Buprenorphine
n=44
Placebo
n=45
p-valuea
Patients with reported
adverse reactionsb
25 (56.8%) 8 (17.8%) ,0.001
Patients who
discontinued treatment
23 (52.3%) 6 (13.3%) ,0.001
Neurological 11 2 0.039
Sedation/somnolence 9 (20.5%) 2 (4.4%) 0.022
Seizure 1 (2.3%) – 0.309
Loss of coordination 1 (2.3%) – 0.309
Psychiatric 17 – 0.003
Personality changes 8 (18.2%) – 0.003
Anxiety 1 (2.3%) – 0.309
Agitation 2 (4.5%) – 0.148
Confusion 5 (11.4%) – 0.020
Hallucinations 1 (2.3%) – 0.309
Gastrointestinal 6 – 0.117
Dry mouth 1 (2.3%) – 0.309
Nausea 3 (6.8%) – 0.075
Vomiting 1 (2.3%) – 0.309
Anorexia 1 (2.3%) – 0.309
Dermatological
Application site rash – 1 (2.2%) 0.320
Other 8 2 0.204
Fall 4 (9.1%) 1 (2.2%) 0.159
Fracture 1 (2.3%) 1 (2.2%) 0.987
Respiratory tract
infection
1 (2.3%) – 0.309
Hospitalization 2 (4.5%) – 0.148
Deterioration/death 6 (13.6%) 4 (8.9%) 0.478
Notes: Bold gures indicate signicantly different prevalence rates (p,0.05).
aPearson’s χ2-test. bEach patient may have had more than one reaction.
Table 4 Symptom combinations reported in the 23 patients who discontinued active buprenorphine due to adverse events
Psychiatric Neurological Deterioration/death Gastrointestinal Fall
X
X
X
X
X X
X X
X X
X X
X X
X X
X X
X X X
X
X
X X
X X
X
X
X
X
X
X
X
received active treatment had 4.7 times higher risk of dis-
continuation compared with those who received placebo
(Table 5; Cox proportional hazards model, unadjusted
HR, 95% CI: 1.66–13.3, p=0.004). Adjusted for age, sex,
MOBID-2, CSDD, and MMSE at baseline, active treatment
was associated with 24.0 times higher risk of discontinuation
(95% CI: 2.45–235, p=0.006). In this model, age, sex, depres-
sive symptoms, and pain were not significantly associated
with discontinuation (age: HR 1.0, 95% CI: 0.99–1.11,
p=0.133; sex: HR 0.32, 95% CI: 0.10–1.58, p=0.149; CSDD:
HR 1.1, 95% CI: 0.90–1.34, p=0.343; MOBID-2: HR 1.1,
95% CI: 0.91–1.45, p=0.246). Lower MMSE scores were
associated with increased risk of discontinuation (HR 0.82,
95% CI: 0.71–0.94, p=0.005), but interaction effects of
MMSE score were tested in a new model and were not signifi-
cant, that is, patients who received active treatment were not
at increased risk of discontinuation if they had lower MMSE
scores (HR 1.04, 95% CI: 0.82–1.31, p=0.767).
Drug use and rates of discontinuation
Total number of prescribed drugs, ACB score, total
number of psychotropic drugs, and use of any individual
psychotropic drug (N06A, N06D, N05A, N05B, N05C, or
N03A; dichotomized) were all not independently associ-
ated with discontinuation of the study treatment (active or
placebo). However, patients who received active treatment
and used antidepressants had 21.6 times increased risk of
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Erdal et al
discontinuation compared with patients who used antidepres-
sants and received placebo (95% CI: 2.75–170, p=0.003;
Table 5). The interaction between active buprenorphine
and antidepressant use remained unchanged when adjusting
for age, sex, and MMSE (HR 23.2, 95% CI: 2.95–182,
p=0.003). In this model, active buprenorphine was not sig-
nificantly associated with increased risk of discontinuation in
patients who did not use antidepressants (HR 2.95, 95% CI:
0.53–16.6, p=0.218), as shown in Figure 3 (Table 5). Interac-
tion effects were calculated separately for each variable for
drug use, and none except antidepressant use had significant
interactions with active buprenorphine.
