H J McQuay DM, Clinical Reader in Pain Relief
R A Moore DPhil, Consultant Biochemist
Pain Research and Nuffield Department of Anaesthetics University of Oxford, UK

Table of Contents

A.Clinical aspects
A.I.1 Neuropathic Pain
A.II. Red Herrings
A.II.1 Tolerance
A.II.2 Addiction
B.Morphine and metabolites
B.I.What are they?
B.I.1 Chemistry
B.I.2 Analysis
B.II. How are they made? - enzymology
B.II.1 Liver
B.II.2 Kidney
B.II.3 Central Nervous System (CNS)
B.III. Where are they found?
B.III.1 Urine studies
B.III.2 Plasma
B.III.3 Central Nervous System (CNS)
B.IV. What do they do? - pharmacology
B.IV. 1Morphine-3-glucuronide (M3G)
B.IV.2 Morphine-6-glucuronide (M6G)
B.IV.3 Morphine and metabolites: plasma and CSF ratios
B.IV.4 Clinical Effects
B.V.1 Liver disease
B.V.2 Kidney disease
B.V.3 Drug interactions
B.VI. Conclusions
Table 1. Metabolism and excretion.
Table 2. Morphine and metabolites in plasma and CSF after single morphine doses
Table 3. Morphine and metabolites in plasma and CSF after multiple morphine doses
Table 4. Summary of plasma morphine/metabolite ratios
Table 5. Summary of CSF/plasma ratios of morphine metabolites
Table 6. CSF concentrations of morphine and morphine-6-glucuronide
Figure 1. Structural formulae for morphine, diamorphine and metabolites
Figure 2. Plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide
Figure 3. Ratio of M3G to morphine in plasma for single intravenous and oral doses, and for multiple oral doses
Figure 4. Ratio of M6G to morphine in plasma for single intravenous and oral doses, and for multiple oral doses
Figure 5. Dose-corrected plasma concentrations for morphine, M3G and M6G for patients with normal renal and hepatic function


The chapter outlines some features of opioid pharmacology, and then details the chemistry, analytical methodology, metabolism, body fluid concentration and influence of pathophysiology on drug metabolism and excretion of morphine. The chapter considers the structure-activity relationships of the morphine molecule in some detail, because of the implications that the active metabolite morphine-6-glucuronide has for clinical practice. The emphasis is the clinical importance of features of the drug's metabolism, toxic or active metabolites, and the practical influence of pathophysiology.


The fact that most patients do achieve at least some degree of pain relief from opioids is a tribute to the efficacy of the drugs. The choice of drug and the prescription regimens remain largely empirical, because there still large gaps in knowledge of the clinical pharmacology of these drugs. These gaps are a function of the variety of chemical structures among opioids and the fact that they are often used in patients whose renal or hepatic function is compromised. Above all most of these drugs are potent, so that doses and concentrations in body fluids are low. Detailed knowledge requires specific and sensitive analytical methods for measuring both parent drugs and metabolites.

Identification of a toxic metabolite of pethidine and an active metabolite of morphine (the two most commonly used opioids) is important for both doctor and patient. It shows the importance of knowledge of both metabolism and excretion for rational prescribing.

The structure of this chapter is that some of the problem areas in opioid clinical pharmacology are discussed first, followed by the metabolic pharmacology of morphine. A previous review [MOORE et al, 1987] covered the chemistry, pharmacology of metabolites, analysis, metabolites in body fluids, enzymology and pathophysiology) of other drugs in the morphine family, buprenorphine, pethidine, methadone and fentanyl (Table 1).

A. Clinical aspects

Much of our prescribing of opioids is based on opinion rather than on evidence. In part this is because opioid use in chronic non-cancer pain is an orphan area, in part because trial design and conduct is not easy in this patient group [MCQUAY & MOORE, 1994], and in part it is historic - many opioids are old drugs, and the registration trials required for new drugs have therefore not been done. It is remarkable how little new evidence on oral and intramuscular opioid use has emerged since earlier reviews [MCQUAY, 1989; NAGLE & MCQUAY, 1990; MCQUAY, 1991]. An added complication is that there are many routes by which these drugs can be given. The fact "that it can be done" very often pre-empts the more important question "should it be done?". Enthusiasts for the new route carry it into practice without adequate comparison of risk and benefit with 'established' routes. Again these arguments have been well rehearsed [MCQUAY, 1990]. Much of the 'new' evidence for spinal or transdermal opioids does not answer the real clinical questions.

A.I. Effectiveness

Just how effective are opioids in managing chronic pain, cancer or non-cancer? The usual claim from audits of the World Health Organisation guidelines for oral opioids in cancer pain is that two-thirds of patients achieve good or moderate pain relief. Why does the pain of the other one-third of patients respond poorly to opioids? The commonest explanation of pain which is poorly responsive is that it is because the pain is neuropathic in character.

A.I.1 Neuropathic Pain

There are two extreme positions on opioid responsiveness or sensitivity. One suggests that opioid sensitivity is a relative phenomenon, and therefore that any pain can be controlled by opioids provided that there is an adequate dose escalation and control of adverse effects [PORTENOY et al, 1990]. The other extreme insists that some pains are intrinsically insensitive to opioids and that this insensitivity can be predicted from the clinical characteristics of the pain [ARNER & MEYERSON, 1988]. Nociceptive pain is thought to be sensitive to opioids while neuropathic pain is regarded as insensitive. If neuropathic pain shows an analgesic response with opioid then this has been attributed to mood improvement rather than to a direct effect on pain pathways [KUPERS et al, 1991].

Both extremes of this controversy are supported by a very small number of controlled trials each of which has methodological limitations. These studies have used either single doses [KUPERS et al, 1991; TASKER et al, 1983], infusions of different opioids [ARNER & MEYERSON, 1988; PORTENOY et al, 1990] or have measured pain without simultaneous assessment of adverse effects [ARNER & MEYERSON, 1988; KUPERS et al, 1991; TASKER et al, 1983; ROWBOTHAM et al, 1991]. The flaw with studies which use a single (fixed) dose or infusion rate is that they may underestimate responses in patients with previous opioid exposure. These patients may need more opioid to achieve analgesic effect than the opioid naive.

Using patient-controlled analgesia (PCA) with simultaneous nurse observer measurement of analgesia and adverse effects we gave two concentrations of morphine in a double-blind randomised cross-over fashion and compared the clinical responses produced by both concentrations of morphine [JADAD et al, 1992].

The results did not support the assumption that neuropathic pains are always opioid insensitive. Half of the pains judged as neuropathic achieved a good response. Nociceptive pains collectively showed a better analgesic response, because all of them achieved a good response in at least one of the sessions. No nociceptive pain had a poor response in this study.

It had been suggested that the analgesic response of neuropathic pains to opioids can be explained by the changes in mood induced by the opioids [KUPERS et al, 1991]. When the results of patients with consistent responses were compared, changes in mood reflected changes in pain intensity and relief regardless of the clinical character of the pain, nociceptive or neuropathic. Mood improved when pain intensity decreased or pain relief increased. No patient had a change in mood in the absence of a change in pain intensity or pain relief, and patients with nociceptive pains in fact showed a greater change in mood than those with neuropathic pain. Therefore, the theory that relief of neuropathic pains by opioids is due to changes in mood was not supported by our findings.

A.II. Red Herrings

A.II.1 Tolerance

Clinicians argue that tolerance to opioids, if it occurs, is driven by disease rather than by pharmacological tolerance. The first problem is that tolerance is used by some to mean any increase in dose, whereas others use it in the more technical sense of an increased dose required to produce the same effect.

It is ingenuous to argue that opioid tolerance does not occur in man - fleeting glimpses have been seen which echo the solid findings of both acute and chronic opioid tolerance in animal models [COLPAERT et al, 1980]. The classic Houde experiments showed chronic tolerance when patients' analgesic response to a test dose was measured before and after chronic dosing [HOUDE, 1985; HOUDE et al, 1966]. The pragmatic issues are whether the dose escalation required by some patients, but which produces difficult adverse effects, could be avoided (safely) by blocking a tolerance-induced need for dose escalation, or (more simply) by changing opioid or indeed route of administration. The academic question is why some patients do not require dose escalation, but continue to maintain good relief on the same dose over many months.

A.II.2 Addiction

Clinical pain management has emphasised a difference between the clinical and the laboratory pharmacology of opiates. It is as though there is one opiate pharmacology when the opiate is used to counteract pain, and another when it is not.

