5.1 Pharmacotherapy
Because the occurrence of UPPS may impact the response to treatment and prognosis of MDD, during the initial clinical examination, and while monitoring the progress of treatment all patients should undergo a careful interview regarding the presence of pain complaints. Careful assessment may assist in the selection of effective treatment.
Wise et al. [
84] proposed the following management of patients who present with UPPS and depression. In the first step, patients reporting UPPS should be assessed by physical examination and laboratory tests, making possible n hypothesis regarding the cause of pain and treatment. The important issue is to take painful symptoms seriously and to ascertain that the discomfort the patient experiences is “real pain”. Next, the patients should be informed that UPPS are a common part of depressive symptomatology, and usually respond well to antidepressive drugs. Basic information about the neurobiology of depression and pain may facilitate a patient’s better understanding and acceptance of the cause of symptoms.
Since their introduction in the 1960s, tricyclic antidepressants have also been used for the treatment of pain. Advances in pharmacotherapy in the last decade of the 20th century led to the introduction of new classes of antidepressants, namely selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). These drugs, which were initially administered in the treatment of major depression, were subsequently applied in the treatment of pain syndromes. While the SNRIs appear to be effective in the treatment of chronic pain, the evidence from studies with SSRIs is inconsistent [
85]. Two recently published meta-analyses confirmed the comparable efficacy of tricyclic antidepressants and SNRIs [
86,
87], in the treatment of neuropathic pain, thus certifying the recommendation of these drugs, along with gabapentin and pregabalin, as first-line treatment for this condition [
88].
Functional somatic syndromes presenting with unexplained pain (i.e. fibromyalgia and irritable bowel syndrome) commonly co-occur with depression. The bulk of findings from clinical studies and their meta-analyses have provided evidence for the efficacy of amitriptyline and SNRIs in reducing pain and other symptoms of fibromyalgia [
89‐
92]. By contrast, the authors of the Cochrane Review did not find convincing evidence for SSRIs superiority over a placebo in treating pain, fatigue and sleep problems in patients with fibromyalgia [
93].
Therefore, the conviction remains that dual-action antidepressants are more effective than SSRIs in the treatment of neuropathic pain and of functional pain syndromes such as fibromyalgia. However, pain in neuropathy, fibromyalgia and other functional syndromes probably has a different neurobiological basis than that of UPPS in depression. As far as some common genetic, immune and neurohormonal mechanisms for these conditions have been postulated, one may hypothesise that specific features of a particular painful disorder are related to different contributions of these, and possibly other unique factors. This, in turn, may lead to the assumption that opinions about the superiority of dual-action antidepressants over SSRIs in reducing UPPS in depression may be unjustified.
The aim of several previous studies was to assess to what extent different classes of antidepressants are effective in reducing UPPS, along with improving other symptoms of depression. The first problem, potentially relevant for the optimisation of pharmacotherapy, is whether both noradrenergic and serotonergic drugs have favourable effects on pain in patients with MDD, and a second problem is whether dual-action antidepressants are more effective in the treatment of UPPS than selective drugs. A better understanding of these differences may be helpful in optimising the pharmacotherapy of depressed patients with UPPS.
Two randomised double-blind studies demonstrated that fluoxetine [
94] and citalopram, but not reboxetine [
95] have an analgesic effect in patients with somatoform pain disorder.
The results of the latter study [
95] may suggest that SSRIs are superior to selective noradrenergic drugs in reducing painful symptoms. To verify this issue, we recently compared the effect of nortriptyline and escitalopram on UPPS in a randomised study of patients with MDD who participated in the Genome-based Therapeutic Drugs for Depression (GENDEP) study. Our results provided evidence that both serotonergic and noradrenergic antidepressants are equally effective in the alleviation of UPPS in depression [
96].
Assessment of the efficacy of SNRIs in the treatment of pain in MDD was the aim of several studies. The beneficial effect of venlafaxine on both depression and pain was documented in an observational, prospective study of patients with depressive symptoms and comorbid chronic pain [
97], and in an 8-week study of patients with first-episode depression with painful symptoms [
98]. However, the results of a recent 6-week investigation of the efficacy of 150 mg of venlafaxine in patients with comorbid depression and chronic low back pain showed that only 26.4 % of patients responded in both conditions, suggesting a weak therapeutic effect on pain [
99].
Duloxetine is another potent dual-reuptake inhibitor of serotonin and NA. In the recent decade duloxetine has been widely studied in regard to its effect on UPPS. Placebo-controlled randomised studies have shown that duloxetine significantly reduces pain in depressed patients [
100‐
102]
These observations were confirmed by a meta-analysis of 11 double-blind placebo-controlled studies [
103] but not by a Spielmans’ meta-analysis based on five studies of duloxetine [
104]. The important issue in clinical practice is whether SSRIs, considered as a first-line treatment of depression, are as effective as SNRIs in patients with UPPS. Martinez et al. [
105] conducted a multicenter, randomised, non-blinded, parallel-group 12-week trial to compare the efficacy of duloxetine with generic SSRIs (citalopram, fluoxetine, paroxetine or sertraline). Their data showed no significant differences in the depression remission rate. However, the effect of duloxetine on UPPS was significantly better, in comparison to SSRIs. The aim of several 7- to 9-week head-to-head trials was to compare the efficacy of duloxetine (40–120 mg/day) and paroxetine (20 mg/day) in depressed patients with UPPS. Two pooled analyses of these studies found no significant difference between the two drugs in the reduction of painful symptoms [
106,
107]. This led Krebs et al. [
107] to conclude that the current evidence from clinical trials is insufficient to speculate about the superiority of either agent over the other in the treatment of MDD with accompanying pain,
In those patients with depression who do not respond to initial treatment with SSRIs, switching to another antidepressant, preferably with another mechanism of action, is recommended. This strategy was tested in patients with MDD who reported substantial levels of pain and did not respond, or only partially responded, in the course of 6 weeks of treatment with SSRIs. The results of this study revealed that a switch to duloxetine was associated with significant improvements in painful symptoms, time in pain and interference with functioning because of pain [
108]. The aim of another study was to define the optimal period of time for switching antidepressants in depressed patients with moderate to severe pain, who had initially been treated with escitalopram. It turned out that an early switch to duloxetine in participants whose pain did not improve after 4 weeks is related to an acceleration in the reduction of pain severity and to an increase in the proportion of patients with functional remission, in comparison to patients with a conventional switch after 8 weeks [
109].
The interesting issue regarding the relationship between reduction of pain severity and improvement in depressive symptoms has been addressed in several studies. Specifically, one may hypothesise that (1) the relief of pain is secondary to an improvement in the core symptoms of depression or that (2) the antidepressants have a direct effect on pain, independent from the improvement of other symptoms. Using a path analysis, Mallinckrodt et al. [
110] estimated that in MDD patients treated with duloxetine, between 30 and 70 % of the observed improvement in pain severity was independent of the improvement in the emotional symptoms of depression. Using the same statistical method, Fava et al. [
100] calculated that 50.6 % of the improvement in pain severity was independent of the amelioration of depressive symptoms. Taking the results of these studies together, both direct and indirect analgesic and antidepressant properties appear to be relevant for the treatment of these comorbid conditions.
Summing up, the results of the studies reviewed here do not give sufficient evidence of a better efficacy of SNRIs over SSRIs in the treatment of UPPS in MDD. Therefore, head-to-head trials comparing the antinociceptive effect of different antidepressants on UPPS are warranted