1 The pharmacokinetics, cardio-respiratory effects and analgesic effects of intravenous morphine-6-glucuronide were studied in 20 cancer patients with pain. Four different dose levels (0.5, 1, 2, and 4 mg 70 kg-') were studied. Plasma concentrations of morphine-6-glucuronide were measured for 12 h after dosing. Pulse rate, respiratory rate and blood pressure were monitored, and pain relief was measured using two rating scales and a visual analogue scale. 2 The mean elimination half-life (± s.d.) of morphine-6-glucuronide was 3.2 ± 1.6 h.The mean AUC standardised to a dose of 1 mg 70 kg-' was 390 ± 263 nmol 1-1 h.Mean morphine-6-glucuronide clearance was 96 ± 38 ml min-'. There was a direct relationship between morphine-6-glucuronide plasma clearance and calculated creatinine clearance (r = 0.81, P < 0.001). 38 ± 22% of the dose of morphine-6-glucuronide was recovered unchanged in the urine in 24 h. No morphine or morphine-3-glucuronide was detected in the plasma or urine of any patient after morphine-6-glucuronide treatment. 3 Morphine-6-glucuronide exerted a useful analgesic effect in 17/19 assessable patients for periods ranging between 2 and 24 h. No correlation was observed between dose or plasma morphine-6-glucuronide concentrations, and duration or degree of analgesia.No clinically significant changes in cardio-respiratory parameters were observed. No patients reported sedation or euphoria. Nausea and vomiting were notably absent in all cases. 4 Morphine-6-glucuronide is an effective and well-tolerated analgesic. It is likely that the majority of the therapeutic benefit of morphine is mediated by morphine-6-glucuronide. The absence of nausea and vomiting after morphine-6-glucuronide treatment suggests that this agent may offer significant advantages over intravenous morphine, though oral morphine is likely to remain the mainstay of narcotic analgesic therapy.

Summary The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu 1, mu 2 and delta receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nm and 82 nm for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu or delta receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.Morphine is one of the commonest drugs prescribed by cancer physicians and is an effective potent analgesic. However one or more of the side effects of constipation, nausea and vomiting, and sedation are encountered frequently (Jaffe & Martin, 1991). Respiratory depression is a less common problem but is the most potentially dangerous toxicity. An analgesic with equivalent potency but lower toxicity would therefore be of particular use.The major metabolic products of morphine are morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G). Although M3G is devoid of analgesic activity, M6G is now thought to play a major role in mediating the analgesic effect of morphine (Osborne et al., 1986;Hanks et al., 1987;Hoskin & Hanks, 1990 Pasternak, 1981). This model suggests there is a common receptor labelled by either a prototypic delta agonist such as DADLE (D-Ala2, D-Leu5-enkephalin) or with a mu agonist such as morphine which has high affinity for morphine. This they termed the mu 1 receptor. The receptor labelled with a mu agonist which possessed a lower affinity they termed the mu 2 receptor. Similarly the receptor labelled with a delta agonist possessing lower affinity for morphine they termed the true delta receptor.It has been postulated that several of the adverse affects including respiratory depression of morphine are due to activation of the mu 2 or lower affinity mu opioid receptor (Pasternak & Wood, 1986). Using this classification it was therefore hypothesised that M6G has a lower affinity for the mu 2 receptor than morphine at least partially explaining the lower apparent toxicity seen in man. The aim of the current study was

1 The emetic potencies of morphine and its metabolite morphine 6-glucuronide have been determined in the ferret by constructing dose-response curves for mean total retches and vomits for subcutaneous doses of 0.05 mg kg-' to 5 mg kg-'. Morphine 6-glucuronide induced retching and vomiting at lower doses than morphine and at a maximal dose induced more retching and vomiting than morphine. 2 The emesis induced by both morphine and morphine 6-glucuronide was abolished by the preadministration of naloxone (0.5 mg kg-' s.c.). 3 The 5-HT3 receptor antagonists granisetron and ondansetron (1 mg kg-', s.c.) failed to abolish or reduce emesis induced by either compound. 4 At a high-dose (5 mg kg-'), morphine but not morphine 6-glucuronide failed to induce emesis and abolished the emesis induced by the cytotoxic drug, cyclophosphamide (200mgkg-', i.p.). 5 Preliminary pharmacokinetic studies of intravenous and subcutaneous morphine and morphine 6-glucuronide revealed that morphine 6-glucuronide accounts for less than 1% of the metabolic product of morphine in the ferret. Peak plasma levels of the two compounds after their subcutaneous administration were obtained within 10min. The metabolic profile of morphine was not dose-dependent. There was no relationship between plasma level and emetic response for either compound.

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