Although patients who used antidepressants and received
active treatment had significantly increased risk of discon-
tinuation, we were not able to detect any significant differ-
ence in the total number of adverse events and treatment
discontinuations compared with those who did not use anti-
depressants. Nine of the 14 patients (64.3%) who received
active treatment and used antidepressants reported adverse
events and discontinued treatment. Of the 30 patients who
received active treatment and did not use antidepressants, 16
(53.3%) reported adverse events and 14 (46.7%) discontinued
treatment. Using χ2-tests, the rates of adverse events and
discontinuation in patients who received active treatment and
used antidepressants were compared to those who did not
use antidepressants (groups defined by the number of pre-
scriptions for antidepressants at baseline), but no significant
differences were found ( p=0.599 and 0.419, respectively).
We did not find that patients who used antidepressants
reported any single type of adverse event more frequently,
except confusion which was reported in three patients who
used antidepressants (21.4%) and two patients who did not
use antidepressants (6.7%, p=0.013, χ2-test).
Changes in activity during the rst week
of treatment
Day-to-day activity counts in the first week of treatment,
measured by actigraphy, are shown in Figure 4 with the
7LPHGD\V
3DWLHQWV
&,
&,
%XSUHQRUSKLQH
3ODFHER
Figure 2 Kaplan–Meier survival plot: duration of study treatment.
Table 5 Estimated treatment effect of buprenorphine versus
placebo on discontinuation (Cox regression)
N HR (95% CI) p-value
Unadjusted 89 4.70 (1.66–13.3) 0.004
Model 1a76 7.19 (1.65–31.3) 0.009
Model 2b65 24.0 (2.45–235) 0.006
Modied by antidepressantsc
No antidepressants 89 1.88 (0.63–5.64) 0.257
Antidepressants 89 21.6 (2.75–170) 0.003
Modied by antidepressantsa
No antidepressants 76 2.95 (0.53–16.6) 0.218
Antidepressants 76 23.2 (2.95–182) 0.003
Notes: Modied analyses include interaction effects. aAdjusted for age, sex, and
cognition (MMSE). bAdjusted for age, sex, cognition (MMSE), pain (MOBID-2), and
depression (CSDD). cUnadjusted.
Abbreviations: CSDD, Cornell Scale for Depression in Dementia; MMSE, Mini-
Mental State Examination; MOBID-2, Mobilization-Observation-Behavior-Intensity-
Dementia-2 Pain Scale.
3ODFHER
QR1$
3ODFHER
1$
%XSUHQRUSKLQH1$
+5&,±S
%XSUHQRUSKLQHQR1$
+5&,±S
7LPHGD\V
3DWLHQWV
Figure 3 Cox proportional hazard plot: discontinuation risk stratied on treatment
allocation and antidepressant use.
Abbreviation: N06A, Antidepressant.
0123
Time (days)
Total daytime activity (Total AC)
4567
Placebo Buprenorphine
Figure 4 Daytime activity during the rst week of study treatment.
Notes: Actigraphy recording of total activity from 09:00 to 21:00 hours daily.
Baseline score calculated as mean daily activity during the 7 days before treatment
was started.
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DEP.PAIN.DEM
mean activity counts during the week before treatment
started as the baseline activity score. Patients who received
active treatment had significantly reduced daytime activity
on day 2 of treatment compared with placebo (mixed model;
Total AC: −16,967, p=0.005). This corresponds to a 21.4%
decrease in total daytime activity in those who received
active treatment. Comparing the mean daytime activity in
the first week of treatment with baseline activity, we found
that active treatment was associated with a 12.9% decrease in
mean Total AC, but this effect was not statistically significant
(mixed model; p=0.053).
