REVIEW ARTICLE

Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review Lecia M. Nielsen, MSc*,†; Anne E. Olesen, PhD*; Ruth Branford, MRCP, PhD‡; Lona L. Christrup, PhD†; Hiroe Sato, MD, PhD§; Asbjørn M. Drewes, MD, PhD, DMSc*,¶ *Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; †Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; ‡Department of Palliative Medicine, Royal Marsden Hospital, London, UK; §Interstitial Lung Disease Unit, Royal Brompton Hospital & National Heart and Lung Institute, Imperial College London, London, UK; ¶Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

& Abstract: On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug-metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catecholO-methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non-malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish. & Address correspondence and reprint requests to: Professor Asbjørn Mohr Drewes, MD, Ph.D, DMSc, Mech-Sense, Department of Gastroenterology & Hepatology Medicinerhuset, Mølleparkvej 4, 4th floor, Aalborg University Hospital, Aalborg DK-9000, Denmark. E-mail: amd@mech-sense. com. Submitted: November 13, 2013; Revision accepted: June 4, 2014 DOI. 10.1111/papr.12232

© 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume 15, Issue 6, 2015 580–594

Key Words: pharmacogenetics, analgesia, single nucleotide polymorphism, pharmacokinetics, pharmacodynamics, opioids, review

INTRODUCTION Chronic pain is a major issue worldwide with a prevalence of around 34%.1,2 The pain is often difficult to manage and has a significant and detrimental impact on quality of life.3 Opioid analgesics are used to treat acute and chronic, moderate to severe pain.3–6 However, large inter-individual differences in opioid dose requirement and response contribute to the difficulty of achieving successful pain control.7 This variation is influenced by several factors such as differences in pain perception, sociocultural factors, environmental influences, sex, age, and genetic variation.8–11 Pharmacogenetics is the study of how genetic variation can affect the pharmacokinetic and/or the pharmacodynamic properties of medications (Figure 1). Pharmacokinetic parameters include drug absorption, distribution, metabolism, and excretion.12 Pharmacodynamic variability can be caused by differences in receptor activity, receptor binding affinity, and receptor

Genetics and Opioid Analgesia  581

Pharmacokinetics

Pharmacodynamics

Absorption

Distribution

Excretion

Metabolism

= SNPs at transporter genes (e.g. ABCB1) = SNPs at opioid receptor genes (e.g. OPRM1) = SNPs at CYP (e.g. CYP2D6) and COMT genes

Figure 1. Single nucleotide polymorphisms in multiple genes affecting analgesia in humans. An orally administrated opioid will be absorbed in the gut, where drug transporters such as ABCB1 can restrict the absorption. Once the opioid is absorbed, it is distributed to various organs (e.g. liver, kidney, peripheral nervous system, and the central nervous system) through the bloodstream. In the liver, opioids are metabolized by enzymes including the CYP family. The kidneys are the primary organs for excretion of opioids. Drug transporters in the liver and the kidneys affect the hepatobiliary and renal excretion of opioids. Dashed line separates the pharmacokinetics from the pharmacodynamics. SNP = single nucleotide polymorphism; ABC = ATPbinding cassette; CYP = cytochrome P450; COMT = catechol-Omethyltransferase

density.13,14 Pharmacogenetics as a diagnostic tool has the potential to improve pharmacological pain management by predicting the individual response of a specific substance before initiation of therapy and thus offers hope for successful implementation of individualized treatment in the future.15 One of the challenges of performing genetics association studies in population of patients suffering from pain—especially cancer-related pain—is the prevalence of potential confounding factors with the complexities of mixed pain etiologies, multiple comorbidities, psychological distress, and polypharmacy. To encompass these difficulties, the genetic influence can be investigated in other groups with less potential for confounding. This can, for example, be in acute postoperative pain or experimentally induced pain, where the trends can subsequently be translated into the chronic pain scenery. This updated review summarizes recent experimentally induced pain, postoperative pain, and cancer pain

and chronic non-malignant pain conditions studies in humans to give an overview of the different polymorphisms affecting pharmacokinetics and pharmacodynamics, which can have an impact on the interindividual variations in analgesia. Literature search was conducted in Pub Med (http:// www.ncbi.nlm.nih.gov/sites/entrez) from February 2012 to April 2014, using the Mesh and free-text terms “analgesia,” “analgesics,” “pain medications,” and “pain treatment” combined with the terms “genetic polymorphisms,” “pharmacodynamics,” “pharmacokinetics,” “pharmacogenetics,” “genetic variants,” “single nucleotide variants,” “copy number variants,” “indels,” “insertions,” “deletions,” and “chromosomal aberrations.” Only original articles published in English were included; letters to the editor were excluded. Relevant reviews and the reference lists of relevant papers were examined for other articles of interest. There were no restraints for the year of publication. Studies with healthy volunteers, patients with postoperative pain, and patients with cancer pain or chronic non-malignant pain conditions where the effects of opioids were evaluated were eligible for inclusion. The outcomes of these studies were the analgesic effect assessed as opioid consumption and its effects, such as the administered dose, frequency of administration, duration of the treatment period, changes in pain scores, and side effects. The primary outcomes were opioid consumption or changes in pain scores.

