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. Author manuscript; available in PMC: 2020 Jun 1.
Published in final edited form as: Semin Oncol Nurs. 2019 May 10;35(3):291–299. doi: 10.1016/j.soncn.2019.04.011

Genetic Variants Associated with Cancer Pain and Response to Opioid Analgesics: Implications for Precision Pain Management

Gee Su Yang a, Natalie M Barnes a, Debra E Lyon a, Susan G Dorsey b
PMCID: PMC6688486  NIHMSID: NIHMS1527280  PMID: 31085105

Abstract

Objective:

To review the current knowledge on the association of genetic variants with cancer pain.

Data Sources:

Data-based publications and review articles retrieved from PubMed, CINAHL, and Web of Science, as well as an additional search in Google Scholar.

Conclusion:

Genetic variability can influence differential pain perception and response to opioids in cancer patients, which will have implications in the optimal personalized treatment of cancer pain. More studies are warranted to replicate findings.

Implications for Nursing Practice:

Nurses are poised to educate patients on biomarker testing and interpretation and to use precision pain management strategies based on this information.

Keywords: genetic variant, genetic polymorphism, biomarker, cancer, pain, precision medicine

Introduction

Cancer is a common source of the development of chronic pain, resulting in a decrease in quality of life, functional status, and productivity, as well as an increase in morbidity, mortality, and societal cost of pain treatment.1 As the number of cancer survivors rapidly grows over time (18 million in 2020) in the U.S.,2 management and prevention of cancer pain have been considered a significant public health challenge at individual and population levels.1 A recent meta-analysis of 122 studies on cancer-related pain found that more than 66% of patients with advanced and metastatic cancers and 55% of patients undergoing anticancer treatment reported pain.3 Furthermore, 30% of people with cancer overall experienced chronic daily pain, of whom 48% considering the tumor itself a source of pain, and 24% reporting that their cancer pain is because of treatment.4 Given that cancer pain can arise from multiple sources (eg, pressure of tumors on adjacent tissues, direct damage to the peripheral and central nervous system, stimulation on somatic nociceptive or visceral nociceptors, chemotherapy, radiotherapy, and/or surgery), either directly or indirectly, and cancer patients are more likely to be older and have more comorbidities, which in themselves are associated with pain,1,5,6 difficulty exists in clearly understanding the etiologies of cancer pain. In addition, the multiple and sometimes inter-related phenotypes of cancer pain (pain during active treatment, survivorship, and palliative care) may have distinct genetic variants. Therefore, there are still many questions related to the genetic contributors to cancer-related pain.

Currently, a growing body of literature reporting the results of human genetic association studies have suggested that genetic variability, alone or in interaction with environmental factors, can contribute to differential pain phenotypes and analgesic response.7,8 It is well recognized that genetic factors influence the modulation of pain in the central and peripheral nervous system.9 They can alter the transmission of nociception or central inhibitory signals, affecting individual susceptibility to pain and response to analgesic drugs.1,9,10 For example, single nucleotide polymorphisms (SNPs), commonly examined in genetic association studies as a stable biomarker,11 are involved in increasing or decreasing a risk of pain. In the case of coding SNPs, which can change the amino acid sequence of the gene’s protein product, the result could be alterations in the expression level of an important protein.8 With the rapid advancement of biotechnology platforms and powerful computational analysis for explaining underlying genetic mechanisms,12 genes associated with cancer pain can be targeted for developing effective screening approaches and therapeutic strategies that are individualized in the era of personalized medicine,1 referring to “prevention and treatment strategies that take individual variability into account.”13(p.793) Here, this review is focused on discussing the current knowledge on genetic variability that may play a potential role in differential pain perception and response to opioid analgesics in the treatment of cancer pain.

Search Strategies and Information Sources

We searched data-based publications and review articles with regard to genetic variants that have been implicated in cancer pain. The articles were retrieved from PubMed, CINAHL, and Web of Science; an additional search was conducted in Google Scholar. Genetic association studies on cancer pain phenotype were selected to narrow down the scope of this review. Candidate genetic polymorphisms that were reported to have a significant association with pain in cancer patients were included. The information on gene, SNP rsID, nucleotide change, gene pathway/function (eg, inflammation, neurotransmission, and drug transport and metabolism), associated pain phenotype, type of cancer, and references is presented. Genetic polymorphisms associated with cancer pain were divided into “cancer (itself) pain” and “post-cancer treatment pain” based on the International Association for the Study of Pain classification of chronic pain for the International Classification of Diseases (ICD) (Tables 1 and 2).14 According to the International Association for the Study of Pain definition and general structure of chronic cancer-related pain, cancer-related pain is classified as “cancer pain” resulting from the primary cancer or metastases (eg, visceral cancer pain, bone cancer pain, and neuropathic cancer pain) and “post-cancer treatment pain” related to surgery (post-cancer surgery pain; pain resulting from tissue injury during operations, eg, stretching and retracting, or with the postsurgical progression), chemotherapy (post-cancer medicine pain), and radiotherapy (postradiotherapy pain).14 In addition, the information on genetic polymorphisms associated with response to opioid is described (Table 3). Table 4 provides glossary terms frequently used in this review.

Table 1.

Genetic polymorphisms associated with cancer pain.