Discussion
To our knowledge, this is the first placebo-controlled study
investigating the tolerability and observed adverse events of
buprenorphine TDS in nursing home patients with moder-
ate to severe dementia. Patients who used antidepressants
and received active treatment had the highest risk of dis-
continuation; this suggests a clinically relevant interaction
between antidepressants and buprenorphine in people with
dementia. Buprenorphine significantly reduced daytime
activity as measured by actigraphy on the second day of
treatment compared with placebo, supporting reports from
nursing home staff of increased sedation/somnolence as
the most frequent adverse effect. The poor tolerability of
buprenorphine TDS due to the high risk of neurological and
psychiatric adverse events should be considered carefully by
clinicians before prescribing to people with dementia, and
particularly to patients who are also using antidepressants,
which may further reduce tolerability. This study does not
assess the efficacy of buprenorphine TDS for treating dif-
ferent types of pain in dementia, which should be addressed
in future research.
In the active treatment group, 57% had reported adverse
events. A recent meta-analysis of six randomized controlled
studies (five were placebo controlled) found that 82% of
elderly patients ($65) had adverse events of buprenorphine
TDS.27 The lower rate of reported adverse events in our
study can most likely be attributed to our reliance on proxy
observations of adverse events. Although self-report of symp-
toms is considered the gold standard, people with advanced
dementia often have impaired ability to reliably report their
symptom burden. For example, less than half of patients
with MMSE #6 are able to comprehend any assessment
scale used to self-report painful symptoms.28 In our study,
mean MMSE was 7 at baseline; therefore, many could not
self-report adverse effects of buprenorphine TDS. Mild
adverse effects of buprenorphine are subjective, they may
not be easily observable, and subtle changes such as reduced
appetite, confusion, or agitation could be misinterpreted as
neuropsychiatric symptoms in dementia which may not be
attributed to study treatment by the proxy raters. Because
people with communication difficulty due to advanced
dementia cannot be expected to reliably self-report mild
adverse events, the true prevalence of adverse events is likely
to have been underestimated in our study due to observer bias.
Therefore, this should be interpreted as a tolerability study
presenting adverse events associated with discontinuation
of treatment, rather than the absolute frequency of adverse
events in people with dementia.
Although very frail patients with short life expectancy
were not included in the trial, sudden clinical deterioration
is difficult to predict and must be expected to occur during
an extended follow-up period in nursing home patients with
advanced dementia, regardless of exposure to a clinical
intervention. The number of patients who were withdrawn
from the study because of severe clinical deterioration with
short life expectancy did not differ significantly between
the active treatment and placebo groups, and our sample
size and follow-up period were not designed to investigate
whether buprenorphine use may be associated with increased
mortality. Adverse events were registered on suspicion, based
on detailed reports of clinical changes from nursing home
staff. Even though we did not assess the likelihood of causality
between the study treatment and each reported adverse event,
we conclude that the difference in the total number of adverse
events between active treatment and placebo can likely be
attributed to adverse effects of buprenorphine.
Previous studies indicate that buprenorphine TDS is
well tolerated in elderly patients, with studies reporting
similar or lower rates of adverse events in healthy elderly
patients compared with younger controls.29–31 In elderly
patients without dementia, the most common adverse events
associated with discontinuation of buprenorphine treatment
are gastrointestinal – nausea (8.2%), vomiting (3.9%), and
constipation (2.0%) – followed by neurological symptoms –
dizziness (5.1%), somnolence (2.0%), and headache (2.0%).27
In our study, psychiatric and neurological adverse effects
were frequent, reported in 16 of patients who discontinued
treatment (36.4%). Four patients (9.1%) who discontinued
treatment had gastrointestinal symptoms. This indicates that
psychiatric adverse events of buprenorphine may occur more
frequently in people with dementia compared with cogni-
tively intact elderly patients. As buprenorphine has similar
pharmacokinetic properties in elderly patients including those
with renal impairment,29,32 this reduced tolerability is most
likely explained by pharmacodynamic changes in people
with dementia.33,34
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Erdal et al
Buprenorphine TDS is absorbed slowly, and it reaches
active concentration after ~24 hours and steady state during
the first 72 hours in young healthy patients.35 Although phar-
macokinetics have not been investigated in the very old and
frail, buprenorphine TDS appears to be absorbed at a similar
rate in people aged $75 years compared to a younger con-
trol group.29 The largest drop in daytime activity observed
in our study (recorded ~24–36 hours after administration)
may therefore correspond to the first systemic exposure
to buprenorphine. While the reduction in daytime activity
during the first week of active treatment was not statistically
significant, this was probably due to low sample size.
