Melatonin to prevent delirium in patients with advanced cancer: a double blind, parallel, randomized, controlled, feasibility trial

Abstract

Background Delirium is highly problematic in palliative care (PC). Preliminary data indicate a potential role for melatonin to prevent delirium, but no randomized controlled trials (RCTs) are reported in PC. Methods Patients aged ≥18 years, with advanced cancer, admitted to an inpatient Palliative Care Unit (PCU), having a Palliative Performance Scale rating ≥ 30%, and for whom consent was obtained, were included in the study. Patients with delirium on admission were excluded. The main study objectives were to assess the feasibility issues of conducting a double-blind RCT of exogenous melatonin to prevent delirium in PC: recruitment, retention, procedural acceptability, appropriateness of outcome measures, and preliminary efficacy and safety data. Study participants were randomized in a double-blind, parallel designed study to receive daily melatonin 3 mg or placebo orally at 21:00 over 28 days or less if incident delirium, death, discharge or withdrawal occurred earlier. Delirium was diagnosed using the Confusion Assessment Method. Efficacy endpoints in the melatonin and placebo groups were compared using time-to-event analysis: days from study entry to onset of incident delirium. Results Over 16 months, 60/616 (9.7%; 95% CI: 7.5–12.4%) screened subjects were enrolled. The respective melatonin (n = 30) vs placebo (n = 30) outcomes were: incident delirium in 11/30 (36.7%; 95%CI: 19.9–56.1%) vs 10/30 (33%; 95% CI: 17.3–52.8%); early discharge (6 vs 5); withdrawal (6 vs 3); death (0 vs 1); and 7 (23%) vs 11 (37%) reached the 28-day end point. The 25th percentile time-to-event were 9 and 18 days (log rank, χ2 = 0.62, p = 0.43) in melatonin and placebo groups, respectively. No serious trial medication-related adverse effects occurred and the core study procedures were acceptable. Compared to those who remained delirium-free during their study participation, those who developed delirium (n = 21) had poorer functional (p = 0.036) and cognitive performance (p = 0.013), and in particular, poorer attentional capacity (p = 0.003) at study entry. Conclusions A larger double-blind RCT is feasible, but both subject accrual and withdrawal rates signal a need for multisite collaboration. The apparent trend for shorter time to incident delirium in the melatonin group bodes for careful monitoring in a larger trial. Trial registration Registered on July 21st 2014 with ClinicalTrials.gov: NCT02200172.

Outcomes and measures of delirium interventional studies in palliative care to inform a core outcome set: A systematic review

“…The second most frequent was delirium incidence 28,31,34,36 with a key issue the variability in assessment frequency and measurement approach. 34 The non-delirium outcomes were varied, most commonly mortality, presence and degree of agitation (predominantly measured using the Richmond Agitation-Sedation Scale), and adverse effects of neuroleptics.…”

“…Delirium incidence was determined using a screening tool (Delirium Observation Screening Scale, Confusion Rating Scale, or Nursing Delirium Screening Scale [one study each]) at least daily, followed by a diagnostic assessment using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders -version IV) criteria or the CAM (Confusion Assessment Method) diagnostic algorithm. 28,31,34,36 Measurement for delirium-specific outcome domains generally commenced on admission or at baseline, with highly variable timing of measurement (first measurement timing ranged from 2 hours after intervention to day 4). Two studies did not report measurement frequency.…”

“…The authors declare that there is no conflict of interest. 22,23,25 Open label RCT 24,26 Clustered RCT 27 26 Single blind RCT 29 Historical control study 30 Before and after study 31 Non-randomised study Palliative care unit or inpatient hospice 25,27,28,30,31 Hospital palliative care 24,[32][33][34] Palliative care unit/hospice and hospital 23,26,29 Community palliative care 22…”

“…Direct care [22][23][24][25][26][27][28][29][30][31]34 11 Not reported 32,33 Disciplines involved in service Medical and nursing…”

“…Pharmacological to prevent and/or treat delirium 23-25, 28, 29, 32-34 Bundle to prevent and/or treat delirium #22, 26, 30, 31 Non-pharmacological to prevent and/or treat delirium 27 31 Davies, 2018 26 Lawlor, 2020 28 Van de Vorst, 2020 29 Arai, 2013 34 Davies, 2018 26 --Other symptoms (9) Hui, 2017 25 Davies, 2018 26 Bruera, Lin, 2008 24 Lawlor, 2020 24 Hui, 2017 25 ---…”