Gene SNP rsID Nucleotide Change Pathway/Function Associated Pain Phenotype Type of Cancer Study
IL-8 −251T>A Inflammation Pain severity Lung cancer (white patients) Reyes-Gibby et al, 20075
IL-8 −251T>A Inflammation Pain Lung cancer (NSCLC) Reyes-Gibby et al, 201319
IL-8 −251T>A Inflammation Pain Pancreatic cancer (white patients) Reyes-Gibby et al, 200911
IL-10 rs1800871 Inflammation Pain Lung cancer Rausch et al, 201016
NFKBIA rs8904 C>T Inflammation Pain Lung cancer Reyes-Gibby, Spitz et al, 200918
TNF-α rs1800629 −308G>A Inflammation Pain severity Lung cancer (non-Hispanic white) Reyes-Gibby, Spitz, et al, 200918
PTGS2 rs5275 +837T>C Inflammation Pain severity Lung cancer (non-Hispanic white) Reyes-Gibby et al, 200918
PTGS2 rs5277 Minor “G” Inflammation Pain severity Lung cancer (white) Rausch et al, 201217
LTA rs1799964 Minor “G” Inflammation Pain severity Lung cancer (white) Rausch et al, 201217
IL1R1 rs2110726 C>T Inflammation Preoperative breast pain Breast cancer McCann et al, 201215
IL-13 rs1295686 G>A Inflammation Preoperative breast pain Breast cancer McCann et al, 201215
FAAH rs324420
rs1571138
rs3766246
rs4660928		 C>A (Pro129Thr)
G>A
G>A
C>A		 Drug transport and metabolism Preoperative experimental pain (cold pain sensitivity) Breast cancer Cajanus et al, 201621
COMT rs4680 G>A (Val158Met) Neurotransmission Preoperative pain sensitivity Multiple types of cancer Yao et al, 201520
OPRM1 rs1799971 118A>G (Asn40Asp) Neurotransmission Preoperative pain sensitivity Multiple types of cancer Yao et al, 201520
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Abbreviations: Asn40Asp, a substitution of asparagine (Asn) for aspartate (Asp) at codon 40; COMT, catechol-O-methyltransferase; IL-8, interleukin 8; IL-10, interleukin 10; IL-13, interleukin 13; IL1R1, interleukin 1 receptor type 1; FAAH, fatty acid amide hydrolase; LTA, lymphotoxin alpha; NFKBIA, nuclear factor-kappa-B inhibitor alpha; NSCLC, non–small cell lung cancer; OPRM1, opioid receptor mu 1; Pro129Thr, a substitution of proline (Pro) for threonine (Thr) at codon 129; PTGS2, prostaglandin endoperoxide synthase 2; SNP, single nucleotide polymorphism; TNF-α, tumor necrosis factor alpha; Val158Met: a substitution of valine (Val) for methionine (Met) at codon 158.

Table 2.

Genetic polymorphisms associated with post-cancer treatment pain.

