The visceral pain syndromes have previously been neglected and underestimated. They have only reached clinical and scientific recognition in the last 15–20 years, due to the overwhelming evidence of recent epidemiological data highlighting the widespread existence of these pain syndromes. Patients with visceral pain, present a previously unrecognized and underserved population in need of adequate pain management. In the United States, patients suffering from some of these previously un-recognized pain syndromes (such as chronic prostatitis, interstitial cystitis and vulvodynia) have organized patient support groups, which have urged the US government and the National Institutes of Health to fund research studies aimed at a better understanding of the pathophysiology of these pain syndromes and to fund clinical research studies aimed at identifying specific treatment approaches for these visceral pain syndromes.
Treating patients with visceral pain remains a significant clinical challenge and current therapeutic interventions are often empirical. Pharmacological pain management is typically with drugs, that have shown efficacy for the treatment of chronic neuropathic pain states. Very few drugs have been specifically approved for the treatment of visceral pain syndromes. Examples are Elmiron (pentosan polysulfate sodium), which is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis and Zelnorm (tegaserod maleate), which was on the market for a brief period of time (subsequently withdrawn due to side effects) and was indicated for the short-term treatment of women with IBS.
Based on the epidemiological evidence and convincing basic science data, showing specific potential targets for visceral pain therapy, there is growing interest in the pharmaceutical industry to expand basic science and clinical research efforts for this underserved patient population. The European Agency for the Evaluation of Medicinal Products suggested to include patients with chronic visceral pain in their recommendations “Guidance on clinical investigation of medicinal products for treatment of nociceptive pain” (Available at: http://www.emea.europa.eu/pdfs/human/ewp/061200en.pdf
The task to include patients with visceral pain syndromes into clinical trials requires very thoughtful trial design. Difficulties in clinical trial design for this patient population are the clinical observations, that many of the visceral pain syndromes have periods of flares and remission. In other patients, symptoms become more severe and frequent over time. Thus it is difficult to establish a baseline for the symptoms over a longer observation period. It has been suggested by some investigators to circumvent this problem by evaluating the response to an evoked painful visceral stimulus, such as bladder distension, either in normal volunteers, or in subjects with visceral pain (40
). Conceptually, however, it is not clear, if pharmacological studies evaluating the response to an evoked visceral stimulus can be used to predict the response to spontaneous visceral pain, since the neurophysiological mechanisms are likely to be different. A further challenge is the complexity of the visceral pain syndromes. Often patients suffer not only from visceral pain, but also from other symptoms: for example interstitial cystitis is characterized by urinary urgency, frequency and pain. Thus, determination of the global endpoint for such studies requires careful consideration.
There is a growing body of literature demonstrating that different visceral pain syndromes, as well as pain syndromes in other body regions, often occur together in the same patient. Thus, efforts to understand the pathophysiology and to design therapeutic modalities have recently shifted from an organ-based approach to a more global approach (12
). It is important to keep track of these comorbidities for clinical trial design, since the pathophysiological mechanisms in subjects with different comorbidities might be different.
Many visceral pain syndromes occur preferentially in women in their reproductive ages (41
). There is a desperate need to provide adequate pain management for this patient population, and on the other hand this age group provides specific challenges to clinical trial design.
Recent clinical research studies that have tried to refine or test existing therapies in visceral pain populations (for example: 42, 43). The trial design of these studies, including the challenges and pitfalls, can serve as basis for future studies using currently available drugs and pharmacological agents in development. Several of these studies have obtained frustrating results, and it appears that many therapies are effective in only a subset of patients. Thus, a key issue will be to identify subgroups of patients based on aspects such as the clinical symptoms, quantitative sensory testing parameters, biomarkers and comorbid conditions, who respond to particular therapeutic approaches. A similar approach has been used successfully for drug development for other pain conditions (for example: cluster headache and migraine headache subjects would obviously not be combined in a clinical trial to test a new drug).
Modulation of visceral nociceptive pathways can occur at peripheral, spinal and supra-spinal sites and a wide variety of potential drug targets exists as reviewed above. Compounds, which hit several targets, might be the best option for a successful approach in the short term. However, there is emerging evidence that a more refined approach may be achievable(44
). These are very exciting times for the area of visceral pain (45
), since visceral nociceptive pathways are being identified and compounds are being discovered that are likely to modulate these visceral nociceptive pathways. While there are challenges to clinical trial design for this patient population, as outlined above, knowledge of these challenges should result in well planned, successful studies in the near future.