Depression is associated with the use of antidepressants
in nursing home patients with dementia.17 Because depression
was an inclusion criterion, we may have selected patients
who used more antidepressants relative to other psycho-
tropic drugs. This may have enabled us to find a significant
interaction between antidepressant use and buprenorphine
discontinuation, while potential interactions between
buprenorphine and other psychotropic drugs may have gone
unnoticed. However, patients in the active treatment group
generally used less psychotropic drugs compared with the
placebo group and had a lower prevalence of antidepressant
use (31.8%) than that expected from recent reports in people
with dementia (~40%).36,37 Thus, the observed interaction
between antidepressants and buprenorphine is likely to be
of clinical relevance. While we did not find significant inter-
action effects between other psychotropic drugs and active
buprenorphine, this may be due to insufficient power rather
than the absence of such effects.
As shown in two recent studies, the use of opioid anal-
gesics in the oldest nursing home patients with dementia is
increasing.7,9 Age is associated with increased pain, frailty,
and dementia. In patients with severe pain, or very frail
patients, it may be difficult to achieve full analgesic effect
as the type or dose of analgesics required may not be toler-
ated by the patient. Because patients with dementia have not
been included in safety studies, the evidence base to ensure
appropriate prescribing is lacking. In the DEP.PAIN.DEM
trial, neither did we find a significant change in pain intensity
in either of the buprenorphine or placebo TDS groups dur-
ing follow-up, nor did we find a significant treatment effect
on pain between these groups.39 However, this may be due
to insufficient sample size as the DEP.PAIN.DEM trial was
not powered to assess the effect of buprenorphine on pain.
Further studies should investigate the efficacy and tolerability
of buprenorphine and other opioid analgesics for pain in
nursing home patients with dementia and painful symptoms.
Use of opioids in people with dementia should be based on a
careful risk–benefit evaluation, including regular assessments
of pain and potential adverse effects, in combination with
nonpharmacological strategies as appropriate.34
This study has limitations. The included patients had clini-
cally significant depressive symptoms at baseline, but not all
had pain. Therefore, our results may not be generalizable to
patients who receive buprenorphine for pain. Prescribers may
have had a lower threshold for discontinuation upon adverse
events in this study, for instance, the risk–benefit consider-
ation may have been shifted toward a greater awareness of
adverse events as the treatment was prescribed off-label.
The patients’ level of vulnerability to adverse events, and
the relative prevalence of different types of adverse events,
may also be different in people with advanced dementia
and severe pain as opposed to the current sample which
consisted of people with advanced dementia and depres-
sion without severe pain. Similarly, the adverse effects of
buprenorphine TDS may differ between subgroups of pain
patients (neuropathic/nociceptive; acute/chronic pain). Since
the focus of the DEP.PAIN.DEM trial was to investigate the
efficacy of pain treatment on depression, we did not diag-
nose the type and duration of pain. Therefore, future studies
should investigate the safety and efficacy of buprenorphine
TDS in people with dementia and different types of pain.
Patients who were prescribed buprenorphine rather than acet-
aminophen used more regular analgesics and/or had difficulty
swallowing tablets. This means that we may have selected
more frail/multimorbid patients to receive buprenorphine/
placebo as opposed to acetaminophen/placebo in the DEP.