Gene SNP rsID Nucleotide Change Pathway/Function Associated Pain Phenotype Type of Cancer Study
IL1R2 rs11674595 T>C Inflammation Persistent postsurgical pain Breast cancer Stephens et al, 201432
IL-10 Haplotype A8 rs3024505
rs3024498
rs3024496
rs1878672
rs1518111
rs1518110
rs3024491		 Minor “C”
Minor “G”
Minor “C”
Minor “G”
Minor “A”
Minor “T”
Minor “T”		 Inflammation Persistent postsurgical pain Breast cancer Stephens et al, 201432
IL-6 rs20069840 C>G Inflammation Persistent postsurgical pain Breast cancer Stephens et al, 201 733
CXCL8 rs4073 T>A Inflammation Persistent postsurgical pain Breast cancer Stephens et al, 201733
TNF rs1800610 C>A Inflammation Persistent postsurgical pain Breast cancer Stephens et al, 201733
COMT rs4680 G>A (Val158Met) Neurotransmission Postmastectomy pain, pressure pain hypersensitiVity Breast cancer Fernández-des-las- Peñas et al, 201234
COMT rs165774
rs887200		 G>A
T>C		 Neurotransmission Experimental and acute postoperatiVe pain Breast cancer Kambur et al, 201335
COMT rs4680
rs4818		 Neurotransmission Pain interference and severity Breast cancer Young et al, 20 1743
CACNG2 A-C-C haplotype rs4820242
rs2284015
rs2284017		 A>G
C>G
C>T		 Neurotransmission (calcium channel) Chronic postmastectomy pain Breast cancer Bortsov et al, 201836
KCNA1 rs4766311 C>T Neurotransmission (potassium channel) Persistent breast postsurgical pain Breast cancer Langford et al, 201537
KCND2 rs1072198 A>G Neurotransmission (potassium channel) Persistent breast postsurgical pain Breast cancer Langford et al, 201537
KCNJ3 rs12995382
rs17641121		 T>C
T>C		 Neurotransmission (potassium channel) Persistent breast postsurgical pain Breast cancer Langford et al, 201537
KCNJ6 rs858003 C>T Neurotransmission (potassium channel) Persistent breast postsurgical pain Breast cancer Langford et al, 201537
KCNK9 rs2542424
rs2545457		 A>G
T>C		 Neurotransmission T>C (potassium channel) Persistent breast postsurgical pain Breast cancer Langford et al, 201537
CYP17A1 rs4919686
rs4919683
rs4919687
rs3781287
rs10786712
rs6163
rs743572		 Drug transport and metabolism Arthralgia Patients with breast cancer treated with Als Garcia-Giralt et al, 201341
CYP19A1 rs4775936 Drug transport and metabolism Arthralgia (worsening pain) Patients with breast cancer treated with Als Garcia-Giralt et al, 201341
CYP27B1 rs4646536 Drug transport and metabolism Arthralgia Patients with breast cancer treated with Als Garcia-Giralt et al, 201341
VDR rs11568820 Drug transport and metabolism Arthralgia Patients with breast cancer treated with Als Garcia-Giralt et al, 201341
OPG rs2073618 G>C lnflammation (cytokine receptor) Musculoskeletal pain severity Patients with breast cancer treated with Als Lintermans et al, 201642
P2RY12 rs3732765
rs9859538
rs17283010
rs11713504
rs10935840		 C>T
C>T
C>T
A>G
A>G		 Neurotransmission (purinergic signaling, activating microglia) Pain severity, 24-hour postoperative pain (rs3732765) Cancer pain patients patients Sumitani et al, 201846
AQP7 rs76608797
rs33386144		 C>A
G>A		 Other (water-selective membrane channel) Pain Bone metastases (patients undergoing palliative radiation therapy) Furfari et al, 20 1744
PLAUR rs4760 A>G (Leu193Pro) Other (regulation of cell surface protein and extracellular matrix) Pain Bone metastases (patients undergoing palliative radiation therapy) Furfari et al, 20 1744
ELAC2 rs11545302 T>C Other (tRNA processing and TGF-β signaling) Pain Bone metastases (patients undergoing palliative radiation therapy) Furfari et al, 20 1744
TNF-α rs1800629 −308G>A Inflammation Incidence of neck pain, throat pain Differentiated thyroid cancer (patients receiving 131I radiotherapy) Liu et al, 201845
ATM rs11212570 Other (DNA-damage response) Throat pain Differentiated thyroid cancer (patients receiving 131I radiotherapy) Liu et al, 201845
TNF-β rs1800469
rs2241716		 Inflammation Throat pain Differentiated thyroid cancer (patients receiving 131I radiotherapy) Liu et al, 201845
NF-κB rs230493 Inflammation Throat pain Differentiated thyroid cancer (patients receiving 131I radiotherapy) Liu et al, 201845
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Abbreviations: AI, aromatase inhibitor; ATM, ataxia-telangiectasia mutated gene; AQP7, aquaporin 7; CACNG2, calcium channel voltage-dependent gamma subunit 2; COMT, catechol-O-methyltransferase; CXCL8, C-X-C motif chemokine ligand 8; CYP17A1, cytochrome P450 family 17 subfamily A member 1; CYP19A1, cytochrome P450 family 19 subfamily A member 1; CYP27B1, cytochrome P450 family 27 subfamily B member 1; ELAC2, ElaC Ribonuclease Z 2; IL-6, interleukin 6; IL-10, interleukin 10; IL1R2, interleukin 1 receptor type 2; KCNA1, potassium voltage-gated channel subfamily A member 1; KCND2, potassium voltage-gated channel subfamily D member 2; KCNJ3, potassium voltage-gated channel subfamily J member 3; KCNJ6, potassium voltage-gated channel subfamily J member 6; KCNK9, potassium voltage-gated channel subfamily K member 9; Leu193Pro: a substitution of leucine (Leu) for proline (Pro) at codon 193; NF-κB, nuclear factor kappa B; OPG, osteoprotegerin; PLAUR, plasminogen activator urokinase receptor; P2RY12, purinergic receptor P2Y12; SNP, single nucleotide polymorphism; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; TNF-α, tumor necrosis factor alpha; TNF-β, tumor necrosis factor beta; tRNA, transfer ribonucleic acid; Val158Met, a substitution of valine (Val) for methionine (Met) at codon 158; VDR, vitamin D receptor.

Table 3.

Genetic polymorphisms associated with response to opioids.

Gene SNP rsID Nucleotide Change Pathway/Function Associated Pain Phenotype Type of Cancer Study
OPRM1 rs1799971 118A>G (Asn40Asp) Neurotransmission Opioid requirement Patients with cancer pain Gong et al, 201356
OPRM1 rs1799971 118A>G (Asn40Asp) Neurotransmission Oxycodone requirement Patients with postsurgical breast pain Cajanus et al, 201457
OPRM1 rs1799971 118A>G (Asn40Asp) Neurotransmission Morphine consumption Multiple types of cancer Hajj et al, 201758
OPRM1 rs1799971 118A>G (Asn40Asp) Neurotransmission Morphine pain relief Patients with cancer pain Campa et al, 20 0861
OPRM1 rs1799971 118A>G (Asn40Asp) Neurotransmission Morphine consumption Patients receiving chronic morphine treatment Klepstad et al, 200440
COMT rs4680 G>A (Val158Met) Neurotransmission Morphine requirement Patients with cancer pain Rakvåg et al, 200559
COMT rs4680 G>A (Val158Met) Neurotransmission Morphine requirement Multiple types of cancer Matsuoka et al, 201760
ABCB1 rs1045642 3435C>T Drug transport and metabolism Opioid requirement Patients with cancer pain Gong, et al, 201356
ABCB1/MDR1 rs1045642 3435C>T Drug transport and metabolism Morphine pain relief Patients with cancer pain Campa et al, 20 0861
IL-6 −174G>C Inflammation Opioid consumption Lung cancer Reyes-Gibby et al, 200862
GCH1 haplotype rs8007267
rs3783641
rs10483639		 G>A
A>T
C>G		 Neurotransmission Opioid therapy initiation Patients with cancer pain Lötsch et al, 201063
TAOK3 rs1277441
rs795484		 C>T
A>G		 Other (serine/threonine-protein kinase) Opioid requirement Multiple types of cancer Gutteridge et al, 201865
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Abbreviations: ABCB1, adenosine triphosphate (ATP)-binding cassette subfamily B, member 1; Asn40Asp: a substitution of asparagine (Asn) for aspartate (Asp) at codon 40; COMT, catechol-O-methyltransferase; IL-6, interleukin 6; GCH1, guanosine triphosphate cyclohydrolase 1; MDR1, multi-drug resistance gene; OPRM1, opioid receptor mu 1; SNP, single nucleotide polymorphism; TAOK3, TAO kinase 3; Val158Met: a substitution of valine (Val) for methionine (Met) at codon 158.

