The main finding of this review is that the use of antidepressants in the management of chronic urological pelvic pain is not supported by an adequate number of well designed randomized controlled trials.
Amitriptyline and sertraline are the drugs that have been studied more extensively in chronic urological pelvic pain. Regarding the first, we identified two RCTs that randomized 106 patients recruited [11
] and two prospective case series with a total of 119 patients [13
]. Regarding sertraline, we identified two RCTs with a total of 37 patients [16
]. According to this review most of the studies conducted so far are uncontrolled prospective case series.
Van Ophoven's study [11
] with amitriptyline for interstitial cystitis was a high-quality double blind RCT with a small percentage of dropouts and a considerable number of patients. Engel's study [16
] with sertraline for chronic pelvic pain provides good level of evidence, but it is of lower validity. Lee's study [17
] with sertraline is the only one which was conducted for chronic prostatitis, but it has low validity and methodological deficiencies. Sator-Katzenschlager's RCT [12
] comparing amitriptyline with gabapentin did not include placebo and therefore it is difficult to evaluate efficacy for amitriptyline.
For nortriptyline, duloxetine, and citalopram only uncontrolled studies were identified [18
]. These studies have the lowest level of evidence and no firm conclusions for the efficacy of these antidepressants agents can be extracted. Therefore, their use should still be considered as experimental.
Amitriptyline was found to be effective compared to placebo in interstitial cystitis. However, we could only identify a single RCT and therefore it is very likely that publication bias could offer an alternative explanation.
Regarding acceptability, we found that antidepressants were generally safe drugs with tolerable side effects. The withdrawal rates in most studies were not high and the reported reason for the withdrawal was not relevant to the side effects. Nonetheless, most of the studies were of short-term duration and it is not known whether acceptability would be the same on the long-term. Two amitriptyline studies were of longer duration [12
] and have shown that long-term use may be well tolerated.
A major problem in evaluating the efficacy of antidepressants in chronic urological pelvic pain is the heterogeneity of the studies concerning the classification of chronic pelvic pain syndrome. In this review we focused on studies examining chronic urological pelvic pain. However, some of the included studies consisted of mixed population in terms of pain location, such as patients with pain perceived in gynaecological system.
Antidepressants may be effective in chronic pelvic pain either by acting directly on the neural mechanisms of pain or by reducing depressive symptoms that may influence the experience of pain or the capacity to cope with the pain. Regarding the first, studies have shown that the spinal and neuronal pathways are modulated by activation and/or inhibition of neurons in the periphery, at spinal levels and at supraspinal regulatory sites. Serotonergic pathways and receptor mechanisms play a crucial role within this neuronal network. The antidepressants alleviate symptoms probably via mechanisms such as blockade of acetylcholine receptors, inhibition of reuptake of released serotonin and norepinephrine, and blockade of the histamine H1 receptor [21
Regarding the role of psychological morbidity, epidemiological studies of chronic pain have shown the strong association between depressive symptoms and experience of pain in general [22
] and chronic pelvic pain in particular [23
]. Banks and Kerns have proposed a diathesis-stress framework to explain the nature of this relationship. According to this model individuals with a higher “diathesis” for depression (biologically or genetically determined) are more likely to develop an actual episode of depression in the presence of a stressor such as chronic pain. These authors suggest that the treatment of chronic pain can be improved if depression is considered an essential part of the patient's clinical presentation [24
]. This view may have practical clinical implications since, even if there is little evidence from randomized controlled trials to routinely recommend the use of antidepressants in all patients with chronic pelvic pain syndrome, the presence of comorbid psychological dimension may increase the likelihood of a positive outcome.
The best way of studying the effect of antidepressants is by using carefully designed placebo-controlled double blind studies. More RCTs of longer duration with larger numbers of patients suffering from chronic urological pelvic pain are needed. Future studies should include patient subgroups on the basis of symptom severity or predominant symptom. It may be advisable to stratify the sample with respect to the presence or absence of major depression to further evaluate the efficacy of antidepressants. Studies should also include measures of disability and coping. Combination or multimodal therapy with antidepressants and other potentially beneficial agents (e.g., anti-inflammatory agents, a-blockers) that have independent actions should be evaluated in RCTs. Because a given pharmacologic intervention might selectively alleviate a symptom while causing adverse effects or exacerbating other symptoms, future trials should assess both side effects and overall health-related quality of life by using validated measures.