A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia.

Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated CNS and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain, and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in NaV1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglion (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel NaV1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function NaV1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Design of Phase 3 Studies Evaluating Vixotrigine for Treatment of Trigeminal Neuralgia.

PURPOSE: Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs. PATIENTS AND METHODS: Two double-blind randomized withdrawal studies are planned to evaluate the efficacy and safety of vixotrigine compared with placebo in participants with TN (NCT03070132 and NCT03637387). Participant criteria include ≥18 years old who have classical, purely paroxysmal TN diagnosed ≥3 months prior to study entry, who experience ≥3 paroxysms of pain/day. The two studies will include a screening period, 7-day run-in period, a 4- or 6-week single-dose-blind dose-optimization period (Study 1) or 4-week open-label period (Study 2), and 14-week double-blind period. Participants will receive vixotrigine 150 mg orally three times daily in the dose-optimization and open-label periods. The primary endpoint of both studies is the proportion of participants classified as responders at Week 12 of the double-blind period. Secondary endpoints include safety measures, quality of life, and evaluation of vixotrigine population pharmacokinetics. CONCLUSION: There is a need for an effective, well-tolerated, noninvasive treatment for the neuropathic pain associated with TN. The proposed studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with TN.

Evaluation of the Pharmacokinetic Interaction Between the Voltage- and Use-Dependent Nav1.7 Channel Blocker Vixotrigine and Carbamazepine in Healthy Volunteers.

Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC0-tau ) and maximum observed concentration (Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.

Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.

Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: the trigeminal neuralgia experience.

BACKGROUND: This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia. METHODS: This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics. RESULTS: Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change. CONCLUSIONS: Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.

The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity.

We used a mouse with deletion of exons 4, 5, and 6 of the SCN11A (sodium channel, voltage-gated, type XI, alpha) gene that encodes the voltage-gated sodium channel Na(v)1.9 to assess its contribution to pain. Na(v)1.9 is present in nociceptor sensory neurons that express TRPV1, bradykinin B2, and purinergic P2X3 receptors. In Na(v)1.9-/- mice, the non-inactivating persistent tetrodotoxin-resistant sodium TTXr-Per current is absent, whereas TTXr-Slow is unchanged. TTXs currents are unaffected by the mutation of Na(v)1.9. Pain hypersensitivity elicited by intraplantar administration of prostaglandin E2, bradykinin, interleukin-1beta, capsaicin, and P2X3 and P2Y receptor agonists, but not NGF, is either reduced or absent in Na(v)1.9-/- mice, whereas basal thermal and mechanical pain sensitivity is unchanged. Thermal, but not mechanical, hypersensitivity produced by peripheral inflammation (intraplanatar complete Freund's adjuvant) is substantially diminished in the null allele mutant mice, whereas hypersensitivity in two neuropathic pain models is unchanged in the Na(v)1.9-/- mice. Na(v)1.9 is, we conclude, an effector of the hypersensitivity produced by multiple inflammatory mediators on nociceptor peripheral terminals and therefore plays a key role in mediating peripheral sensitization.

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial.

BACKGROUND: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study. METHODS: We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18-80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16). FINDINGS: The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication. INTERPRETATION: The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials. FUNDING: Convergence Pharmaceuticals.

Upregulation of the voltage-gated sodium channel beta2 subunit in neuropathic pain models: characterization of expression in injured and non-injured primary sensory neurons.

The development of abnormal primary sensory neuron excitability and neuropathic pain symptoms after peripheral nerve injury is associated with altered expression of voltage-gated sodium channels (VGSCs) and a modification of sodium currents. To investigate whether the beta2 subunit of VGSCs participates in the generation of neuropathic pain, we used the spared nerve injury (SNI) model in rats to examine beta2 subunit expression in selectively injured (tibial and common peroneal nerves) and uninjured (sural nerve) afferents. Three days after SNI, immunohistochemistry and Western blot analysis reveal an increase in the beta2 subunit in both the cell body and peripheral axons of injured neurons. The increase persists for >4 weeks, although beta2 subunit mRNA measured by real-time reverse transcription-PCR and in situ hybridization remains unchanged. Although injured neurons show the most marked upregulation,beta2 subunit expression is also increased in neighboring non-injured neurons and a similar pattern of changes appears in the spinal nerve ligation model of neuropathic pain. That increased beta2 subunit expression in sensory neurons after nerve injury is functionally significant, as demonstrated by our finding that the development of mechanical allodynia-like behavior in the SNI model is attenuated in beta2 subunit null mutant mice. Through its role in regulating the density of mature VGSC complexes in the plasma membrane and modulating channel gating, the beta2 subunit may play a key role in the development of ectopic activity in injured and non-injured sensory afferents and, thereby, neuropathic pain.