Table 4.

Glossary terms.

Terminology Description
Genetic association study A type of study that aims to characterize and identify genomic variants that correlate with susceptibility to multifactorial diseases.71
Single nucleotide polymorphism (SNP) A type of human genetic variation that is abundant in the population. It involves the mutation of a single nucleotide in the DNA sequence. They are used as a resource for mapping many complex genetic traits.72
Genetic variability The presence of genetic differences within a population.
Genetic variant An alteration or variant in the typical DNA nucleotide sequence. Can be used to describe a benign or pathogenic alteration.73
Phenotype The physical presentation of an individual who possesses a specific genotype.73
Genotype The genetic composition of an individual.73
rsID Stands for reference SNP ID. It is used by researchers and databases to refer to a specific SNP.74
Major allele The dominant allele of the gene.
Minor allele The recessive allele of a gene.
Heterozygous A genotype that includes one major allele and one minor allele.73
Homozygous A genotype that includes either two major alleles or two minor alleles.73
Biomarker Biologic parameters that can be objectively measured and evaluated, which relate a specific therapeutic intervention to its effect on molecular and cellular pathways and its corresponding clinical presentation.75
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Genetic Variants Associated with Cancer Pain

Associations between genetic polymorphisms and cancer pain before the initiation of anticancer treatments have been described in several studies as shown in Table 1.5,11,15–21 A majority of genes are involved in the inflammatory pathway. It is well documented that chronic inflammation promotes tumor growth and dissemination in patients with cancer, and cancer itself contributes to the release of inflammatory molecules, such as chemokines and cytokines, resulting in the sensitization of sensory nerve terminals.18,22,23 Prior reports have indicated that SNPs involved in the inflammation pathway indirectly regulate cytokine serum expression levels, which may have an impact on individual pain variability and immune functioning.24–26

Lung cancer

Reyes-Gibby and colleagues noted that polymorphisms in the interleukin 8 (IL-8), nuclear factor kappa-B inhibitor alpha (NFKBIA), tumor necrosis factor-alpha (TNF-α), and prostaglandin-endoperoxide synthase 2 (PTGS2) genes have been suggested as candidates for predicting cancer pain in patients with lung cancer.5,18,19 White patients homozygous for the minor allele at IL-8 −251T>A and TNF-α −308G>A (rs1800629) showed 2.35 and 1.67 times higher risk for pain compared with those homozygous for the major allele, respectively, in which pain was measured by the Brief Pain Inventory (n = 446).5,18 The polymorphisms are reported to affect gene expression, which may cause higher serum levels of IL-8 and TNF-α.27 On the contrary, non-Hispanic white cancer patients homozygous for the minor allele at PTGS2 rs5275 (odds ratio [OR] = 0.33, 95% confidence interval [CI], 0.11 to 0.97) and at NFKBIA exon+50C>T (rs8904) (OR = 0.64, 95% CI, 0.43 to 0.93) exhibited a reduced risk for pain (n = 667). (In the paper by Reyes-Gibby et al, “an additive model for NFKBIA Ex6 +50C>T (rs8904) was predictive of severe pain.”)18

Rausch and colleagues16,17 studied the association of SNPs in cytokine genes with pain severity in white lung cancer survivors (n = 1,149). The IL-10 SNP (rs1800871) was a significant predictive factor for pain severity in early survivors (<3 years since diagnosis; OR = 0.97–0.99) and middle-term survivors (3 to 5 years since diagnosis; OR = 0.94–0.99).16 Patients possessing at least one minor allele at rs1799964 in the lymphotoxin alpha (LTA) gene, a member of the TNF family playing a central role in inflammation, showed a protective effect for pain (lower pain scores on the medical outcomes study short-form general health survey [SF-8]) while those possessing at least one minor allele at rs5277 in the PTGS2 gene, encoding the cyclooxygenase 2 (COX2) enzyme, had a higher risk for developing pain.17

Pancreatic cancer

In a study by Reyes-Gibby et al,11 484 patients who were newly diagnosed with pancreatic cancer were evaluated on the association of cytokine gene polymorphisms with pain severity. The pain score was rated on a 0–10 numeric scale, with the higher score indicating the severe pain. Among IL-1β, IL-6, IL-8, 1L-10, IL-18, TNF-α and NF-κB SNPs, the IL-8 SNP (−251T>A) was significantly associated with a risk for pain in patients with pancreatic cancer. Patients with the TT or TA genotype were two times more likely to experience severe pain compared with those with the AA genotype (OR = 2.43, 95% CI, 1.3 to 4.7).

