Journal of Pain and Symptom Management
Volume 39, Issue 1 , Pages e8-e11, January 2010

Pharmacogenetic Testing Is of Limited Utility for Predicting Analgesic Response to Morphine

Clinical Pharmacology Unit, Hospital General de Alicante, Alicante, Spain

Department of Anesthesiology and Resuscitation Pain Unit, Hospital General de Alicante, Alicante, Spain

CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

Clinical Pharmacology Unit, Hospital General de Alicante, Alicante, Spain

published online 30 October 2009.

Article Outline

 

To the Editor:

Interindividual differences in analgesic drug response can complicate the clinical management of pain because of an unsatisfactory response in 10%–30% of the patients treated.1, 2 Genetic factors regulating the drug's pharmacodynamics (neurotransmitter receptors, neurotransduction systems) and pharmacokinetics (transport proteins, metabolizing enzymes) contribute to this variability, because their function and expression may be influenced by variation in the gene sequence.3, 4, 5

We present a case that allowed investigation of those genetic polymorphisms with previous evidence of clinical relevance and the potential to partially explain the variable sensitivity to morphine in a nonresponsive patient.6, 7 It also illustrates the difficulties related to the poor standardization of pharmacogenomic analysis used to individualize drug therapy in pain management.

Once morphine arrives at its site of action, it activates the G-protein-coupled mu-opioid receptor (MOR, OPRM1 gene) crossing the blood-brain barrier (BBB). This is regulated by the P-glycoprotein, a membrane-bound drug transporter (multidrug resistance transporters MDR1/ABCB1 gene) that pumps the drug out of the central nervous system (CNS).8, 9 Activation of the MOR inhibits neural pain transmission through a signaling cascade that includes the central interaction with catecholamines, such as dopamine, noradrenaline, or adrenaline (metabolized by the enzyme cathecol-O-methyltransferase [COMT] gene).10, 11 Furthermore, another G-protein-coupled receptor, the GPR74 (NPFF2 receptor gene), is activated during early inflammatory pain, and acute morphine administration produces a rapid mRNA upregulation in the brainstem region.12 With regard to metabolizing enzymes, hepatic glucuronidation of morphine is mainly mediated by another polymorphic gene (the uridine diphosphate [UDP] glucuronosyltransferase 2B7 gene).13

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Case Report 

A 47-year-old man had undergone surgery for a gastrointestinal stromal tumor. He had received morphine for the treatment of his severe postoperative pain but had a very poor analgesic response. Despite a rapid increase in the dose of intravenous morphine (50 mg for the first two hours followed by 30 mg for the next three hours), a patient-controlled analgesia morphine pump (basal infusion rate of 1.0 mg/hour and rescue doses of 0.5 mg with a lockout period of 10 minutes; total dose 4.5 mg/hour) was required. The heart rate, arterial blood pressure, ventilatory frequency, sedation, and visual analogue scale (VAS) pain scores were evaluated.

The poor analgesic effect of morphine was not related to the clinical characteristics of the patient. For that reason, we considered it beneficial to identify the genetic variants suspected of affecting the drug response (Table 1): mu-opioid receptor (OPRM1), adenosine triphosphate-binding cassette B1 (ABCB1/MDR1), COMT, neuropeptide FF receptor (NPFF2), and UDP glucuronosyltransferase 2 family polypeptide B7 (UGT2B7) genes. Any of them could have been associated with the low morphine sensitivity, but this pharmacogenomic analysis could not explain the poor response to morphine in our patient.

Table 1. Genetic Variations (SNPs) in the Case, Contigs That Contain the SNPs, dbSNP Reference Sequence (rs), % in Caucasian Population, and Disorder/Phenotype Associations of the Variants
GeneSNPContig/rsCaucasianCase SNPDisorder/Phenotype
Mu-opioid receptor gene (OPRM1, chr 6q24-q25, exon 1)A118GNT_025741.1410%–14%A/A HomRequires 18% (AG alleles) and 93% (GG alleles) higher morphine doses7, 19
Asn40Asprs 1799971Asn Hom
Adenosine triphosphate-binding cassette B1 (ABCB1/MDR1, chr 7q21.1, exon 26)C3435TNT_007933.1450%–60%T/T HomDecreased intestinal P-glycoprotein expression. A reduction in mRNA stability and in ABCB1 levels involved in opioid absorption and distribution9, 20
Noncodingrs 1045642
Catechol-O-methyltransferase (COMT, chr 22q11.21, exon 4)G1222ANT_011519.10G 52%A/A HomVal form has a three- to fourfold variation in the enzyme activity and Met a lower enzymatic activity17
Val158Metrs 4680A 48%Met Hom
Neuropeptide FF receptor gene (NPFF2, chr 4, exon 1)Del/Ins-/ANT_006216.14No dataA/A HommRNA NPFFR2 upregulation during pain. Acute morphine activated the genes supraspinally12
Ins69Lysrs 35424833Ins69Lys
UDP glucuronosyltransferase 2 family, polypeptide B7 (UGT2B7, chr 4, promoter and exon 1)A-842GNT_077444G 50%A/A HomSignificantly increased promoter activity, resulting in elevated levels of the metabolizing enzyme21
Promoterrs 7438135A 50%
G211TNT_077444.3G 100%G/G HomT allele associated with low morphine sensitivity22
Ser71Alars 12233719Ser Hom

SNP = single nucleotide polymorphism.

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Comment 

Our case supports the idea of a complex genetic basis of pain. The patient's requirement for morphine was apparently not explained by the interplay of the selected candidate genes, and it must be explained by other or nongenetic conditions (age, organ function, concomitant therapy, drug interactions, or nature of the disease).14 Furthermore, several other conditions can influence the pain experienced by humans to which they adapt or respond, which is regulated by interactions between multiple regions within the brain through different neurochemical pathways or psychosocial factors.15

According to the patient's genotype combination depicted in Table 1 (homozygote for MOR1: A118 allele and for MDR1: T3435 allele), a larger amount of morphine would be absorbed crossing the BBB and binding to a functional MOR, as a result of the less effective drug extrusion from cells.16 The MDR1 3435T allele is associated with a reduction in mRNA stability and the production of differing concentrations of morphine transporter P-glycoprotein. Consequently, the ineffective pump could increase the concentration of morphine and its CNS's glucuronide.7 This will have a greater effect when the basal expression of the MOR gene is upregulated by the presence of the Met variant (A1222 allele) of the COMT gene, thus increasing the receptor-binding potential. This would lead to the morphine being more effective.11, 17 Also, homozygosity for the Met158 allele of the COMT gene has been associated with three- to fourfold reduced enzyme activity. Under these conditions, the patient would, therefore, need a lower dose of morphine to gain pain relief.4, 17 In the same way, the “G” allele in UGT2B7 G211T single nucleotide polymorphisms conserved the binding site and enzymatic domain, whereas the “A” allele in the A-842G promoter region did not affect promoter activity or morphine-metabolizing enzyme levels. However, the “A” insertion in the NPFF2-R gene, which causes an amino acid insertion (69Lys ins), could disrupt one of the regulatory elements affecting mRNA processing, translation, or degradation, thus causing a change in the level or activity of a second messenger or other downstream target of the complex signaling cascade.

In our case, the variability in morphine response was not associated with the known genetic variability documented. Genetic tests in pain management need to find their way into clinical practice, which may make a proactive approach to individualized therapy possible. More research is necessary, however, because nowadays, there is not any solid procedure that applies the known polymorphisms to the prediction of analgesic response to morphine.

Even though the mapping of the gene variations is predicted to be a personalized profiling tool for improvement in the clinical outcome of pain therapy, the exact molecular consequences of most functional variants reported are not yet known, and the expectations of the few genetic variants with positive results should be relatively low.18 Some genetic variants provide small alterations to the level of pain, but as we found, this is sometimes difficult to reproduce. For this reason, advances in data collection and modeling techniques are ongoing challenges that are essential for translating the strands of information generated into a better understanding of those biological factors that influence the patient's need for opioids.

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References 

  1. World Health Organization. Cancer pain relief. 2nd ed. Geneva, Switzerland: World Health Organization; 1996;
  2. Cherny N, Chang V, Frager G, et al. Opioid pharmacotherapy in the management of cancer pain: a survey of strategies used by pain physicians for the selection of analgesic drugs and routes of administration. Cancer. 1995;76:1283–1293
  3. Brinkmann U, Roots I, Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today. 2001;6:835–839
  4. Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83:559–566
  5. Bianchi M, Fornasari D, Antonini R, et al. The pharmacogenetics of morphine-induced analgesia: a case report. J Pain Symptom Manage. 2008;36:e10–e12
  6. Befort K, Filliol D, Decaillot FM, et al. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signalling. J Biol Chem. 2001;276:3130–3137
  7. Reyes-Gibby CC, Shete S, Rakvåg T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007;130:25–30
  8. Rana B, Shiina T, Insel P. Genetic variations and polymorphisms of G protein-coupled receptors: functional and therapeutic implications. Annu Rev Pharmacol Toxicol. 2001;41:593–624
  9. Wang D, Johnson AD, Papp AC, et al. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005;15:693–704
  10. Ross JR, Riley J, Taegetmeyer A, et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer. 2008;112:1390–1403
  11. Zubieta J, Heitzeg M, Smith Y, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240–1243
  12. Nystedt J, Lemberg K, Lintunen M, et al. Pain- and morphine-associated transcriptional regulation of neuropeptide FF and the G-protein-coupled NPFF2 receptor gene. Neurobiol Dis. 2004;16:254–262
  13. Holthe M, Rakvåg TN, Klepstad P, et al. Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J. 2003;3:17–26
  14. Coulbault L, Beaussier M, Verstuyft C, et al. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther. 2006;79:316–324
  15. García-Larrea L, Peyron R, Mertens P, et al. Functional imaging and neurophysiological assessment of spinal and brain therapeutic modulation in humans. Arch Med Res. 2000;31:248–257
  16. Janicki PK, Schuler G, Francis D, et al. A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain. Anesth Analg. 2006;103:1011–1017
  17. Rakvåg TT, Klepstad P, Baar C, et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. 2005;116:73–78
  18. Lötsch J, Geisslinger G. Current evidence for a modulation of nociception by human genetic polymorphisms. Pain. 2007;132(1–2):18–22
  19. Chou WY, Wang CH, Liu PH, et al. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology. 2006;105(2):334–337
  20. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97:3473–3478
  21. Hirota T, Ieiri I, Takane H, et al. Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metab Dispos. 2003;31:677–680
  22. Duguay Y, Báár C, Skorpen F, Guillemette C. A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther. 2004;75:223–233

PII: S0885-3924(09)00796-9

doi:10.1016/j.jpainsymman.2009.08.004

Journal of Pain and Symptom Management
Volume 39, Issue 1 , Pages e8-e11, January 2010

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