POLYMORPHISMS AFFECTING PHARMACOKINETIC FACTORS Drug Transporters Drug transporters are important proteins that can influence absorption, distribution, and elimination of drugs. Drug transporters present in the gastrointestinal tract might affect the bioavailability of orally administrated opioids, which are substrates for the transporters. This can either be by restricting (efflux transporters) or facilitating (influx transporters) absorption from the gut. In the same manner, drug transporters present at the blood–brain barrier might affect the distribution of opioids from the blood to the central nervous system (CNS). Finally, drug transporters present in the liver and the kidneys are involved in hepatobiliary and renal excretion of opioids and their metabolites.16–18 The ATP-binding cassette (ABC) family of efflux transporters is a major family of drug transporters. The

Genetics and Opioid Analgesia  583

Furthermore, the SNP C3435T was investigated in four studies in postoperative patients who underwent thyroidectomy, colorectal surgery, knee arthroscopy, or abdominal hysterectomy. No differences were observed either in analgesic consumption or in pain scores between variants in any of these studies.28–31 Cancer Pain and Chronic Non-malignant Pain Conditions. A trial in patients suffering from cancer has shown greater pain relief in patients homozygous for the 3435T allele (TT) compared to patients homozygous and heterozygous for the 3435C allele (CC and CT), when receiving morphine.32 However, these findings could be not confirmed in subsequent studies.33,34 A large prospective, multicentre, cross-sectional study investigated opioid dose requirements and the ABCB1 C3435T polymorphism in 352 patients. Patients were treated with various opioids for 1–600 months, for pain of different origins, and opioid doses were converted to oral morphine equivalent. It showed that carriage of the variant T allele (CT and TT) was associated with lower opioid dose requirements.34 Nonetheless, Klepstad and colleagues could not confirm these findings in a study of 2294 patients with cancerrelated pain.35

Finally, methadone doses are subject to ABCB1 genetic modulations. The methadone dose was increased in carriers of the 2 copies of the AGCGC (wild type) haplotype and decreased in carriers (1 or 2 copies) of the AGCTT haplotype.36 Furthermore, the methadone dose was higher in carriers of CGT, TTC, and TGT haplotypes composed of ABCB1 C1236T, G2677T/A, and C3435T.37 A study in patients suffering from methadone dependency verified these results.38 Drug-Metabolizing Enzymes Most opioids undergo extensive first-pass metabolism in the liver after absorption, thereby reducing the systematic bioavailability. The liver enzymes specifically involved in opioid metabolism promote two forms of metabolism: (1) phase 1 metabolism (modification reactions) which involves, for example, cytochrome P450 (CYP) enzymes, and (2) phase 2 metabolism (conjugation reactions) such as the glucuronidation reaction catalyzed by uridine diphosphate glucuronosyltransferase (UGT) enzymes.39,40 Different opioids are metabolized by different enzymatic pathways, in some instances with the creation of active metabolites (Figure 2). There are substantial interindividual differences in the ability to metabolize

Figure 2. Metabolic pathway for codeine, morphine, tramadol, oxycodone, and fentanyl. The CYP2D6 enzyme metabolizes codeine, morphine, tramadol, and oxycodone, whereas the CYP3A4 enzyme is responsible for metabolizing tramadol, oxycodone, and fentanyl. Uridine diphosphate glucuronosyltransferase (UGT) enzyme is the primary metabolic enzyme for morphine. CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase.

Genetics and Opioid Analgesia  583

Furthermore, the SNP C3435T was investigated in four studies in postoperative patients who underwent thyroidectomy, colorectal surgery, knee arthroscopy, or abdominal hysterectomy. No differences were observed either in analgesic consumption or in pain scores between variants in any of these studies.28–31 Cancer Pain and Chronic Non-malignant Pain Conditions. A trial in patients suffering from cancer has shown greater pain relief in patients homozygous for the 3435T allele (TT) compared to patients homozygous and heterozygous for the 3435C allele (CC and CT), when receiving morphine.32 However, these findings could be not confirmed in subsequent studies.33,34 A large prospective, multicentre, cross-sectional study investigated opioid dose requirements and the ABCB1 C3435T polymorphism in 352 patients. Patients were treated with various opioids for 1–600 months, for pain of different origins, and opioid doses were converted to oral morphine equivalent. It showed that carriage of the variant T allele (CT and TT) was associated with lower opioid dose requirements.34 Nonetheless, Klepstad and colleagues could not confirm these findings in a study of 2294 patients with cancerrelated pain.35

Finally, methadone doses are subject to ABCB1 genetic modulations. The methadone dose was increased in carriers of the 2 copies of the AGCGC (wild type) haplotype and decreased in carriers (1 or 2 copies) of the AGCTT haplotype.36 Furthermore, the methadone dose was higher in carriers of CGT, TTC, and TGT haplotypes composed of ABCB1 C1236T, G2677T/A, and C3435T.37 A study in patients suffering from methadone dependency verified these results.38 Drug-Metabolizing Enzymes Most opioids undergo extensive first-pass metabolism in the liver after absorption, thereby reducing the systematic bioavailability. The liver enzymes specifically involved in opioid metabolism promote two forms of metabolism: (1) phase 1 metabolism (modification reactions) which involves, for example, cytochrome P450 (CYP) enzymes, and (2) phase 2 metabolism (conjugation reactions) such as the glucuronidation reaction catalyzed by uridine diphosphate glucuronosyltransferase (UGT) enzymes.39,40 Different opioids are metabolized by different enzymatic pathways, in some instances with the creation of active metabolites (Figure 2). There are substantial interindividual differences in the ability to metabolize

Figure 2. Metabolic pathway for codeine, morphine, tramadol, oxycodone, and fentanyl. The CYP2D6 enzyme metabolizes codeine, morphine, tramadol, and oxycodone, whereas the CYP3A4 enzyme is responsible for metabolizing tramadol, oxycodone, and fentanyl. Uridine diphosphate glucuronosyltransferase (UGT) enzyme is the primary metabolic enzyme for morphine. CYP = cytochrome P450; UGT = uridine diphosphate glucuronosyltransferase.