The respiratory depression which haunts prescribers in acute pain management is seen readily in studies of volunteers who are not in pain. For patients with opiate-sensitive pain, given appropriate doses of opiate, respiratory depression is minimal. The balance between pain and opiate respiratory effects is seen clearly in chronic pain. Patients maintained on oral morphine, with no clinical respiratory depression, and who then receive successful nerve blocks, must have their morphine dose reduced. Failure to reduce the dose will result in respiratory depression [HANKS et al, 1981; MCQUAY, 1988]. One explanation is that the respiratory centre receives nociceptive input [ARITA et al, 1988]. Presence of this input counterbalances any respiratory depressant effect of the opiate. Absence of this input, because of the successful nerve block, leaves the respiratory depressant effect of the opiate unopposed. This has been shown beautifully in volunteers [BORGBJERG et al, 1996].

The clinical message is that opiates need to be titrated against pain. Doses higher than necessary for the relief of pain run the risk of respiratory depression. Prophylactic use of opiates, infusion without regard to pain experienced, doses greater than those required for analgesia (as in deliberate ITU use to facilitate ventilation of a patient), use for purposes other than analgesia (e.g. sedation), or use in non-nociceptive pain, all therefore carry potential risk. Concern about respiratory depression should not inhibit the appropriate use of opioids to provide analgesia when the pain may reasonably be thought to be opiate sensitive. A postoperative patient still complaining of pain when the previous dose can be assumed to have been absorbed needs more drug.

Similarly the drug-seeking behaviour synonymous with street addiction is not found in patients after pain relief with opiates, in childbirth, after operations or after myocardial infarction [PORTER & JICK, 1980]. Street addicts are not in pain. The political message is that medical use of opiates does not create street addicts. Medical use may indirectly increase availability to those who are already addicts, but restricting medical use hurts patients.

B. Morphine and metabolites

B.I. What are they?

B.I.1 Chemistry

To make sense of morphine metabolism the structure-activity relationships must be understood. Alterations to the structure change the pharmacological activity and may have important clinical sequelae. The basic principles have been known for some time, and were well summarised in a WHO Bulletin published as long ago as 1955 [BRAENDEN et al, 1955].

The most important positions on the morphine molecule, because of their implications for both activity and morphine metabolism, are the phenolic hydroxyl at position 3, the alcoholic hydroxyl at position 6, and at the nitrogen atom (Figure 1).

Both hydroxyl groups can be converted to ethers or esters (e.g. heroin, diacetylmorphine) and these changes alter clinical effect. Changes on the hydroxyl groups are opposite in direction; additions at the phenolic 3-hydroxyl group reduce pharmacological activity considerably, by perhaps more than 90%. By contrast, modification at the alcoholic 6-hydroxyl position results in an activation of the molecule, with the resulting compound being 2-4 times more potent as an analgesic than morphine after parenteral dosing in standard tests.
Figure 1. Structural formulae for morphine, diamorphine and metabolites.

These rules are not absolute, however, and some substitutions at the 6-hydroxyl (e.g. conjugation with long aliphatic acids) reduce activity because of steric and other considerations. Short chain fatty acid substitutions (such as 3,6-dibutanoylmorphine) have been used to increase the lipophilicity and potency of morphine [OWEN & NAKATSU, 1984; TASKER AND NAKATSU, 1984].

The tertiary character of the nitrogen atom is crucial for morphine's analgesic activity. Chemical modifications which make the nitrogen quaternary (as with N -oxide) greatly diminish analgesic potency because of reduced penetration into the central nervous system. Changes to the methyl substituent on the nitrogen are also important; replacement of the methyl group with 3-carbon alkyl groups not only reduces the analgesic action, but actually produces compounds which antagonise the actions of morphine, such as nalorphine.

B.I.2 Analysis

Studies of morphine kinetics and metabolism require adequate methods of analysis. Results from inadequate analytical methods should be interpreted with caution. The kinetic and dynamic differences demonstrated between different species increase the difficulties.

Svensson et al [SVENSSON et al, 1982] developed a high-performance chromatographic procedure (HPLC) which measured morphine and its 3- and 6-glucuronides simultaneously. These analyses were facilitated by the high concentrations found in plasma when patients take large oral morphine doses. Similar results were also described using differential radioimmunoassay [HAND et al, 1987a], where samples were measured with morphine antisera of different specifics. A specific radioimmunoassay for the determination of morphine-6-glucuronide in human plasma has been reported [CHAPMAN et al, 1995].

B.II. How are they made? - enzymology

Morphine glucuronides are formed by enzyme catalysed transfer of glucuronic acid from uridine diphosphoglucuronic acid (UDP); the enzymes responsible are microsomal UDP glucuronyl transferases (UDPGT). This is a series of functionally distinct enzymes found in liver, kidney, intestines and other organs. The products of glucuronidation are excreted by the urine and bile. Whether the glucuronide is excreted by urine or bile depends upon the molecular weight and polarity of the conjugate. Compounds with larger molecular weight (more than 300 Da) and low water solubility are more often excreted in the bile. Morphine glucuronides, being very water soluble, are expected to be excreted in the urine.

B.II.1 Liver

It is generally assumed that morphine conjugation occurs primarily in the liver, though the evidence is not compelling. For instance, the Michaelis constant for hepatic glucuronidation in human and animal tissue is of the order of 2 mmol.L -1 [SAWE et al, 1982], which is some tens of thousands of times greater than the usual plasma concentrations of morphine. The implication of this high Michaelis constant is that, at therapeutic concentrations of around 200 nmol.L -1 , the liver microsomal glucuronidation systems would work far too slowly to account for the rates of morphine glucuronidation. As an example of this, rat hepatocytes were able to glucuronidate nalorphine but not morphine, even at high intracellular concentrations [IWAMOTO AND KLAASEN, 1978].

Different morphine conjugates may arise from the actions of different enzymes. When the natural (-) and the synthesised (+) morphine enantiomers were tested for glucuronidation, the (+) enantiomer was preferentially conjugated at the 6-position of the conjugate rather than the 3-position [RANE et al, 1985]. This work serves to emphasise the complexity of morphine metabolism at the sub-cellular (rather than the whole-body) level.

Coughtrie et al [COUGHTRIE et al, 1989] showed that morphine glucuronide formation was influenced by both enantiomer and body 'region'. In rat liver microsomes, natural (-)-morphine formed only the 3-O-glucuronide, whereas the unnatural (+)-morphine formed glucuronides at both the 3-OH and 6-OH positions, with the 6-O-glucuronide being the principal product. In human liver microsomes, both the 3-OH-and 6-OH positions were glucuronidated by each of the enantiomers, the 3-O-glucuronide being the major product with (-)-morphine, and the 6-OH position preferred by the (+)-enantiomer. Two UDP-glucuronosyltransferase isoenzymes were responsible for the glucuronidation of morphine in rat liver. Morphine UDP-glucuronosyltransferase produced glucuronides at both the (-)-3-OH and (+)-6-OH positions, the other formed only the (+)-morphine-3-glucuronide. In human kidney, there was glucuronidation ability at the 3-OH but not the 6-OH position.

Dechelotte et al [DECHELOTTE et al, 1993] compared morphine uptake and biotransformation to M3G and M6G in isolated cells from guinea pig stomach, intestine, colon, and liver. Morphine was glucuronidated to M3G by gastric, intestinal, colonic, and liver cells, and to M6G by all except gastric cells. They found that small and large intestine epithelium, like liver, formed M6G, and that gastric, intestinal, and colonic epithelia inactivated morphine to M3G.

Knodell et al [KNODELL et al, 1982] ligated the inferior vena cava above the entrance to the hepatic veins, and reduced the hepatic blood flow to less than 50% of controls; morphine clearance was unaltered, and the conclusion was that there were extra-hepatic sites for morphine metabolism. Similar conclusions have been made in man, where the disposition and elimination of indocyanin green and morphine were studied in healthy controls and cirrhotic patients [PATWARDHAN et al, 1981]. There was a significant decrease in indocyanin green clearance, but no alteration in morphine kinetics, again with the suggestion of some extrahepatic site of glucuronidation. This is unlikely to be the intestine, as drugs (like morphine) with low lipophilicity are not subject to extensive gut wall glucuronidation [RANCE AND SHILLINGFORD, 1977]. The inability of the gut to metabolise morphine is supported by in-vivo data [KNODELL et al, 1982].

