The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders.

BACKGROUND: Mechanisms underlying alleviation of neuropathic pain by repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) and right secondary somatosensory cortex (S2) are only partly known. Patients with chronic neuropathic pain often have comorbidities like depression and sleep problems. Through functional connectivity, rTMS of M1 and S2 may activate dorsolateral prefrontal cortex, the target for treating depression with rTMS. Thus, the analgesic effect of rTMS could be mediated indirectly via improvement of psychiatric comorbidities or sleep. We examined whether rTMS has an independent analgesic effect or whether its clinical benefits depend on effects on mood or sleep. We also evaluated if comorbid psychiatric or sleep disorders predict the treatment outcome. METHODS: Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized controlled crossover rTMS study. Patients' psychiatric history was evaluated by a specialist in psychiatry. Intensity and interference of pain, mood, and the quality of sleep and life were evaluated at baseline and after 2 active (primary somatosensory cortex [S1]/M1 and S2) and placebo rTMS treatments. A logistic regression analysis was done to investigate predictors of treatment outcome. RESULTS: The analgesic effect of the right S2 stimulation was not associated with improvement of psychiatric conditions or sleep, whereas S1/M1 stimulation improved sleep without significant analgesic effect (P = 0.013-0.046 in sleep scores). Psychiatric and sleep disorders were more common in patients than in the general population (P = 0.000-0.001 in sleep scores), but these comorbidities did not predict the rTMS treatment outcome. CONCLUSION: We conclude that rTMS to the right S2 does not exert its beneficial analgesic effects in chronic neuropathic orofacial pain via indirect improvement of comorbid psychiatric or sleep disorders.

Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation.

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has analgesic effect; however, the efficacy of other cortical targets and the mode of action remain unclear. We examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, we assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (P = 0.0071) or the sham (P = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than those at pretreatment baseline (P = 0.0127 for the intensity of pain and P = 0.0074 for the interference of pain) or after the S1/M1 (P = 0.001 and P = 0.0001) and sham (P = 0.0491 and P = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.

Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain.