Systematic review of factors affecting the ratios of morphine and its major metabolites

Pain 74 (1998) 43–53

Systematic review of factors affecting the ratios of morphine and its major metabolites Clara C. Faura a ,*, Sally L. Collins b, R. Andrew Moore b, Henry J. McQuay b a

Departamento de Farmacologia, Instituto de Neurociencias, Universidad Miguel Herna´ndez, Campus de San Juan, 03080 Alicante, Spain Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ, UK

b

Received 23 May 1997; revised version received 28 August 1997; accepted 4 September 1997

Abstract In a systematic review of 57 studies with information on 1232 patients we examined the effect of age, renal impairment, route of administration, and method of analysis on the ratios of morphine-3-glucuronide:morphine (M3G:M) and morphine-6-glucuronide:morphine (M6G:M) and the relative concentrations of M3G and M6G. Across all studies the range of the ratios of metabolites to morphine was wide (0.001–504 for M3G:M, and 0–97 for M6G:M). Neonates produced morphine glucuronides at a lower rate than older children or adults. Metabolite ratios were higher in renal impairment. Routes of administration which avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, buccal or sublingual. Metabolite production was similar for single and multiple dosing. There was no evidence of differences between methods of assay. There was a high correlation between the two glucuronide metabolites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine was present in CSF at a fourfold higher concentration than the glucuronide metabolites.  1998 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Systematic review; Morphine; Morphine-3-glucuronide; Morphine-6-glucuronide

1. Introduction Although morphine is an old drug we are surprisingly ignorant about its pharmacology, both kinetic and dynamic. Morphine pharmacology is complicated by active metabolites and inter-individual variability. The two major metabolites are morphine-3-glucuronide (M3G) and morphine6-glucuronide (M6G) (Shimomura et al., 1971; Smith et al., 1990; Gong et al., 1991; Faura et al., 1996b). M6G probably contributes to the global effects of morphine (Portenoy et al., 1992; Bowsher, 1993; Faura et al., 1996a). Variability in the kinetics of morphine and its metabolites (McQuay et al., 1990) may be due to age (Koren et al., 1985; McRorie et al., 1992), presence of renal impairment (Ball et al., 1985; Chauvin et al., 1987), route of administration (Hoskin et al., 1989; Osborne et al., 1990), duration of treat* Corresponding author. Tel: +34 6591 9489; fax: +34 6591 9492; e-mail: [email protected]

ment (Hanks et al., 1987; Osborne et al., 1992), and method of analysis (Aherne and Littleton, 1985; Joel et al., 1985). Most individual studies used relatively small numbers of patients with specific conditions and treatment regimens, making it difficult to show clearly which factors affect morphine and metabolite kinetics. The analgesic activity of morphine conjugates remains intriguing despite many years’ investigation. Whereas diamorphine (Inturrisi et al., 1984) and morphine-3-glucuronide (M3G) do not bind to opioid receptors, 6-monoacetylmorphine, morphine, morphine-6-glucuronide (M6G) and normorphine do (Christensen and Jorgensen, 1987). M3G has no analgesic activity (Schulz and Goldstein, 1972), but it does have CNS stimulatory effects not mediated through opioid receptors (Wolff et al., 1995). Reports of antagonism of morphine analgesia by M3G (Smith et al., 1990; Gong et al., 1992) are best interpreted as functional, because there is good evidence that there is no direct pharmacological antagonism (Hewett et al., 1993; Suzuki et al., 1993; Faura et al.,

0304-3959/98/$19.00  1998 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959 (97 )0 0142-5

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1996b). This is not surprising given the fact that M3G does not bind to opioid receptors. The more recent evidence of M6G action on opioid receptors was anticipated by the observations that it was antagonised by nalorphine and demonstrated cross tolerance with morphine (Shimomura et al., 1971). M6G, unlike M3G, was 3–4 times more potent than morphine as an analgesic after subcutaneous injection in mice, and 45 times more potent after intracerebroventricular injection (Shimomura et al., 1971). The difference in the potency ratio was attributed to slower entry of the glucuronide into the CNS compared with morphine (Shimomura et al., 1971), and nalorphine-6sulphate had been shown to be a more potent antagonist than nalorphine itself (Oguri, 1980). This greater analgesic potency has been confirmed, with 10–20 times greater intrathecal potency of M6G in the rat compared with morphine (Pasternak et al., 1987; Sullivan et al., 1989). Systematic reviews involve the synthesis of data from a number of trials or studies, increasing the number of subjects and thereby increasing the power to determine the ‘true’ result. This provides a higher quality of evidence on which to base decisions, potentially avoiding the need for further interventional research. Given the pharmacological activity of the morphine metabolites, the analysis of the metabolite:morphine (M3G:M and M6G:M) and metabolite (M3G:M6G) ratios could be useful in understanding morphine pharmacokinetics and pharmacodynamics (Bowsher, 1993; McQuay and Moore, 1997). Our prior hypotheses were that ratios of metabolites to morphine and/or metabolite ratios would differ according to the maturity of the patient, impaired elimination, first-pass metabolism, metabolic autoinduction, and the specificity of the method of analysis. We did a systematic review of studies in a variety of clinical situations to investigate to what extent morphine, M3G and M6G are present in plasma and cerebro-spinal fluid (CSF) and to clarify some of the factors which may affect the metabolic ratios of morphine.