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NIELSEN ET AL.

opioids, which may be driven by genetic polymorphisms in genes for the CYP and the UGT enzyme systems. Overall polymorphisms in drug-metabolizing enzymes are estimated to account for 10- to 10,000fold variations in drug activity.41 CYP Enzymes. Two enzymes (CYP2D6 and CYP3A4) have been well studied. CYP2D6 is involved in the metabolism (O-dealkylation) of several opioids including codeine to morphine, tramadol to O-desmethyltramadol, and oxycodone to oxymorphone (Figure 2), all of which can be regarded as active metabolites. More than 63 CYP2D6 alleles have been described including deletions and insertions, which create inactive gene products, and copy number variation, which causes multiple functional copies of one allele.41 The sum effect of this genetic variation on protein function is altered enzyme activity. Therefore, phenotypes have been classified into four major groups: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP3A4 is responsible for N-dealkylation of opioids such as fentanyl, tramadol, and oxycodone. Many CYP3A4 alleles have been identified, such as CYP3A4*1B, CYP3A4*2, and CYP3A*3. However, the CYP3A4*1G variant has been suggested to affect the CYP3A activity but the exact molecular basis is still unknown.41 CYP3A4*1G variation has a high frequency in Asian with an allele frequency of 22% in the Chinese and 25% in the Japanese.42

CYP2D6 Enzyme. Experimentally induced pain – As shown in Table 2, several experimental studies have investigated the association between opioid analgesia and the CYP2D6 phenotype. One pharmacogenetic study evaluated the role of variations in CYP2D6 gene in 28 healthy volunteers (14 extensive metabolizers and 14 poor metabolizers) receiving placebo, codeine, and morphine. No difference was found between the two phenotypes.43 The clinical analgesic effect of oxycodone is mainly attributed when it is converted to oxymorphone by the polymorphic CYP2D6 enzyme. A few experimental studies have shown that the analgesic effect of oxycodone differs between CYP2D6 phenotypes.44,45 Samer et al. found a 1.5- to 6-fold increase in the analgesic oxycodone effect in ultrarapid metabolizers as compared with extensive metabolizers and a 2- to 20-fold reduction of the analgesic effect in poor metabolizers as compared to extensive metabolizers.44 Zwisler and colleagues showed that extensive metabolizers had a greater analgesic effect of oxycodone in pain detection and tolerance thresholds to electrical stimulation and in pain to the cold pressor test when compared to poor metabolizers. However, there was no difference between extensive metabolizers and poor metabolizers in the pain to repetitive electrical stimulation and the discomfort rating of the cold pressor test.45 Finally, the analgesic effect of tramadol was reported to be associated with the healthy volunteer’s phenotype. Enggaard and colleagues reported a differ-

Table 2. Summary of Human Experimentally Induced Pain Studies Assessing Polymorphisms in Drug-Metabolizing Enzyme Genes and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Codeine, morphine Oxycodone

CYP2D6

PM, EM

CYP2D6

Oxycodone

CYP2D6

PM, IM, EM, UM PM, EM

Tramadol

CYP2D6

Tramadol

CYP2D6

Study Population

Route

Results

Reference

Oral

No difference in heat pain thresholds between phenotypes

43

Oral

Difference in analgesic effect between phenotypes

44

33 healthy subjects

Oral

45

PM, EM

20 healthy subjects

IV

PM, EM

27 healthy subjects

Oral

Difference in electrical pain detection and pain tolerance thresholds, and in AUC0–2 min. No difference in pain summation threshold and in discomfort rating Difference in discomfort VAS rating at 90 minute after treatment between phenotypes. No difference in pain detection, tolerance, and summation thresholds, and in peak pain and discomfort VAS rating at 15, 30, and 60 minute between phenotypes. Difference in pain tolerance thresholds for PMs between tramadol and placebo. Difference in discomfort VAS rating for EMs between tramadol and placebo. Difference in pain tolerance thresholds for PMs between tramadol and placebo. Difference in pressure pain detection and tolerance thresholds, and in peak pain and pain area.

28 healthy subjects 10 healthy subjects

AUC, area under the curve; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; UM ultra-rapid metabolizer; VAS, visual analog scale.