Breast cancer

In a study by McCann et al,15 polymorphisms in interleukin 1 receptor 1 (IL1R1) and IL-13 genes appeared to play a role in modifying individual pain perception. In women prior to breast cancer surgery (n = 398), carriers with the CT or TT genotype for the IL1R1 rs2110726 were at a lower risk for pain compared with those with the CC genotype. On the contrary, carriers with the GA or AA genotype for a SNP in IL-13 (rs1295686) had a 57% increased risk of reporting breast pain before surgery.15 Cajanus et al21 have indicated that SNPs in the FAAH gene, which is involved in the metabolism of the endocannabinoid anandamide, played a role in endogenous analgesia (inhibition of the activity of FAAH promotes endocannabinoid-mediated analgesic effects)28 and exhibited a significant association with experimental cold pain sensitivity in female Finnish patients with breast cancer before breast-conserving surgery or mastectomy (n = 900). Patients homozygous for the minor allele at rs3766246, rs324420 (Pro129Thr), rs4660928, and rs1571138 in the FAAH gene exhibited significantly lower cold pain sensitivity compared with those homozygous or heterozygous for major allele of these polymorphisms?21

Other

Polymorphisms in catechol-O-methyltransferase (COMT) and opioid receptor mu (μ) 1 (OPRM1) genes were associated with the preoperative pain sensitivity in cancer patients. The COMT gene encodes an enzyme that inactivates catechols, such as dopamine, noradrenaline, and adrenaline,29 and the OPRM1 gene encodes the receptor of opioid, of which polymorphisms may modulate the efficacy of opioid analgesics in cancer pain.30 Chinese patients with two copies of the minor allele at COMT Val158Met (ie, a substitution of methionine [Met] for valine [Val] at codon 158) and OPRM1 118A>G loci were reported to have higher pain sensitivity before cancer surgery (n = 300).20

Genetic Variants Associated with Post-cancer Treatment Pain

Many studies have found associations between post-cancer treatment pain and genetic polymorphisms. The influence of genetic polymorphisms on post-cancer surgery pain and post-cancer medicine pain has been largely evaluated on breast cancer, as shown in Table 2. Some genes associated with post-cancer treatment pain seem to be involved in the drug metabolism and transport pathway. Polymorphisms of those genes may change pharmacokinetics of drugs in terms of drug efficacy and safety, and interact with molecules related to pain-transporting analgesics.10,31

Breast cancer

Post-cancer surgery pain.

Stephens and colleagues32,33 found that polymorphisms in inflammatory pathway genes, such as interleukin 1 receptor type 2 (IL1R2), IL-6, IL-10, C-X-C motif chemokine ligand 8 (CXCL8), and TNF, have been associated with persistent pain following mastectomy or lumpectomy in patients with breast cancer (n = 398). Postoperative pain was assessed monthly using the breast symptoms questionnaire, postsurgical pain questionnaire, and Numerical Rating Scale through the 6-month follow-up point. Patients homozygous for the minor allele at rs11674595 in the IL1R2 gene were demonstrated to have a substantially increased risk for severe pain compared with those homozygous or heterozygous for the major allele at the SNP locus (OR = 36.1, 95% CI, 2.02 to 643.37).32 On the contrary, patients who possess IL-10 haplotype A8, consisting of seven SNPs (ie, rs3024505, rs3024498, rs3024496, rs1878672, rs1518111, rs1518110, and rs3024491), showed a decreased risk for severe breast pain by 79% per each dose of this haplotype.32 Notably, patients homozygous for the minor allele in IL-6 rs2069840, CXCL8 rs4073, and TNF rs1800610 were less likely to develop pain compared with those homozygous or heterozygous for the major allele in these genes, as much as 79%, 60%, and 63%, respectively.33

SNPs in the COMT gene may contribute to the variability in pain sensitivity and severity following breast cancer surgery. In a study by Fernández-de-las Peñas et al,34 patients who received a simple mastectomy or quadrantectomy (n = 128, Spain) were assessed using the visual analogue scale and experimental pain tests (pressure pain thresholds in the neck and shoulder areas). It was observed that patients with Met/Met genotype (rs4680) had greater neck pain and lower pressure pain threshold than those with Val/Met or Val/Val genotype. Kambur et al35 also determined the influence of COMT polymorphisms on experimental and acute pain in female Finnish patients with breast cancer undergoing surgery (n = 1,000). In this study, polymorphisms within the COMT gene (rs165774 and rs887200) were significantly correlated with heat pain (+48 °C) and cold pain (+2–4 °C), respectively.