2. Methods Studies were identified by searching the Oxford Pain Relief Database (1950–1995) (Jadad et al., 1996), EMBASE (1981–1997), MEDLINE (1981–1997) and Biological Abstracts (1985–1997). The date of last electronic search was March 1997. We used combinations of the words ‘morphine’, ‘metabol*’, ‘M3G’, ‘M6G’, ‘morphine-6-glucuronide’, ‘morphine-3-glucuronide’, ‘kinetic*’ and ‘pharmacokinetic*’ in a broad free text search without limitation to language. Additional reports were identified from the citation lists of retrieved articles. Our inclusion criteria were: published data, human studies (adults, children or neonates), the administration of morphine (any route, dosage and period) and determination of the concentration of morphine and morphine-3-glucuro-

nide or morphine-6-glucuronide in plasma, serum or CSF. We defined neonates as children within 1 month of birth, or described as newborn or neonate in the original report; children was as defined by the original authors. Impaired renal function was as defined by the original authors. We extracted the following data from each study: the number and type of subjects (patients or healthy volunteers), their age, the route of administration of morphine, dosage, duration of treatment, fluid sampled, sampling time, renal function, the method of sample analysis and the concentration or ratios of morphine and the glucuronide metabolites. Concentration data was presented in a variety of ways in the original reports. Where possible the data were extracted in molar units (nmol/l). If necessary the values were converted from units of weight by division by the appropriate molar mass. Where possible the area under the curve (AUC) was extracted or calculated by the trapezoidal method. If the AUC was not available either the mean, maximum, minimum or steady state concentration was extracted. Within any trial we extracted the same parameter for morphine, M3G and M6G to ensure comparability. The molar ratios for M3G:morphine (M3G:M), M6G: morphine (M6G:M) and M3G:M6G were then calculated. Where papers provided only molar ratios these were extracted. Where information was provided for both CSF and plasma the CSF:plasma ratios for morphine, M3G and M6G were calculated using the same parameter for both CSF and plasma within any trial. We then investigated the effect of age, renal function, route of administration, duration of treatment and method of analysis on the distribution of the M3G:M, M6G:M and M3G:M6G ratios. Our hypotheses were that morphine metabolism would be different in neonates from children or adults, that renal failure or impairment would alter ratios, that ratios after injected morphine would be different from those after oral morphine, that prolonged administration of oral morphine would also affect the ratios, and that different methods of analysis would give different results. Weighted mean ratios were calculated by multiplying the ratio from each study by the number of patients in that study, then summing the results for all studies in the sub-group and dividing that sum by the total number of patients in all the summed studies. Because we were aware of the very large disparity in the number of patients included in the various reports, our intention was to analyse information graphically rather than by any statistical technique. Calculations were performed using Excel 5.0 on a Power Macintosh 7100/80.

3. Results and discussion Fifty-seven studies met the inclusion criteria and provided information on 1232 patients in 91 different clinical groups with extractable data (mean group size, 12 patients; median, 9; range, 1–136; Table 1). References for the stu-

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C.C. Faura et al. / Pain 74 (1998) 43–53 Table 1 Number of studies, of patients, mean weighted ratios and range of values of M3G:M6G in the different subgroups Factor

Subgroup

Number of studies

Total number of patients

M3G:M6G (mean weighted ratio)

M3G:M6G (range)

Age

Neonates Children Adults Normal Impaired Normal and oral Normal and intravenous Impaired and oral Impaired and intravenous Oral Buccal Sublingual Subcutaneous Intravenous Transdermal Rectal Intramuscular Epidural Intrathecal Sublabial Single dose and oral Single dose and intravenous Multiple dose and oral Multiple dose and intravenous HPLC and oral HPLC and intravenous RIA and oral RIA and intravenous