PAIN.DEM trial. However, this prescribing strategy mirrors
clinical practice with a stepwise increase from non-opioid
to opioid analgesics and the choice of transdermal formu-
lation for patients who cannot swallow tablets; therefore,
our sample should be similar to nursing home patients with
dementia who receive buprenorphine TDS. We included a
mixture of opioid-naïve patients, patients who had previously
discontinued or received sporadic as-needed treatment with
an opioid, and patients who received ongoing buprenorphine
treatment; this is likely to have affected the observed pattern
of adverse events which is not representative of an opioid-
naïve population. Despite randomization, we found that
patients who received active treatment used significantly
less psychotropic and anticholinergic drugs, and fewer used
antidepressants. This could potentially influence the results,
as these drugs are associated with adverse outcomes in
people with dementia.38 However, because these drugs were
more prevalent in the control group, the high occurrence of
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DEP.PAIN.DEM
adverse events in the active treatment group is likely caused
by buprenorphine. We have not controlled for changes in
concomitant drug use during study treatment. Physicians
were instructed to avoid changes, particularly to psychotropic
and analgesic drugs, but drug changes were not assessed in
the 17 patients who discontinued treatment before week 6
assessment. The DEP.PAIN.DEM trial was designed with
90% power to detect a 2-point difference in depression
(CSDD) from baseline to 13-week follow-up between active
treatment (acetaminophen or buprenorphine) and placebo.39
For the secondary outcomes reported in the present study,
no a priori power analyses have been conducted. This is an
important limitation, and the findings from the current analy-
ses should therefore be interpreted with caution, in particular
for the subgroup analyses with lower sample sizes. Because
the estimated effect sizes have very wide CIs, the exact
magnitude of increased risk remains uncertain. However,
we have identified significant between-group differences in
reported adverse events and discontinuation risk. Although
adverse events were assessed by proxy, and are therefore
likely to be affected by observer bias, the placebo-controlled
design provides strong evidence that the difference in adverse
events is caused by the active drug rather than observer bias.
Therefore, we find it important to share the presented results.
Further studies are needed to provide evidence of the safety
and efficacy of transdermal buprenorphine for different types
of pain in people with dementia.
Conclusion
Buprenorphine appears to be poorly tolerated in people with
dementia, with a higher prevalence of psychiatric adverse
events compared with previous studies in cognitively
intact elderly patients. Initiation of buprenorphine therapy
is associated with reduced daytime activity. Although no
dose adjustment is recommended for buprenorphine in
elderly patients, our data suggest that people with dementia
are susceptible to adverse events even at the lowest initial
dose. When buprenorphine is administered to people with
dementia, the patients’ general condition pre- and posttreat-
ment should therefore be monitored carefully, including
assessments of intended and adverse treatment effects,
particularly in patients using antidepressants.
Acknowledgments
We wish to thank the patients, their relatives, and the nursing
home staff for their willingness and motivation that made
this work possible. The DEP.PAIN.DEM trial and AE and
EF received grants from the Research Council of Norway.
BSH would like to thank the G.C. Rieber Foundation and
the Norwegian Government for supporting our work at the
Centre for Elderly and Nursing Home Medicine, University
of Bergen, Norway. DA is a Royal Society Wolfson Research
Merit Award Holder and would like to thank the Wolfson
Foundation and the Royal Society for their support. Parts of
the work by DDS were carried out at the Biostatistics and
Data analysis core facility (BIOS), University of Bergen. This
work was funded by the Research Council of Norway (spon-
sor’s protocol code 221951) and has received a grant from
the University of Bergen. The funders played no role in the
design of the study; the collection, analysis, and interpretation
of the data; writing of the report; and the decision to submit
the article for publication.
This paper represents independent research [part] funded
by the National Institute for Health Research (NIHR)
Biomedical Research Centre at South London and Maudsley
NHS Foundation Trust and King’s College London. The
views expressed are those of the author(s) and not necessarily
those of the NHS, the NIHR or the Department of Health
and Social Care.
Author contributions
BSH, DA, and CB contributed in the conception of the
study and in obtaining funding. All authors contributed to
the study design, in carrying out the study, and in writing
the manuscript. DDS, AE, EF, and BSH contributed to the
statistical analysis. BSH and AE are guarantors for the study.
All authors have approved the final article.
Disclosure
Although Mundipharma Research Limited has supplied
study medication, the company has had no influence on
study design, data collection, analyses and interpretation of
data, or final publications. The authors report no conflicts of
interest in this work.
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