B.II.2 Kidney

There is, unfortunately, no clear evidence for an alternative organ of metabolism. Rabbit kidney tubules are able to metabolise morphine to glucuronides at the same sort of concentrations found in plasma in vivo [SCHALI AND ROCH-RAMEL, 1982], and the perfused rat kidney can actively excrete morphine [RATCLIFFE et al, 1985]. These data, however, do not substantiate the idea of significant renal glucuronidation in man.

Milne et al [MILNE et al, 1993] used sheep to study the regional formation and extraction of M3G and M6G. There was significant extraction of morphine by the liver and kidney, net extraction of M3G and M6G by the kidney, and net formation of M3G by the gut. In a subsequent paper [MILNE et al, 1995] they infused morphine or M3G into sheep and calculated regional net extraction ratios and total and regional clearances. They found prolonged elimination of M3G formed in situ from morphine compared with after M3G infusion. M3G was not converted back into morphine or M6G.

Mazoit et al [MAZOIT et al, 1990] measured the hepatic extraction ratio of morphine directly in six patients having radiological procedures. The hepatic extraction ratio was 0.65 +/- 0.11. No concentration gradient was observed between the artery and the superior mesenteric vein, showing that no gut wall metabolism of morphine occurred. Total body clearance was 38% greater than the hepatic clearance, and they concluded that the extrahepatic extraintestinal clearance of morphine probably occurred through the kidney.

Van Crugten et al [VAN CRUGTEN et al, 1991] studied the renal handling of morphine, M3G and M6G in an isolated perfused rat kidney. They found renal handling of morphine to be a complex combination of glomerular filtration, active tubular secretion, and possibly active reabsorption, with the glucuronide metabolites, larger and less lipophilic than morphine, undergoing net tubular reabsorption.

B.II.3 Central Nervous System (CNS)

The ability of M6G to penetrate the blood-brain barrier unchanged was confirmed using radioactively labelled M6G [YOSHIMURA et al, 1973]. The analgesic activity of M6G did not appear to be due to hydrolysis of the conjugate in the brain or elsewhere; only conjugated morphine was found in rat brain after intraperitoneal M6G injections [SHIMOMURA et al, 1971]. Evidence of transformation of M6G to morphine in brain tissue has been conflicting. Wahlstrom et al [WAHLSTROM et al, 1988] showed ability of CNS to metabolise M6G to morphine. Sandouk et al [SANDOUK et al, 1991] found, after intracerebroventricular administration of morphine in four cancer patients, that brain was able to metabolise morphine to M 3-G and M 6-G.

B.III. Where are they found?

B.III.1 Urine studies

In man more than 90% of an administered dose of morphine is excreted in the urine. Only about 10% is unchanged morphine, and M3G is the major metabolite (Table 1). M6G was thought to be a minor metabolite, with less than 1% of the dose being in this form in post-addict males on high doses; more recent studies, using plasma samples, suggest that this figure is much too low [HAND et al, 1987a]. Using differential radioimmunoassay, the amounts of morphine, and 3- and 6-glucuronide found in the urine of patients on oral morphine therapy were in the mean ratio of 1:20:1.5 [Hand, McQuay, Moore, unpublished observations). The diglucuronide (morphine-3,6-diglucuronide) was also found in urine to a small extent [YEH et al, 1979].

Morphine-3-ethereal sulphate (the major metabolite of morphine in the cat and chicken [MORI et al, 1972]) accounts for perhaps 5% of a dose of morphine in man [YEH et al, 1977]. Ethereal sulphates are formed through the action of hepatic microsomal sulphokinases [BOERNER et al, 1975]. Morphine-6-sulphate, though sought, has not been identified in any species.
Table 1. Metabolism and excretion.

Normorphine and normorphine-6-glucuronide have also been found in human urine [YEH et al, 1977]. Normorphine is formed by hepatic microsomal oxidation and can account for about 5% of urinary excretion products of morphine in man [BOERNER et al, 1975].

Minor metabolites of morphine, such as codeine (3- O -methyl morphine) and morphine N -oxide have been identified in the urine of humans taking large doses of morphine chronically [YEH et al, 1977]. They account for minor proportions (less than 1%) of an administered dose of morphine in man.

B.III.2 Plasma

In plasma, only morphine, M3G and M6G have been identified. M6G was not thought to be present until recent years. Studies using HPLC demonstrated that appreciable levels of M6G were found in the plasma of cancer-pain patients on high oral doses of morphine. The M6G levels were higher than those of morphine itself, and about 10% of the concentration of M3G [SVENSSON et al, 1982].

One study which encapsulates the plasma data [HASSELSTRÖM & SÄWE, 1993], found, after single intravenous 5 mg and oral 20 mg doses of morphine in 7 healthy volunteers, that clearance of morphine to form M3G and M6G was 57.3% and 10.4%, respectively, and renal clearance was 10.9% of total systemic plasma clearance. Twenty percent of a dose remained as unidentified residual clearance. The proportions of the dose found as M6G and M3G were the same by either route. A major finding was a slowly declining phase of morphine and metabolites that was evident both In both plasma and urine the terminal half-lives were long, morphine 15.1 +/- 6.5 h, M3G 11.2 +/- 2.7 h and M6G 12.9 +/- 4.5 h. A greater proportion of morphine and metabolites was excreted during the slowly declining phase after the oral dose than the intravenous dose, which they suggested was due to enterohepatic recycling. The renal clearance of M6G and morphine was exceeded creatinine clearance, which they attributed to an active secretion process.

The time course for the plasma concentrations (measured by using differential radioimmunoassay) of morphine, M3G and M6G after a single oral dose of 10 mg morphine is shown in Figure 2.
Figure 2. Plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide

B.III.3 Central Nervous System (CNS)

Barjavel et al [BARJAVEL et al, 1994] used transcortical microdialysis after subcutaneous morphine, M3G and M6G in rats. Maximum brain opiate concentrations were reached at the same time, 0.75 h. Penetration and elimination rates in the extracellular space of the rat brain cortex for the hydrophilic metabolites were similar to those of morphine. They concluded that in spite of their structural differences the glucuronide metabolites were capable of crossing the blood-brain-barrier at the same rate as morphine, but in greater quantity.

Stain et al [STAIN et al, 1995] found that subcutaneous M6G at the same doses as morphine produced a greater degree of analgesia with longer duration of action on behavioural tests. Concentrations of morphine and M6G in brain extracellular fluid were measured using microdialysis. They concluded that M6G was much more potent than morphine in the rat and attributed the difference to the higher levels of M6G in plasma and brain extracellular fluid.

B.IV. What do they do? - pharmacology

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 & JORGENSEN, 1987].

There is also the prospect of M6G working at a different receptor. Rossi et al [ROSSI et al, 1995] used antisense oligodeoxynucleotides directed against distinct Gi alpha subunits of the morphine receptor to distinguish between morphine and M6G analgesia. The insensitivity of M6G towards the MOR-1 antisense probe and differential sensitivity towards G-protein alpha subunit antisense oligodeoxynucleotides led them to believe that M6G acts through a different opioid receptor than morphine.

B.IV.1 Morphine-3-glucuronide (M3G)

M3G has no analgesic activity [SCHULZ AND GOLDSTEIN, 1972], but it does have central nervous system (CNS) stimulatory effects not mediated through opioid receptors [WOOLF, 1981; YAKSH et al, 1986; YAKSH & HARTY, 1988]. 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]. This is not surprising given the fact that M3G does not bind to opioid receptors.

B.IV.2 Morphine-6-glucuronide (M6G)

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-6-sulphate had been shown to be a more potent antagonist than nalorphine itself [OGURI, 1980]. This greater analgesic potency has been confirmed, with 10 to 20 times greater intrathecal potency of M6G in the rat compared with morphine [PASTERNAK et al, 1987; SULLIVAN et al, 1989].

B.IV.3 Morphine and metabolites: plasma and CSF ratios

The greater potency of M6G compared with morphine has important clinical implications [OSBORNE et al, 1990; MCQUAY et al, 1990]. It has long been known quantitatively to be an important metabolite [BOERNER et al, 1975; SHIMOMURA et al, 1971]. Many studies have now investigated the ratios of parent to metabolite plasma concentrations (Table 2).
Table 2. Morphine and metabolites in plasma and CSF after single morphine doses

Table 2 and Figures 3 and 4 show the ratios of metabolites to morphine in plasma after single doses of morphine, and the ratios of CSF:plasma concentrations for the two metabolites. Despite a variety of assays used and disparate study designs, a pattern does emerge. After single oral doses the median M6G:morphine plasma concentration ratio was 5.4 (range 0.96-11, n=11), and for M3G:morphine 25.0 (range 9.9-56, n=11) (Table 4).
Figure 3. Ratio of M3G to morphine in plasma for single intravenous and oral doses, and for multiple oral doses.
Figure 4. Ratio of M6G to morphine in plasma for single intravenous and oral doses, and for multiple oral doses.