Notably, persistent postmastectomy pain appears to be associated with SNPs in calcium and potassium channel genes. In 482 white women, the presence of a 3-SNP haplotype (A-C-C) (rs4820242, rs2284015, and rs2284017) in the voltage-dependent calcium channel gamma subunit 2 (CACNG2) gene significantly increased a risk of developing chronic mastectomy pain measured by the Brief Pain Inventory and Numerical Rating Scale at 38 months after surgery.36 Langford et al37 indicated that specific SNPs in potassium channel genes, which are involved in the modulation of neuronal excitability, may be susceptible to postsurgical breast pain. As for mild pain, patients who possess the minor allele for a SNP in the potassium voltage-gated channel subfamily A member 1 (KCNA1) (rs4766311), potassium inwardly rectifying channel subfamily J member 3 (KCNJ3) (rs12995382), or potassium channel subfamily K member 9 (KCNK9) (rs2542424) remained significantly associated with a reduced risk of developing pain. On the contrary, patients who possess one or two copies of the minor allele for a SNP in the potassium voltage-gated channel subfamily D member 2 (KCND2) (rs1072198), KCNJ3 (rs17641121), KCNJ6 (rs858003), or KCNK9 (rs2545457) had a 2.3-, 8.5-, 10.0-, or 2.2-fold higher risk of developing pain, respectively. As for severe pain, patients heterozygous or homozygous for the minor allele at rs17376373 in the KCND2 gene had an 88% lower risk for pain, and patients having KCNJ3 haplotype A2 (rs3111020 and rs11895478) were reported to show an 89% decrease per each dose of this haplotype. On the contrary, patients with one or two copies in KCNJ6 rs2835925 and KCNK9 rs2014712 showed a significantly increased risk of developing pain.

Post-cancer medicine pain.

Chemotherapy treatment may cause differential individual susceptibility to pain. It is well documented that one of the major adverse effects in the treatment with third-generation aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemetane, is musculoskeletal pain. Nearly 50% of patients with breast cancer receiving AIs report joint pain and stiffness, and 20% to 30% discontinue the medication, which may increase cancer recurrence rate and mortality.38–40 In a prospective cohort study on the association between SNPs and AI-associated arthralgia (n = 334, Spain),41 SNPs in genes related to the metabolism of estrogens and vitamin D (eg, cytochrome P450 family 17 subfamily A member 1 [CYP17A1], cytochrome P450 family 27 subfamily B member 1 [CYP27B1], vitamin D receptor [VDR], and osteoprotegerin [OPG]) appeared to predict the risk of AI-associated arthralgia. Seven SNPs (rs4919687, rs4919683, rs4919687, rs3781287, rs10786712, rs6163, and rs743572) in the CYP17A1 gene were significantly associated with pain severity. In the multivariate analysis, β coefficients of each polymorphism were −0.60 (P = .015) for rs4919687, −0.67 (P= .003) for rs4919683, −0.71 (P = .003) for rs4919687, −0.63 (P = .004) for rs3781287, −0.66 (P= .003) for rs10786712, −0.65 (P = .003) for rs6163, and −0.62 (P = .005) for rs743572, indicating that these CYP17A1 polymorphisms were significantly associated with lower pain increase. In addition, a significant association was observed between visual analogue scale increase and polymorphisms in CYP27B1 (rs4646536) and VDR (rs11568820). Notably, the polymorphism at rs2073618 in the OPG gene, known as TNF receptor superfamily member 11B (TNFRSF11B), was also significantly associated with pain severity in which patients with the CG or GG genotype experienced more pain (visual analogue scale) compared with those with the CC genotype.42

Two COMT polymorphisms, including rs4680 and rs4818, are also known to contribute to pain severity after surgery and chemotherapy in patients with breast cancer (n = 51).43 Patients with the AA genotype in COMT rs4680 exhibited increased pain-related interference, and patients with the GG genotype in COMT rs4818 showed decreased pain severity and interference after surgery and chemotherapy treatment.

Bone metastases

Postradiotherapy pain.

Genetic polymorphisms have been associated with postradiotherapy pain in cancer in several studies.44,45 In patients with bone metastases undergoing palliative radiotherapy, whose primary cancer sites were breast, lung, and prostate (n = 52), nine polymorphisms across the aquaporin 7 (AQP7), plasminogen activator urokinase receptor (PLAUR), and ElaC ribonuclease Z 2 (ELAC2) genes may be associated with pain. Especially, rs7668797 in the AQP7 gene, rs4760 A>G in the PLAUR gene, and rs1154302 T>C in the ELAC2 gene, were the most significant polymorphisms in predicting postradiotherapy pain.44 In patients with differentiated thyroid cancer undergoing 131I radiotherapy (n = 203),45 patients heterozygous for the minor allele for the TNF-α rs1800629 were more likely to report pain in the neck area compared with those homozygous for the major allele. In addition, SNPs in ataxia-telangiectasia mutated (ATM) rs11212570, NF-κB rs230493, and transforming growth factor (TGF-β) rs1800469 and rs2241716 may contribute to individual susceptibility in throat pain at 6 weeks post-radiotherapy.45

Multiple Types of Cancer

Post-cancer surgery pain.