6 11 49 48 10 28 21 4 5 28 3 2 5 21 1 4 1 2 1 1 13 16 16 5 22 17 4 4

49 90 1073 1107 56 667 180 10 38 667 62 13 43 180 12 41 19 32 1 6 156 145 511 35 464 142 189 38

3.1 6.2 6.3 6.3 5.7 6.1 7.5 4.0 5.7 6.1 6.7 5.5 5.4 7.6 4.6 6.4 5.0 4.3 6.1 – 6 7.3 6.2 8.5 6.2 7.0 6.1 9.6

2.6–3.5a 2.3–20 0.5–13.3 0.5–20 1.5–9.7 3.8–9.3 0.5–20 2–9.7 1.5–8.7 3.8–9.3 4.3–11.3 5.5–5.6 2.7–13.3 0.5–20 – 5.7–7 – 4–9.3 – – 3.9–9.2 4.5–12.4 3.8–9.3 0.5–20 3.8–9.2 0.5–20 5.2–9.3 7.9–12.4

Renal function Renal function and routes

Routes

Single/multiple doses

Method of assay

a

Two studies where no M6G could be detected have been omitted.

dies are given in Appendix A and details of the information extracted from each paper can be found on the World Wide Web (http://www.jr2.ox.ac.uk/Bandolier/painres/mormet/ mormet.html). Across all studies the range of the ratios of metabolite to morphine was wide. For M3G:M it was from 0.001 to 504 and for M6G:M it was from 0 (that is where M6G could not be detected) to 97. 3.1. Effect of age Neonates (,1 month) had a weighted mean ratio of 1 for M3G:M (range 0.2–3.1; 49 patients) and 0.22 for M6G:M (0–1.2; 49), but two studies could not detect M6G in neonates. Children (.1 month) had a weighted mean ratio of 15.9 for M3G:M (0.2–504; 90) and 3.3 for M6G:M (0.03– 97; 90). Adults had a weighted mean ratio of 22.6 for M3G:M (2.8–198; 848) and 4.1 for M6G:M (0.3–47; 1050). There was almost complete overlap between children and adults, but neonates had discernibly lower ratios of metabolites to morphine (Fig. 1). For this reason, subsequent analyses omitted neonates. The pharmacokinetics and pharmacodynamics of drugs frequently dependent on age. Morphine is eliminated largely by hepatic metabolism and its principal metabolites by renal excretion. Both processes are functionally immature in the

neonatal period and reach adult values at different times after birth (Olkkola et al., 1995). Ethical and practical considerations mean that morphine pharmacokinetics have been studied infrequently in neonates and children. Koren et al. (1985) found neonates to have a significantly longer elimination half-life of morphine than older children and adults. At the same dosage schedule morphine concentrations in neonates were three times higher than in older children. Similar differences between neonates and children were reported by Lynn and Slattery (1987). Pokela et al. (1993) showed that the clearance and half-life of morphine approached adult values after the age of 1 month. McRorie et al. (1992) studied glucuronidated morphine metabolite concentrations in urine and suggested that the formation of both glucuronides increased with age. In our systematic review we demonstrate the metabolic immaturity of the neonate, and that children older than 1 month metabolise morphine like adults. 3.2. Effect of renal impairment In patients with normal renal function the weighted mean ratios were 20.8 for M3G:M (0.2–70; 884 patients) and 3.7 for M6G:M (0.03–10.9; 1085). With impaired renal function the weighted mean ratios were 40 for M3G:M (10.6–

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Fig. 1. Ratios of M3G (left) and M6G (right) to morphine in neonates, children and adults. Black diamonds show the weighted mean ratios for each group. The size of the symbol is proportional to the number of patients in the original study.