The corresponding ratios after single intravenous doses were about six times lower at 0.6 (range 0.29 - 2.0) for M6G:morphine plasma concentration ratio and 6.1 (2.8 - 11.1) for M3G:morphine (Tables 2 and 4). The difference reflects the first-pass metabolism which applies to the oral route but not the intravenous.

The median plasma concentration ratios for multiple oral doses (Tables 3 and 4) were 5.1 (1.9 - 17) for M6G:morphine and 31.4 (22.1 - 121) for M3G:morphine.
Table 3: Morphine and metabolites in plasma and CSF after multiple morphine doses
Table 4. Summary of plasma morphine/metabolite ratios

These are similar to those found after single oral doses. This implies that there is little difference in metabolism between the single and multiple dosing contexts. It also means that studies of this phenomenon done after either single or multiple doses will be equally valid extrapolated to the other situation. The M6G:morphine plasma ratios of 3.6 and 5 lead straight back into the argument about how much M6G contributes to the total analgesic effect of a dose of morphine (Table 6) [HAND et al, 1987b; MCQUAY et al, 1987; OSBORNE et al, 1988].

The crucial observation for morphine in man is whether the active metabolite morphine-6-glucuronide appears in the central nervous system to interact with opioid receptors and thus produce analgesia. In Table 2 the csf:plasma ratios of M6G and M3G after single doses are shown, and after multiple doses in Table 3. Summmarised (Table 5) there is clear evidence that M6G does indeed penetrate into CSF from plasma.
Table 5. Summary of CSF/plasma ratios of morphine metabolites

There is some hint that M6G penetrates to a greater extent than M3G, perhaps by a multiple of between 2 and 4. Looking at the difference in CSF:plasma ratios between single and multiple doses, the small amount of data shows higher values for both M6G and M3G in CSF after multiple doses. The values for multiple epidural and intrathecal dosing are, not surprisingly, much higher.

B.IV.4 Clinical Effects

Given the greater potency the puzzle then is how much does M6G contribute to the total analgesia resulting from a dose of morphine? Simple calculation suggests that M6G may contribute substantially (Table 6). If the relative potency of M6G to morphine in the CSF of man is similar to that after intrathecal injection in rodents, i.e., about 10-20 fold greater potency [SULLIVAN et al, 1989], then it may be argued that about 60% of the analgesia from multiple doses of morphine may be due to M6G (Table 6).

Against this several clinical studies have failed to show any relationship between M6G plasma concentrations and analgesia or other opioid effects [SOMOGYI et al, 1993; VAN DONGEN et al, 1994], or indeed between M6G:morphine plasma concentration ratio and effect, although others have been more successful [PORTENOY et al, 1992; FAURA et al, 1996], and some have approached this through modelling techniques [WESTERLING et al, 1995]. There are still no adequate randomised double-blind studies of the analgesic and other effects of M6G given on its own.

Hanna et al [HANNA et al, 1990] compared the analgesic efficacy of intrathecal M6G 500 ug with morphine 500 ug in a single-blind crossover study of three patients with chronic cancer pain. The mean (SD) requirement for patient controlled analgesia with pethidine was 393.3 (227.4) mg/24 h during the morphine part of the trial and 226.7 (113.6) mg/24 h with M6G.

Peat et al, [PEAT et al, 1991] studied the respiratory responses to intravenous morphine (0.12 mg/kg), M6G (0.03 mg/kg) and placebo in 6 volunteers, using a single blind randomised crossover design. Five volunteers also had M6G 0.06 mg/kg. After placebo or M6G (at both doses) there was no change in end-tidal CO2 whilst the subjects were breathing air. After morphine there was a significant rise. Morphine reduced the ventilatory response to 5.5% CO2 significantly at all times tested. M6G (at both doses) reduced the response to CO2 at 20 and 40 min after administration, but to a significantly lower extent than morphine.

Thompson et al [THOMPSON et al, 1995] compared analgesia (ischaemic limb) and respiratory function after 10 mg of intravenous morphine or M6G (1, 3.3 and 5 mg) in a double-blind, randomised study of 10 volunteers. Morphine produced significant increase in arterial PCO2 at 45 minutes, and in transcutaneous PCO2 from 15 minutes to 4 hours. Blood gas and transcutaneous PCO2 were unchanged after M6G at all 3 doses.

Osborne et al [OSBORNE et al, 1992] compared the cardio-respiratory and analgesic effects of four different dose levels (0.5, 1, 2, and 4 mg /70 kg) of intravenous M6G in an open study of 20 cancer patients with pain. M6G exerted a 'useful' analgesic effect in 17/19 patients for periods ranging between 2 and 24 h. No correlation was observed between dose or plasma M6G 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.

These preliminary studies do suggest an analgesic effect of M6G, but the claim that M6G has less respiratory depressant potential than morphine will have to be addressed at equianalgesic dosing, and it is not clear that this has been achieved.

B.V. Pathophysiology

B.V.1 Liver disease

Traditional teaching is that use of morphine in patients with liver disease may result in excessive sedation and precipitate hepatic encephalopathy [LAIDLAW et al, 1961; TWYCROSS AND LACK, 1983]. Two studies of morphine kinetics in patients with cirrhosis [PATWARDHAN et al, 1981; HASSELSTROM et al, 1986] have shown only very minor alterations of morphine kinetics in cirrhotic patients.

Subsequent work, however, has shown kinetic change with liver disease. Hasselstrom et al [HASSELSTROM et al, 1990] studied oral and intravenous kinetics of morphine in seven cirrhotic patients with a history of encephalopathy. Morphine plasma clearance was significantly lower, its terminal elimination half-life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. Plasma M3G:morphine ratios were significantly lower in the cirrhotic patients after oral, but not after intravenous, doses. Mazoit et al [MAZOIT et al, 1987] compared plasma morphine concentrations in six volunteers with those in eight cirrhotic patients. Cirrhotics had significantly longer morphine terminal half-life, attributed to lower total body clearance.

B.V.2 Kidney disease

Morphine clearance is decreased and its analgesic effects increased in elderly patients [KAIKO et al, 1982], who have decreased renal function. In renal failure, morphine produced effects and side-effects of unexpected degree and duration [MOSTERT et al, 1971; DON et al, 1975; MCQUAY AND MOORE, 1984; REGNARD AND TWYCROSS, 1984]. The evidence suggests that this is because of the accumulation in plasma of morphine glucuronides, and especially M6G [SAWE et al, 1986; OSBORNE et al, 1986; BODD et al, 1990].

D'Honneur et al [D'HONNEUR et al, 1994] compared plasma and CSF concentrations of morphine glucuronides in patients with normal renal function and those with renal failure. Plasma concentrations of glucuronides were significantly higher. CSF concentrations of M6G and M3G continued to rise over at least 24 hours. At 24 hours CSF M6G concentrations were fifteen times greater in patients with renal failure than in those with normal renal function.

Hanna et al [HANNA et al, 1993] gave 30 ug/kg M6G to 12 patients with chronic renal failure (dialysis-dependent) and 6 with good renal function after renal transplantation. The M6G elimination half-life was significantly shorter, and the clearance greater, for the transplanted group compared with the dialysed and non-dialysed groups.

McQuay [MCQUAY et al, 1990] studied 151 patients with chronic cancer pain during chronic treatment with oral morphine. Dose of morphine, age, sex, renal and hepatic dysfunction, and other drugs accounted for 70% of the variance in plasma concentrations of morphine, M3G and M6G. Plasma creatinine greater than 150 umol/L was associated with significant increase in M3G and M6G plasma concentrations (Figure 4).
Figure 4. Dose-corrected plasma morphine, M3G and M6G concentrations with renal or hepatic dysfunction

Milne [MILNE et al, 1992] gave morphine by constant intravenous infusion to 15 intensive-care patients with diverse renal function. There were significant linear relationships between measured renal creatinine clearance and the renal clearances of morphine, M3G and M6G.

