Accumulation of active (toxic) metabolites of opioids might explain cases of opioid toxicity when high doses are used for long periods of time. Other mechanisms of late toxicity of opioids may be found at the receptor level. Whatever the cause, a change of opioids using equianalgesic doses can be expected to improve symptoms of toxicity in some patients, while maintaining pain control. We reviewed the experience with this technique in patients admitted to the Palliative Care Unit of the Edmonton General Hospital. Of 191 patients, 80 underwent opioid rotation (OR) for cognitive failure, hallucinations, myoclonus, nausea and vomiting, local toxicity, and persistent pain. These leading symptoms improved in 58/80 patients (73%, P < 0.01). Pain control, as measured on a 10-cm visual analogue scale (VAS), improved from 4.4 +/- 2.3 to 3.6 +/- 2.0 (P < 0.004) at a dose significantly lower than that predicted to be equianalgesic (577 +/- 1535 mg before OR versus 336 +/- 593 mg after OR, P < 0.04). We conclude that symptoms of opioid toxicity can be relieved by OR, and that a choice of two or three different opioids is necessary to obtain satisfactory long-term pain control.