504; 54) and 9.7 for M6G:M (1.2–97; 55). The ratios tended to be higher in renal impairment than with normal renal function. 3.3. Effect of route of administration and renal impairment Most of the available information was for the oral and intravenous routes. The effect of renal impairment on ratios was more pronounced when analysed by route of administration (Fig. 2). In patients given oral morphine with normal renal function the weighted mean ratios were 28.4 for M3G:M (8.3–70; 513 patients) and 4.9 for M6G:M (0.9–10.9; 667). For those with impaired renal function the weighted mean ratios were 67.8 for M3G:M (46–140; 9) and 23.9 for M6G:M (9.9–47; 10). In patients with normal renal function given intravenous morphine the weighted mean ratios were 6 for M3G:M (0.2–15; 173) and 0.9 for M6G:M (0.03–2.6; 193). For those with impaired renal function the weighted mean ratios were 39.4 for M3G:M (10.6–503; 37) and 7.6 for M6G:M (1.2–97; 37). It has been known clinically for more than 150 years that patients with poor renal function have greater effect from a given dose of morphine than those with normal renal function (Salmon, 1688; Toogood, 1898; Yeo, 1907; McQuay and Moore, 1984). Whether this greater effect is due to morphine or its metabolites, and whether this is a general rather than an idiosyncratic phenomenon, has been controversial. Elimination of morphine glucuronides has been consistently reported as decreased in renal impairment (Chauvin et al., 1987; Bodd et al., 1990; McQuay et al., 1990; Milne et al., 1992; Hanna et al., 1993; Osborne et al., 1993) and, as in

Fig. 2. Ratios of M3G (upper) and M6G (lower) to morphine according to normal or impaired renal function and oral or intravenous administration. Black diamonds show the weighted mean ratios for each group. The size of the symbol is proportional to the number of patients in the original study.

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Fig. 3. Ratio of M6G to morphine in different routes of administration (excluding patients with renal impairment). Black diamonds show the weighted mean ratios for each group. The size of the symbol is proportional to the number of patients in the original study.

our systematic review, some studies observed higher ratios of glucuronides to morphine in this clinical situation (McQuay et al., 1990; Peterson et al., 1990; Portenoy et al., 1991). What is clearly shown here is that renal impairment results in higher plasma concentrations of morphine glucuronides compared to morphine. Because of the pharmacological activity of M6G (Shimomura et al., 1971; Gong et al., 1991), the higher ratios observed in renal impairment may account for the unexpected effects of morphine observed in those patients (McQuay and Moore, 1984; Osborne et al., 1986; Bodd et al., 1990). With normal renal function there was a clear demarcation between routes which tended to produce higher ratios (oral, buccal, sublingual) and those that tended to produce lower ratios (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal; Fig. 3). Extensive first pass metabolism is the presumed basis of this difference between routes in metabolite to morphine ratios. While buccal and sublingual administration theoretically avoid first pass metabolism, they have a significant oral component. Studies analysing differences in metabolite production between rectal and oral have been contradictory. Ellison and Lewis (1984) found no significant differences in M3G plasma concentrations between the two routes, but they did not analyse metabolite to morphine ratios. With rectal administration the concentrations of M3G were lower and concentrations of morphine higher than after oral administration; this would give a lower M3G:M ratio for rectal administration. An important issue for rectal morphine is the fact that the relative potency ratio for oral to rectal of 1:1 is not solidly supported by the pharmacokinetic behaviour (Expert Working Group of the European Associa-

tion for Palliative Care, 1996). Specifically, a given dose of oral morphine will produce relatively greater concentrations of M6G, the active metabolite, than the same dose of morphine given rectally. Whether or not the relative analgesic efficacy is the same remains unclear. 3.4. Single and multiple doses For oral administration there was no difference in ratios between single and multiple doses of morphine. For single oral doses of morphine the weighted mean ratios were 28 for M3G:M (8.3–55; 125 patients) and 5.2 for M6G:M (0.9–10.1; 156). For multiple oral doses of morphine the weighted mean ratios were 29 for M3G:M (10.7–70; 388) and 4.8 for M6G:M (1.6–10.9; 511). For intravenous administration there was no difference in ratios between single and multiple doses of morphine. For single intravenous doses the weighted mean ratios were 5.4 for M3G:M (0.2–11; 139) and 0.8 for M6G:M (0.03–1.4; 159). For multiple intravenous doses the weighted mean ratios were 8.5 for M3G:M (2.4–15; 34) and 1.4 for M6G:M (0.6–2.6; 34). For kinetic investigations it therefore appears that single dose studies should be predictive of multiple dosing. 3.5. Method of analysis There was no difference in the ratios between methods of analysis based on high performance liquid chromatography (HPLC) or immunoassay (RIA). For oral administration HPLC gave a M3G:M ratio of 32 (8.3–70; 324 patients) and RIA 22.9 (22.7–22.9; 175) and for intravenous admin-

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Fig. 4. Ratios of M3G (upper) and M6G (lower) to morphine according to analytical method, high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA), and oral or intravenous administration. Black diamonds show the weighted mean ratios for each group. The size of the symbol is proportional to the number of patients in the original study.