Osborne et al [OSBORNE et al, 1993] compared the pharmacokinetics of morphine and its glucuronide metabolites in three groups of patients with kidney failure (nondialyzed, receiving dialysis, and transplantation) with a group of normal healthy volunteers. Patients with kidney failure had a significantly increased morphine area under the curve (AUC) compared with control subjects. There was also an increase in M3G and M6G that was several times greater than the increase in morphine AUC. This metabolite accumulation was reversed by kidney transplantation.

Peterson et al [PETERSON et al, 1990] found in 21 patients on oral or subcutaneous morphine that plasma concentrations of M3G and M6G, when divided by the morphine concentration, were significantly related to the calculated creatinine clearance of the patient.

Sear et al [SEAR et al, 1989a] compared intravenous morphine 10 mg kinetics in nine patients with end-stage renal failure with five healthy anaesthetised patients. There were no differences between the two groups for morphine elimination half-life or clearance. Peak concentrations of M3G and M6G were significantly greater in the renal transplant patients, as were the AUCs (0-24 h).

Somogyi et al [SOMOGYI et al, 1993] studied 11 cancer patients on long term oral morphine. They could not detect a relationship between the renal clearance of morphine, M3G and M6G, and that of creatinine. Renal tubular handling of all 3 opioids varied widely between patients, and there was evidence of either net renal tubular secretion or reabsorption.

This renal work highlights the role of the kidney in removing the major morphine metabolites. The evidence would seem to be that once renal function declines to a creatinine clearance of 50 ml min -1 or below, then accumulation of morphine metabolites, and especially M6G [BODD et al, 1990] will become significant. Clinical problems should arise only if fixed dose schedules are used at too high an initial dose level.

B.V.3 Drug interactions

Earlier reports of interactions between cimetidine and morphine were rebutted [MOJAVERIAN et al, 1982]. Wahlstrom et al [WAHLSTROM et al, 1994] studied the interactions of tricyclic antidepressants with morphine glucuronidation. All tricylics studied inhibited morphine glucuronidation, nortriptyline in non-competitive and amitriptyline and clomipramine in competitive or mixed manner. Inhibition occurred at a concentration ratio of tricyclic to morphine close to that seen in patients on treatment.

B.VI. Conclusions

Much of the detail of morphine metabolism and excretion is still to be worked out. The clinical implication thus far is that the accumulation of the active metabolite M6G in renal dysfunction may produce both analgesia and unwanted effects. Fixed dose schedules with high initial doses should be avoided if renal problems are suspected. The precise contribution of M6G to the 'total' effect of a dose of morphine remains a puzzle.


