{'fraction_non_alphanumeric': 0.032670454545454544, 'fraction_numerical': 0.01459194214876033, 'mean_word_length': 5.005816207832493, 'pattern_counts': {'":': 0, '<': 8, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Effects of pain treatment on sleep in nursing home patients with dementia and depression: A multicenter placebo‐controlled randomized clinical trial

Objective To investigate the effects of pain treatment on sleep in nursing home (NH) patients with dementia and depression. Methods A multicenter, 2‐armed, double‐blinded, placebo‐controlled, randomized clinical trial conducted between August 2014 and September 2016. One hundred six long‐term patients from 47 NHs in Norway with dementia and depression according to the Mini‐Mental State Examination and the Cornell Scale for Depression in Dementia were included. Patients received stepwise pain treatment in which those who did not use analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets; those who already used pain treatment were allocated to buprenorphine transdermal system (max. 10 μg/h/7 days) or placebo transdermal patches. Sleep was assessed continuously for 14 days by actigraphy, 1 week of baseline measurement, and 1 week of ongoing treatment. The following sleep parameters were evaluated: total sleep time, sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset, early morning awakening (EMA), and number of wake bouts. Results In the intervention group (paracetamol/buprenorphine), SE (70%‐72%), SOL (32‐24 min), and EMA (50‐40 min) improved compared with the control group (SE, 70%‐67%; SOL, 47‐60 min; EMA, 31‐35 min). Treatment effects were significant (P < .01, P < .05, and P < .05, respectively). Conclusion Compared with placebo, pain treatment improved sleep as measured with actigraphy. This implies that sleep, pain, and depression in NH patients should be critically evaluated and that pain treatment should be considered to be a potentially beneficial treatment.

associated with sleep disturbances, especially among people with cognitive impairment. 18,19 Previous research suggests overlapping neural networks for depression, sleep disturbance, and dementia. 20 Among various neuropsychiatric symptoms, sleep and depressive symptoms are often considered to coincide as a "mood-cluster." 21 Pain represents an important cause of poor sleep for people with and without dementia. 22 Previous studies indicate that there is a bidirectional relationship between pain and sleep disturbances. 23 Approximately 60% of NH patients experience pain every day. 24 The prevalence may vary, however, as pain can be difficult to evaluate in people with dementia, who have reduced ability to describe their symptoms.
It is therefore important that NH staff seek to identify pain through appropriate methods 25 and exclude pain as a factor contributing to sleep disturbances before prescribing sleep medications. Overall, the presence of pain, dementia, and depression, together with sleep disturbances, may lead to a downward spiral regarding health and well-being. 15,19 In a cluster-randomized clinical trial conducted by Husebo et al, 26 a stepwise protocol of treating pain was found to improve mood, sleep, and depression in people with dementia and agitation. The study did, however, not include objective sleep measurements and was not placebo-controlled. Consequently, the aim of the present study was to investigate the effect of pain treatment on sleep in NH patients with dementia and depression in a placebo-controlled randomized clinical trial with objective sleep measurements.
We hypothesized that pain treatment would improve total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), waking after sleep onset, early morning awakening (EMA), and number of bouts awake. In addition, we conducted several subgroup analyses. In 1 subgroup analysis, the aim was to investigate the effects of pain treatment on different sleep outcomes for patients with poor sleep at baseline, defined as SE < 85%. In a second analysis, the aim was to investigate if pain treatment improved sleep more in patients who were in pain at baseline, defined as Mobilization-Observation-Behaviour-Intensity-Dementia-2 Pain Scale (MOBID-2) score ≥ 3. In a final analysis, we aimed to investigate if there were any differences within the active treatment group, ie, between patients receiving active buprenorphine and active placebo, respectively.