plasma plotted for the area under the concentration/time curve or plasma concentrations for all subgroups in all trials. There was a constant relationship (r2 = 0.99). This is directly relevant to the question of whether morphine glucuronidation is under the control of one or more enzyme systems (Coughtrie et al., 1989; Coffman et al., 1997), and whether preferential production of morphine-3glucuronide occurs in some circumstances (Bowsher, 1993). Although morphine glucuronidation varies quantitatively and qualitatively across different mammalian species (Milne et al., 1996), an early in vitro human study suggested that two isozymes of uridine diphosphate glucuronosyltransferase (UDPGT) were responsible for the metabolism of morphine (Coughtrie et al., 1989). Coffman et al. (1997) have, however, recently identified a UDPGT (UGT2B7) capable of catalysing the glucuronidation of both the 3and 6-positions of opioids. This systematic review showed the formation of M3G and M6G to be highly correlated (Fig. 5), reflecting results from in vivo and in vitro studies (McQuay et al., 1990; Yue et al., 1990). This supports a single UDPGT for the formation of M3G and M6G, and rules out a preferential production of M3G (Bowsher, 1993). The argument is that if two different enzyme systems synthesised M3G and M6G, these two systems would be likely to have different levels of genetic expression in different groups and individuals, and be subject to different levels of inhibition or activation. This would result in the ratio of the two metabolites varying considerably. We found no such variation. The regression of M6G against M3G, whether using areas under the concentration-time curve, or from single or mean plasma concentrations, produced a highly significant linear relationship (r2 = 0.99). This was despite combining information from all patients, including neonates, patients with renal impairment and different routes of administration. The

istration HPLC gave a M3G:M ratio of 6.9 (0.2–15; 121) and RIA 3.8 (2.8–4.3; 52). For oral administration HPLC gave a M6G:M ratio of 5.3 (0.9–10.9; 464) and RIA 4.2 (2.4–10; 181) and for intravenous administration HPLC gave a M6G:M ratio of 1 (0.03–2.6; 135) and RIA 0.5 (0.3–1.2; 58) (Fig. 4). Despite any real evidence, it is often stated that immunological methods of measuring morphine and its metabolites result in values significantly different from those obtained by chromatographic methods (Aherne and Littleton, 1985; Joel et al., 1985; Glare and Walsh, 1991; Milne et al., 1996). The present study rebuts these views and suggests that current RIA methods give values indistinguishable from those obtained with HPLC. 3.6. Ratio of M3G:M6G This ratio remained constant in all subgroups analysed. Fig. 5 shows the relationship between M3G and M6G in

Fig. 5. Relationship between M6G and M3G using values of area under the curve (white circles) or plasma concentration (black diamonds) in all trials which measured both (r2 = 0.99).

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mean (SD) requirement for patient controlled analgesia with pethidine was 393.3 (227.4) mg/24 h during the morphine limb of the trial and 226.7 (113.6) mg/24 h during the M6G limb. Morphine may also be metabolised in the central nervous system. Sandouk et al. (1991) found that brain was able to metabolise morphine to M3G and M6G after intracerebroventricular administration of morphine in four cancer patients.

4. Comment

Fig. 6. Ratios of concentrations in CSF to concentrations in plasma of morphine, M3G and M6G. Black diamonds show the weighted mean ratios for each group. The size of the symbol is proportional to the number of patients in the original study.

conclusion is that the ratio of M3G to M6G remains within fairly constant limits with M6G at about 15% of the concentration of M3G (Table 1). 3.7. CSF:plasma ratios There was a subset of nine studies which gave concentrations of morphine and its glucuronidated metabolites in both CSF and plasma. The ratios for these are shown in Fig. 6. There was a wide range. For morphine the weighted mean CSF:plasma ratio was 0.46 (0.03–1.04; 118 patients), for M3G it was 0.13 (0.03–1.1; 118) and for M6G it was 0.12 (0.02–0.35; 120). Morphine and its glucuronides enter the CSF, though the entry mechanism is not clear. Morphine appears to have a somewhat higher (about fourfold) CSF concentration relative to that in plasma compared with the glucuronides, but, because morphine-6-glucuronide has greater analgesic potency, the argument that M6G contributes to the analgesia from a dose of morphine would seem to be justified. We know that M6G has analgesic activity when injected into the CSF. In a single-blind crossover study of three patients with chronic cancer pain Hanna et al. (1990) compared the analgesic efficacy of intrathecal M6G 500 mg with morphine 500 mg given via a catheter on separate days. The

