Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain

BACKGROUND: In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled.

METHODS: Assessments for pain, sedation and other morphine induced side effects were made several times for 19 cancer patients treated with changing doses of oral sustained release (SR) morphine and twice for 17 non-cancer patients treated with stable doses of SR morphine. Blood samples were obtained simultaneously and analysed for contents of morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC).

RESULTS: Significant correlations were found between the daily dose of SR morphine and plasma morphine (r = 0.469, p < 0.01), plasma M-6-G (r = 0.677, p < 0.01), and plasma M-3-G ((r = 0.827, p < 0.01), in the cancer patient group, but only between the daily dose of SR morphine and plasma M-3-G (0.662, p < 0.01) and plasma M-6-G (0.571, p < 0.01) in the non-cancer patient group. Normalised M-3-G/M and M-6-G/M ratios for the cancer patient group were independent of duration of treatment and daily dose of SR morphine. Likewise in the non-cancer patient group duration of treatment did not influence the metabolite ratios. Correlations between pain score and plasma morphine, M-6-G and M-6-G/M were weak in the cancer patient as well as in the non-cancer patient group making it impossible to draw any conclusion regarding the potential contributory analgesic effect of M-6-G. Dryness of the mouth was the most frequent adverse effect reported in the non-cancer as well as the cancer patient group. In the latter group patients complaining of dryness of the mouth had significantly higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. This difference persisted (or was close to significance) when excluding patients receiving antidepressants.

CONCLUSION: In the cancer patient group neither dose nor treatment period seems to influence morphine glucuronidation. Likewise in the non-cancer patient group receiving stable doses of morphine duration of treatment does not seem to influence morphine glucuronidation. Dryness of the mouth was positively correlated to high plasma concentrations of morphine and M-6-G.