Oral morphine in cancer pain: influences on morphine and metabolite concentration

Abstract

One hundred fifty-one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G and M6G) were measured. The ratio of plasma morphine to metabolites was not affected by dose. Generalized linear interactive modeling analysis using morphine dose, age, sex, renal and hepatic dysfunction, and concomitant medication as explanatory variables accounted for 70% of the variance in plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Increasing morphine dose was a significant factor for increased plasma concentrations of morphine, M3G, and M6G. Other significant factors were: age greater than 70 years (increased M3G and M6G plasma concentrations), plasma creatinine greater than 150 mumol/L (increased M3G and M6G plasma concentrations), male sex (decreased morphine and M6G plasma concentrations), raised creatinine plus coadministration of tricyclic antidepressants (increased M3G plasma concentrations), ranitidine (increased morphine plasma concentrations), and raised creatinine plus coadministration of ranitidine (increased M6G plasma concentrations).

Morphine or Oxycodone in Cancer Pain?

“…The ratio of morphine to M6G concentrations ranged from 1 : 5.5 to 1 : 6.7, which is in agreement with previous studies (15,16).The high number of patients with undetectable plasma morphine concentrations prior to the morning drug dosing is probably due to the low daily CR opioid dose in these patients (mean daily morphine dose 75 mg) since three of these patients had very low oxycodone concentrations, too. In previous clinical studies of cancer patients, it has been found that even low daily doses of CR morphine have resulted in measurable plasma morphine concentrations (17,18) but the assay limit for morphine has been lower (1 ng:ml) (19) than in the present study (5 ng:ml).…”

“…In cancer patients, however, the steady-state plasma morphine levels may be affected by the disease or other factors (e.g. chronic constipation) that can in uence the absorption of CR tablets (15).…”

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

“…No significant correlation was found between the 6-glucuronidation of ethylmorphine and morphine. The ratios of morphine and its glucuronides were similar to those observed after administration of morphine [31,32]. No difference was found between subjects with high or low urinary recoveries of morphine plus morphine-glucuronides with respect to the morphine-3-glucuronide/morphine-6-glucuronide ratio.…”

Morphine metabolism in neonates and infants.

“…In this respect the ratio of M3G:M6G found in neonates is markedly lower than previously demonstrated in adults or children. In adults, chronic oral morphine treatment produces variable plasma ratios of M3G:M6G, with reported mean ratios of 10:1 (Hand et al, 1987), 6:1 and 5:1 (McQuay et al, 1990). A study of a single intravenous dose of morphine in adults found a plasma ratio of M3G:M6G of 8.5 (Hasselstrom et al, 1990).…”