Impact of antidepressant medication on the analgetic effect of repetitive transcranial magnetic stimulation treatment of neuropathic pain. Preliminary findings from a registry study

Introduction

Neuropathic pain is considered difficult to treat. Major factor impacting outcomes is the presence of comorbidities such as poor sleep, depressed mood, and anxiety [1, 2]. In addition, the negative impact of neuropathic pain is higher in patients with greater pain severity [3].

Level-A evidence has been suggested for the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the experienced neuropathic pain [4]. However, according to Gatzinsky et al. [5] the effect is transient and shows a great heterogeneity between studies. Further, a recent meta-analysis indicates that stimulation frequency, intervention site, and location of lesion were important factors affecting the therapeutic effect [6]. In rTMS treatment, focal cortical areas and connected large-scale neuronal networks are noninvasively stimulated [7]. Low-frequency (LF) (<1 Hz) repetitive TMS (rTMS) reduces neuronal excitability, whereas HF (>5 Hz) rTMS increases cortical excitability [8].

Pharmacological treatments that affect the central nervous system may aid in reducing pain intensity in neuropathic pain conditions psychotropic medications exert significant effects on cortical excitability and plasticity, but the effects of drugs vary substantially across medication classes and may have differential consequences for clinical response to rTMS [9]. According to systematic reviews, the analgesic efficacy of tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin has been demonstrated [10, 11].

Antidepressants are effective in both neuropathic and non-neuropathic pain and have diverse mechanisms that are independent of their antidepressant effects [12]. The mechanism behind the analgesic effect of antidepressants is thought to involve their enhancement of the activity of norepinephrine and serotonin in the descending pain modulation pathways of the spinal cord [12]. Patients with chronic pain without depression have experienced significant pain reduction with tricyclic antidepressant drugs, suggesting an independent analgesic effect for antidepressants [13, 14]. The results of the efficacy of the analgesic effects of dual serotonin norepinephrine reuptake inhibitors (SNRI) and selective serotonin reuptake inhibitors (SSRI) are more limited and inconsistent [15].

The concomitant effects of rTMS treatment and use of central nervous system (CNS) active drug therapy comprise uncertainties. CNS active drugs may have an impact on cortical excitability when using rTMS. Motor threshold, motor evoked potential size, motor evoked potential intensity curves, cortical silent period, short-interval intracortical inhibition, intracortical facilitation, short-interval intracortical facilitation, long-interval intracortical inhibition, and short latency afferent inhibition represent possible drug effects on cortical excitability [16].

Methods

Results

A total of 31 patients underwent the full rTMS protocol. For three patients who reported an increase in pain, the treatment was discontinued. No serious side effects were reported during the treatment or follow-up.

The baseline data of the patients are presented in Table 1. The mean age of the patients was 49.5 years (range 17–82 years). There were no statistically significant differences in the baseline data between the groups of antidepressant users and nonusers.

The difference in the baseline BDI scores between groups was not significant, but antidepressant users’ BDI scores corresponded to minor depression and nonusers’ BDI scores to mild depression, here according to the reference values (0–13 and 14–19 respectively) presented in the BDI manual [25].

The ATC categories for various antidepressants used among the patients are reported in Table 2. The most prevalent medication was the category of nonselective monoamine reuptake inhibitors, including amitriptyline (7 patients) and nortriptyline (1 patient).

A decrease either in pain intensity or pain interference was observed in 20 patients after 5 treatment sessions. Post-treatment, there was a significant decrease in pain intensity in the group of antidepressant nonusers only. There was a slight, nonsignificant trend of decrease in interference in both groups. The differences in pain intensity and pain interference, here adjusted for BDI scores, on NRS between the antidepressant users and nonusers groups are presented in Figure 1.

Figure 1:

The pain intensity and interference (adjusted for BDI scores) with and without depression medication, at baseline, after 5 sessions of rTMS, and after 10 sessions of rTMS.

After 10 sessions of rTMS, there was a difference in pain intensity in favor of the group of antidepressant nonusers (p=0.019), with an average NRS decrease of −1.65 (95 % CI: −2.99 to −0.31, p=0.016). An insignificant increase of +0.33 (95 % CI: −0.80 to 1.46) in NRS was found in the group of antidepressant users. No statistically significant difference in pain interference was found between the groups. In both groups, there was a slight nonsignificant trend of a decrease of interference. In the group of antidepressant nonusers, the change was −0.94 (95 % CI: −2.57 to +0.68), and in the group of antidepressant users, the change was −0.79 (95 % CI: −2.53 to +0.94).

After 10 treatment sessions, the impression of change measured with GIC was positive in 20 patients. The GIC showed a positive change in the group of antidepressant nonusers, while in the group of antidepressant users, there was no change. The difference in GIC between these two groups was statistically significant (p=0.002) at the end of the treatment sessions.

