Problem 4.3
An opioid positive control group
in chronic cancer pain

Say that one wishes to study the effects of Drug L, another potential enhancer of opioid analgesia, in patients with chronic pain caused by slow-growing metastatic disease to bone. Patients have been expertly treated and they are already on the dose of oral morphine that best balances pain relief and side effects. As the pain textbooks advise, 75% of their total daily dose is being given as a sustained-release preparation, (MS-SR) and 25% as supplementary, as-needed immediate-release doses (MS-IR).

Devising the test drug and placebo treatments is relatively easy. One could just add daily capsules of a 24-hour release preparation of Drug L or placebo to patients’ current morphine regimen. For a positive control (MS-SR column), one might add an additional amount of morphine to the placebo treatment, e.g. by substituting sustained-release morphine capsules whose strength is increased by 50%. Expected starting doses for a patient originally on MS-SR, 90 mg/day, and MS-IR, 30 mg/day, are shown in the table below:

Group MS-SR MS-IR Test drug Placebo 90 mg/day 30 mg/day placebo Drug L 90 mg/day 30 mg/day Drug L Positive control 135 mg/day 30 mg/day placebo

Question 4.3.1

What is a potential pitfall of this design?

Some patients in the positive control group may develop adverse reactions to opioids, because their total dose will be higher than their baseline dose of 120 mg/day, which had been optimized before study entry.

A positive control intervention that increases the sustained-release opioid dose by 50% may not be large enough to detect.