Recently, the association between polymorphisms in the purinergic P2Y12 receptor (P2RY12), a site where microglial chemotaxis is induced in the nervous system, and pain severity were investigated in Japanese cancer patients who reported pain (n =355). Five SNPs (rs3732765, rs9859538, rs17283010, rs11713504, and rs10935840) of the P2RY12 gene were demonstrated to have a significant association with cancer pain and postoperative pain severity. Patients homozygous for the minor allele of these SNPs reported greater pain compared with those homozygous for the major allele or heterozygous for the minor alleles.46

Genetic Variants Associated with Response to Opioid Treatment

Cancer patients need adequate treatment for controlling pain because unrelieved pain may affect disease outcomes and may likely develop into chronic persistent pain.47 Opioids are currently used as the most effective treatment as first-line therapy for cancer pain.48–50 Opioids bind to receptors in mu (μ), kappa (κ), or delta (δ) subtypes in the central nervous system, producing signaling.51 Once opioids bind to their G-protein coupled receptors, neuronal cell membranes are hyperpolarized and neurotransmitter release is reduced, leading to an analgesic effect.51–53 The majority of opioid analgesics are the mu agonist,50 which are divided into a couple of classes depending on the extent to which they interact with their receptors. The pure mu agonist opioids, which are commonly used for managing patients who are not chronically taking opioid drugs (ie, opioid naïve) or restricted in exposure to opioids, include morphine, hydromorphone, oxycodone, hydrocodone, codeine, fentanyl, and methadone.50 Buprenorphine is an example of partial agonists, which are used for treating opioid addiction, and tramadol and tapentadol depend on both mu agonism and monoaminergic mechanism.50 In addition, the response to these opioids is associated with their metabolism in relation to the cytochrome P450 (CYP) enzymes, which may alter opioid formation and its concentration in circulation.51,54 For example, increased CYP2D6 activity is observed in “extensive metabolizers” and “ultra-rapid metabolizers.”54 Some cancer patients suffer from undertreated pain because of a poor response to opioid analgesics. Genetic biomarkers may help increase an understanding of the differential sensitivity to the opioids (eg, tolerance and consumption) to prevent inadequate cancer pain management.54 To date, studies on the genetic influence on the analgesic effects and efficacy of opioid treatment have primarily considered OPRM1, COMT, and ATP binding cassette subfamily B member 1 (ABCB1) genes.

Recently, a meta-analysis including 12 studies (n = 2,118) has indicated that the OPRM1 118A>G polymorphism (rs1799971) may affect variability in the opioid analgesic effect in cancer patients.55 Patients homozygous or heterozygous for the minor allele in OPRM1 118A>G (rs1799971) are reported to require more opioids to relieve pain than those homozygous for the major allele (standardized mean difference = −0.3, 95% CI, −0.45 to −0.15). For example, it was reported that Chinese cancer patients (n = 112) with the AG, GG, and AA genotypes needed 97.33 ± 69.07 mg/24 hours, 152.34 ± 83.13 mg/24 hours, and 72.48 ± 64.05 mg/24 hours of opioids, respectively, indicating that opioid consumption of patients homozygous for the major allele was significantly lower than that of those with at least one minor allele.56 In another study by Cajanus et al,57 women with the GG genotype consumed the highest amount of oxycodone (0.16 mg/kg); however, women with the AA genotype needed the lowest amount of oxycodone (0.12 mg/kg) after breast cancer surgery (P = .003). Similarly, in the study of Hajj et al,58 the AG genotype of OPRM1 rs1799971 required a higher dose of morphine at 24 hours to achieve adequate analgesic efficacy compared with the AA genotype (AG genotype = 51.37 ± 46.35 mg, AA genotype = 29.97 ± 26.96 mg; P = .01) in 89 patients with multiple types of cancer (eg, breast, gastrointestinal tract, lung, hematology, gynecology, and others).

The COMT SNP (rs4680; Val158Met) has been also shown to influence the efficacy of opioids in patients with cancer pain. Carriers with the Val/Val genotype required a higher dose of morphine (155 ± 160 mg/24 hours; n = 44) than carriers with the Val/Met (117 ± 100 mg/24 hours; n = 96) and Met/Met genotype (95 ± 99 mg/24 hours; n = 67) (P = .025).59 Matsuoka et al60 have suggested that 50 opioid-naive patients with Val/Val, Val/Met, and Met/Met genotypes required 35.2 ± 11.5 mg, 29.5 ± 2.3 mg, and 25.0 ± 7.1 mg of morphine, respectively, in which the presence of the Val/Val genotype contributed to the higher dose of morphine requirement for cancer pain relief compared with the presence of Val/Met and Met/Met genotypes (P = .013).

The polymorphism of the ABCB1 gene (3435C>T), encoding the efflux transporter P-glycoprotein, may explain interindividual differences in the response to opioids. Cancer patients homozygous for the minor allele showed greater pain relief by morphine therapy than those homozygous for the major allele (n = 137).61 The Numerical Rating Scale pain scores in patients with the TT genotype and the CC genotype were decreased by 4.39 ± 2.21 and 2.31 ± 1.73, respectively, following morphine treatment. However, the pain relief effect by morphine was not significantly different between patients with the TC genotype and those with the CC genotype.61 Similarly, the potential relationship of the polymorphism in ABCB1 (3435C>T) with opioid requirement was demonstrated in Chinese patients with cancer pain (n = 112). Patients homozygous for the minor T allele were less likely to require a lower dose of opioids at 24-hour compared with those with at least one major C allele (TT genotype = 66.04 ± 52.57 mg/kg; CT genotype = 103.87 ± 71.38 mg/kg; CC genotype = 100.43 ± 82.24 mg/kg).56