A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy.

Diabetic polyneuropathy (DPN) is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Differences in the clinical symptoms and signs associated with DPN suggest distinct pathophysiological mechanisms underlying nerve damage and dysfunction that are likely to have therapeutic relevance. The aim of this study was to develop a tool for the bedside assessment of painful neuropathies such as DPN that captures the diversity of phenotypes. Sixty-one patients with type 2 diabetes and painful neuropathy, 19 patients with painless DPN, 25 patients with type 2 diabetes but no clinical evidence of neuropathy, and 20 healthy control subjects completed a structured interview (47 items) and a standardized physical examination (39 items). After analyzing critical features of pain and painless symptoms and examining the outcome of physical tests of sensory function, we determined principal components of the phenotypic variance among patients. Increased sensitivity to mechanical or thermal stimuli and, to a lesser extent, the sensory quality of pain or paresthesia were the most discriminating elements of DPN phenotypes. Correlation patterns of symptoms and signs indicated the involvement of functionally distinct nerve fiber populations. We combined interview questions and physical tests identifying these differences in a shortened assessment protocol that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). The protocol StEPS generates a phenotypic profile of patients with neuropathy. Separate intensity ratings for spontaneous painful symptoms and pain evoked by standard stimuli support a detailed documentation of neuropathic pain and its response to analgesic treatment.

The pattern of expression of the voltage-gated sodium channels Na(v)1.8 and Na(v)1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models.

A spared nerve injury of the sciatic nerve (SNI) or a segmental lesion of the L5 and L6 spinal nerves (SNL) lead to behavioral signs of neuropathic pain in the territory innervated by adjacent uninjured nerve fibers, while a chronic constriction injury (CCI) results in pain sensitivity in the affected area. While alterations in voltage-gated sodium channels (VGSCs) have been shown to contribute to the generation of ectopic activity in the injured neurons, little is known about changes in VGSCs in the neighboring intact dorsal root ganglion (DRG) neurons, even though these cells begin to fire spontaneously. We have now investigated changes in the expression of the TTX-resistant VGSCs, Nav1.8 (SNS/PN3) and Nav1.9 (SNS2/NaN) by immunohistochemistry in rat models of neuropathic pain both with an intermingling of intact and degenerated axons in the nerve stump (SNL and CCI) and with a co-mingling in the same DRG of neurons with injured and uninjured axons (sciatic axotomy and SNI). The expression of Nav1.8 and Nav1.9 protein was abolished in all injured DRG neurons, in all models. In intact DRGs and in neighboring non-injured neurons, the expression and the distribution among the A- and C-fiber neuronal populations of Nav1.8 and Nav1.9 was, however, unchanged. While it is unlikely, therefore, that a change in the expression of TTX-resistant VGSCs in non-injured neurons contributes to neuropathic pain, it is essential that molecular alterations in both injured and non-injured neurons in neuropathic pain models are investigated.

Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23.