Arita H, Kogo N, Ichikawa K (1988) Locations of medullary neurons with non-phasic discharges excited by stimulation of central and/or peripheral chemoreceptors and by activation of nociceptors in cat. Brain Research 442:1-10
Arner S, Meyerson BA (1988) Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 33:11-23
Babul N, Darke AC (1993) Disposition of morphine and its glucuronide metabolites after oral and rectal administration: evidence of route specificity. Clin Pharmacol Ther 54:286-92
Barjavel M, Sandouk P, Plotkine M, Scherrmann JM (1994) Morphine and morphine metabolite kinetics in the rat brain as assessed by transcortical microdialysis. Life-Sci 55:1301-8
Bigler D, Christensen CB, Eriksen J, Jensen N-H (1990) Morphine, morphine-6-glucuronide and morphine-3-glucuronide concentrations in plasma and cerebrospinal fluid during long-term high-dose intrathecal morphine administration. Pain 41:15-18
Bodd E, Jacobsen D, Lund E, Ripel A, Mørland J, Wiik-Larsen E (1990) Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. Human & Experimental Toxicology 9:317-21
Boerner U, Abbott S, Roe RL (1975) The metabolism of morphine and heroin in man. Drug Metabolism Reviews 4:39-73
Borgbjerg FM, Nielsen K, Franks J (1996) Experimental pain stimulates respiration and attenuates morphine induced respiratory depression. A controlled study in human volunteers. Pain 64:123
Braenden OJ, Eddy NB, Halbach H (1955) Synthetic substances with morphine-like effect. Bulletin of the World Health Organisation 13:937-98
Chapman DJ, Cross MJ, Joel SP, Aherne GW (1995) A specific radioimmunoassay for the determination of morphine-6-glucuronide in human plasma. Ann Clin Biochem 32:297-302
Christensen CB, Jorgensen LN (1987) Morphine-6-glucuronide has high affinity for the opioid receptor. Pharmacology and Toxicology 60:75-76
Colpaert FC, Niemegeers CJE, Janssen PAJ, Maroli AN (1980) The effects of prior fentanyl administration and of pain on fentanyl analgesia: tolerance to and enhancement of narcotic analgesia. Journal of Pharmacology & Experimental Therapeutics 213:418-426
Coughtrie MWH, Ask B, Rane A, Burchell B, Hume R (1989) The enantioselective glucuronidation of morphine in rats and humans. Biochemical Pharmacology 38:3273-3280
Dechelotte P, Sabouraud A, Sandouk P, Hackbarth I, Schwenk M (1993 Jan-Feb) Uptake, 3-, and 6-glucuronidation of morphine in isolated cells from stomach, intestine, colon, and liver of the guinea pig. Drug-Metab-Dispos 21:13-7
D'Honneur G, Gilton A, Sandouk P, Scherrmann JM, Duvaldestin P (1994 Jul) Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology 81:87-93
Don HF, Dieppa RA, Taylor P (1975) Narcotic analgesics in anuric patients. Anesthesiology 42:745-747
Faura CC, Moore RA, Horga JF, Hand CW, McQuay HJ (1996) Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain. Journal of Pain and Symptom Management 11:95-102
Gong Q-L, Hedner T, Hedner J, Björkman R, Hedner T (1992) Morphine-3-glucuronide may functionally antagonise morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 48:249-255
Goucke CR, Hackett LP, Ilett KF (1994) Concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide in serum and cerebrospinal fluid following morphine administration to patients with morphine-resistant pain. Pain 56:145-9
Hand CW, Blunnie WP, Claffey LP, McShane AJ, McQuay HJ, Moore RA (1987b) Potential analgesic contribution from morphine-6-glucuronide in CSF [letter]. Lancet 2:1207-8
Hand CW, Moore RA, McQuay HJ, Allen MC, Sear JW (1987a) Analysis of morphine and its major metabolites by differential radioimmunoassay. Annals of Clinical Biochemistry 24:153-60
Hanks GW, Twycross RG, Lloyd JW (1981) Unexpected complication of successful nerve block. Anaesthesia 36:37-39
Hanna MH, D'Costa F, Peat SJ, Fung C, Venkat N, Zilkha TR, Davies S (1993) Morphine-6-glucuronide disposition in renal impairment. Br J Anaesth 70:511-4
Hanna MH, Peat SJ, Woodham M, Knibb A, Fung C (1990) Analgesic efficacy and csf pharmacokinetics of intrathecal morphine-6-glucuronide: comparison with morphine. British Journal of Anaesthesia 64:547-550
Hasselstrom J, Eriksson S, Persson A, Rane A, Svensson JO, Sawe J (1990) The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. British Journal of Clinical Pharmacology 29:289-297
Hasselstrom J, Eriksson LS, Persson A, Rane A, Svensson JO, Sawe J (1986) Morphine metabolism in patients with liver cirrhosis. Acta Pharmacologica et Toxicologica, Suppl V:101
Hasselström J, Säwe J (1993) Morphine pharmacokinetics and metabolism in humans. Enterohepatic recycling and relative contribution of metabolites to active opioid concentrations. Clinical Pharmacokinetics 24:344-54
Hewett K, Dickenson AH, McQuay HJ (1993) Lack of effect of morphine-3-glucuronide on the spinal antinociceptive actions of morphine in the rat: an electrophysiological study. Pain 53:59-63
Hoskin PJ, Hanks GW, Aherne GW, Chapman D, Littleton P, Filshie J (1989) The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers. British Journal of Clinical Pharmacology 27:499-505
Houde RW (1985) The analgesic connection: the Nathan B. Eddy memorial lecture. 55. In: Harris LS (ed) Problems of drug dependence. NIDA Research Monograph, p 4-13
Houde RW, Wallenstein SL, Beaver WT (1966) Evaluation of analgesics in patients with cancer pain. In: Lasagna L (ed) International Encyclopedia of Pharmacology and Therapeutics. Pergamon Press, Oxford, p 59-98
Inturrisi CE, Max M, Umans J, Schultz M, Shin S, Foley KM, Houde R (1984) The pharmacokinetics of heroin in patients with chronic pain. New England Journal of Medicine 310:1213-1217
Iwamoto K, Klaasen CD (1978) Uptake of morphine and nalorphine by isolated rat hepatocytes. Journal of Pharmacology & Experimental Therapeutics 206:181-189
Jadad AR, Carroll D, Glynn CJ, Moore RA, McQuay HJ (1992) Morphine responsiveness of chronic pain: double-blind randomised crossover study with patient-controlled analgesia. Lancet 339:1367-71
Jones SF, McQuay HJ, Moore RA, Hand CW (1988) Morphine and ibuprofen compared using the cold pressor test. Pain 34:117-22
Kaiko RF, Wallenstein SL, Rogers AG, Grabinski PY, Houde RW (1982) Narcotics in the elderly. Medical Clinics of North America 66:1079-1089
Knodell RG, Farleigh RM, Steele NM, Bond JH (1982) Effects of liver congestion on hepatic drug metabolism in the rat. Journal of Pharmacology & Experimental Therapeutics 221:52-57
Kupers RC, Konings H, Adriaensen H, Gybels JM (1991) Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain. Pain 47:5-12
Laidlaw J, Read AE, Sherlock S (1961) Morphine tolerance in hepatic cirrhosis. Gastroenterology 40:389-396
Mazoit JX, Sandouk P, Scherrmann JM, Roche A (1990 Dec) Extrahepatic metabolism of morphine occurs in humans. Clin-Pharmacol-Ther 48:613-8
Mazoit JX, Sandouk P, Zetlaoui P, Scherrmann JM (1987 Apr) Pharmacokinetics of unchanged morphine in normal and cirrhotic subjects. Anesth-Analg 66:293-8
McQuay HJ (1990) The logic of alternative routes. Journal of Pain & Symptom Management 5:75-7
McQuay HJ (1991) Opioid clinical pharmacology and routes of administration. British Medical Bulletin 47:703-17
McQuay HJ (1989) Opioids in chronic pain. British Journal of Anaesthesia 63:213-26
McQuay HJ (1988) Potential problems of using both opioids and local anaesthetic [letter]. British Journal of Anaesthesia 61:121
McQuay HJ, Carroll D, Faura CC, Gavaghan DJ, Hand CW, Moore RA (1990) Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clinical Pharmacology & Therapeutics 48:236-44
McQuay H, Moore A (1984) Metabolism of narcotics [letter]. British Medical Journal 288:237
McQuay H, Moore A (1994) Need for rigorous assessment of palliative care. BMJ 309:1315-6
McQuay HJ, Moore RA, Hand CW, Sear JW (1987) Potency of oral morphine [letter]. Lancet 2:1458-9
Milne RW, McLean CF, Mather LE, Nation RL, Runciman WB, Rutten AJ, Somogyi AA (1995 Mar) Comparative disposition of morphine-3-glucuronide during separate intravenous infusions of morphine and morphine-3-glucuronide in sheep. Importance of the kidney. Drug-Metab-Dispos 23:334-42
Milne RW, Nation RL, Somogyi AA, Bochner F, Griggs WM (1992) The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients. Br J Clin Pharmacol 34:53-9
Milne RW, Sloan PA, McLean CF, Mather LE, Nation RL, Runciman WB, Rutten AJ, Somogyi AA (1993 Nov-Dec) Disposition of morphine and its 3- and 6-glucuronide metabolites during morphine infusion in the sheep. Drug-Metab-Dispos 21:1151-6
Mojaverian P, Fedder IL, Vlasses PH, Rotmensch HH, Rocci ML, Swanson BN, Ferguson RK (1982) Cimetidine does not alter morphine disposition in man. British Journal of Clinical Pharmacology 14:809-813
Moore RA, Hand CW, McQuay HJ (1987) Opioid metabolism and excretion. In: Budd K (ed) Update in Opioids. Clinical Anaesthesiology. Baillere Tindall, London, p 829-858
Mori M, Oguri K, Yoshimura H, Shimomura K, Kamata O, Ueki S (1972) Chemical synthesis and analgesic effect of morphine ethereal sulfates. Life Sciences 11:525-533
Mostert J, Evers JL, Hobika JH, Moore RH, Ambrus JL (1971) Cardiorespiratory effects of anaesthesia with morphine or fentanyl in chronic renal failure and cerebral toxicity after morphine. British Journal of Anaesthesia 43:1053-1060
Nagle CJ, McQuay HJ (1990) Opiate receptors; their role in effect and side-effect. Current Anaesthesia & Critical Care 1:247-252
Oguri K (1980) Conjugated metabolites of morphine and their pharmacological activity. Yakugaku Zasshi 117-25
Osborne R, Joel S, Trew D, Slevin M (1988) Analgesic activity of morphine-6-glucuronide. Lancet 1:828
Osborne RJ, Joel SP, Slevin ML (1986) Morphine intoxication in renal failure: the role of morphine-6-glucuronide. British Medical Journal 292:1548-9
Osborne R, Joel S, Trew D, Slevin M (1990) Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clinical Pharmacology and Therapeutics 47:12-19
Osborne R, Joel S, Grebenik K, Trew D, Slevin M (1993) The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clinical Pharmacology and Therapeutics 54:158
Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M (1992) The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 34:130-8
Owen JA, Nakatsu K (1984) Morphine diesters. II. Blood metabolism and analgesic activity in the rat. Can J Physiol Pharmacol 62:452-456
Pasternak GW, Bodnar RJ, Clark JA, Inturrisi CE (1987) Morphine-6-glucuronide, a potent mu agonist. Life Sciences 41:2845-2849
Patwardhan RV, Johnson RF, Hoyumpa A, Sheehan JJ, Desmond PV, Wilkinson GR, Branch RA, Schenker S (1981) Normal metabolism of morphine in cirrhosis. Gastroenterology 81:1006-1011
Peat SJ, Hanna MH, Woodham M, Knibb AA, Ponte J (1991) Morphine-6-glucuronide effects on ventilation in normal volunteers. Pain 45:101
Peterson GM, Randall CT, Paterson J (1990) Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 38:121-4
Portenoy RK, Foley KM, Inturrisi CE (1990) The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 43:273-286
Portenoy RK, Foley KM, Stulman J, Khan E, Adelhardt J, Layman M, Cerbone DF, Inturrisi CE (1991a) Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure. Pain 47:13-19
Portenoy RK, Khan E, Layman M et al. (1991b) Chronic morphine therapy for cancer pain: plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations. Neurology 41:1457
Portenoy RK, Thaler HT, Inturrisi CE, Friedlander-Klar H, Foley KM (1992) The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clinical Pharmacology and Therapeutics 51:422-431
Porter J, Jick H (1980) Addiction rate in patients treated with narcotics. New England Journal of Medicine 302:123
Poulain P, Hoskin PJ, Hanks GW, A-Omar O, Walker VA, Johnston A et al. (1988) Relative bioavailability of controlled release morphine tablets (MST Continus) in cancer patients. British Journal of Anaesthesia 61:569-74
Poulain P, Ribon AM, Hanks GW, Hoskin PJ, Aherne GW, Chapman DJ (1990) CSF concentrations of morphine-6-glucuronide after oral administration of morphine. Pain 41:115-6
Rance MJ, Shillingford JS (1977) The metabolism of phenolic opiates by rat intestine. Xenobiotica 7:529-536
Rane A, Gawronska-Szlarz B, Svensson J (1985) Natural (-) and unnatural (+) enantiomers of morphine: comparative metabolism and effect of morphine and phenobarbital treatment. Journal of Pharmacology & Experimental Therapeutics 234:761-765
Ratcliffe PJ, Sear JW, Hand CW, Moore RA (1985) Morphine transport in the isolated perfused rat kidney. Proceedings of EDTA-ERA 22:1109-14
Regnard CFB, Twycross RG (1984) Metabolism of narcotics. British Medical Journal 288:860-860
Rossi GC, Standifer KM, Pasternak GW (1995 Sep 29) Differential blockade of morphine and morphine-6 beta-glucuronide analgesia by antisense oligodeoxynucleotides directed against MOR-1 and G-protein alpha subunits in rats. Neurosci-Lett 198:99-102
Samuelsson H, Hedner T, Venn R, Michalkiewicz A (1993) CSF and plasma concentrations of morphine and morphine glucuronides in cancer patients receiving epidural morphine. Pain 52:179-85
Sandouk P, Serrie A, Scherrmann JM, Langlade A, Bourre JM (1991) Presence of morphine metabolites in human cerebrospinal fluid after intracerebroventricular administration of morphine. Eur J Drug Metab Pharmacokinet 3:166-71
Säwe J (1986) Morphine and its 3- and 6-glucuronides in plasma and urine during chronic oral administration in cancer patients. In: Foley KM, Inturrisi CE (Eds) Advances in Pain Research & Therapy, Vol. 8. Opioid Analgesics in the Management of Clinical Pain. Raven Press, New York, p 45-55
Sawe J, Dahlstrom B, Rane A, Svensson J-O (1983) Steady state kinetics and analgesic efect of oral morphine in cancer patients. European Journal of Clinical Pharmacology 24:537-542
Sawe J, Kager L, Svensson J-O, Rane A (1995) Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation. British Journal of Clinical Pharmacology 19:495-501
Sawe J, Odar-Cederlof I, Svensson JO, Arner B (1986) Kinetics of morphine in patients with renal failure. Acta Pharmacologica et Toxicologica Suppl V:102
Sawe J, Pacifici GM, Kager L, von_Bahr C, Rane A (1982) Glucuronidation of morphine in human liver and interaction with oxazepam. Acta Anaesthesiologica Scandinavica S74:47-51
Schali C, Roch-Ramel F (1982) Transport and metabolism of [3H]morphine in isolated, nonperfused proximal tubular segments of the rabbit kidney. Journal of Pharmacology & Experimental Therapeutics 223:811-815
Schulz R, Goldstein A (1972) Inactivity of narcotic glucuronides as analgesics and on guinea-pig ileum. Journal of Pharmacology and Experimental Therapeutics 183:404-410
Sear JW, Hand CW, Moore RA, McQuay HJ (1989a) Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites. British Journal of Anaesthesia 62:28-32
Sear JW, Hand CW, Moore RA (1989b) Studies on morphine disposition: plasma concentrations of morphine and its metabolites in anesthetized middle-aged and elderly surgical patients. J Clin Anesth 1:164-9
Sear JW, Hand CW, Moore RA, McQuay HJ (1989c) Studies on morphine disposition: influence of general anaesthesia on plasma concentrations of morphine and its metabolites. British Journal of Anaesthesia 62:22-27
Shimomura K, Kamata O, Ueki S, Ida S, Oguri K, Yoshimura H, Tsukamoto H (1971) Analgesic effect of morphine glucuronides. Tohoku Journal of Experimental Medicine 105:45-52
Smith MT, Watt JA, Cramond T (1990) Morphine-3-glucuronide - a potent antagonist of morphine analgesia. Life Sciences 47:579-585
Somogyi AA, Nation RL, Olweny C, Tsirgiotis P, van Crugten J, Milne RW, Cleary JF, Danz C, Bochner F (1993) Plasma concentrations and renal clearances of morphine, morphine-3-glucuronide and morphine-6-glucuronide in cancer patients receiving morphine. Clinical Pharmacokinetics 24:413-20
Stain F, Barjavel MJ, Sandouk P, Plotkine M, Scherrmann JM, Bhargava HN (1995 Aug) Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-D-glucuronide in the rat. J-Pharmacol-Exp-Ther 274:852-7
Sullivan AF, McQuay HJ, Bailey D, Dickenson AH (1989) The spinal antinociceptive actions of morphine metabolites morphine-6-glucuronide and normorphine in the rat. Brain Research 482:219-24
Suzuki N, Kalso E, Rosenberg PH (1993) Intrathecal morphine-3-glucuronide does not antagonize spinal antinociception by morphine or morphine-6-glucuronide in rats. European Journal of Pharmacology 249:27-250
Svensson J-O, Rane A, Sawe J, Sjoquist F (1982) Determination of morphine, morphine-3-glucuronide and (tentatively) morphine-6-glucuronide in plasma and urine using ion-pair high performance liquid chromatography. Journal of Chromatography 230:427-432
Tasker RAR, Nakatsu K (1984) Evaluation of 3, 6-dibutanoylmorphine as an analgesic in vivo: comparison with morphine and 3, 6-diacetylmorphine. Life Sciences 34:1659-67
Tasker RR, Tsuda T, Hawrylyshyn P (1983) Clinical neurophysiological investigation of deafferentation pain. In: Bonica JJ, Lindblom U, Iggo A ((Eds.)) Advances in Pain Research & Therapy. Vol. 5. Proc 3rd World Congress on Pain. Raven Press, New York, p 713-738
Thompson PI, Joel SP, John L, Wedzicha JA, Maclean M, Slevin ML (1995) Respiratory depression following morphine and morphine-6-glucuronide in normal subjects. Br J Clin Pharmacol 40:145-52
Twycross RG, Lack S (1983) Symptom Control in Far Advanced Cancer; Pain Relief. Pitman, London,
Van Crugten JT, Sallustio BC, Nation RL, Somogyi AA (1991 Nov-Dec) Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney. Drug-Metab-Dispos 19:1087-92
van Dongen RT, Crul BJ, Koopman-Kimenai PM, Vree TB (1994) Morphine and morphine-glucuronide concentrations in plasma and CSF during long-term administration of oral morphine. Br J Clin Pharmacol 38:271-3
Wahlstrom A, Lenhammar L, Ask B, Rane A (1994) Tricyclic antidepressants inhibit opioid receptor binding in human brain and hepatic morphine glucuronidation. Pharmacol Toxicol 75:23-7
Wahlstrom A, Winblad B, Bixo M, Rane A (1988) Human brain metabolism of morphine and naloxone. Pain 35:121-127
Westerling D, Persson C, Hoglund P (1995) Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide after intravenous and oral administration to healthy volunteers: relationship to nonanalgesic actions. Ther Drug Monit 17:287-301
Wilkinson TJ, Robinson BA, Begg EJ, Duffull SB, Ravenscroft PJ, Schneider JJ (1992) Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients. Cancer-Chemother-Pharmacol 31:251-4
Wolff T, Samuelsson H, Hedner T (1995 Aug) Morphine and morphine metabolite concentrations in cerebrospinal fluid and plasma in cancer pain patients after slow-release oral morphine administration. Pain 62:147-54
Woolf CJ (1981) Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Research 29:491-495
Yaksh TL, Harty GJ, Onofrio BM (1986) High doses of spinal morphine produce a nonopiate receptor mediated hyperesthesia; clinical and theoretic implications. Anesthesiology 64:590-597
Yaksh TL, Harty GJ (1988) Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine. Journal of Pharmacology & Experimental Therapeutics 244:501-507
Yeh SY, Gorodetzky CW, Krebs HA (1977) Isolation and identification of morphine 3- and 6-glucuronide, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans. Journal of Pharmaceutical Sciences 66:1288-93
Yeh SY, Krebs HA, Gorodetzky CW (1979) Isolation and identification of morphine. N-oxide [[alpha]]- and ß-dihydromorphines, ß- or [[gamma]]-isomorphine, and hyroxylated morphine as morphine metabolites in several mammalian species. Journal of Pharmaceutical Sciences 68:133-40
Yoshimura H, Ida S, Oguri K, Tsukamoto H (1973) Biochemical basis for analgesic activity of morphine-6-glucuronide -- I. Penetration of morphine-6-glucuronide in the brain of rats. Biochemical Pharmacology 22:1423-30
Table 1. Metabolism and excretion.
Drug              Metabolic paths     Faeces       Urine                         
                                      % of dose    % of dose                     
Morphine          glucuronidation     trace        90% in 24 h of which: 10%     
                  sulphation                       morphine 70% glucuronides     
                  N-dealkylation                   10% 3-sulphate 1%             
                                                   normorphine 3% normorphine    
Codeine           O-demethylation     trace        86% in 24 h of which: 5-10%   
                  glucuronidation                  codeine 60% codeine           
                                                   glucuronide 5-15% morphine    
                                                   (mainly conjugated) trace     
Heroin            O-deacetylation     trace        80% in 24 h of which: 5-7%    
                  glucuronidation                  morphine 90% morphine         
                                                   glucuronides 1%               
                                                   6-acetylmorphine 0.1% heroin  
Buprenorphine     glucuronidation     70% mainly   2-13% in 7 days of which      
                  N-dealkylation      unchanged    mainly:                       
                                                   N-dealkylbuprenorphine (and   
Pethidine         N-demethylation                  70% in 24 h of which: 10%     
                  hydrolysis                       pethidine 10% norpethidine    
                                                   20% pethidinic acid 16%       
                                                   pethidinic acid glucuronide   
                                                   8% norpethidinic acid 10%     
                                                   norpethidinic acid            
                                                   glucuronide plus small        
                                                   amounts of other metabolites  
Methadone         N-dealkylation      30%          60% in 24 h of which: 33%     
                                                   methadone 43% EDDP 10% EMDP   
                                                   plus small amounts of other   
Fentanyl          N-dealkylation      9%           70% in 4 days of which:       
                  hydroxylation                    5-25% fentanyl 50%            
                                                   eridine) plus other           

