(1)
Lifetree Clinical Research, Salt Lake City, UT, USA
(2)
American Academy of Pain Medicine, Glenview, IL, USA
Abstract
Physicians who treat chronic pain using opioids recognize that patients vary considerably in their responses to medications and painful stimuli. An increasing body of scientific literature supports the observation that the success or failure of opioid pharmacotherapy for pain may be rooted in individual genetic variations (Clin J Pain 26(Suppl 10):S16–S20, 2010; Curr Opin Anaesthesiol 20(5):478–484, 2007; Pain 109(3):488–496, 2004). Given the advances, genetic research appears to lay a foundation for future pain therapy informed by an appreciation of each person’s unique genome. In essence, applied pharmacogenetics – the intersection of pharmaceuticals and genetics – heralds personalized medicine. The genome determines a person’s potential response to a pain stimulus or analgesic; however, it is social and environmental experiences that will influence the final expression (Arthritis Res Ther 8(5):218, 2006). Environmental factors contribute to pain because pain is a multifactorial experience, largely influenced by affective input from anticipatory and emotional areas of the brain. The precise size of the contribution of genetics and environment to pain sensitivity is uncertain and is influenced by the type of pain stimulus (Pain 136(1–2):21–29, 2008). The field of pharmacogenetics is constantly evolving. The process of isolating candidate genes that contribute to such specific responses as pain sensitivity and speed of drug metabolism is painstaking. Studies also suggest that gender and ethnic differences in pain sensitivity have a genetic contribution, expressed through genetic determinations of cognitive, limbic, and affective neural networks (Pain 109(3):488–496, 2004). However, additional studies found ethnic variations in pain response to be insignificant when controlling for potentially confounding variables, including pain-coping mechanisms (Pain Med 6(1):88–98, 2005). Failure to replicate some findings underlines the difficulty of determining which genetic markers promise clinical utility. Even well-supported innovations and insights from the research laboratory do not yet translate to clinical practice in most instances. Patients who suffer from intractable pain and the physicians who treat them are still locked in a clinical environment where conventional treatments for chronic pain tend to work only for some patients and then sporadically and imperfectly. As advances in research continue and the cost of genome sequencing drops, the association between genetic profiles and pain profiles should grow clearer. The aim of this chapter is to provide the reader with an overview of the potential clinical implications of understanding the unique genetic pain processing of the individual and how pharmacogenetic therapy might inform personalized medical care.
Genetics of Pain Processing
Individuals within any population exhibit common variations in DNA sequences (polymorphisms). Polymorphisms occur with molecules that involve transduction of sensory information and genes largely responsible for analgesia. Single-nucleotide polymorphisms (SNPs) are segments of the gene that are linked to a variety of responses in pain sensitivity and modulation. Most research takes place using animal models, healthy human volunteers, and postoperative patients; however, certain SNPs point to vulnerabilities for developing chronic pain diseases. The aim of this chapter is to provide the reader with an overview of the potential clinical implications of understanding the unique genetic pain processing of the individual and how pharmacogenetic therapy might inform personalized medical care.
Candidate Genes Implicated in Pain Processing
Several candidate genes have been studied extensively for their involvement in pain processing, and some have been associated with specific pain complaints (Belfer et al. 2004). However, research is inconclusive, and candidate genes associated with pain sensitivity do not necessarily coincide with the factors leading to the development of chronic widespread pain (Holliday et al. 2009).
What follows is a sample of candidate genes studied for pain processing and their associations with specific pain complaints.
Transient Receptor Potential Vanilloid 1
Transient receptor potential vanilloid (TRPV) is a family of transient receptor potential ion channels sensitive to temperature and chemical activation found throughout the body. The first member of the family discovered was the TRPV1 receptor, which is also called the capsaicin receptor. In the work by Kim et al., gender, ethnicity, and temperament were shown to contribute to individual variation in thermal and cold pain sensitivity by interactions with TRPV1 SNPs (Kim et al. 2004). TRPV1 has two SNPs in its exons that produce amino acid substitutions: One is in codon 315 (TRPV1 Met315Ile) and the other in 585 (TRPV1 Ile585Val). Female European Americans with the TRPV1 Val585 allele showed longer cold withdrawal times than the other ethnic groups, including African American, Hispanic and Asian American, in the cold-pressor experimental pain model. Sex differences were also found with European males tolerating longer times of cold submersion than females. Harm avoidance and reward dependence were measures of temperament also found to be associated with the polymorphisms.
