Levomepromazine

Morphine is the drug of choice for patients with severe acute or chronic pain, especially those with intractable pain associated with malignant diseases. The drug is metabolised by the liver into morphine-3-glucuronide and morphine-6-glucuronide. The glucuronides are mainly eliminated via bile and urine.[1] Morphine-6-glucuronide binds to opiate receptors and can be detected in the cerebral fluid after systemic administration; its analgesic effect is 40 times as potent as that of morphine itself.[2] In contrast, morphine-3-glucuronide, which represents the major plasma and urinary metabolite of morphine, antagonises the effect of morphine and morphine-6-glucuronide.[3]

According to the World Health Organisation's recommendations for treatment of cancer pain, the morphine dose should be adapted to the individual patient. Therefore, if patients complain of an insufficient analgesic response to standard morphine dosage, they should receive higher doses, which may exceed hundreds of milligrams of morphine hourly.[4] In a few adults treated with higher dosages for prolonged periods of time, morphine induced hyperalgesia or allodynia develops.[5 6]

Allodynia has been provoked in Sprague-Dawley rats. These animals are unable to metabolise morphine to morphine-6-glucuronide, and thus morphine-3-glucuronide is the major morphine metabolite. A noticeable inverse relation was observed between the mean degree of analgesia and ratio of plasma morphine-3-glucuronide to morphine.[7] Consequently, a raised morphine-3-glucuronide to morphine-6-glucuronide ratio seems to be responsible for the phenomenon of hyperalgesia and allodynia.

There are only a few reports analysing the ratio of morphine and its metabolites in adult patients and children of various ages.[8-10] Children metabolise morphine differently from adults, and the morphine-3-glucuronide to morphine ratio, in particular, is dependent on age. In addition, the plasma morphine-3-glucuronide to morphine-6-glucuronide ratio in children is half the ratio in adults.[6-8]

Allodynia and hyperalgesia induced by high amounts of morphine have already been described in adult patients.[11] However, to our knowledge, morphine induced hyperalgesia has not been reported in children so far.[5] In addition, in many previous articles concerning adult patients with hyperalgesia, the morphine and metabolite plasma concentrations were not measured.[12]

Case report

A 9 month old girl presented with astrocytoma of the hypothalamus that had been incompletely resected and remained inoperable because of its position. Progressive tumour growth resulted in impaired speech, gross motor functions, and swallowing at the age of 21 months. Parenteral nutrition became necessary because of persistent vomiting. When routine nursing resulted in pain, treatment with tramadol was started, and a continuous infusion of morphine in a dose of 10 g/kg per hour was instigated when tramadol proved ineffective. When sporadic seizures further complicated the course of the disease on day 16 and day 20, phenobarbital (10-15 mg/kg per 8 hours; day 16) and then flunitrazepam (0.04 mg/kg per hour; day 47) were added, but no impact on pain relief was achieved. A stepwise increase in the morphine dose resulted in sufficient pain relief for periods of only a few days during the next three weeks. Even when the dose was further augmented up to a maximum of 6950 g/kg per hour (2.5 g per day) during the following 4 weeks, the child showed extreme discomfort, cried, and moaned during routine care procedures such as nappy changing, feeding, or washing. In this situation morphine induced hyperalgesia and allodynia was suspected, and the morphine dose was reduced (day 53). At irregular intervals over the next month the dose was reduced by 50% until a dose of 280 g/kg per hour was reached (day 78). When morphine was reduced the following drugs were given: methotrimeprazine (levomepromazine; 0.1 mg/kg per 8 hours) to improve sedation, dexamethasone (1 mg/kg per 6 hours) to reduce intracranial pressure, and dypirone (20 mg/kg per 8 hours) as a peripheral analgesic agent (figure).

Within 1 week the symptoms of allodynia had resolved and the child was able to tolerate care procedures well. Concentrations of plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide were determined on four different occasions (days 60, 69, 81, and 99) and were high, particularly the ratio of morphine-3-glucuronide to morphine (table). When the morphine dose was further reduced, the milos also fell, but after some delay, possibly because of renal insufficiency.[13] Until her death at the age of 28 months, the patient was almost free of pain and sufficiently sedated.

M=morphine; M6G=morphine-6-glucuronide; M3G=morphine-3-glucuronide.

