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Genetic Variability in the Activity of Monoamines: A Window into the Complexity of Pain

Flood, Pamela MD, MA; Clark, David MD, PhD

doi: 10.1213/ANE.0000000000000447
Editorials: Editorial
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From the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California.

Accepted for publication July 29, 2014.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Pamela Flood, MD, MA, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Dr., Palo Alto, CA 94305. Address e-mail to pamela.flood@stanford.edu.

The physiology that underlies pain perception is complex and clearly influenced by both genetic and environmental factors. This issue of Anesthesia & Analgesia includes 2 articles that identify relationships between single nucleotide polymorphisms (SNPs) in the gene for Catechol-O-methyltransferase (COMT) and manifestations of acute1 and recurrent pain.2 It is one of the most highly investigated genes in pain research. The COMT enzyme breaks down catecholamines, plays a role in estrogen metabolism, and has been variably implicated in experimentally induced pain in a gender- and modality-specific manner.3 This work is important because the clinical expression of both acute and more persistent types of pain is highly variable, even in the setting of a monogenetic etiology such as sickle cell disease or after similar injuries such as a relatively standardized surgical procedure. The consequences of either under- or overtreatment of pain are severe. Both reports illustrate some of the promises as well as the substantial pitfalls associated with genetic research in pain.

The most commonly studied COMT SNP with respect to pain is rs4680: A > G, which results in amino acid substitution Val158Met (Fig. 1). This variant, considered alone, is associated with reduced activity of the COMT enzyme. However, 3 other synonymous variants that do not result in coding changes, rs6269: A > G in the promoter region for S-COMT, rs4633: C > T, and rs4818: C > G in the coding region for both S (soluble) and MB (membrane bound) forms of COMT contribute to haplotypes (groups of linked SNPs) that are present in 92% of the Caucasian population.4 These haplotypes are referred to as low pain sensitivity (LPS:G_C_G_G), average pain sensitivity (APS:A_T_C_A), and high pain sensitivity (HPS:A_C_C_G) and are associated with normal, 3-fold, and 20-fold reduced COMT enzyme activity. It is important to consider that while expression of rs4680 A > G has been associated with reduced enzyme function and increased pain sensitivity when considered alone, it contributes to both the LPS and HPS haplotypes that are associated normal and enhanced pain sensitivity respecitively.5

Figure 1

Figure 1

The finding of association between low COMT enzyme activity and pain sensitivity is biologically plausible and has been supported by preclinical5 and volunteer studies.3 Low activity of COMT would be expected to result in excess of synaptic and extrasynaptic norepinephrine, epinephrine, and dopamine. Norepinephrine and epinephrine modulate pain principally through the activation of α(1/2) and β(2/3) adrenergic receptors.6 Activation of α2 receptors with selective agonists such as dexmedetomidine results in analgesia. However activation of α1 and/or β receptors can either increase or decrease pain sensitivity.6 The effect of adrenergic activity is also regionally variable; increasing adrenergic activity in the spinal cord is associated with decreased pain sensitivity. In contrast, increased adrenergic activity in the peripheral nervous system is associated with increased pain sensitivity. Given these considerations, it is not obvious whether decreased COMT activity leading to excess catecholamine would be expected to result in pain reduction or exacerbation. The balance of positive and negative modulation is likely important, and the most relevant sites controlling pain and analgesic responses have not been defined. With these complexities in mind, we turn to the findings of the current studies.

Candiotti et al.1 assessed the association between 2 common COMT SNPs with morphine consumption after nephrectomy, a procedure associated with significant postoperative pain. They found that in the first 24 hours after surgery, patients homozygous for the expression of G at rs4680 (resulting in expression of less efficient COMT enzyme) used 36% more opioid than those who were homozygous for A. The difference persisted to the 48-hour assessment. In addition, patients homozygous for G at rs4818 SNP used more morphine than heterozygotes during the first 6 hours. These data seem reasonable as lower rates of catecholamine degradation have been linked to more pain or higher analgesic requirements in other studies, and there appears to be an allelic “dose-response.” Pain reports, however, were not different. Homozygotes for the C allele at rs4818 used more antiemetic than homozygotes for G, though the significance of the observation is somewhat unclear as differences in opioid consumption did not seem to provide an explanation. While the aforementioned findings are interesting, it is surprising that the authors did not evaluate genotype at rs6269 and rs4633 so that the contribution of the LPS, APS, and HPS haplotypes, suggested to be important by other investigators, could then be considered.

