Currow, D.C., Plummer, J.L., Cooney, N.J., Gorman, D., & Glare, P.A. (2007). A randomized, double-blind, multi-site, crossover, placebo-controlled equivalence study of morning versus evening once-daily sustained-release morphine sulfate in people with pain from advanced cancer. Journal of Pain Symptom Management, 34, 17–23.

Each participant took one placebo and a 24 hour-dose of sustained-release morphine daily, 12 hours apart. For one week participants took the active dose in the morning; for one week they took the active dose in the evening. For each participant, the study lasted 17 days. The time of administration was randomized in double-blind manner. The study was completed over 12 months.

The sample was composed of 42 people with advanced cancer who were suffering from opioid-responsive pain and who were taking stable opioid doses. Twenty-six of the 42 completed the study, providing adequate power (80%) for analysis.

Patients in the sample were in five regional palliative care programs in Australia.

Randomized multisite double-blind, placebo-controlled crossover equivalence and effectiveness study that comprised broad inclusion criteria

• 100 mm visual analog scale (VAS), to measure pain during the last two days (steady state) in both arms of the study (Investigators collected pain scores every four hours while the patient was awake.)
• VAS and categorical scales, to measure other pain parameters, quality of sleep, nausea, vomiting, constipation, confusion, and somnolence

• Mean VAS: morning dosing = 16 mm; evening dosing = 14 mm (p = 0.76, difference of adjusted means = 2 mm, 95% CI –2, 6). Data indicate no significant differences in pain control, pain during day, pain-disturbing sleep, or with breakthrough medication use.
• In regard to nausea, authors noted a significant treatment difference but no period or sequence effect. Authors observed no difference, associated with morning or evening administration of morphine, in use of antiemetics.
• Authors observed no significant treatment, period, or sequence effects regarding side effects other than nausea.
• Ten participants indicated a preference for a time period; eight preferred evening administration of morphine.

This study suggests that once-daily sustained-release morphine can be administered, to people with significant opioid-responsive pain and advanced cancer, with equal overall effect in the morning or the evening.

The findings regarding nausea may be a statistical rather than a clinical finding—a Type I error. Of the 42 randomized patients, 16 withdrew. Nine withdrew from the am-pm arm and seven withdrew from the pm-am arm. In the am-pm arm, three cited efficacy as the reason for withdrawal. In the pm-am arm, one cited efficacy as the reason for withdrawal. The difference in withdrawals, am-pm vs. pm-am, was not significant (p = 0.97). Authors questioned whether the study should have been powered to show a smaller difference, though the patients were already optimized on opioids.

Patients in the study population suffered typical end-of-life pain. Future researchers should define a subgroup (e.g., those with poorly controlled pain, those on high doses of opioids, those who are still trying to function at work). Other than in regard to nausea, secondary measures indicated no differences relating to administration time. Future research could assess effects on sleep patterns, quality of life, activities of daily living, and fatigue.