Efficacy and Safety of Analgesic Treatment for Depression in People with Advanced Dementia: Randomised, Multicentre, Double-Blind, Placebo-Controlled Trial (DEP.PAIN.DEM)

Abstract

Background: Chronic pain and depression often co-occur, and pain may exacerbate depression in people with dementia.

Objective: The objective of this study was to assess the efficacy and safety of analgesic treatment for depression in nursing home patients with advanced dementia and clinically significant depressive symptoms.

Methods: We conducted a multicentre, parallel-group, double-blind, placebo-controlled trial in 47 nursing homes, including 162 nursing home patients aged ≥ 60 years with dementia (Mini-Mental State Examination ≤ 20) and depression (Cornell Scale for Depression in Dementia ≥ 8). Patients were randomised to receive active analgesic treatment (paracetamol or buprenorphine transdermal system) or identical placebo for 13 weeks. The main outcome measure was the change in depression (Cornell Scale for Depression in Dementia) from baseline to 13 weeks, assessed using linear mixed models with fixed effects for time, intervention and their interaction in the models. Secondary outcomes were to assess whether any change in depression was secondary to change in pain (Mobilisation-Observation-Behaviour-Intensity-Dementia-2 Pain Scale) and adverse events.

Results: The mean depression change was - 0.66 (95% confidence interval - 2.27 to 0.94) in the active group (n = 80) and - 3.30 (- 4.68 to -1.92) in the placebo group (n = 82). The estimated treatment effect was 2.64 (0.55-4.72, p = 0.013), indicating that analgesic treatment had no effect on depressive symptoms from baseline to 13 weeks while placebo appeared to ameliorate depressive symptoms. There was no significant reduction in pain in the active treatment group (paracetamol and buprenorphine combined) vs. placebo; however, a subgroup analysis demonstrated a significant reduction in pain for paracetamol vs. placebo [by - 1.11 (- 2.16 to - 0.06, p = 0.037)] from week 6 to 13 without a change in depression. Buprenorphine did not have significant effects on depression [3.04 (- 0.11 to 6.19), p = 0.059] or pain [0.47 (- 0.77 to 1.71), p = 0.456] from 0 to 13 weeks. Thirty-five patients were withdrawn from the study because of adverse reactions, deterioration or death: 25 (31.3%) during active treatment [23 (52.3%) who received buprenorphine], and ten (12.2%) in the placebo group. The most frequently occurring adverse events were psychiatric (17 adverse reactions) and neurological (14 adverse reactions).

Conclusion: Analgesic treatment did not reduce depression while placebo appeared to improve depressive symptoms significantly by comparison, possibly owing to the adverse effects of active buprenorphine. The risk of adverse events warrants caution when prescribing buprenorphine for people with advanced dementia.

Trial registration: ClinicalTrials.gov NCT02267057 (registered 7 July, 2014) and Norwegian Medicines Agency EudraCT 2013-002226-23.

Conflict of interest statement

Conflict of interest

Clive Ballard has received consultancy honoraria from Acadia, Lundbeck, Heptares, Roche, Lilly, Otsuka, GSK, Pfizer and Synexus; speaker fees from Lundbeck, Lilly and Otsuka; and grant support from Acadia Pharmaceuticals 2014–2017. Ane Erdal, Elisabeth Flo, Dag Aarsland, Dagrun D. Slettebo and Bettina S. Husebo have no conflicts of interest directly relevant to the content of this article. The sponsors had no influence on the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Prior to enrolment, the trial was registered in ClinicalTrials.gov (NCT02267057), and was approved by the Norwegian Medicines Agency (EudraCT 2013-002226-23) and the Regional Committee for Medical and Health Research Ethics (REC-West 2013/1474).

Consent to participate

Informed consent was obtained from all individual participants included in the study. Verbal and written informed consent was obtained in direct conversation with all patients who were deemed to have medical decision-making capacity. If participants did not have the capacity to give consent, the participant’s next of kin or legal guardian provided informed consent in accordance with ethics committee requirements and Norwegian legislation at the time of the study. We expected that patients with Mini-Mental State Examination scores ≥ 16 would be able to give informed consent [41], but nevertheless we included the closest relatives of all patients in a discussion about consent and provided written information about the trial to ensure full transparency. To empower those patients with a reduced ability to consent, we attempted to adjust the information procedure to enable them to understand the purpose and implications of study participation. We included a verbal and written statement assuring that their decision to give consent would not affect the quality of the medical care provided to the patient. Even though informed consent had been given, all participants were free to decline drug administration and other procedures at any time during the trial, irrespective of cognitive state.

Figures

Fig. 1

Trial profile. Each patient was categorised by the first exclusion criterion that was fulfilled, after which no more assessments were made. CSDD Cornell Scale for Depression in Dementia, MMSE Mini-Mental State Examination, NHs nursing homes

Fig. 2

Change in depressive symptoms (Cornell Scale for Depression in Dementia) throughout the study period. CI confidence interval, MMSE Mini-Mental State Examination, MOBID-2 Mobilisation-Observation-Behaviour-Intensity-Dementia-2 Pain Scale

Fig. 3

Change in pain intensity [Mobilisation-Observation-Behaviour-Intensity-Dementia-2 Pain Scale (MOBID-2)] throughout the study period in patients with moderate-to-severe pain at baseline (MOBID-2 ≥ 3). CI confidence interval