Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: a report on 176 cases

In spite of recent advances in surgical technique, effective pain treatment in patients suffering from lumbar spine pathology still remains a considerable clinical problem. Surgical intervention criteria in those patients are clear-cut in case of cauda equina syndrome or progressive motor deficit, but elective surgery is based on individual decision [6, 13, 23, 26, 27]. The latter approach is partly caused by the use of various pain-assessment tools, and even those considered as a “gold standard” in evaluation of surgery results still lack validation [6]. Problems with decision-making in patient classification for surgery or conservative treatment may also result from interindividual differences in pain threshold that may be determined at least partly by genotype.

The first direct evidence that COMT polymorphism affects neural processing of pain was reported by Zubieta et al. [31], who noted that COMT 158met (rs4680) homozygotes were characterized by higher pain sensitivity, diminished regional μ-opioid system responses to pain, as well as a higher μ-opioid receptor binding potential, in comparison with heterozygotes and 158 val homozygotes. Additionally, Loggia et al. [15] provided information on COMT val158met polymorphism involvement in pain perception in response to heat stimuli. The authors found that met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures. Therefore, met/met patients might be characterized by lower pain threshold and higher risk of chronic pain development. Our own observations in patients suffering from chronic lumbar pain did not support the aforementioned reports, since no significant associations between COMT val158met polymorphism and VAS/ODI score have been found, except for better response to treatment in GG (val/val) cases.

However, analyzing solely pre- and postoperative pain intensity it can be seen, that AA subjects were characterized by markedly lower pain intensity measures vs. G allele carriers. Contribution of other COMT genotypes to pain perception does also support a modulatory effect of these genetic parameters. Significantly lower preoperative pain intensity was experienced by 4633 TT, 4680 AA and higher in 4818 GG subjects, whereas postoperative pain intensity was markedly decreased in 4633 TT, 4818 CC, 4680 AA and 6269 AA carriers. Also, local pain perception in LDH patients was associated with COMT polymorphism, and preoperative VAS_BACK was the most prominent in patients characterized by 6269 GG and 4818 CC genotypes. Likewise, COMT polymorphism significantly modulated response to surgery (VAS_BACK change), i.e., the best outcomes were observed in 6269 CC, 4633 CC, and 4680 GG carriers. These observations are supported by linear regression analysis, which demonstrated that COMT rs4633 T allele and rs4680 A allele are independent risk factors for VAS_BACK change (Table 4). The observed differences in pain perception in patients of various genetic constitutions may enable identification of subjects particularly predisposed to chronic pain development, and thus requiring more intensive analgesic treatment. Our findings are in agreement with the report by Jacobsen et al. [12], who revealed that COMT val158met polymorphism could contribute to discogenic subacute low back pain and sciatica in degenerative disc disease, since val/val patients (like in the present study) were characterized by the largest reduction in postoperative pain in comparison with met/val and met/met carriers. Associations between COMT gene SNPs and pain were also evaluated by Dai et al. [7], using ODI and VAS, in a group of patients subjected to surgical treatment for LDH. The authors reported that patients homozygous for COMT rs4633 T allele were characterized by most prominent mean improvement in ODI score one year after surgery, which was not observed in our study (response measured by ODI change was similar in all rs4633 genotypes). Contrary to the present results Dai et al. [7] did not reveal significant impact of other studied SNPs, i.e., rs6269, rs4818 and rs4680 on pain perception.

Recent studies suggest that COMT haplotypes, rather than individual SNPs, would be more appropriate for the prediction of COMT biological effects [8, 31]. Even silent mutations that usually do not change the amino-acid sequence may affect function through alterations in COMT mRNA structure and stability, thus influencing disease risk or treatment efficacy. Diatchenko et al. [8] revealed a strong association between a specific COMT haplotype - G_C_G_G and pain sensitivity, and an inverse correlation between pain sensitivity and COMT activity in healthy subjects. Low sensitivity to experimental pain was associated with G_C_G_G haplotype (high activity haplotype), whereas A_C_C_G haplotype (low activity) was associated with high pain sensitivity. Dai et al. [7] also reported that COMT haplotype status was associated with pain perception in patients undergoing surgical treatment for lumbar degenerative disc disease. Patients with A_T_C_A haplotype responded most effectively to the surgical procedure, and were followed by subjects carrying G_C_G_G haplotype and A_C_C_G, haplotype, as measured by ODI score. Our findings are contrary to observations of Dai et al., who found that A_C_C_G haplotype patient were characterized by significantly higher postoperative VAS_BACK pain, and responded less effectively to treatment (VAS_BACK change). Likewise, linear regression analysis applied in the present study indicated that COMT A_C_C_G haplotype was an independent risk factor for VAS_BACK and possibly ODI changes (Table 3). Recently, a study of McLean et al. [17] has confirmed the opinion that individuals with COMT pain vulnerable genotype A_C_C_G were at increased risk of acute pain and needed preventive interventions. The authors evaluated an association between COMT genotype and acute neck pain intensity in individuals after motor vehicle collision, and found that individuals characterized by COMT A_C_C_G haplotype were more likely to report moderate-to-severe neck pain, headache, and dizziness. Moreover, patients with genotype coding low COMT enzyme activity were found to have longer time to physical and emotional recovery. Likewise, Tchivileva et al. [24], studying an association between common COMT haplotypes and response to β-blocker treatment in a common chronic musculoskeletal pain disorder, found that carriers of low and medium COMT activity haplotype showed the most prominent response to propranolol in all pain measures except for thermal threshold. Patients carrying COMT A_C_C_G haplotype demonstrated not only more efficient response to pharmacological treatment but also better surgical treatment outcome.

Pain analysis is problematic due to its subjective nature and broad range of factors modulating it, such as ethnicity as evidenced by known differences in both pain perception and reporting between African Americans and Caucasians [5, 9]. This may be related to COMT rs4680 158met frequency in various populations, ranging from 0.01 to 0.62 [21]. This fact creates difficulties in developing reliable scales characterizing pain. As Polish population in 98 % consists in Caucasian and additionally ethnic differences in catechol-O-methyltransferase activity is confirmed [1, 18] we found it reasonable to focus only on one ethnic group. Undoubtedly, to confirm our results, further studies in Asian or African American populations should be designed.

In conclusion, the aim of this study was to find a potential correlation between genetic polymorphism of the COMT enzyme and pain perception. This association was observed in patients with the COMT SNP rs4633 CC, rs4680 GG, who demonstrated greater reduction of low back pain in 1 year after surgery. This fact may have potential clinical implication in decision-making, e.g., selection of those subjects for earlier surgery. We believe that the lack of correlation between COMT activity and reduction of leg pain (VAS_LEG) after surgery can be explained by the pivotal role of direct nerve root decompression during surgery. As for the present study, the studied group of patients is too small to draw arbitrary conclusions regarding genetic diversity in COMT and its role in predicting clinical outcome after lumbar discectomy. The observed associations suggest that it is not possible to make a clinical decision on operation or conservative treatment based solely on the COMT gene polymorphism. However, the COMT genotype may serve as a tool indicating patients who will benefit more from surgery, being one of the factors behind decision-making, along with other parameters (like radiological findings, clinical status); to some extent, pharmacogenetics may play a supportive role as a prognostic factor. However, given a relatively small group size, larger studies are needed in order to confirm the value of the present study observations.