MORPHINE-6-GLUCURONIDE CONCENTRATIONS AND OPIOID-RELATED SIDE-EFFECTS- A SURVEY IN CANCER-PATIENTS

The active morphine metabolite, morphine-6-glucuronide (M-6-G), may co ntribute to both the analgesia and the adverse effects observed during morphine (MOR) therapy. To evaluate the relationship between M-6-G an d adverse effects, we measured steady-state plasma concentrations of M OR and M-6-G and concurrently noted the presence or absence of moderat e to severe cognitive impairment or myoclonus in 109 cancer patients w ho were receiving either oral (n = 71) or parenteral (n = 38) morphine . MOR and M-6-G plasma concentrations were determined by HPLC with ele ctrochemical detection. The presence of cognitive impairment or myoclo nus was analyzed in relation to molar M-6-G/MOR ratio, age, morphine d ose, the use of other centrally acting drugs, renal function (blood ur ea nitrogen (BUN) and serum creatinine), hepatic function (serum bilir ubin, serum glutamic oxalacetic transaminase (SGOT), and alkaline phos photase) and serum lactate dehydrogenase (LDH). The patient population consisted of 60 women and 49 men. The mean age was 51.5 years (range: 10-85 years). The mean morphine dose (total dose-prior 48 h) was 486 mg (range: 40-4800 mg) for the oral group and 931 mg (range: (10-9062 mg) for the parenteral group. The mean molar M-6-G/ MOR ratios were 6. 1 (SD: 18.2; range: 0.01-153.3) for the oral treatment group and 2.7 ( SD: 4.16; range: 0.05-23.8) for the parenteral treatment group. Overal l, the M-6-G/MOR ratio demonstrated a moderate but significant correla tion with BUN (r = 0.4; P < 0.001) and creatinine (r = 0.45; P < 0.001 ) levels, but not with the other clinical variables examined. Although the prevalence of myoclonus among patients receiving oral morphine wa s 3-fold higher than those receiving parenteral morphine (P < 0.05), m ultivariate analyses demonstrated that neither myoclonus nor cognitive impairment was significantly associated with M-6-G/MOR ratio when adj usted for other variables. In contrast, there were significant associa tions between increasing age, elevated bilirubin or LDH levels, and th e presence of cognitive impairment. Finally, analysis of a small subgr oup of patients with very high M-6-G concentrations (> 2000 ng/ml) and presenting with either respiratory depression or obtundation, suggest ed that elevated M-6-G levels were associated with these severe advers e effects primarily in the setting of metabolic dysfunction. Together, these data confirm the previously reported correlation between deteri orating renal function and increasing M-6-G/MOR ratio, but do not supp ort the conclusion that increasing ratio alone is a determinant of two prevalent opioid-related adverse effects: myoclonus and cognitive imp airment.