SC9NA
Extreme mutations of SCN9A are found in people with congenital insensitivity to pain and in those who exhibit extreme pain states (Reimann et al. 2010). More common SNPs of the gene are associated with altered pain perception and heightened pain sensitivity (Reimann et al. 2010). In a recent study of 1,277 patients with osteoarthritis, sciatica, phantom pain, pancreatitis, or pain after lumbar discectomy, the A allele of rs6746030 was associated with significantly increased pain as compared with the more common G allele (combined p = 0.0001) (Reimann et al. 2010). Heightened pain sensitivity was also observed in 186 healthy women with the same variant, indicating a possible sex-specific expression with this SNP. Females have been reported to be more sensitive to pain than males (Nielsen et al. 2008; Fillingim et al. 2009); however, some findings are inconsistent, including sex differences in pain treatment response (Fillingim et al. 2009).
Interleukin-1
Research suggests an association between interleukin-1 (IL-1) gene locus polymorphisms to the pathogenesis of low back pain. In a subgroup of a Finnish cohort study, 131 middle-age men from three occupational groups (machine drivers, carpenters, and office workers) who carried the IL-1RNA(1812) allele showed increased pain frequency, more days with pain, and limitation of daily activities (Solovieva et al. 2004).
KCNK18
A recent study found that a mutation in the KCNK18 gene inhibits TRESK, a protein that helps regulate pain sensitivity (Ronald et al. 2010). The investigators linked the gene variant to migraine with the discovery that a large family of sufferers of migraine with aura carry it. TRESK is found in the trigeminal ganglia and dorsal root ganglia, areas of the brain linked to the development of pain and migraine. The hope is that increasing TRESK activity might serve to decrease neuron excitability, reducing migraine severity or frequency.
Catechol-O-Methyltransferase gene
Catechol-O-methyltransferase (COMT) is an enzyme that metabolizes catecholamines; inhibited COMT has been associated with heightened experimental pain sensitivity and risk for developing temporomandibular joint disorder (TMD) (Diatchenko et al. 2005). Reduced COMT activity has produced enhanced mechanical and thermal pain sensitivity in rats, an effect that was blocked by administering β2– and β3-adrenergic antagonists but not β1-adrenergic, α-adrenergic, or dopaminergic receptor antagonists (Nackley et al. 2007).
The COMT polymorphism VA1158met introduces an amino acid variation associated with greater pain sensitivity. Research suggests that this polymorphism affected cerebral pain processing by increasing activity in the anterior cingulate cortex in 57 subjects (27 males) homozygous for the met158 allele (Mobascher et al. 2010).
The findings that COMT variations mediate pain modulation seem well supported. However, haplotype analysis has failed to confirm evidence of the association between chronic widespread pain and COMT SNPs associated with pain sensitivity (Nicholl et al. 2010).
Genetics of Drug Response
Interpersonal genetic variations impact not only how patients perceive and experience painful stimuli but how they absorb, metabolize, and excrete medications. Research shows 30–40% of subjects in clinical pain trials are non-responders (Argoff 2010), evidence of the large inter-individual variabilities in response to analgesic medications. Common variants in the genes encoding mu-receptors, transporters, and metabolizing enzymes are linked to the individual’s opioid response and, thus, may largely dictate analgesic needs.
Data, however, are inconsistent. For example, a recent study using the association technique in 2,294 opioid-treated patients failed to show any association between a group of polymorphisms in candidate genes (OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1) with opioid efficacy (Klepstad et al. 2011). This finding may illustrate the difficulty in using the association technique in identifying potential genetic markers for analgesic sensitivity. The sample size in the study would be considered large for most studies but may have not been large enough to detect a genetic signal.