Table 2. Morphine and metabolites in plasma and CSF after single morphine doses
Reference     Patient    Route     N   Dose   Time   Origin   M6G:M   M3G:M    M6G    M3G
               group                   (mg)            of     plasma  plasma  CSF :   CSF
                                                      ratio                   plasma 
BABUL &       voluntee    oral     6    10    24 hr  AUC       2.7    18.3           
DARKE, 1993   rs                                                                         
                         rectal    6    10    24 hr  AUC       1.3    9.3                
D'HONNEUR     elective    oral     8    30    4 hr   single    5.4    22      0.07    0.1
et al, 1994   surgery,                               sample                              
              elective    oral     6    30    4 hr   single    9.9    25      0.018  
              surgery,                               sample                              
HASSELSTROM   voluntee    oral     7    20    72 hr  AUC       3.6    29.9               
& SAWE, 1993  rs                                                                     
                           iv            5    72 hr  AUC       0.7    7.7                
HAND et al,   elective     im     15    10    95     single    0.37   4.3     0.023  
1987b         surgery                         min    sample                              
                          oral    11   30 CR  140    single    0.96   9.9     0.008  
                                              min    sample                              
   HOSKIN et  voluntee  oral/buc   6    10    12 hr  AUC        11                       
    al, 1989        rs    cal                                                            
                           iv      6     5    12 hr  AUC        2                        
OSBORNE et    voluntee    oral    10   11.7   12 hr  AUC       9.7    55.8               
al, 1990      rs                                                                         
                           iv     10     5    12 hr  AUC       1.4    7.9                
POULAIN et    patients    oral     2    10    12 hr  AUC        10            0.27       
al, 1990                                                                                 
SÄWE et al,   patients    oral     6   20/25  24 hr  AUC       2.5    24.4          
                           iv      6     4    24 hr  AUC              11.1               
SEAR et al,   anesthet     iv      5    10    24 hr  AUC       0.43   3.3                
1989a         ised                                                                       
              anesthet     iv      9    10    24 hr  AUC       1.78   10.6               
 SEAR et al,  anesthet     iv     10    10    180    AUC       0.58   4.5                
       1989b  ised                            min                                        
              anesthet     iv     10    10    180    AUC       0.37   3.6                
              ised                            min                                        
 SEAR et al,  anesthet     iv     10    10    180    AUC       0.54   4.3                
       1989c  ised                            min                                        
              awake        iv      9    10    180    AUC       0.29   2.8                
WESTERLING    voluntee     iv     14    10    72 hr  AUC       1.4    7.6                
et al, 1995   rs                                                                         
                          oral    14    30    72 hr  AUC       6.4    32.4               
                        oral CR   14    30    72 hr  AUC       5.4    28.1               
 im = intramuscular, iv = intravenous; CR = controlled release; AUC = area under the     