| METHODS
This study used data collected in the period from 1 week before the intervention until 1 week after the intervention. The study is part of a 13-week, multicenter, parallel-group, double-blind, placebo-con-  Table 1. At the participating NHs, the researchers were granted access to patient medical records to perform prescreening. In cases where no recent (<14 days old) blood analyses (electrolytes, hemoglobin, serum creatinine, and serum alanine aminotransferase) were available, new analyses were requisitioned. Patients who were not excluded in the medical record review were screened for depression by using the Cornell Scale for Depression in Dementia (CSDD) 27 and for dementia by using the Mini-Mental State Examination (MMSE). 28 If the inclusion criteria (CSDD ≥ 8 and MMSE < 20) were fulfilled, the patient was reassessed after written consent had been given. A drop from ≥8 to ≥6 in CSDD was permitted between screening and baseline. If a patient fulfilled all of the inclusion criteria and none of the exclusion criteria, and inclusion and study treatment were approved by the physician responsible for the patient, the patient was enrolled in the study (see the flow chart in Figure 1 for an overview of enrolment and reasons for exclusion).
A fixed-dose regimen was used in the study period. The patients were offered a 1-g tablet/placebo at breakfast, lunch, and supper (8 a.m. noon and 6 p.m.). The patients received a stepwise pain treatment, in which those who were taking paracetamol ≤1 g/day prior to inclusion were allocated to paracetamol tablets/placebo tablets. The study treatment was prescribed in addition to the basic dose. Patients who were taking nonopioid analgesics/paracetamol >1 g/day, and/or NSAID/buprenorphine, but had difficulty with swallowing tablets were assigned to the buprenorphine/placebo transdermal system. In line with the administrative guidelines, the buprenorphine transdermal patch/placebo patch was changed on a fixed day every week. For patients who were taking buprenorphine transdermal 5 μg/h prior to inclusion, the study treatment was given as an additional 5-μg/h transdermal patch (active or placebo). After inclusion, all patients continued their usual medical treatment (including any regular or "as needed" [PRN] analgesic). To ensure stability and control in the study, the clinicians were advised to keep doses of psychotropic and analgesic drugs unchanged during the study period. If any clinical changes occurred, eg, new conditions or injuries, they were to be treated adequately. All withdrawals and reasons were registered.
All sleep-related outcomes were assessed with Actiwatch Spectrum (Philips Respironics). Activity was registered continuously for 14 consecutive days, during which the intervention started on day 8. Data were thus recorded for all sleep parameters for duration of 1 week before and 1 week after the study treatment commenced.
The actigraphs were placed on the dominant/mobile wrist. To enable better scoring of the patients' actual time spent in bed, the NH staff were instructed (verbally and written) to register bedtimes and rising times by pushing the event button on the actigraph (light off/lights on).

Key points
• Sleep disturbances are very common among people with dementia.
• Compared with placebo, pain treatment improved sleep in NH patients with dementia and depression, as measured by actigraphy.
• Sleep, pain, and depression in NH patients should be evaluated systematically, and pain treatment should be considered as a potentially beneficial treatment.
The Actiware 6 (Respironics) was used for sleep scoring. Sensitivity was set to medium, and sleep/waking status was determined for each 1-minute epoch. A trained technician scored all the activity protocols.
A standardized hierarchical approach was used to set rest intervals for the actigraphy data, using (1) event markers when possible, or (2) light and activity data, or (3) 27 The assessment was conducted by using only information provided by NH staff members who knew the resident very well.
Pain was assessed by the MOBID-2, a validated staff-administered instrument for measuring pain in people with advanced dementia. 25 The instrument provides a total score based on all of the observations ranging from 0 to 10, where 10 represents the worst possible pain. 25 A score of ≥3 has been used as a cut-off to indicate clinically relevant pain. 25 Cognitive function was assessed by using the validated MMSE. 28 The MMSE is a brief, cognitive screening test with a 30-point scale that consists of 20 tasks and was developed to distinguish potential dementia from normal functioning. 29 Five patients started the MMSE screening and scored very poorly and subsequently withdrew from the MMSE screening. This led to missing data. For these patients, cognitive function was assessed by proxy through conversations with primary doctors and nurses as an alternative to MMSE screening.
The patients were randomly allocated to each arm in a 1:1 ratio, using computer-generated random numbers. The randomization list was produced by a statistician, without any involvement of the research team. There was no use of stratification factors. The research team was provided with a blinded, sequential list of pack identification numbers, and the patients were consecutively assigned to the next pack number in the list upon inclusion. The study was double-blinded, and all researchers, patients, and NH staff were masked regarding the group allocation.
Descriptive statistics were calculated for all relevant variables.
Comparisons of sleep parameters pre-and posttreatments were performed as a mixed within-between subjects ANOVA (placebo versus active treatment and pretreatment versus posttreatment). Differences between pre-and posttreatments within each treatment group were assessed with paired t tests for each of the experimental groups separately. Furthermore, we conducted additional 2 × 2 mixed within-between subjects ANOVA analyses. One of these analyses investigated patients who had sleep disturbances at baseline, defined as SE < 85%, 30 and compared the effect of active and placebo treatments for those patients. A second analysis compared the effect of the treatments for a subgroup of patients whose MOBID-2 score was ≥3, ie, patients who had pain at baseline.