What follows is a discussion of common polymorphisms studied for their effects on opioid response
OPRM1 118G
The mu-opioid receptor allele A118G influences variations in postoperative analgesic needs (Zhang et al. 2010). Postsurgical patients who were 118G homozygotes needed more morphine to control pain after total knee arthroplasty (Chou et al. 2006, knee) and hysterectomy (Chou et al. 2006, hysterect) compared with 118A homozygotes.
Cytochrome P450, Including CYP2D6
Polymorphic cytochrome P450 enzymes are linked to differences in speed of drug metabolism (Fishbain et al. 2004), supporting the clinical observation that equal doses of opioids do not produce equal pain control for all patients. Among the drugs metabolized through CYP450 enzymes are codeine, tramadol, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs (Stamer & Stüber 2007).
Numerous polymorphisms within CYP2D6 influence opioid effectiveness, and researchers have identified four categories of opioid responders: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) (Ingelman-Sundberg 2005). PMs are at risk for toxicity from drug accumulation, while UMs can fail to achieve adequate analgesia.
Methods of Analysis
Studies designed around twins using structural equation modeling have the advantage of enabling the analysis of genetic vs. environmental contribution to the development of a phenotype. Shared alleles and environmental effects are analyzed based on whether the twins are monozygotic (sharing 100% of alleles) or dizygotic (sharing on average 50% of alleles) (Nielsen et al. 2008). Twin studies, besides being purely correlational, are not randomly derived and, therefore, not generalizable to the larger population.
In contrast, association studies are performed in subjects unrelated to one another and are restricted to a limited set of candidate genes (Belfer et al. 2004). Association studies have greater power than family linkage studies to detect even slight genetic effects but must have far greater density of markers. Another limitation of association studies is that, often, SNPs have only a small predictive value for the studied effect.
Sex and Ethnic Variations of Pain and Medication Responses
Observable differences in pain and medication response between the sexes and among ethnic groups are linked to allelic variants. For example, approximately 7% of white Americans could be classified as PMs, compared with only 2% of black Americans based on polymorphisms within CYP2D6 (Evans et al. 1993). In contrast, in a study of healthy Ethiopians, 29% of the investigated population had duplicated or multiple copies of CYP2D6 genes, linked to ultrarapid metabolism (Aklillu et al. 1996). African Americans when compared to non-Hispanic whites have been associated with greater experimental pain sensitivity and clinical pain with indication that the difference is endogenous (Campbell et al. 2008).
Women have more postsurgical pain than men, requiring 30% more morphine on a per-weight basis to achieve similar analgesia (Cepeda & Carr 2003). Females have been shown to respond more to kappa-agonist opioids than males (Gear et al. 1996), yet they seem to have more sensitivity to pain than males (Nielsen et al. 2008). Research in animal studies (mice) and humans also show the sex difference could stem from the melanocortin-1 receptor (MC1R) gene (Mogil et al. 2003). Women with two nonfunctional MC1R alleles – a phenotype associated with red hair and pale skin – achieved significantly greater analgesia from the administration of the kappa-agonist pentazocine than did women without the gene variant or men (Mogil et al. 2003).
Sex hormones are suspected contributors to painful conditions seen primarily in women. Fluctuations in ovarian hormones associated with the menstrual cycle appear to influence pain response (Martin 2009). One study suggested that a polymorphism in the estrogen receptor increases the risk of women developing TMDs (Ribeiro-Dasilva et al. 2009). Although sex hormones have not been directly linked to the development of fibromyalgia, a connection to fibromyalgia syndrome may lie in the discovery that sex hormones influence serotonergic receptor response, which affects sleep and pain perception (Akkuş et al. 2000; Buskila and Sarzi-Puttini 2006).
The variability in gender and race response to drugs may explain why it is difficult to predict a drug effect when the drug is studied in a relatively homogenous population. Industry would be wise to consider gender and race difference in responses to pain stimuli and analgesics in drug development.
Environmental Vs. Genetic Contributions to Pain Processing
Some interpersonal variance in opioid response and pain sensitivity is explained by factors outside genetic vulnerability, including age, the severity of the pain stimulus, psychological coping mechanisms, concurrent medications, and differences among patients in the disease process. Medical and psychiatric comorbidities may exacerbate or modulate pain perception, and lifestyle habits such as diet and exercise also contribute.
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