Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (␣2-␦-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the ␣2-␦-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.

Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met. IntroductionDrug discovery and development continue to be a challenge, with increasingly high investments in R&D and increased numbers of submissions failing to translate into the delivery of novel chemical entities onto the market. The wide availability of generic and overthe-counter analgesics based on non-steroidal antiinflammatories (NSAIDs), acetaminophen, and "weak" opiates (and their combinations) provides many individuals with an accessible source of relief for mild to moderate pain. However, many patients with chronic conditions such as osteoarthritis remain poorly treated (1, 2).Opiates continue to provide an important choice for the treatment of moderate to severe pain but are associated with a number of unwanted side effects such as constipation, nausea, vomiting, itching, and somnolence (3), and negative effects on patients' wellbeing, including sleep quality and ability to concentrate, which can be of such significance that they result in treatment discontinuation (4). Indeed, a recent Internet survey indicated that patients taking opiates for pain (and prescribing physicians) are willing to "trade-off " pain relief for a better toleration profile, with 50% of patients and physicians reporting that improved side effects represent the biggest unmet need (5).Neuropathic pain has a complex pathophysiology and is difficult to treat (6). It has been estimated that about one-third of patients are likely to achieve 50% pain relief with monotherapy (7); for example, in patients treated with the first-line therapy pregabalin, the patient global impression of change rating of much improved or very much improved was about 35% in postherpetic neuralgia, 50% in painful diabetic neuropathy, and 40% in fibromyalgia (8). A recent review identified a 66% increase in published randomized, placebo-controlled trials in a range of neuropathic pain populations over the last five years and concluded that only a limited improvement in the relief of pain had been achieved and that a large proportion of patients remained poorly treated (9).The challenge for drug discovery and development can therefore be very simply stated: we need to bring forward analgesics that will provide more effective pain relief, are safe...

BackgroundBladder pain syndrome (BPS) pathology is poorly understood. Treatment strategies are empirical, with limited efficacy, and affected patients have diminished quality of life.ObjectiveWe examined the hypothesis that inflammatory mediators within the bladder contribute to BPS pathology.Design, setting, and participantsFifteen women with BPS and 15 women with stress urinary incontinence without bladder pain were recruited from Cork University Maternity Hospital from October 2011 to October 2012. During cystoscopy, 5-mm bladder biopsies were taken and processed for gene expression analysis. The effect of the identified genes was tested in laboratory animals.Outcome measures and statistical analysisWe studied the expression of 96 inflammation-related genes in diseased and healthy bladders. We measured the correlation between genes and patient clinical profiles using the Pearson correlation coefficient.Results and limitationsAnalysis revealed 15 differentially expressed genes, confirmed in a replication study. FGF7 and CCL21 correlated significantly with clinical outcomes. Intravesical CCL21 instillation in rats caused increased bladder excitability and increased c-fos activity in spinal cord neurons. CCL21 atypical receptor knockout mice showed significantly more c-fos upon bladder stimulation with CCL21 than wild-type littermates. There was no change in FGF7-treated animals. The variability in patient samples presented as the main limitation. We used principal component analysis to identify similarities within the patient group.ConclusionsOur study identified two biologically relevant inflammatory mediators in BPS and demonstrated an increase in nociceptive signalling with CCL21. Manipulation of this ligand is a potential new therapeutic strategy for BPS.Patient summaryWe compared gene expression in bladder biopsies of patients with bladder pain syndrome (BPS) and controls without pain and identified two genes that were increased in BPS patients and correlated with clinical profiles. We tested the effect of these genes in laboratory animals, confirming their role in bladder pain. Manipulating these genes in BPS is a potential treatment strategy.

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