The Circadian Rhythm of Breakthrough Pain Episodes in Terminally-ill Cancer Patients

Opioid therapy must be adjusted to the rhythm of a cancer patient's pain to ensure adequate symptom control at the end of life (EOL). However, to-date no study has explored the rhythm of breakthrough pain (BTP) episodes in terminally-ill cancer patients. This prospective longitudinal study was aimed at verifying the existence of a circadian rhythm of BTP episodes in terminally-ill cancer patients. Consecutive adult cancer patients at their EOL treated with long-acting major opioids to control background pain (Numeric Rating Scale ≤ 3/10) were recruited from two Italian palliative care services. Using a personal diary, patients recorded the frequency and onset of BTP episodes and the analgesic rescue therapy taken for each episode over a 7-day period. Rhythms identified in BTP episodes were validated by Cosinor analysis. Overall, 101 patients were enrolled; nine died during the study period. A total of 665 BTP episodes were recorded (average of 7.2 episodes, mean square error 0.8) per patient, with 80.6% of episodes recorded between 8:00 a.m. and 12:00 a.m. At Cosinor analysis, a circadian rhythm of BTP episodes was observed, with a Midline Estimating Statistics of the Rhythm (MESOR) of 1.5, a double amplitude of 1.8, and an acrophase at 12:30 p.m. (p < 0.001). Oral morphine was the most frequent analgesic rescue therapy employed. In terminally-ill cancer patients, BTP episodes follow a circadian rhythm; thus, tailoring the timing of opioid administration to this rhythm may prevent such episodes. This circadian rhythm of BTP episodes in terminally-ill cancer patients should be confirmed in larger samples.