a simple method for the assessment of palliativecare patients. J Palliat Care 1991;7(2):6e9.

2. Davis MP, Walsh D. Treatment of nausea andvomiting in advanced cancer. Support Care Cancer2000;8:444e452.

3. Kris MG, Hesketh PJ, Somerfield MR, et al.American Society of Clinical Oncology guidelinefor antiemetics in oncology: update 2006. J ClinOncol 2006;24(18):2932e2947.

4. Khot UP, Lang AW, Murali K, et al. Systematicreview of the efficacy and safety of colorectal stents.Br J Surg 2002;89(9):1096e1102.

5. Sebastian S, Johnston S, Geoghegan T, et al.Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectalobstruction. Am J Gastroenterol 2004;99(10):2051e2057.

6. Athreya S, Moss J, Urquhart G, et al. Colorectalstenting for colonic obstruction: the indications,complications, effectiveness and outcomed5-yearreview. Eur J Radiol 2006;60:91e94.

7. Lo SK. Metallic stenting for colorectal obstruc-tion. Gastrointest Endosc Clin N Am 1999;9(3):459e477.

8. Mauro MA, Koehler RE, Baron TH. Advances ingastrointestinal intervention: the treatment of gastro-duodenal and colorectal obstructions with metallicstents. Radiology 2000;215(3):659e669.

9. Hasler WL, Chey WD. Nausea and vomiting.Gastroenterology 2003;125:1860e1867.

10. Quigley EM, Hasler WL, Parkman HP. AGAtechnical review on nausea and vomiting. Gastroen-terology 2001;120:263e286.

e10 Vol. 36 No. 1 July 2008Letters

The Pharmacogeneticsof Morphine-Induced Analgesia:A Case Report

To the Editor:Oral morphine is one of the mainstays of

pharmacological treatment of moderate-to-severe cancer pain, according to guidelinesfrom the World Health Organization.1 Theclinical response to morphine administrationis highly variable and the lack of a good analge-sic response to morphine is a problem of greatimportance in palliative medicine.2 Althoughmany nongenetic factors, including age, organfunction, concomitant therapy, drug interac-tions, and the nature of the disease, may influ-ence the effects of morphine, there are nowseveral examples in which interindividual

differences in drug response are due to se-quence variants in genes encoding drug tar-gets, drug-metabolizing enzymes, or drugtransporters.3 It is important to note that, un-like the other factors influencing drug re-sponse, inherited determinants remain stablethroughout a person’s lifetime.

Several mutations of the m-opioid receptor(MOR-1) have been described, and potentialassociations between MOR-1 polymorphismsand efficacy of morphine have been hypothe-sized.4 However, direct examination of thispossibility in patients is necessary to determinehow the polymorphisms in the m-opioid recep-tor affect analgesia.

The hepatic glucuronidation of morphine ismainly mediated by uridine diphosphate glu-curonyltransferase (UGT) 2B7, producing twomajor 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 thesubstrates of P-glycoprotein (also known asMDR1 or ABCB1), and in P-glycoproteinknockout mice, the antinociceptive effects ofmorphine are enhanced.7 In the light ofP-glycoprotein involvement in morphine distri-bution, polymorphisms in the MDR1 gene arelikewise candidates for modulation of opioideffects.8

So far, only a few clinical consequences ofgenetic modifiers of morphine metabolismand action have been directly investigated inhumans. We recently undertook a prospectivestudy for identifying possible pharmacogeneticmodulators of morphine response in patientswith cancer pain.

Case Report and Genetic Analysis

A 55-year-old woman with lung carcinomaand bone metastases had received morphinefor the treatment of her severe pain (basal inten-sity value¼ 90 mm, assessed by a 0e100 mmvisual analog scale), but she had very poor anal-gesic response. In fact, despite a rapid increasein the daily dose of oral morphine from20 mg/day to 75 mg/day, the mean visual ana-log scale over 10 days was 83.2� 1.9 (mean� SEM). The morphine escalation indexpercent (MEI %), calculated as suggested byMercadante et al.,9 was 27.5%. Both the value

Vol. 36 No. 1 July 2008 e11Letters

of the mean visual analog scale and that ofMEI% clearly identified this patient as a poor-responder to morphine.