Gathering together all the published information on ratios of morphine and its metabolites allowed a semi-quantitative analysis of several issues relating to morphine. It demonstrated that neonates produce morphine glucuronides at a lower rate than older children or adults. We would therefore question whether further kinetic studies on children are necessary. It demonstrated that metabolite ratios are higher in renal impairment. Routes of administration which avoid first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, buccal or sublingual. Multiple dosing did not affect the production of metabolites. There was no evidence of differences between methods of assay. This study also demonstrated the high correlation between the two metabolites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine is present in CSF at a fourfold higher concentration than the glucuronide metabolites. We did not perform any statistical analysis on differences between, for instance, neonates and children or adults, or on the effects of renal failure. This was because many of the studies had a small number of patients (median nine patients in each clinical group) and these were counterbalanced by a few large studies. Additional complications of different routes of administration of morphine, methods of analysis and clinical circumstances made statistical analysis even less practicable. There are some limitations. It is always difficult to be sure that all studies which address a particular issue have been found, particularly when the drug has been used for such a long time. Here we had information for analysis on 1232 patients, so that even if some small studies were missed, they would be unlikely to have altered the results. The systematic review also highlights a research agenda. Partly this has to do with the novelty of systematic reviews in clinical pharmacology. In particular we were inhibited from attempting any statistical analysis, and methods need to be developed which allow this. For morphine, the relative analgesic contribution of morphine and M6G remains an enigma. Current belief is that M6G must surely contribute to the analgesia from a given dose of morphine. The extent of that contribution, its timing, and whether we can harness it to improve patient care, remain unresolved.

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Acknowledgements Financial support for the study was from Pain Research Funds, European Union Biomed 2 contract BMH4 CT95 0172, NHS Research and Development Health Technology Assessment Programme 94/11/4, and CICYT SAF96–0183 (Spain). Clara C. Faura was funded by Generalitat Valenciana (Spain).

Appendix A List of the 57 studies that were included in the systematic review Babul, N. and Darke, A.C., Disposition of morphine and its glucuronide metabolites after oral and rectal administration: evidence of route specificity, Clin. Pharmacol. Ther., 54 (1993) 286–292. Bath, R., Abu-Hard, M., Chari, G. and Gulati, A., Morphine metabolism in acutely ill preterm newborn infants, J. Pediatr., 120 (1992) 795–799. Bigler, D., Broen Christensen, C., Eriksen, J. and Jensen, N.H., Morphine, morphine-6-glucuronide and morphine-3glucuronide concentrations in plasma and cerebrospinal fluid during long-term high-dose intrathecal morphine administration, Pain, 41 (1990) 15–18. Bodd, E., Jacobsen, D., Lund, E., Ripel, A., Morland, J. and Wiik-Larsen, E., Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure, Hum. Exp. Toxicol., 9 (1990) 317–321. Bourget, P., LesneHulin, A. and Quinquis-Desmaris, V., Study of the bioequivalence of two controlled-release formulations of morphine, Int. J. Clin. Pharmacol. Ther., 33 (1995) 588–594. Breda, M., Bianchi, M., Ripamonti, C., Zecca, E., Ventafridda, V. and Panerai, A.E., Plasma morphine and morphine-6-glucuronide patterns in cancer patients after oral, subcutaneous, sublabial and rectal short-term administration, Int. J. Clin. Pharmacol. Res., 11 (1991) 93–97. Breheny, F., McDonagh, T., Hackett, L.P. and Ilett, K.F., Disposition and clinical effects of morphine, morphine-6glucuronide and morphine-3-glucuronide following an intentional overdose of slow release oral morphine in a patient with renal failure, Drug Invest., 6 (1993) 291– 295. Campbell, W.I., Rectal controlled-release morphine: plasma levels of morphine and its metabolites following the rectal administration of MST Continus 100 mg, J. Clin. Pharm. Ther., 21 (1996) 65–71. Choonara, I.A., McKay, P., Hain, R. and Rane, A., Morphine metabolism in children, Br. J. Clin. Pharmacol., 28 (1989) 599–604. Choonara, I., Lawrence, A., Michalkiewicz, A., Bowhay, A. and Ratcliffe, J., Morphine metabolism in neonates and infants, Br. J. Clin. Pharmacol., 34 (1992) 434–437. Collins, J.J., Geake, J., Grier, H.E., Houck, C.S., Thaler, H.T., Weinstein, H.J., Twum Danso, N.Y. and Berde, C.B.,

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