46

47

Genetics and Opioid Analgesia  585

ence in discomfort ratings between two phenotypes (extensive metabolizers and poor metabolizers) at 90 minutes after treatment with tramadol during the cold pressor test. However, no differences were observed in the pain detection and tolerance thresholds, pain summation threshold, peak pain, and discomfort ratings at 15, 30, and 60 minutes after the administration of tramadol.46 An increased pain tolerance threshold by tramadol was shown in poor metabolizers. On the other hand, the study reported an increase in pressure pain detection and tolerance threshold for extensive metabolizers.47 Postoperative pain – Persson et al. assessed the pharmacogenetics in codeine metabolism in 11 women undergoing hysterectomy and showed that one poor metabolizer consumed 4–20 times more codeine than the 10 extensive metabolizers. The poor metabolizer dropped out of this postoperative study after 1.4 hours because of a lack of effect of codeine (Table 3).48 A study in 142 adult women, who underwent elective surgery, showed that ultrarapid metabolizers required less morphine in the acute postoperative period (4 hours) compared to poor metabolizers, intermediate

metabolizers, and extensive metabolizers.49 However, this could not be confirmed in a study of 96 children.50 Altered consumption of oxycodone may occur in patients with modulated CYP2D6 activity. However, results from Zwisler and colleagues following 270 patients for 24 hours after primarily thyroid surgery or hysterectomy showed no association between modulated CYP2D6 activity and oxycodone consumption.51 Tramadol is another commonly used analgesic which depends on CYP2D6 activity. Its active metabolite Odesmethyltramadol has higher affinity at l-opioid receptors than tramadol. Thus, blocked CYP2D6 activity will modulate the analgesic response of tramadol. The analgesic consumption of tramadol was higher in poor metabolizers compared to other phenotypes (extensive or intermediate metabolizers).52–54 Slanar and colleagues could not confirm altered consumption between phenotypes. However, they showed that poor metabolizers had better analgesia with tramadol than ultrarapid and extensive metabolizers.31 No other postoperative pain studies have been able to replicate these results.52,53

Table 3. Summary of Human Postoperative Pain Studies Assessing Polymorphisms in Drug-Metabolizing Enzyme Genes and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Study Population

Codeine Codeine

CYP2D6 CYP2D6

PM, EM PM, EM

96 children 11 women

Morphine

CYP2D6

PM, IM, EM, UM

142 women

Oxycodone

CYP2D6

PM, EM

270 patients

Tramadol

CYP2D6

PM, EM

271 patients

Tramadol

CYP2D6

C188T

63 patients

Tramadol

CYP2D6

PM, IM, EM, UM

177 patients

Tramadol

CYP2D6

PM, EM, UM

156 patients

Fentanyl

CYP3A4

CYP3A4*1G

143 patients

Fentanyl

CYP3A4

CYP3A4*1G

79 women

Fentanyl

CYP3A4

CYP3A4*1G

176 patients

Fentanyl

CYP3A4

94 patients

Fentanyl

CYP3A4, CYP3A5

CYP3A4*1/*1, CYP3A4*1/*18 CYP3A4*18, CYP3A5*3

196 females

Route

Results

Reference

i.m. IV/ PCA IV/ PCA IV

No difference in pain scores between phenotypes Difference in consumption between phenotypes

50 48

Difference in consumption between phenotypes

49

No difference in consumption or AUC between phenotypes Difference in consumption between phenotypes. No difference in pain intensity between phenotypes Difference in consumption between phenotypes. No difference in pain scores between phenotypes Difference in consumption between phenotypes

51

No difference in consumption between phenotypes. Difference in pain scores at 24 hours between phenotypes No difference in pain scores between phenotypes. Difference in consumption between phenotypes No difference in pain scores between phenotypes. Difference in consumption at 2 and 4 hours No difference in pain scores between phenotypes. Difference in consumption between phenotypes No difference in pain scores or consumption between phenotypes No difference in consumption in both variants

31

IV/ PCA IV/ PCA IV/ PCA NA

IV/ PCA IV/ PCA IV/ PCA IV/ PCA IV/ PCA

52 53 54

42 56 57 58 30

EM, extensive metabolizer; i.m., intramuscular; IM, intermediate metabolizer; NA, not available; PCA, patient-controlled analgesia; PM, poor metabolizer; UM, ultra-rapid metabolizer.

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Table 4. Summary of Human Cancer Pain and Chronic Non-Malignant Pain Conditions Studies Assessing Polymorphisms in Drug-Metabolizing Enzyme Genes and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Study Population

Route

Results

Reference

Oxycodone

CYP2D6

PM, EM, UM

450 patients with cancer

No difference in pain intensity between phenotypes

55

Various

CYP2D6

PM, EM

CYP2D6 CYP3A5 CYP2B6 CYP2C9 CYP2C19

PM, IM, EM, UM

No difference in opioid doses or pain scores between phenotypes Difference in doses (CYP2D6) No difference in doses for the other genes

34

Methadone

352 patients with pain of various origins 158 patients

Oral, subcutaneous or IV Various NA

38

EM, extensive metabolizer; IM, intermediate metabolizer; NA, not available; PM, poor metabolizer; UM, ultra-rapid metabolizer.