The relationship between acute pain and individual COMT SNPs and haplotypes has been assessed after other types of injuries, procedures and surgeries including lumbar discectomy, tonsillectomy, major abdominal and urological procedures, chest tube removal after cardiac surgery, labor pain, breast cancer surgery, oral surgery, and pain after motor vehicle accident with highly variable results (Table 1).7–17 Some studies found more pain and/or analgesic use associated with genotypes for which reduced enzyme activity is predicted. Other studies found no association. Some even found the reverse relationship. Indeed our years of study of COMT variants have not provided a clear and consistent picture of the impact of genetic variation of this gene on pain. Moreover, the cohort studied by Candotti et al. had mixed gender. Experimental studies have suggested that the effect is both gender- and modality-dependent with an effect found more reliably in female animals and women.4 A gender difference is intriguing as COMT metabolized catechol-estrogens in addition to catecholamines neurotransmitters. However, no effect was identified in a study of 22 COMT SNPs and acute pain after breast cancer surgery in 1000 women.12

Table 1

Table 1

The relationship between the likelihood of utilizing emergency room resources in patients with sickle cell disease and the COMT rs4680 A > G SNP as well as the rs6380 variant in the gene for the dopamine D3 receptor (DRD3) receptor, that results in a Ser9Gly substitution, was reported by Wang et al. in this issue of the journal.2 Though the findings were preliminary in nature, sickle cell patients who expressed the G allele at rs4680 in COMT that results in reduced enzyme activity were twice as likely to utilize emergency room resources for acute pain crisis. Interestingly, patients who were heterozygous at DRD3 were less likely to have an acute pain crisis.

The consideration of variability in a pain phenotype with both COMT and a dopamine receptor is interesting in that dopamine, like all catecholamines, is a substrate for COMT and receptor binding potential has been associated with variability in pain phenotypes.18–22 DRD3 Gly9Gly receptor activation induces a greater increase in cAMP than the wild type receptor and has been associated with higher pain thresholds in fibromyalgia.18 It is unfortunate that the authors did not assess the interaction between the 2 polymorphisms and pain behavior, though perhaps the sample did not provide adequate power for that exercise. Interpretation is made more difficult by the fact that expression of fetal hemoglobin and other variants such as β-thalassemia are known to alter the pain phenotype in sickle cell disease.23 These and other factors not evaluated as covariates might have changed the results.

The manifestation of recurrent and chronic pain phenotypes other than sickle cell disease with respect to variability in the COMT gene has been widely studied in fibromyalgia, temporomandibular disorders, cancer pain, and other syndromes. Similar to the results from acute pain and analgesia studies, the results have been somewhat variable (Table 2).24–53 However, unlike studies in acute pain, of 30 studies evaluating chronic pain syndromes, only 1 found that reduced COMT enzyme activity was associated with reduced pain or analgesic utilization that was statistically significant.

Table 2

Table 2

Pertinent to both reports, several studies have suggested that COMT genotype is not related to pain severity itself, but exerts its effects through modulation of psychological factors such as anxiety and depression with which catechol metabolism is strongly associated.26,27 Both anxiety and depression are strongly associated with pain and analgesic use. For example, a study of fibromyalgia patients and pain-free controls found that patients homozygous for COMT 158Met scored worst on tests for anxiety, depression catastrophizing, perceived health, and functional status, while those homozygous for Val158 scored more favorably.28 The largest study of acute pain in 1000 breast cancer patients12 did not find an association between COMT SNPs known to affect enzyme activity and postoperative pain, but did not assess symptoms of anxiety and/or depression.

Another source of variability is that the primary outcome variables are quite different between studies. Behavioral outcomes as complex as pain and analgesic requirement can be analyzed in many different ways. Because authors often highlight those associations that are statistically significant, it is not surprising that different studies present different outcomes. Not only does post hoc selection of “important findings” make comparison among studies difficult, but it is almost certain to introduce bias into the published results for behavioral studies. Although the primary outcome variable was clearly addressed in the current studies, the presence of multiple behavior outcomes in other studies raises the specter of improper statistical adjustment for multiple comparisons, potentially exaggerating the significance of positive findings.

Given the complex biology that underlies nociceptive transmission and pain manifestation, it is not surprising that the interpretation of findings in studies of COMT genotype and pain manifestation are not straightforward. Although there is ample scientific rational to consider the relationship, particularly in chronic pain syndromes such as those listed in Table 2, it may be that we are looking at the wrong end point. Although the effect of catecholamine concentration on pain transmission is variable, the relationship with psychological modulators such as anxiety, depression, and catastrophizing may be better supported. Consider how this may have affected the current reports; perhaps sickle cell patients who express the 158Met form of COMT experienced similar nociceptive input, but were more motivated to seek treatment thus explaining the higher incidence of reported crises.

Future studies on catecholaminergic modulation of pain might best include complete genotyping of the 4 SNPs that have been found to relate to enzyme activity. In addition, they should include in their analysis gender and psychological variables that are known to be influenced by COMT genotype. To properly assess these variables, a careful multivariable analysis will be required that is powered to allow consideration of these factors. Finally, there is a growing expectation that nonexploratory reports include replication datasets to confirm or refute the findings of the primary analyses.

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RECUSE NOTE

Dr. Pamela Flood is the wife of Dr. Steven Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by James G. Bovill, Guest Editor-in-Chief, and Dr. Shafer was not involved in any way with the editorial process or decision.

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DISCLOSURES

Name: Pamela Flood, MD, MA.

Contribution: This author helped write the manuscript.

Attestation: Pamela Flood approved the final manuscript.

Name: David Clark, MD, PhD.

Contribution: This author helped write the manuscript.

Attestation: David Clark approved the final manuscript.

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