She was evaluated for the following singlenucleotide polymorphisms (SNP):

1. SNP A118 G (rs1799971) causing anamino acid change from asparagine to as-partic acid at protein position 40 (N40D)in m-opioid receptor gene. This changeoccurs in the extracellular N-terminusportion of the receptor and leads to theloss of an N-glycosylation site. Patients ofgenotype AG and GG are known to re-quire 18% and 93%, respectively, higherdoses of morphine than patients withthe genotype AA.10

2. SNP G211 T (rs12233719) of the UGT2B7morphine metabolizing enzyme, whichcauses a missense mutation and changein amino acid in the resulting protein.The SNP, located in the gene region cor-responding to exon 1, results in a substitu-tion from alanine to serine at position 71and causes a change from a lipophilicresidue to a hydrophilic residue in thesubstrate binding site domain of theenzyme. The SNP has been studied ina 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 thepatient with low morphine sensitivity.11

3. SNP A-842 G (rs7438135), which is lo-cated in the regulatory region of the geneencoding the UGT2B7 enzyme. The poly-morphism has been seen to be associatedwith significantly increased promoter ac-tivity, which would result in elevated levelsof the morphine metabolizing enzyme.12

4. The SNP C3435 T (rs1045642), which isa polymorphism not causing a change inthe amino acid coded for, but leading toa reduction in mRNA stability, and thusto a decrease in the levels of the mem-brane transporter protein MDR1 (orABCB1), a polypeptide involved in theabsorption and distribution of variousdrugs including morphine.13

In addition to the SNP analysis, the plasmaconcentrations of morphine and its mainmetabolites (morphine-3-glucuronide andmorphine-6-glucuronide) following four days

of morphine administration were measuredby high performance liquid chromatography.14

The patient was heterozygote (genotypeA/G) for the MOR-1 polymorphism A118 Gand was thus likely to require higher doses ofmorphine for effective pain relief, comparedwith a noncarrier of the G allele. Regardingthe UGT2B7 morphine metabolizing hepaticenzyme, she was homozygote for the G ances-tral allele of the G211 T SNP, which altersamino acid residues in the enzymes binding site.This should not have altered enzyme function-ing. She also was a homozygote carrier (geno-type G/G) for the UGT2B7 promoterpolymorphism A-842 G, which leads to higherpromoter activity and thus elevated levels ofthe enzyme. This was likely to result in increasedrates of morphine metabolism. In accordancewith this hypothesis, we found a morphine:mor-phine-3-glucuronide ratio of 1:12 (with a meanratio of 1:4.9� 0.5 in the other patients of ourstudy population), and a morphine:morphine-6-glucuronide ratio of 1:2.1 (with a mean ratioof 1:1.55� 0.07 in the other patients of ourstudy population). Regarding the MDR1 drugtransporter, the patient was found to be a hetero-zygote carrier of the C allele for the polymor-phism C3435 T, which is associated with highermRNA transcript stability and thus increasedlevels of protein for the membrane drug trans-porter. The consequence of this was likely tobe a reduced ability of the patient to absorband distribute morphine adequately to differentbody regions, including the central nervoussystem.

Comment

The potential of pharmacogenetics to im-prove the clinical outcome of drug therapyhas already been recognized and will presentan important medical advance in the postge-nomic era.15 Specific drug recommendationsbased on genotypes will be a future tool toguide clinicians involved in pain therapy withopioid drugs.16 Such a development will leadto a more patient-tailored drug therapy, whichhopefully will result in fewer adverse drug reac-tions and better drug efficacy.

Our observations are in agreement with thehypothesis that genetic background is oneimportant variable that may influence the

e12 Vol. 36 No. 1 July 2008Letters

response to morphine administration. In par-ticular, it suggests that the analgesic responseto morphine is significantly reduced only whenpolymorphisms regarding drug metabolism,drug transport, and the m-opioid receptor arepresent in the same patient. In fact, in ourstudy, we identified single gene polymor-phisms in other patients showing a good anal-gesic response to morphine administration(data not shown). Because genetic factorsmay affect the response to opioid drugs differ-ently, the ability to identify patients who do notrespond to morphine will enable us to offerthem an alternative opioid as first-line treat-ment, thus minimizing the frequency and du-ration of distress experienced during thetitration phase.

Acknowledgment

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

Mauro Bianchi, MDDiego Fornasari, MD, PhDRuth Adele Antonini, BMedScDepartment of PharmacologyFaculty of MedicineUniversity of MilanMilan, Italy

Benedetta Terziroli Beretta-Piccoli, MDSistiana Nava, RNHospice TicinoLugano, Switzerland

Hans Neuenschwander, MDPalliative Care ServiceOncology Institute of Southern SwitzerlandLugano, Switzerland

doi:10.1016/j.jpainsymman.2008.02.002

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