Cancer pain and chronic non-malignant pain conditions – Methadone doses are affected by CYP2D6 phenotypes. Ultrarapid metabolizers need higher doses of methadone compared to extensive metabolizers (Table 4).38 No other cancer pain or chronic pain study has shown a difference in pain intensity or in opioid doses when investigating different phenotypes.34,55 CYP3A4 Enzyme. Postoperative pain – To our knowledge, all studies, which have evaluated CYP3A4 variation on analgesic response to fentanyl, have been postoperative studies. Three studies found that patients with CYP3A4*1G/*1G (AA and mutant homozygote) required significant lower consumption of fentanyl than patients with CYP3A4*1/*1 (GG and wild type) and CYP3A4*1/*1G (AG and heterozygotes) alleles.42,56,57 On the other hand, all three studies reported no differences in pain scores between variants (Table 3). Tan et al. could not verify these findings.58 Finally, one study evaluated the CYP3A4*18 and CYP3A5*3 polymorphisms in Korean gynecological patients and found no association between these polymorphisms and postoperative fentanyl consumption.30

POLYMORPHISMS AFFECTING PHARMACODYNAMIC FACTORS l-opioid Receptor (OPRM1) Gene More than 100 polymorphisms have been identified in the human l-opioid receptor gene (OPRM1). The most widely studied SNP is the A118G nucleotide substitution, in which the nucleotide adenine (A) is replaced with guanine (G) in exon 1 at nucleotide position 118. This nucleotide substitution results in an exchange of amino acid asparagine (Asn) to aspartate (Asp) at the site of amino acid 40, causing reduced signaling efficacy

and probable reduced expression of the l-opioid receptor.12,59–61 The A118G SNP has an allele frequency of 10–15% in the Caucasian population.27 Another studied SNP in the OPRM1 gene is the A304G. This mutation leads to a substitution of asparagines (Asn) to aspartate (Asp) at the 102nd amino acid.62,63 Experimentally Induced Pain. Zwisler et al. assessed the antinociceptive effect of oxycodone in 33 healthy volunteers exposed to experimental pain in relation to A118G genotyping. It was demonstrated that heterozygous subjects (AG) had a lower increase in pain tolerance thresholds after oxycodone to electrical sural nerve stimulation than subjects homozygous for the A allele (AA).27 However, there were no differences in pain detection and pain summation thresholds during electrical sural nerve stimulations or discomfort and pain ratings during cold pressor testing (Table 5).27 The association between alfentanil analgesia and A118G has been studied by Oertel and colleagues, who did an open-label, single-occasion study, where 20 healthy volunteers received a computerized infusion of alfentanil. At each concentration level, analgesia was evaluated by electrically and chemically induced pain.64 It was reported that individual with the GG genotype (n = 6) needed two- to fourfold higher alfentanil concentrations compared to AA (wild type, n = 10) to produce the same degree of analgesia.64 Two studies in 20 and 16 healthy subjects were conducted to elucidate the influence of A118G SNP on the antinociceptive effect of morphine-6-glucuronide.65,66 In both studies, acute pain was induced by an electrical current through two surface electrodes placed on the skin overlaying the tibia. Results showed that individuals heterozygous for A118G (AG) exhibited reduced analgesic responses to the drug following

Genetics and Opioid Analgesia  587

Table 5. Summary of Human Experimentally Induced Pain Studies Assessing Polymorphisms in the l-Opioid Receptor (OPRM1) Gene and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Oxycodone

OPRM1

A118G

Alfentanil

OPRM1

A118G

M6G

OPRM1

A118G

M6G

OPRM1

A118G

Study Population

Route

Results

Reference

33 healthy subjects

Oral

27

20 healthy subjects 20 healthy subjects 16 healthy subjects

IV

No difference in pain detection, pain summation, and discomfort rating between genotypes. Difference in pain tolerance threshold between genotypes Difference in consumption between genotypes

IV

Difference in analgesic responses between genotypes

65

IV

Difference in analgesic responses between genotypes

66

64

M6G, morphine-6-glucuronide.

Table 6. Summary of Postoperative Pain Studies Assessing Polymorphisms in l-Opioid Receptor (OPRM1) Gene and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Study Population

Route

Results

Reference

Morphine Morphine Morphine Morphine

OPRM1 OPRM1 OPRM1 OPRM1

A118G A118G A118G A118G

101 patients with acute pain 102 surgical patients 74 patients 80 women

NA PCA PCA PCA

70 71 29 9

Morphine

OPRM1

A118G

120 patients

PCA

Morphine Morphine Morphine Fentanyl Fentanyl Fentanyl Fentanyl

OPRM1 OPRM1 OPRM1 OPRM1 OPRM1 OPRM1 OPRM1

A118G A118G A118G A118G A118G A118G A118G

994 women 588 women 973 women 280 Japanese patients 196 Korean females 189 patients 174 Chinese women

PCA PCA PCA PCA IV/PCA IV PCA

Fentanyl Fentanyl

OPRM1 OPRM1

A118G A118G

60 patients 189 patients

PCA PCA

Sufentanil Alfentanil Oxycodone Various Various

OPRM1 OPRM1 OPRM1 OPRM1 OPRM1

57 laboring women 99 patients 268 patients 138 Japanese patients 79 patients

Epidural PCA IV Various Various

80 77 28 81 78

Morphine Fentanyl Fentanyl

OPRM1 OPRM1 OPRM1

A118G A118G A118G A118G A118G C17T A304G A304G A304G

No difference in pain scores or morphine doses No difference in pain scores or morphine doses No difference in pain scores Difference in consumption No difference in pain scores Difference in consumption No difference in pain scores Difference in requirements and pain scores Difference in requirements and pain scores Difference in requirements and pain scores No difference in pain scores or consumption No difference in consumption Difference in pain scores Difference in consumption No difference in pain scores Difference in consumption Difference in consumption No difference in 24-h pain scores Difference in ED50 Difference in doses and mean pain scores No difference in consumption or pain scores Difference in consumption Difference in pain score for A118G