| RESULTS
In total, 2323 patients were screened for eligibility, of whom 162 were eligible to participate as part of the broader study. The final sample of the actigraphy subproject included 106 participants (see Figure 1). Of the 106 patients, 49 were randomly assigned to the placebo group and 57 to the active treatment group. In the active treatment group, 2 patients dropped out due to their reaction to the treatment. In the total sample of patients with actigraphs, the mean age was 85.5 years (SD = 7.3), 76% were female, the mean CSDD score was 11.2 (SD = 3.7), the mean MMSE score was 7.6 (SD = 6.0), the mean MOBID-2 score  Table 2.
In the total sample (n = 106), SE, SOL, and EMA all improved for the active treatment group compared with the placebo group (see Table 2). The analysis of the treatment for the subgroup of patients with preexisting sleep disturbances (SE < 85%) identified at baseline    A mixed within-between subjects 2 × 2 ANOVA comparing the placebo and active treatments for the patients with pain (MOBID-2 score ≥ 3).
**Post = 1 to 7 days active/placebo treatment. A mixed within-between subjects 2 × 2 ANOVA comparing the buprenorphine and paracetamol groups for the patients who received active treatment.
(n = 89) confirmed the main effects (see Table 3). In addition, TST improved significantly for the active treatment group compared with the placebo group (see Table 3). Interestingly, when analyzing the effect of treatment for the subgroup of patients who experienced pain at baseline (n = 46), we found no significant differences between active and placebo treatment for any of the sleep outcomes (see Table 4). In a final analysis, we investigated if there were any differences within the active treatment group (see Table 5). We found a significant increase in TST for patients who received active buprenorphine compared with those who received active paracetamol (see Table 5).

| DISCUSSION
The results of the present study gave partial support to our hypothe-

| LIMITATIONS
Our study has some limitations. The use of multiple sleep-related outcome measures is a potential study limitation, which can potentially lead to type I errors. We do not correct for multiple comparisons in our study. However, a simple Bonferroni correction would be overly conservative and would increase the risk of type II errors. 36 Therefore, we urge the reader to take the lack of such correction into account in the interpretation of the findings of the study.
In actigraphy recordings, immobility of the participants marks the beginning of the sleep period. Sleep onset latency has been particularly difficult to ascertain with actigraphy, because patients may just be lying still in bed and it can be recorded as sleep. 37 In addition, previous studies show that actigraphy is less precise in differentiating between sleep and wakefulness when SE is reduced. [37][38][39] Both of these factors may lead to an overestimation of sleep.
The comprehensive combination of inclusion and exclusion criteria made it difficult to recruit patients to the study. Of the 2323 patients screened for potential eligibility, a total of 895 did not have depression according to CSDD. In addition, there has been a change in the prescription of pain medication for NH patients during the last decade that influenced inclusion. Sandvik et al 40  This renders the generalizability of our study questionable because our sample may not be representative for the general NH population.
Furthermore, the subgroup analysis is based on a low number of respondents, which implies that we cannot exclude type 2 errors.
Another central limitation in the study is that it does not include pain assessment during the week after the intervention. As a consequence, we do not know how pain progressed after the intervention. Future research should include a larger sample of patients with pain at baseline to account for a large attrition rate and follow-up with pain assessments after the intervention is given. A further limitation of our study was that we did not conduct a priori power analyses, which would have been beneficial for assessing if the statistical tests have sufficient power. However, our sample is similar to or larger than samples in comparable studies. The reader should, however, interpret the findings with caution, in particular for the subgroup analyses with lower sample sizes.

| CONCLUSION
Compared with placebo, pain treatment improved actigraphy-measured sleep in NH patients with dementia and depression. This implies that sleep, pain, and depression in NH patients should be evaluated critically and that pain treatment should be considered as a potentially beneficial treatment for residents with poor sleep. Future research should focus on the underlying mechanisms and explore the subjective value of such treatment for the NH patient.