Pharmacogenetics of Chronic Pain and Its Treatment

Table 1

Overview of recently released (2010–2012) studies assessing the influence of various gene polymorphisms on pain perception in humans.

Gene	Refrence	Polymorphisms	Populations	Results
	Hocking et al., 2010 [1]	Totally 11 SNPs	𝑛=8572, 1958 British birth cohort (83% Caucasians)	No associations of either chronic widespread pain or pain status with COMT genotypes or haplotypes
	Finan et al., 2010 [2]	rs4680	𝑛=46 female fibromyalgia patients (93.0% Caucasians)	Individuals with met/met genotype experienced a greater decline in positive effect on days when pain was elevated more than did either val/met or val/val individuals, COMT  genotype contributing 1% of variance over and above the effect of pain on PA
	Fijal et al., 2010 [3]	rs6269, rs4633, rs4818, rs4680, and haplotypes	𝑛=159/93 female/male Caucasians with major depressive disorder	Associations between a haplotype created using rs6269, rs4633, rs4818, and rs4680, and the proportion of female patients with “Pain While Awake” and “Overall Pain” at baseline. No association was found in males
	Fernandez-de-las-Penas et al., 2011 [4]	rs4680	𝑛=70 children with chronic tension type headache, 𝑛=70 healthy children	Children with chronic tension type headache (CTTH) met/met genotype-longer headache history compared with met/val (𝑃=0.001) or val/val (𝑃=0.002), children with CTTH, met/met genotype showed lower pressure pain test score over upper trapezius and temporalis muscles than children with CTTH with met/val or val/val genotype.
COMT	Barbosa et al., 2012 [5]	rs4680 and rs4818	𝑛=112 fibromyalgia patients; 𝑛=110 healthy individuals	SNP rs4818, the frequency of variant genotype CC was 73.21 and 39.09% for patients with FS and controls, respectively, Fibromyalgia Impact Questionnaire score was higher in patients with the homozygous variant genotype for SNPs rs4680 (87.92 points) and rs4818 (86.14 points)
	Loggia et al., 2011 [6]	rs4680	𝑛=54 healthy subjects	met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation, and precuneus
	Dai et al., 2010 [7]	rs6269, rs4633, rs4818, rs4680, and haplotypes	𝑛=69 patients with low back pain who underwent an intervention	rs4633 T allele—greater improvement in ODI (Oswestry disability index) score 1 year after surgery ATCA haplotype-APS-average pain sensitivity (9.3% in the study population)—greater improvement in ODI. The greatest mean improvement in ODI-ATCA-homozygotes
	Omair et al., 2012 [8]	rs4633, rs4680, rs4818, rs6269, rs2097603, and haplotypes	𝑁=93 patients with low back pain	Association of rs4633 and rs4680 with posttreatment improvement in VAS, for better improvement among heterozygous patients compared to the homozygous ones, no association was observed for the analysis of the common haplotypes
	Martinez-Jauand et al., 2013 [9]	rs6269, rs4633, rs4818 rs4680, and; haplotypes	𝑁=113 fibromyalgia patients; 𝑛=65 healthy controls	Fibromyalgia individuals with the met/met genotype (Val158Met SNP) or the high- and average-pain sensitivity-associated haplotypes showed higher sensitivity to thermal and pressure pain stimuli than patients carrying the LPS haplotype or val alleles (Val158Met SNP)
OPRM1	Klepstad et al., 2004 [10]	A118G (rs1799971)	𝑁=99 Caucasians	Brief pain inventory average pain scores higher in AG heterozygotes
	Olsen et al., 2012 [11]	A118G	𝑁=258 patients with lumbar disc herniation and sciatic pain, Caucasians	*/G women had 2.3 times as much pain as the */G men 12 months after the disc herniation, while A/A women and A/A men had almost exactly the same recovery rate
	Menon et al., 2012 [12]	A118G	𝑛=153 chronic migraine females, Caucasians	G118 allele carriers were more likely to be high pain sufferers compared to homozygous carriers of the A118 allele (OR = 3.125, 95% CI = 1.41, 6.93, 𝑃=0.0037)
	Finan et al., 2010 [2]	A118G	𝑛=46 female patients with fibromyalgia 93.0% Caucasians	Patients with an 118G allele reported higher positive affect score across diary days than those homozygous for 118A