103 women 190 laboring women 108 laboring women

IT IT IT

No difference in pain scores or morphine doses No difference in median duration Difference in ED50

62 62 63

72 67 68 69 74 30 73 75 79 76

ED50, median effective dose; IT, intrathecal; NA, not available; PCA, patient-controlled analgesia.

painful electrical stimulation compared to those homozygous for A118G (AA or GG).65,66 Postoperative Pain. The association between SNP A118G and pain scores were investigated in three studies in women treated with morphine and showed that patients with the AA genotype had the lowest average pain score and patients with GG had the highest (Table 6).67–69 However, five other studies could not confirm these associations.9,29,70–72 There are also results from five studies showing that patients homozygous for the G allele (GG) consumed more morphine

compared to patients homozygous for the A allele (AA).9,67–69,72 However, confirmatory findings were not reported in two other studies.70,71 When assessing the A118G SNP and its affect on the antinociceptive effect of fentanyl, only one group reported a difference in pain scores. Patients homozygous for the A allele (AA) rated the lowest pain intensity compared with patients with carriage of the variant 118G allele (AG or GG) at 15 and 30 min. after surgery.73 These differences could, however, not be confirmed by three other studies investigating fentanyl association with A118G SNP.74–76 Ginosar and col-

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leagues showed similar results in a prospective observational study including 99 patients treated with alfentanil. Patients homozygous for A allele was associated with less severe pain.77 Controversially, being homozygous for the A allele was associated with a higher pain score in a study of 79 patients administered various opioids.78 Three studies have demonstrated that patients homozygous for the G allele (GG) consume significantly more fentanyl than patients with AA or AG allele.75,76,79 Additionally, one study showed that carriage of the G allele (GG) required more alfentanil.77 However, this could not be replicated in two other studies.30,74 A study investigated the A118G SNP in 57 laboring women, where median effective dose (ED50) for epidural sufentanil was calculated. They showed that women homozygous for 118A allele (AA) required a higher ED50 of sufentanil compared to women heterozygous or homozygous for the 118G variant (AG or GG).80 An association between postoperative analgesic requirements and A118G SNP has been shown. Patients homozygous for 118G (GG) required significantly more analgesics than patients homozygous and heterozygous for 118A (AA and AG) to experience a similar degree of

pain relief.81 No association between A118G and oxycodone consumption was reported in a study of 268 patients with postoperative pain after primarily thyroidectomy.28 Finally, OPRM1 A304G SNP was reported to have an effect on intrathecal fentanyl requirements. Women homozygous for 304A allele (AA) required a higher ED50 of intrathecal fentanyl compared to women heterozygous or homozygous for the 304G allele (AG or GG).63 However, A304G SNP had no effect on median duration of intrathecal fentanyl given for labor analgesia or on the pain score and morphine doses after cesarean delivery.62 Cancer Pain and Chronic Non-malignant Pain Conditions. Two studies have found that patients homozygous for the 118G allele (GG) required more morphine than patients homozygous for the 118A allele (AA) in patients with cancer pain (Table 7).14,82 The pain intensity was investigated in 137 patients with cancer receiving morphine, and it showed that patients homozygous for the 118A allele (AA) possess the highest average decrease of pain after morphine therapy compared to patients with carriage of the G allele (AG or

Table 7. Summary of Cancer Pain and Chronic Non-Malignant Pain Conditions Studies Assessing Polymorphisms in Opioid Receptor Genes and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Study Population

Route

Results

Reference

Morphine

OPRM1

A118G

207 cancer patients

NA

14

Morphine

OPRM1

99 cancer patients

NA

Morphine

OPRM1

A118G

137 cancer patients

Various

Morphine

OPRM1

rs6912029, rs1799971 (A118G), rs589046, rs563649, rs9479757, rs2075572 rs533586 rs10504151, rs7836120, rs6473799, rs1365098, rs7016778, rs7824175, rs16918875, rs963549 rs1042114, rs533123, rs419335, rs2236857, rs2234918 A118G

264 cancer patients

Oral

Difference in consumption Difference in consumption for the A118G No difference in consumption for the other genotypes Difference in decrease of pain (ΔNRS) Difference in residual pain

121 non-cancer, chronic patients 2294 cancer patients

Various

No difference in opioid usage and pain scores No difference analgesic requirements

70

352 patients with pain of various origins 96 cancer patients

Various

No difference in opioid doses or pain scores

34

Oral

Difference in analgesic response

83

OPRD1 OPRK1

A118G,

172G>T, IVS2 + 31G>A, IVS2-291G>C

Fentanyl

OPRM1

Various

OPRM1

Various

OPRD1 OPRK1 OPRM1

rs1799971 (A118G), rs540825, rs562859, rs548646, rs1323042, rs618207, rs639855, rs9479757, rs497976 rs533123, rs678849, rs2236857 rs7815824 A118G

OPRM1

A118G

Tramadol/ acetaminophen

Various

82

32 84

35

NA, not available; ΔNRS, the difference between two pain scores using the numeric rating scale; OPRD1, d-opioid receptor; OPRK1, j-opioid receptor gene; various opioids cannot be specified as the articles only write various opioids or opioids for moderate to severe pain following World Health Organization treatment ladder.