Table 3: Morphine and metabolites in plasma and CSF after multiple morphine doses
Reference        Route      N      Time     Origin of   M6G:M   M3G:M     M6G    M3G     

                                              ratio     plasma  plasma   CSF :   CSF :   

                                                                        plasma   plasma  

BIGLER et     intrathecal   1    5 hr       AUC          0.75   4.6       0.8    0.25    

al, 1990                                                                                 

FAURA et      oral          39   60         single       5.8    46                       

al, 1995                         minutes    sample                                       





GOUCKE et     oral          9    4 hr       single       3.8    22.1     0.14    0.16    

al, 1994                         after      sample                                       


                                 dose, CR                                                

              subcutaneou   2                                                            


MCQUAY et     oral         151   random     single       5.1    28.4                     

al, 1990                                    sample                                       

PETERSON et   oral          21   trough     single        4     28.8                     

al, 1990                                    sample                                       



PORTENOY et   oral (2)/     3    random     single       1.9             0.08 (ventric)  
al, 1991b     iv (1)                        sample                                       
              oral (3) /    8    random     single                       0.12 (lumbar)   
              iv (5)                        sample                                       
PORTENOY et   intravenous   8    random     single       1.2                             

al, 1991a     infusion                      sample                                       

PORTENOY et   3 hr iv       14   7 hr       AUC          0.54                            

al, 1992      infusion                                                                   

POULAIN et    oral          10   12 hr      AUC          8.1    45                       

al, 1988                                                                                 

SAMUELSSON    epidural     14-3  trough     single        2     8.4      0.33    0.27    

et al, 1993                 5               sample                                       

SAWE et al,   oral          2    4-6 hr     AUC           4     34                       

1983          solution                                                                   

SAWE, 1986    oral          15   4 hr       AUC          2.7    24.2                     

TISEO et      oral          71   random /   single       6.1                             

al, 1995                         trough     sample                                       

              parenteral    38   random /   single       2.7                             

                                 trough     sample                                       

WILKINSON     oral          10   12 hr      AUC          6.2    49                       

et al, 1992                                                                              

              rectal        10   12 hr      AUC          4.2    29                       

WOLFF et      oral          34   trough     single        17    121      0.09    0.14    

al, 1995                                    sample                                       

 Blank cells indicate where no information was given or found. Dosing was variable for   
 these patients with chronic cancer pain. Median values were taken where available. CR   
                                 = controlled release.                                   

Blank cells indicate where no information was given or found. Dosing was variable for these patients with chronic cancer pain. Median values were taken where available.
Table 4. Summary of plasma morphine/metabolite ratios
                        Morphine-6-glucuronide         Morphine-3-glucuronide         
Status  Route  Studies  Mean     Median   Range    Mean     Median   Range    
Single  IV       11     0.9      0.6      0.29 -   6.3      6.1      2.8 -    
                                          2                          11.1     
Single  oral     11     6.1      5.4      0.96 -   27.3     25.0     9.9      
                                          11                         -55.8    
Multip  oral     11     5.9      5.1      1.9 -    43.7     31.4     22.1 -   
le                                        17                         121      

Table 5. Summary of CSF/plasma ratios of morphine metabolites
                                Morphine-6-glucuronide          Morphine-3-glucuronide   
Status    Route       Studies   Mean    Median    Range     Mean    Median    Range    
Single    IM             1      0.023                       0.005                      
Single    oral           4     0.0915   0.044    0.008 -   0.0393   0.014    0.004 -   
                                                   0.27                        0.1     
Multiple  oral           2      0.115            0.09/0.1   0.15             0.14/0.1  
                                                    4                           6      
Multiple  epidural       1      0.33                        0.27                       
Multiple  intratheca     1     0.8                          0.25                       

Table 6. CSF concentrations of morphine and morphine-6-glucuronide
                                        Morphine    M-6-G         
CSF concentration relative to              1        0.12          
CSF potency relative to morphine*          1        13            
Contribution to analgesia **               1        1.56          
Percent of total analgesia                 39       61            

Values for CSF concentrations are from muultiple oral dosing (Table 5). * intrathecal potency relative to morphine for morphine-6-glucuronide (M6G) from [SULLIVAN et al, 1989]. ** The contribution to analgesia is calculated by multiplying the CSF concentration relative to morphine by the relative potencies.
Figure 1. Structural formulae for morphine, diamorphine and metabolites.

Figure 2. Plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide

Plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide after a single oral dose of 10 mg morphine sulphate pentahydrate in 12 volunteers (mean+/-sem). Redrawn from [JONES et al, 1988].
Figure 3. Ratio of M3G to morphine in plasma for single intravenous and oral doses, and for multiple oral doses.

Figure 4. Ratio of M6G to morphine in plasma for single intravenous and oral doses, and for multiple oral doses.

Figure 5. Dose-corrected plasma concentrations (nmol.L-1 / mg.day-1) for morphine, M3G and M6G for patients with normal renal and hepatic function (n=95), renal dysfunction (n=15) and hepatic dysfunction (n=30). Redrawn from [MCQUAY et al, 1990].

Significantly higher plasma concentrations of M3G and M6G in renal dysfunction (** P<0.01, Newman-Keuls test).