Discussion

Morphine induced hyperalgesia, allodynia, and myoclonia have been described in adult patients.[5 11] Hyperalgesia is defined as an increased response to a stimulus which is normally painful, and allodynia is defined as pain caused by a stimulus which does not normally provoke pain. These phenomena were observed after large amounts as well as after small doses of morphine. In view of the young age of our patient we can only speculate that she suffered more from allodynia than hyperalgesia since even routine nursing procedures seemed to cause pain.

The observation that hyperalgesia can be caused by morphine itself or by its metabolites is so far supported only by data from animal studies. Smith et al showed in experiments with Sprague-Dawley rats that morphine-6-glucuronide given intracerebroventricularly had a good analgesic effect.[3] The administration of morphine-3-glucuronide alone produced allodynia, hyperalgesia, and tremor in rats. In addition, these authors showed that morphine-3-glucuronide is a potent antagonist of the analgesic effect of morphine or, more specifically, morphine-6-glucuronide.[3] Further experiments showed that high doses of morphine have a lesser analgesic effect than low doses. After high doses of morphine, the morphine-3-glucuronide to morphine plasma ratio was higher than after low doses. Thus, a high morphine-3-glucuronide to morphine ratio could be the explanation for this phenomenon. However, other studies focusing on neoplastic neuronal changes show that receptor mediated cellular and intracellular signal cascades, such as those observed after nerve injury and inflammation, might also contribute to morphine induced hypemlgesia.[14 15]

To our knowledge, the case presented here is the first to show that children are also prone to morphine induced hyperalgesia and allodynia. There are only a few reports detailing plasma concentrations of morphine and its metabolites in children. Choonara et al found a mean plasma morphine-3-glucuronide to morphine ratio of 23.9 (SD 6.4) in children aged between I year and 16 years.[9] The plasma ratio was threefold to fivefold lower in premature neonates and infants than in older children.[10]

When morphine induced allodynia was suspected in our patient, the absolute morphine plasma concentration was not extremely high, although large doses had been given. However, the morphine-3-glucuronide to morphine ratio was very high at 42 (table). The ratios approached normal values 3 weeks after the dose of morphine has been reduced. Since the absolute plasma concentration of morphine did not correlate with the administered dose during the course of the treatment it might be more useful for ruling out allodynia to determine the metabolite ratios.

The WHO recommendation for treating tumour pain advises that the dose of morphine should be raised until the patient is free of pain.[4] This works in most patients, but the possibility of morphine induced hyperalgesia or allodynia must not be overlooked.[16] The morphine metabolite morphine-3-glucuronide may play an important part in the development of these phenomena. In contrast to adults, children exhibit an age dependent difference in drug metabolisation and kinetics. The case presented here suggests that experimental results from animals on morphine induced hyperalgesia and allodynia also hold true for man. It also emphasises the importance of considering morphine induced hyperalgesia and allodynia in children who receive high doses of morphine without achieving sufficient pain relief.

In most clinical laboratories quantitative measurements of morphine and its metabolites are not performed routinely. The method of high performance liquid chromatography we used provides a specific, sensitive, and rapid assay. It is useful for the simultaneous determination of morphine and its metabolites in plasma and can rule out raised concentrations of morphine-3-glucuronide.

We thank Dr Christan Mignat for advice on the assays for morphine and its metabolites and Joanna Voerste for language editing of the manuscript.

MS initiated and coordinated the paper and acts as guarantor. The paper was written jointly by SH, CM, and MS; they discussed the core ideas and interpreted the findings. KO undertook the morphine analysis. UH collected blood samples, participated in the data analysis, and together with SH and CM looked after the patient.

What is allodynia?

Allodynia is the term used when any normally painless stimulus is experienced as painful. Hyperalgesia is the experience of unusually heightened pain from a known painful stimulus. These two symptoms (together with myoclonus, seizures, agitation, and delirium) are well documented but rare side effects of opioids, particularly if renal function is poor (Current Opinion in Anaesthesiology 1998;11:436-45). Allodynia and hyperalgesia are thought to represent a hyperexcitable state, possibly induced via an antiglycinergic mechanism. The symptoms generally resolve rapidly when the dose of the opioid is reduced or another opioid is substituted, or both.