There was a significant difference between the groups regarding continuing rTMS treatment after the initial 10 sessions. The percentage of patients continuing rTMS treatment was 29 % (5/17) in the antidepressant users group and 71 % (12/17) in the antidepressant nonusers group.

Discussion

Simultaneous use of antidepressants seems to attenuate the analgesic effects of therapeutic rTMS in patients with neuropathic pain. No change in pain interference was found between the groups. The difference in GIC regarding a positive change between these two groups was statistically significant, thus resembling the results on NRS regarding changes in the pain intensity and interference.

Although the difference in BDI scores between groups was not significant at baseline, antidepressant user scores corresponded to minor depression, while nonuser scores corresponded to mild depression. The difference in scores was controlled for in our analyses. Therefore, differences in depression baseline scores are unlikely to be one of the reasons for our findings of a more effective pain reduction in antidepressant nonusers.

These are novel findings, and there are little research data on the effects of antidepressants in rTMS treated patients. Typically, rTMS is administrated to pain patients using pain and other medication (i.e., antidepressants, anticonvulsants). Most real-world studies have been conducted on patients who have not benefited from pain medication; according to recommendations, additive rTMS has been administrated parallel to current medication in naturalistic settings. Little is known about how concurrent medication affects the efficacy of rTMS treatment in chronic pain conditions [9]. In Phillips et al.’s [28] study, patients with comorbid pain and major depressive disorder (MDD) using SNRI during rTMS treatment showed a significant decrease in pain scores from baseline to post-treatment. However, the authors stated that it was unclear whether this was related to antidepressant treatment effects.

Some studies have shown that in patients with MDD, the use of benzodiazepines is associated with worse rTMS treatment outcomes when compared with the use of psychostimulants [29]. Specifically, the use of lorazepam has been shown to significantly reduce the effectiveness of and response rate to rTMS targeted to the dorsolateral prefrontal cortex (DLPFC) for the treatment of MDD in a large sample of real-world data [30]. Recently, a study reported that independently of confounding factors, neuroleptic medication attenuates the antidepressant effects of rTMS [31]. In patients experiencing pain, rTMS treatment is typically targeted at the primary motor cortex, but even stimulation of the left DLPFC, used in treating MDD, has also successfully reduced pain symptoms in experimental and clinical settings [32, 33].

It has been shown that HF-rTMS treatment affects the serotonergic system, more specifically the 5-HT2A receptor BI in the DLPFC and in the hippocampus [34]. Antidepressants have complex, not yet fully understood effects on cortical excitability and specific neurophysiological, TMS-derived parameters, such as intracortical inhibition and facilitation [35]. Further, antidepressants can have an impact on the cortical silent period (CSP) [36, 37], possibly modulating cortical “receptivity” for rTMS stimuli and actuate long-term cortical excitability and plasticity effects [9, 30].

Unilateral stimulation of the M1 or DLPFC induces bilateral analgesic effects. According to a review by Moisset et al. [7], rTMS stimulation of the M1 induces changes in several diencephalic areas involved in pain perception, such as the thalamus, anterior cingulate, insular, and prefrontal cortices. All are areas rich in opioid receptors. In addition, areas containing gamma-aminobutyric acid (GABA), serotonin, and dopamine receptors are activated [7]. When stimulating DLPFC in induced pain settings, changes in the activity of the structures involved in the integration and modulation of pain signals, including insular and cingulate cortices, as well as the thalamus, have been found [38, 39].

Differences were found between groups only in terms of a reduction of pain intensity, while pain interference showed a similar decrease in both groups. Differences in pain intensity can plausibly be explained by a negative interaction of pharmacological action and rTMS-derived effects. One underlying reason for the similar benefits regarding pain interference may be the activating effect of study participation on participants. Research shows that more engaged patients may have better health outcomes and better care experiences than those patients who are less engaged [40]. Participation in a study may alter the behavior of the participants because of an initial activation-related increase in motivational behavior. This behavior change has also been described as the Hawthorne effect [41], according to which the knowledge of participating in an experiment modifies the behavior of the participant from what it would have been without this knowledge.

Because both antidepressants and rTMS treatments have derivative effects on the common functions (i.e., serotonin and noradrenaline) of neural networks (i.e., prefrontal cortex, descending pathways) [11] the likely reasons for our findings are changes in the activation of these areas.

In summary, besides local neural factors, rTMS influences even long-distance functional connectivity [42], and the brain is affected by treatment as a global dynamical system [43]. The exact mechanism behind our findings remains to be elucidated, and further studies are warranted. However, therapeutic rTMS for neuropathic pain conditions is plausibly sensitive to interference with antidepressant drug therapies.

Conclusions

Independently of confounding factors, a simultaneous use of antidepressants attenuated the analgesic effects of therapeutic rTMS in patients with neuropathic pain. The use of antidepressants did not affect pain interference. The exact mechanism of our findings remains to be elucidated, and further studies are warranted. However, therapeutic rTMS is plausibly sensitive to negative interference with antidepressant therapies.