In this study, we determined that common COMT
haplotypes are associated with different response to β-blocker treatment in a common chronic musculoskeletal pain disorder. This is the first study that has identified a genetic marker that is associated with the efficacy of propranolol treatment in patients with TMD. The present findings are consistent with a recent study that reported that TMD and fibromyalgia patients showed a dysregulation of β-adrenergic activity which contributed to altered cardiovascular, catecholamine, and clinical pain responses to psychological and physical stressors. Concordant with our data, acute treatment with intravenous low-dose propranolol also produced improvement in clinical pain report [41
The outcome of this proof-of-concept study supports the feasibility and merit of conducting a larger trial. The trend for improvement in the PSR pain intensity rating and significant improvement in the pain index supports a likely therapeutic effect of propranolol in a substantial percentage of TMD patients. It is interesting to note that the pain index , which is a product of two measures that each yielded smaller estimates of effect and larger p-values in comparing treatment periods, reached the threshold of statistical significance. This apparent paradox can be explained by the fact that the individual measures were only moderately correlated (Pearson's r = 0.5), and it is a tenet of psychometric theory that orthogonal measures that each are moderately associated with a third variable will yield a stronger association when the two are combined. While it might be tempting to conclude that the pain index is a statistically superior measure of propranolol efficacy, we caution that the result may be idiosyncratic, and recommend that the index be evaluated in studies with larger samples conducted in other populations.
While propranolol treatment did not affect measures of sensitivity to experimental pain, a “dose-response” effect by the number of COMT LPS alleles was observed in the majority of measures of experimental and clinical pain, with a greater improvement in subjects not carrying a LPS haplotype, an intermediate effect in the heterozygotes, and no beneficial effect in LPS homozygotes. The relative benefit for TMD patients without the LPS haplotype identified a large subgroup (~33% of our sample, ) where β-blocker treatment was advantageous. In comparison, 20% of the patients showed either no effect or a worsening of their pain condition in response to propranolol therapy.
The neural mechanisms by which propranolol produces an analgesic effect under conditions of low COMT activity and high catecholamine bioavailability are poorly understood. However, both central and peripheral mechanisms have been proposed. In support of a peripheral mechanism, the intraplantar injection of epinephrine (EPI) produced a peripherally mediated hyperalgesia in rats, which was blocked by propranolol [47
]. Similarly, the intramuscular injection of low-dose propranolol in rats with carageenan-induced inflammation of the gastrocnemius muscle reduced inflammatory pain locally [41
]. Both propranolol and a selective β2
-adrenoreceptor antagonist reportedly impaired pain behavior in a rodent model of TMD [48
]. Finally, propranolol may produce analgesia by blocking tetrodotoxin-resistant sodium channels in sensory neurons; however, this is unlikely to contribute to our findings since relatively high doses are required to observe such effects [49
The analgesic effect of propranolol may also be mediated via
a central mode of action. Propranolol impairs memory storage and reconsolidation of negative emotional events in rodents and humans [50
]. Propranolol is also known to have central nervous system modulating activities and anxiolytic effects [55
]. Intraplantar formaline injection in rats increased extracellular norepinephrine (NE) levels within the ventral part of the bed nucleus of the stria terminalis (vBNST), brain area which had been implicated in stress responses and negative affective states, and the injection of the β-adrenergic antagonist timolol into this brain region dose-dependently attenuated the negative affective component of pain [57
Catecholamine-induced influence on the autonomic control of the BP may indirectly regulate pain since increase in BP has been associated with reduced pain sensitivity [58
]. In this study, the chosen dosage of propranolol (20 mg twice a day) was intentionally low to minimize any reduction in BP which may alter endogenous pain modulation via
the baroreceptor reflex, thereby increasing pain [59
In contrast to the effects of propranolol on pain perception, its effect on anxiety, depression, and perceived stress were not associated with COMT
haplotypes. These results are consistent with the observation that psychological scores do not vary among various COMT
haplotype groups in healthy female volunteers, and that psychological factors influenced the risk of TMD onset independent of the COMT
]. A recent open trial of β-adrenergic receptor/5-HT1A
presynaptic autoreceptor antagonist, pindolol, in the fibromyalgia patients reported no change in the anxiety and depression scores although a significant effect on pain sensitivity was observed [62
]. The lack of change in psychological variables in our study may be partly explained by the relatively low levels of psychological distress reported by this cohort, the low dose of propranolol administered, and the lack of effect of propranolol on the psychological status of TMD patients.
In line with the variable effect of propranolol on pain perception, it is generally recognized that the pharmacodynamic responses to β-adrenergic receptor blockade are highly inconsistent. For example, 30-60% of patients with hypertension who were treated with β-blocker monotherapy failed to achieve adequate BP control [63
]. In migraineurs, response rates to propranolol therapy ranged from 33 to 44% [65
]. Variable effects in response to propranolol treatment have also been reported for anxiety, psychocardiac disorders, aggressive behavior, and substance withdrawal [56
]. This variability may be accounted for, in part, by COMT
In this study, a haplotype-based analysis was used instead of a single SNP analysis because the linkage disequilibrium between several markers showed stronger association with a disease than individual SNPs, as was observed by Shifman et al.
]. Consistent with this view, we previously showed a functional effect of COMT
haplotypes on enzyme activity and protein levels [39
]. Nevertheless, in this cohort with only one subject carrying the HPS haplotype, an association analysis based on Val(108/158)Met polymorphism would lead to a very similar result compared to a haplotype-based approach.
This study has a few limitations. First, this study was designed as a proof-of-concept trial recruiting a relatively small number of subjects. Therefore, our findings need to be replicated in a larger sample set. Second, our results are based on a 1-week low-dose propranolol treatment. Future studies with a longer duration of treatment and higher dosage levels are desirable. Third, this study included only Caucasian females because the majority of TMD patients are women [6
]. Hence, the results may not be generalized to men or non-Caucasian females. Future studies with diverse ethnicity and involving both sexes are needed.
In conclusion, COMT gene polymorphism contributes to the variable pharmacodynamic responses to propranolol in patients with chronic musculoskeletal pain. COMT haplotypes may serve as genetic predictors of treatment outcome and permit the identification of the subgroup of patients who will benefit from propranolol therapy. The results of this study may also explain the variability of treatment responses to β-blockers for a broad spectrum of diseases.