In addition to those genes, IL-6, guanosine triphosphate (GTP), cyclohydrolase 1 (GCH1), and TAO kinase 3 (TAOK3) genes may explain variability in the efficacy of opioids in cancer patients with pain. In a study by Reyes-Gibby et al,62 lung cancer patients with GC and GG genotypes of IL-6 −174G>C required 73.17 mg/24 hours and 69.61 mg/24 hours, respectively; however, those with the CC genotype received 181.67 mg/24 hours, indicating that the dose of opioids of the CC genotype was 4.7 times higher than that of GC and GG genotypes to achieve the equivalent pain relief (n =140). Furthermore, the GCH1 haplotype, consisting of three SNPs (rs8007267, rs3783641, and rs10483639) may affect the initiation time of opioid therapy after cancer diagnosis.63 The GCH1 gene is known to encode the enzyme protein that catalyzes the formation from GTP to tetrahydrobiopterin (BH4).63 In a mouse animal model, reduced BH4 expression has shown a protective effect against pain.64 Patients homozygous for the genetic variants were shown to initiate morphine treatment at 78 ± 65.2 months after their cancer diagnosis, while those heterozygous for the genetic variants or non-carriers started the treatment at 37 ± 46.5 months and 30.4 ± 43.8 months after the diagnosis, respectively, suggesting that GCH1 variants may result in decreased BH4, postponing the development of cancer pain (n = 251).63 In addition, polymorphisms in the TAOK3 gene, encoding serine/threonine-protein kinase, were significantly associated with the amount of opioid used for cancer pain. Patients homozygous for the minor allele in TAOK3 rs796484 (G>A) and rs1277441 (T>C) had higher opioid requirements in patients with cancer pain (n = 110).65 However, negative evidence also exists on the association of genetic variability with opioid use in the treatment of cancer pain. In a European genetic association study (n = 2,294), cancer patients treated with morphine, oxycodone, fentanyl, or others did not show any associations between opioid dose and 112 SNPs across the 25 genes, including OPRM1, COMT, and ABCB1.31

Implications for Nursing Practice and Research

This review summarizes the current knowledge on genetic polymorphisms that have been implicated in cancer pain, post-cancer treatment and surgical pain, and response to opioid analgesics. Most genetic association studies published to date have been focused on cancer pain in non-Hispanic white patients with solid tumors (eg, breast cancer, lung cancer), indicating that more research is warranted to elucidate the influence of genetic variability on pain in patients experiencing other types of cancers (eg, hematologic cancer, head and neck cancer) and patients with diverse ethnic/racial background, including African American, Hispanic, and Asian. Although the role of polymorphisms within some specific genes (eg, COMT and OPRM1) on cancer pain has been validated in several studies with adequate samples of patients, the majority of genetic polymorphisms in current genetic association studies need to be replicated to confirm these findings.

As described earlier, genetic variability is seemingly one of contributing factors that alter individual susceptibility to pain and response to opioid drugs in patients with cancer. In the era of precision medicine, biomarker-based diagnosis and treatment will be quickly replacing the traditional medicine, so-called “trial and error.”12 Given that genetic biomarkers can help determine the efficacy and toxicity of analgesic drugs and predict the treatment response and symptom outcomes, cancer pain could be effectively managed with selected therapies that are personalized.12,51,66 If tests related to polymorphic genes with good sensitivity and specificity are clinically available for cancer pain, patients with cancer pain could benefit from improved quality of life and reduced health care utilization and costs.61,67 With a growing number of biomarkers developed for clinical use, health care providers will play a key role in identifying patients at high risk of cancer pain and evaluating the outcome of therapies or interventions, as well as educating patients on the interpretation of biomarker testing data.68 Especially, nurses are in a unique position to apply this information to planning and using tailored pain management interventions and to help patients and families make a decision on selection of treatments over the cancer trajectory.69 Therefore, nurses should be prepared to have genomic and genetic competencies in assessment, education, and management of this specific patient population in clinical practice.69

Although several candidate genes have been recognized with regard to cancer pain and analgesic responses, genetic association studies are still challenging because of the complex traits of genes and phenotypes. There are a number of environmental, psychological, and clinical factors that interact with genes involved in pain perception and analgesic effects.54 Mostly, studies evaluating the association of genotypes with pain phenotype and opioid use likely provide confusing or limited information and do not consider effects of gene-gene or SNP-SNP interactions.54,70 In addition, large sample sizes to increase the power of studies and clear definition of clinical phenotype are important to genetic association studies.54 Indeed, there is no consensus on cancer pain and how to address it (no specific assessment tools for cancer pain) in the studies included in this review. Nurse scientists should consider these issues when conducting genetic association studies.

Conclusion

Pain is the most common symptom in cancer patients, probably because of the cancer itself and cancer treatment. Genetic variability may have significant effects on differential pain perception and response to opioid treatment, but more studies are warranted to confirm the current findings in cancer pain. The information about genetic variants could offer optimal personalized treatment of cancer pain by determining drug efficacy and predicting the outcome of cancer pain. With growing evidence of genetic associations with symptoms, nursing practice and research should be integrated into personalized medicine in the treatment of cancer pain.

Funding Source:

This research was supported by the National Institutes of Health/National Institute of Nursing Research (F32NR018367 to G.S.Y. and P30NR016579 to S.G.D.).

Footnotes

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