Genetics and Opioid Analgesia  589

GG).32 However, no other studies in chronic pain patients have confirmed these findings.34,70 Liu and colleagues investigated the effect of A118G SNP on the efficacy of tramadol/acetaminophen combination tablets in chemotherapy-induced neuropathy. The results showed that patients with AG or GG genotype had a significantly reduced response to tramadol/acetaminophen and required more rescue analgesics compared to patients AA genotype.83 The combined effect of SNPs in multiple genes has over the years been well studied. One group studied the joint effect of the COMT1 (see below) and OPRM1 gene and found that carriers of COMT A allele (Val) and OPRM1 G allele needed the lowest morphine dose to achieve pain relief.14 In addition, another study investigated the joint effect of polymorphisms in OPRM1 and ABCB1 and found that carriage of the variant OPRM1 118G allele (AG or GG) combined with carriage of the variant ABCB1 3435C alleles (CT or CC) for the ABCB1 gene was the poorest responders to morphine.32 In 2012, Droney and colleagues stressed the importance of investigating SNPs in multiple candidate genes at the same time. They showed that SNP rs9479757 (OPRM1) and rs7824175 (OPRK1) had a significant association with residual pain in 264 patients with cancer treated with morphine.84 However, two other studies showed that (1) none of 112 investigated SNPs in 25 genes, such as OPRM1, OPRD1, OPRK1, COMT, and ABCB1, had a significant association with analgesic requirements in 2294 patients with cancer,35 and (2) there were no differences

in the morphine consumption related to the IVS2 + 31G>A, and IVS2-691G>C SNPs.82

172G>T,

Catechol-O-Methyltransferase (COMT) Gene Catechol-O-methyltransferase (COMT) is one of several enzymes that metabolize catecholamines such as dopamine, epinephrine, and norepinephrine. COMT is a key modulator of neurotransmission of dopamine and norepinephrine, and polymorphisms in COMT have been reported to have an effect on the l-opioid neurotransmitter response to pain stimulation. The most widely investigated polymorphism in this gene causes a nucleotide substitution of adenosine (A) to guanosine (G) in codon 158 and thereby an amino acid substitution of valine (Val) to methionine (Met). This SNP is associated with a threefold to fourfold reduction in enzyme activity.12, 85, 86 Pain studies regarding COMT polymorphisms are shown in Table 8. Experimentally Induced Pain. The association between COMT Val158Met and experimentally induced pain was studied in 43 healthy volunteers. They found induced analgesia in all groups without a difference between genotypes.86 Postoperative Pain. In postoperative studies, the COMT Val158Met has shown to be associated with pain scores but not with morphine or oxycodone consumption.71,87 Patients with the Met/Met reported higher pain scores than wild-type patients (Val/Val).71,78 Further-

Table 8. Summary of Human Experimentally Induced Pain, Postoperative Pain, and Cancer Pain and Chronic Non-Malignant Pain Conditions Studies Assessing Polymorphisms in Catechol-O-Methyltransferase (COMT) Gene and Theirs Influence on the Antinociceptive Effect of Analgesics Opioid

Gene

Variant

Experimentally induced pain Remifentanil COMT Val158Met Postoperative pain Morphine COMT Val158Met Various

Oxycodone Cancer pain and Morphine Morphine Morphine Morphine Various Various

COMT

4 SNPs 8 haplotypes

Study Population

Route

Results

Reference

43 healthy subjects

IV

No difference in analgesic response

86

102 surgical patients

PCA

71

79 patients

NA

Difference in pain scores. No difference in consumption Difference in pain score (Val158Met). Difference in consumption (rs4818) Difference in pain score and consumption (haplotypes) No difference in consumption

COMT 22 SNPs 1000 patients chronic non-malignant pain conditions COMT Val158Met 207 cancer patients COMT Val158Met 207 cancer patients COMT 11 SNPs 197 cancer patients COMT 15 SNPs 228 cancer patients COMT Val158Met 352 patients with pain of various (G472A) origins COMT 6 SNPs 2294 cancer patients

NA, not available; PCA, patient-controlled analgesia.

IV NA Oral Oral NA Various Various

Difference in requirements Difference in requirements Difference in requirements No difference in morphine doses No difference in opioid doses and 24 hours pain scores No difference analgesic requirements

78

87 14 88 89 85 34 35

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NIELSEN ET AL.

more, eight haplotypes have been associated with variation in pain score and the consumption of opioids.78 Cancer Pain and Chronic Non-malignant Pain Conditions. Finally, morphine requirements were reported to be associated with COMT Val158Met SNP in cancer patients. Two studies showed that the Val/Val variant was associated with higher morphine requirements when compared to Met/Met.14,88 However, the Val/Met was also associated with higher requirements.14 Controversially, patients with Met/ Met variant were shown to require more morphine compared with patients with Val/Val or Val/Met variant.89 None of these findings could be confirmed in other studies.1–3

