Journal of Pain and Symptom Management
Volume 36, Issue 1 , Pages e10-e12, July 2008

The Pharmacogenetics of Morphine-Induced Analgesia: A Case Report

Department of Pharmacology, Faculty of Medicine, University of Milan, Milan, Italy

Hospice Ticino, Lugano, Switzerland

Palliative Care Service, Oncology Institute of Southern Switzerland, Lugano, Switzerland

published online 27 May 2008.

Article Outline

 

To the Editor:

Oral morphine is one of the mainstays of pharmacological treatment of moderate-to-severe cancer pain, according to guidelines from the World Health Organization.1 The clinical response to morphine administration is highly variable and the lack of a good analgesic response to morphine is a problem of great importance in palliative medicine.2 Although many nongenetic factors, including age, organ function, concomitant therapy, drug interactions, and the nature of the disease, may influence the effects of morphine, there are now several examples in which interindividual differences in drug response are due to sequence variants in genes encoding drug targets, drug-metabolizing enzymes, or drug transporters.3 It is important to note that, unlike the other factors influencing drug response, inherited determinants remain stable throughout a person's lifetime.

Several mutations of the μ-opioid receptor (MOR-1) have been described, and potential associations between MOR-1 polymorphisms and efficacy of morphine have been hypothesized.4 However, direct examination of this possibility in patients is necessary to determine how the polymorphisms in the μ-opioid receptor affect analgesia.

The hepatic glucuronidation of morphine is mainly mediated by uridine diphosphate glucuronyltransferase (UGT) 2B7, producing two major metabolites, morphine-6-glucuronide (active at opioid receptors) and morphine-3-glucuronide (inactive).5 For the UGT2B7 gene, genetic polymorphisms have been described.6

It also is known that morphine is one of the substrates of P-glycoprotein (also known as MDR1 or ABCB1), and in P-glycoprotein knockout mice, the antinociceptive effects of morphine are enhanced.7 In the light of P-glycoprotein involvement in morphine distribution, polymorphisms in the MDR1 gene are likewise candidates for modulation of opioid effects.8

So far, only a few clinical consequences of genetic modifiers of morphine metabolism and action have been directly investigated in humans. We recently undertook a prospective study for identifying possible pharmacogenetic modulators of morphine response in patients with cancer pain.

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Case Report and Genetic Analysis 

A 55-year-old woman with lung carcinoma and bone metastases had received morphine for the treatment of her severe pain (basal intensity value=90mm, assessed by a 0–100mm visual analog scale), but she had very poor analgesic response. In fact, despite a rapid increase in the daily dose of oral morphine from 20mg/day to 75mg/day, the mean visual analog scale over 10 days was 83.2±1.9 (mean±SEM). The morphine escalation index percent (MEI %), calculated as suggested by Mercadante et al.,9 was 27.5%. Both the value of the mean visual analog scale and that of MEI% clearly identified this patient as a poor-responder to morphine.

She was evaluated for the following single nucleotide polymorphisms (SNP):

1.SNP A118G (rs1799971) causing an amino acid change from asparagine to aspartic acid at protein position 40 (N40D) in μ-opioid receptor gene. This change occurs in the extracellular N-terminus portion of the receptor and leads to the loss of an N-glycosylation site. Patients of genotype AG and GG are known to require 18% and 93%, respectively, higher doses of morphine than patients with the genotype AA.10

2.SNP G211T (rs12233719) of the UGT2B7 morphine metabolizing enzyme, which causes a missense mutation and change in amino acid in the resulting protein. The SNP, located in the gene region corresponding to exon 1, results in a substitution from alanine to serine at position 71 and causes a change from a lipophilic residue to a hydrophilic residue in the substrate binding site domain of the enzyme. The SNP has been studied in a comparison of two cancer patients, one of whom was sensitive to morphine, whereas the other was a poor responder. The T allele proved to be present in the patient with low morphine sensitivity.11

3.SNP A-842G (rs7438135), which is located in the regulatory region of the gene encoding the UGT2B7 enzyme. The polymorphism has been seen to be associated with significantly increased promoter activity, which would result in elevated levels of the morphine metabolizing enzyme.12

4.The SNP C3435T (rs1045642), which is a polymorphism not causing a change in the amino acid coded for, but leading to a reduction in mRNA stability, and thus to a decrease in the levels of the membrane transporter protein MDR1 (or ABCB1), a polypeptide involved in the absorption and distribution of various drugs including morphine.13

In addition to the SNP analysis, the plasma concentrations of morphine and its main metabolites (morphine-3-glucuronide and morphine-6-glucuronide) following four days of morphine administration were measured by high performance liquid chromatography.14

The patient was heterozygote (genotype A/G) for the MOR-1 polymorphism A118G and was thus likely to require higher doses of morphine for effective pain relief, compared with a noncarrier of the G allele. Regarding the UGT2B7 morphine metabolizing hepatic enzyme, she was homozygote for the G ancestral allele of the G211T SNP, which alters amino acid residues in the enzymes binding site. This should not have altered enzyme functioning. She also was a homozygote carrier (genotype G/G) for the UGT2B7 promoter polymorphism A-842G, which leads to higher promoter activity and thus elevated levels of the enzyme. This was likely to result in increased rates of morphine metabolism. In accordance with this hypothesis, we found a morphine:morphine-3-glucuronide ratio of 1:12 (with a mean ratio of 1:4.9±0.5 in the other patients of our study population), and a morphine:morphine-6-glucuronide ratio of 1:2.1 (with a mean ratio of 1:1.55±0.07 in the other patients of our study population). Regarding the MDR1 drug transporter, the patient was found to be a heterozygote carrier of the C allele for the polymorphism C3435T, which is associated with higher mRNA transcript stability and thus increased levels of protein for the membrane drug transporter. The consequence of this was likely to be a reduced ability of the patient to absorb and distribute morphine adequately to different body regions, including the central nervous system.

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Comment 

The potential of pharmacogenetics to improve the clinical outcome of drug therapy has already been recognized and will present an important medical advance in the postgenomic era.15 Specific drug recommendations based on genotypes will be a future tool to guide clinicians involved in pain therapy with opioid drugs.16 Such a development will lead to a more patient-tailored drug therapy, which hopefully will result in fewer adverse drug reactions and better drug efficacy.

Our observations are in agreement with the hypothesis that genetic background is one important variable that may influence the response to morphine administration. In particular, it suggests that the analgesic response to morphine is significantly reduced only when polymorphisms regarding drug metabolism, drug transport, and the μ-opioid receptor are present in the same patient. In fact, in our study, we identified single gene polymorphisms in other patients showing a good analgesic response to morphine administration (data not shown). Because genetic factors may affect the response to opioid drugs differently, the ability to identify patients who do not respond to morphine will enable us to offer them an alternative opioid as first-line treatment, thus minimizing the frequency and duration of distress experienced during the titration phase.

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Acknowledgment 

This research is supported by a grant from the Eagle Foundation, Geneva, Switzerland.

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References 

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PII: S0885-3924(08)00211-X

doi:10.1016/j.jpainsymman.2008.02.002

Journal of Pain and Symptom Management
Volume 36, Issue 1 , Pages e10-e12, July 2008

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