Both allodynia and hyperalgesia should be considered if a patient is already using high doses of the opioid or if the beginnings of hyperexcitability are observed. Better control of symptoms may be achieved by using combinations of analgesics with different mechanisms of action or neural blockade techniques rather than simply increasing the dose of the opioid in patients whose pain is uncontrolled.

Allodynia and hyperalgesia have been observed with several opioids, including morphine. In the case of morphine, there is little direct evidence that these effects are due to either the accumulation of morphine or its metabolites. They may be caused by both (Pain 1998;74:43-53), or by particular morphine to metabolite ratios. It is suggested, however, that two common metabolites--morphine-3-glucuronide and morphine-6-glucuronide are implicated. Animal studies have shown that high concentrations of morphine-3-glucuronide can antagonise morphine, thus reducing the analgesic effect of morphine (Pain 1995;62(5):1-60; Journal of Pharmaceutical Sciences 1998;87:813-20); and to some extent this may be happening in humans. Under normal circumstances, however, morphine is effective, despite the fact that up to 75% of it is metabolised to morphine-3-glucuronide in humans and the concentrations of morphine-3-glucuronide greatly exceed those of morphine. It is not always appropriate to extrapolate what happens in animals to humans. The metabolism of morphine, and indeed the receptor population via which the parent drug (or its metabolites) are acting, may be quite different in the two species.

Abi Berger science editor, BMJ

[Graph OMITTED]

[1] Christrup LL. Morphine metabolites. Acta Anaesthesiol Scand 1997;41:116-22.

[2] Glare PA, Walsh TD. Clinical pharmacokinetics of morphine. Ther Drug Monitoring 1991;13:1-23.

[3] Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide--a potent antagonist of morphine analgesia. Life Sci 1990;47:579-85.

[4] Berde C, Ablin A, Glazer J, Miser A, Shapiro B, Weismann S, et al. American Academy of Pediatrics report of the Subcommittee on Disease-Related Pain in Childhood Cancer. Pediatrics 1990;86:818-25.

[5] Sjogren P, Jensen NH, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 1994;59:313-6.

[6] Sjogren P, Thunedborg LP, Christrup L, Hansen SH, Franks J. Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiol Scand 1998;42:1070-5.

[7] Smith GD, Smith MT. Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat. Pain 1995;62:51-60.

[8] Venn RF, Michalkiewicz A, Hardy P, Wells C. Concentrations of morphine, morphine metabolites and peptides in human cerebrospinal fluid and plasma. Pain 1990;43(suppl 5):188.

[9] Choonara I, McKay P, Hain R, Rane A, Bowhay A. Morphine metabolism in children. Br J Clin Pharmacol 1989;28:599-604.

[10] Choonara I, Lawrence A, Michalkiewicz A, Bowhay A, Ratcliffe J. Morphine metabolism in neonates and infants. Br J Clin Pharmacol 1992;34:434-7.

[11] Bowsher D. Paradoxical pain. BMJ 1993;306:473-4.

[12] Morley JS, Miles JB, Wells JC, Bowsher D. Paradoxical pain [letter]. Lancet 1992;340:1045.

[13] Sawe J, Odar-Cederloef I. Kinetics of morphine in patients with renal failure. Eur J Clin Pharmacol 1987;32:377-82.

[14] Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259-74.

[15] Warncke T, Stubhaug A, Jorum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain 1997;72:99-106.

[16] Savage SR. Long-term opioid therapy: assessment of consequences and risks. J Pain Symptom Manage 1996;11:274-86.

(Accepted 21 January 1999)

Department of Paediatrics, Christian-Albrechts-University, 24105 Kiel, Germany

Sabine Heger resident

Ulf Helwig resident

Meinof Suttorp associate professor

Department of Anaesthesiology, Christian-Albrechts-University

Christoph Maier associate professor

Department of Pharmacology, Christian-Albrechts-University

Karin Otter research assistant

Correspondence to: S Heger, Division of Neuroscience, Oregon Regional Primate Research Center, Oregon Health Sciences University, 595 NW 185th Avenue, Beaverton, OR 97066, USA S.Heger@rocketmail.com

BMJ 1999;319:627-93

COPYRIGHT 1999 British Medical Association
COPYRIGHT 2000 Gale Group