CONCLUSION The study of pain genetics is important in helping to elucidate the mechanisms behind pain susceptibility and analgesic response. So far, the candidate gene approach has mainly been employed to test associations between genetic polymorphisms and clinical phenotypes. The current review suggests that polymorphisms in candidate genes known to influence opioid pharmacokinetics (ABCB1, CYP2D6, CYP3A4) and opioid pharmacodynamics (OPRM1, OPRK1, COMT) might have a clinically significant impact on the anti-nociceptive effects of opioids. In many complex traits, including the effect of opioids on pain, population-based genetic association studies have had mixed success and reproducibility has been poor. As shown in this review, the genetic variants with the most evidence for having an association with opioid response are OPRM1 A118G, CYP2D6 metabolizer status, and formation of an active 2D6 metabolite. However, even for each of these variants, there are studies providing conflicting evidence. Different studies are influenced by confounders to a varying degrees. Experimental pain studies provide a controlled environment and allow the examination of several modalities of painful stimulus separately. The potential for confounding factors increases in clinical studies, including acute postoperative pain, cancer pain and chronic pain conditions. Experimental pain studies therefore might provide the foundation to identify candidate SNPs, which subsequently can be tested in clinical pain studies. Results from twin studies have suggested that up to 60% of the variability in response to painful stimuli

might be genetically mediated. However, genetic and environmental factors are only moderately correlated across pain modalities, suggesting different genes influence different types of pain.90 This review suggests that there are distinct genetic associations with the opioid response to different modalities of painful stimuli. For example, in ABCB1 G2677T/A the variant T allele is associated with better response to oxycodone with the cold pressor test, but not electrical stimulation.27 Differences in the population studied may also be a factor in non-replication, which is a significant problem in pain genetics. Additionally the translational failure could be due to the complexity of pain, which is thought to be regulated by more than 400 genes.91 In general no more than 25 candidate genes are investigated in a single study. Gender differences in pain sensitivity are well known and many experimental studies of pain perception have shown that noxious stimuli are perceived as more painful in women compared to men.92–94 Wise et al. reported that women had a lower mean pain threshold, lower pain tolerance and had greater unpleasantness with pain than men during a thermal experimental pain study.94 Furthermore, some chronic conditions are more common in women than in men.95,96 There can also be substantial age-related differences in the activity of drug-metabolizing enzymes. For example the activity of CYP2D6 in children between 3 and 12 years of age is higher than 100% of the adult values.97 However, no association between codeine analgesia and phenotype could be found in a postoperative study in children from 3 to 12 years old.50 Thus, it is still speculative if the age-related differences in activity of drug-metabolizing enzymes affect analgesic outcome. Important differences in allele frequencies between ethnic groups also have to be considered when comparing results. For example, the prevalence of CYP2D6 poor metabolizers ranges from 0 to 1% in Asians to ~ 10% in Caucasians.53 This low frequency of poor metabolizers in Chinese is due to the absence of alleles CYP2D6*3 and *4, which leads to enzyme inactivity in Caucasians. The most common allele in the Chinese populations is the CYP2D6*10 allele and has a frequency ranging from 51 to 70%.53 This may in part explain the non-replication of results across different ethnicities. Pain susceptibility and opioid analgesic response are complex traits, which are likely to be the product of a network of both gene–gene and gene–environment interactions. Complex traits are controlled by many genes,

Genetics and Opioid Analgesia  591

each having a small additive effect on trait variance. Hence, there are many more genes and variants to be discovered that can explain the phenotypic variance in the analgesic effect of opioids. Interactions between genetic variants are now being investigated; however, this has so far been limited to two candidate SNPs at a time.14,32 The scope of gene–gene/environment interactions in opioid genetics presents a huge challenge for pharmacogenetic studies, with significant increases in required sample sizes and the need for complex statistical analyses where several covariates can be included. Analgesia is only one element of opioid response. There are several side effects such as constipation, nausea/vomiting, and drowsiness/confusion, which are influenced by genetic factors. It is becoming more and more evident that different genes/mechanisms contribute to each element of opioid response.98 All aspects of opioid response need to be included in the development of a useful clinical tool to guide prescribing. The evidence is not yet sufficiently robust to determine association of pain-related genotypes and variability in opioid analgesia in human studies. However, the findings are promising and call for future well-designed and sufficiently powered studies, focusing on different polymorphisms, as no single SNP seems to be responsible for analgesic responsiveness. Furthermore, polymorphisms in both pharmacokinetic and pharmacodynamic parameters should be assessed at the same time in the future studies as both of them are essential for the analgesic effect. Future Perspectives Current drug discovery or drug repurposing increasingly use computational systems biology analysis.91 Additionally, the computational approach might identify associated genes that could facilitate identification of pain biomarkers. Contemporary genetic knowledge provides us with acquired information to pursue the computational approach to drug development. Studies of few genetic polymorphisms will not have a major clinical relevance as a solitary biomarker, but combining different pain biomarkers is a major step toward mechanism-based therapy, where the treatment is based on a prediction of the individual opioid effect (or lack of opioid effect). However, while the separation of data is complex and nonlinear, this might be overcome by transforming the data into a higher dimensional space, followed by classification of individual changes by a support vector machine.99

ACKNOWLEDGEMENTS This study was funded by The Danish Council for Strategic Research.

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