The voltage-gated sodium channel NaV1.8 (SNS, PN3) is thought to be a molecular correlate of the dorsal root ganglion (DRG) tetrodotoxin resistant (TTX-R) Na+ current. TTX-R/NaV1.8 is an attractive therapeutic drug target for inflammatory and neuropathic pain on the basis of its specific distribution in sensory neurones and its modulation by inflammatory mediators. However, detailed analysis of recombinant NaV1.8 has been hampered by difficulties in stably expressing the functional protein in mammalian cells. Here, we show stable expression and functional analysis of rat NaV1.8 (rNaV1.8) in the rat DRG/mouse N18Tg2 neuroblastoma hybridoma cell line ND7-23. Rat NaV1.8 Na+ currents were recorded (789 +/- 89 pA, n=62, over 20-cell passages) that qualitatively resembled DRG TTX-R in terms of gating kinetics and voltage-dependence of activation and inactivation. The local anaesthetic drug tetracaine produced tonic inhibition of rNaV1.8 (mean IC50 value 12.5 microM) and in repeated gating paradigms (2-10 Hz) also showed frequency-dependent block. There was a correlation between the ability of several analogues of the anticonvulsant/analgesic compound lamotrigine to inhibit TTX-R and rNaV1.8 (r=0.72, P<0.001). RT-PCR analysis of wild type ND7-23 cells revealed endogenous expression of the beta1 and beta3 accessory Na+ channel subunits-the possibility that the presence of these subunits assists and stabilises expression of rNaV1.8 is discussed. We conclude that the neuroblastoma ND7-23 cell line is a suitable heterologous expression system for rNaV1.8 Na+ channels in that it allows stable expression of a channel with biophysical properties that closely resemble the native TTX-R currents in DRG neurones. This reagent will prove useful in the search for pharmacological inhibitors of rNaV1.8 as novel analgesics.

Expression of the sodium channel beta3 subunit in injured human sensory neurons.

Voltage-gated sodium channel alpha-subunits play a key role in pain pathophysiology, and are modulated by beta-subunits. We previously reported that beta1- and beta2-subunits were decreased in human sensory neurons after spinal root avulsion injury. We have now detected, by immunohistochemistry, beta3-subunits in 82% of small/medium and 67% of large diameter sensory neurons in intact human dorsal root ganglia: 54% of beta3 small/medium neurons were NGF receptor trkA negative. Unlike beta1- and beta2, beta3-immunoreactivity did not decrease after avulsion injury, and the beta3:neurofilament ratio was significantly increased in proximal injured human nerves. beta3-subunit expression may thus be regulated differently from beta1, beta2 and Nav1.8. Targeting beta3 interactions with key alpha-subunits, particularly Nav1.3 and Nav1.8, may provide novel selective analgesics.

Decreased potassium channel IK1 and its regulator neurotrophin-3 (NT-3) in inflamed human bowel.

Calcium-activated potassium currents of intermediate conductance (IK1) have been described in the rodent enteric nervous system, where they may regulate afterhyperpolarisation of intrinsic primary afferent neurons. Using specific antibodies for immuno-cytochemistry, we now report IK1-like immunoreactivity for the first time in enteric neurons of human colon, and a significant decrease of IK1-positive cells in myenteric plexus in inflamed colon from patients with Crohn's disease and ulcerative colitis (p = 0.031). Neurotrophin-3 (NT-3), which regulates IK1 expression, was also observed in fewer neurons of the myenteric ganglia in Crohn's bowel (p = 0.048), and in inflamed colonic extracts by Western blotting (p = 0.004); the numbers of neurons expressing the NT-3 high affinity receptor trk C were unchanged. Our findings may explain the diarrhoea and colicky abdominal pain produced by inflammatory bowel disease, and by IK1-blocking pyridine drugs prescribed for neuromuscular disorders.

Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats.

In an attempt to understand mechanisms underlying peripheral sensitization of primary afferent fibers, we investigated the presence of the tetrodotoxin-resistant Na+ channel subunits Nav1.8 (SNS) and Nav1.9 (SNS2) on axons in digital nerves of normal and inflamed rat hindpaws. In normal animals, 14.3% of the unmyelinated and 10.7% of the myelinated axons labeled for the Nav1.8 subunit. These percentages significantly increased in 48 h inflamed animals to 22.0% (1.5-fold increase) and 57.5% (6-fold increase) for unmyelinated and myelinated axons, respectively. In normal animals, Nav1.9 labeled 9.9% of the unmyelinated and 2.1% of the myelinated axons and following inflammation, the proportion of Nav1.9-labeled unmyelinated axons significantly decreased to 3.0% with no change in the proportion of labeled myelinated axons. These data indicate that Nav1.8 and Nav1.9 subunits are transported to the periphery in normal animals and are differentially regulated during inflammation. The massive increase in Nav1.8 expression in myelinated axons suggests that these may contribute to peripheral sensitization and inflammatory hyperalgesia.

Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum.