	Janicki et al., 2006 [13]	A118G	𝑛=121 chronic, non-cancer pain patients, 𝑛=101 opioid-naive subjects with acute postoperative; pain, Caucasians	The frequency of 118G is significantly lower in the subjects with chronic pain than in the group with acute postoperative pain—0.079 versus 0.158; 𝑃=0.009
GCH1	Heddini et al., 2012 [14]	rs8007267; rs3783641; rs10483639	𝑛=98 women with provoked vestibulodynia, healthy controls 𝑛=102	Significant interaction effect of GCH1 gene polymorphism and hormonal contraceptive therapy on coital pain among patients with current treatment (𝑛=36)
TRPV1	Carreno et al., 2012 [15]	rs222741	𝑛=1040 cases—Caucasians, 1037 controls	Association of rs222741 with the overall migraine group
SCN9A	Reeder et al., 2013 [16]	rs6746030	𝑛=53 biopsy specimens, 𝑛=26 control specimens	AA or AG genotypes were present in 39.6% patients with cystitis/bladder pain syndrome—statistically significant difference compared with the controls: 11.5%
KCNS1	Costigan et al., 2010 [17]	rs734784	𝑛=1359 six independent cohorts	rs734784 significantly associated with higher pain scores in five of six independent patient cohorts, lumbar back pain with disc herniation—association with greater pain outcome in homozygote patients. The combined 𝑃 value for pain association in all six cohorts
CACNG2	Nissenbaum et al., 2010 [18]	Totally 12 SNPs	𝑛=549 breast cancer patients: 𝑛=215 control group 𝑛=334	rs4820242, rs2284015, rs2284017, rs2284018, and rs1883988 showed significant association with chronic pain
ADR𝛽2	Diatchenko et al., 2006 [19]	Totally 8 SNPs and their; haplotypes H1, H2, and H3	𝑛=181 cohort of females (Caucasians)	H1/H2 and/or H1/H3—lowest temporomandibular disorder incidence—1.3%, H1/H1 elevated risk of developing temporomandibular disorder (RR = 8.0, 95% CI = 1.2–52.2, 99% CI = 0.815–79.7), H3/H3, H2/H3, and H2/H3 H1 elevated risk of developing temporomandibular disorder (RR = 11.3, 95% CI = 1.95–67.9, and 99% CI = 1.38–102
	Hocking et al., 2010 [1]	rs12654778 and rs1042713	𝑛=8572, 1958 British birth cohort (82.6% Caucasians)	ADRB2 SNPs rs12654778 and rs1042713 were associated either with chronic widespread pain alone or with pain status
HTR2A	Nicholl et al., 2011 [20]	Totally 47 SNPs	𝑛=164, control group 𝑛=172	rs12584920T (T/*, T/T) increased likelihood of having chronic widespread pain (OR) = 1.64, 95% confidence interval (95% CI) = 1.01–2.60 (𝑃=0.03) in the discovery cohort, and OR = 1.46, 95% CI = 1.07–2.00 (𝑃=0.018) in the validation cohort, similar association between rs17289394 and the maximum number of pain sites reported in both cohorts

VAS: visual analogue scale, OR: odds ratio, RR: relative risk, CI: confidence interval, SNP: single-nucleotide polymorphism, fMRI: functional magnetic resonance. GCH1: GTP cyclohydrolase 1, the rate limiting enzyme in the biosynthesis of tetrahydrobiopterin is an essential cofactor in the synthesis of serotonin, nitric oxide, and catecholamines. These neurotransmitters are known to modulate pain perception. TRPV1: transient receptor potential cation channel, subfamily V, member 1, acts as an integrator of multiple painful stimuli in chronic pain conditions. SCN9A: sodium channel, voltage-gated, type IX, alpha subunit encodes the voltage-gated sodium channel. Homozygotes with 2 loss-of-function alleles are congenitally indifferent to pain without other neurological deficit. KCNS1: voltage-gated potassium channel 1. CACNG2: calcium channel, voltage-dependent, gamma-subunit 2, encodes the gamma-2 transmembrane AMPA receptor protein (TARP) stargazin. This protein is known to be involved in the modulation of the ion channel function of glutamatergic AMPA receptors. ADRB2-beta2-adrenergic receptor is a target for epinephrine. HTR2A: 5-hydroxytryptamine (serotonin) receptor 2A. P2X7: cAMP responsive element binding protein 1.