Background: Ultram [tramadol hydrochloride (HCl)] is a centrally acting analgesic that is widely prescribed for the treatment of moderate to moderately severe chronic pain. Although tramadol is generally well tolerated, some patients discontinue use early in the course of treatment because of nausea and vomiting.
Objective: To investigate the effect of three initial titration rates of tramadol HCl on the incidence of discontinuation due to nausea and/or vomiting in patients who previously did not tolerate tramadol HCl.
Method: A multicentre, outpatient, randomized double-blind study was conducted, comprised of two phases: a 14-day open-label run-in phase and a 28-day double-blind phase. In the run-in phase the dose of tramadol was titrated over 4 days to the target of 200 mg/day. Patients who discontinued tramadol HCl due to nausea and/or vomiting in the open-label phase were eligible to enter the 28-day double-blind phase after a 10-day wash-out. Patients were randomized to one of three groups using a 10-, 16- or a 13-day titration schedule in order to achieve a target dosage of either 200 mg/day (10- and 16-day titration groups) or 150 mg/day (13-day titration group). The number of discontinuations due to nausea and/or vomiting in each group were compared.
Results: Significantly fewer patients (22%) discontinued because of nausea and/or vomiting in the 13- and 16-day titration groups compared to the 10-day group (P=0.008 and P=0.006, respectively). The time to discontinuation was also significantly delayed in the 13- and 16-day groups compared to the 10-day group (P=0.006 and P=0.007, respectively). The outcome of the 13-day titration to 150 mg/day was essentially the same as that of the 16-day titration to 200 mg/day, suggesting that this is a true rate effect rather than being dose related.
Conclusion: This study demonstrated that a slower titration rate of tramadol HCl improves tolerability in patients who previously discontinued therapy due to nausea and/or vomiting. This study also demonstrates that the rate of titration of tramadol HCl rather than the target dose is the major determinant of tolerability.