The SK/IK family of small and intermediate conductance calcium-activated potassium channels contains four members, SK1, SK2, SK3 and IK1, and is important for the regulation of a variety of neuronal and non-neuronal functions. In this study we have analysed the distribution of these channels in human tissues and their cellular localisation in samples of colon and corpus cavernosum. SK1 mRNA was detected almost exclusively in neuronal tissues. SK2 mRNA distribution was restricted but more widespread than SK1, and was detected in adrenal gland, brain, prostate, bladder, liver and heart. SK3 mRNA was detected in almost every tissue examined. It was highly expressed in brain and in smooth muscle-rich tissues including the clitoris and the corpus cavernosum, and expression in the corpus cavernosum was upregulated up to 5-fold in patients undergoing sex-change operations. IK1 mRNA was present in surface-rich, secretory and inflammatory cell-rich tissues, highest in the trachea, prostate, placenta and salivary glands. In detailed immunohistochemical studies of the colon and the corpus cavernosum, SK1-like immunoreactivity was observed in the enteric neurons. SK3-like immunoreactivity was observed strongly in smooth muscle and vascular endothelium. IK1-like immunoreactivity was mainly observed in inflammatory cells and enteric neurons of the colon, but absent in corpus cavernosum. These distinctive patterns of distribution suggest that these channels are likely to have different biological functions and could be specifically targeted for a number of human diseases, such as irritable bowel syndrome, hypertension and erectile dysfunction.

Multiple mechanisms have been tested in pain--how can we improve the chances of success?

Recent advances in understanding the pathophysiology of pain have led to a wealth of molecular targets for novel analgesic drugs and many clinical drug trials. There have been successes, like the gabapentinoids for neuropathic pain and calcium channel blockers for otherwise intractable pain states; and drugs which show promise in clinical trials, like nerve growth factor inhibitors and p38 kinase inhibitors. Unfortunately there have also been a number of failures. We suggest factors which might predispose to success, for example some clinical precedence for the mechanism in pain or a genetic link for the mechanism, for example a mutation linked to a pain syndrome. We also stress the importance of demonstrating molecular target engagement with a novel compound and suggest pain biomarkers which can be used for mechanistic drug profiling.

Novel design for a phase IIa placebo-controlled, double-blind randomized withdrawal study to evaluate the safety and efficacy of CNV1014802 in patients with trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) is a rare severe unilateral facial pain condition. Current guidelines in trigeminal neuralgia management recommend sodium channel blockers--carbamazepine or oxcarbazepine--as the first-line treatment. However, the currently available drugs are often associated with poor tolerability resulting in sub-optimal pain control. CNV1014802 is a novel sodium channel blocker that is being assessed in the treatment of trigeminal neuralgia. Due to the severity of the condition, it is not ethical to conduct a traditional placebo-controlled randomized controlled trial. It is also difficult to use an active control such as carbamazepine, the current gold standard, because of its complex pharmacology and potential for drug interactions. METHODS/DESIGN: The trial uses a randomized withdrawal design to assess efficacy in this rare condition. There is a 21-day open-label phase followed by a randomized 28-day placebo-controlled phase for responders. Thirty patients will be randomized. The primary outcome measure will be pain relief, but secondary measures of quality of life will be of significant importance given the effect of this condition on activities of daily living. Safety and adverse event endpoints are described. DISCUSSION: There have been very few well-controlled, randomized, placebo-controlled studies in trigeminal neuralgia, and the majority of drugs have had other primary uses. Due to the severity of the pain, minimizing the time a patient is administered placebo was a key factor in designing this study. This study will not only provide data on the efficacy of CNV1014802 in trigeminal neuralgia, but will also provide information on the effectiveness and acceptability of a novel trial design in trigeminal neuralgia. TRIAL REGISTRATION: Trial number NCT01540630.

Transient receptor potential channels: targeting pain at the source.

Pain results from the complex processing of neural signals at different levels of the central nervous system, with each signal potentially offering multiple opportunities for pharmacological intervention. A logical strategy for developing novel analgesics is to target the beginning of the pain pathway, and aim potential treatments directly at the nociceptors--the high-threshold primary sensory neurons that detect noxious stimuli. The largest group of receptors that function as noxious stimuli detectors in nociceptors is the transient receptor potential (TRP) channel family. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting drugs, and discusses the development pathways needed to test candidates as analgesics in humans.