Pharmacotherapy in Neuropathic Pain

Tanezumab, a NGF antibody preparation, has been tested in randomized controlled trials in many pain indications, including BPS/IC [7] and neuropathic pain syndromes such as diabetic neuropathy [3]. BPS/IC is characterized by chronic discomfort attributed to the bladder, and is usually associated with worsening on bladder filling and relief with urination. The severity of the symptoms varies both within and between subjects, and the sensations that patients experience often change over time, variably described as “pain”, “discomfort”, “cramping” or “fullness” [6]. The etiology of the disease is unclear, and multiple underlying pathophysiologic mechanisms have been proposed, including bladder wall dysfunction, tissue and nerve injury, and mast cell degranulation [8]. Although not well understood, it is thought that the process critically involves both peripheral and central sensitization. NGF released from bladder epithelium, activated mast cells, and/or detrusor smooth cells upon stretch binds to TrkA receptors on bladder afferent neurons, likely contributing to this neuronal sensitization [18].

In a randomized, double-blind, placebo-controlled, parallel-group trial, 64 patients suffering from moderate to severe BPS/IC symptoms received a single dose of 200 mcg/kg intravenous tanezumab or placebo [8]. The patients were followed for 16 weeks, although the primary endpoint occurred at the six week study visit. At various points in the trial, patients recorded daily pain and urinary symptom scores. At the six week visit, on the primary endpoint, patients treated with tanezumab showed a trend towards decreased average daily pain scores vs. placebo. Additionally, they were more likely to report a 30% or 50% reduction in pain scores from baseline and were more likely to report moderate or marked improvement on a global response assessment questionnaire, although none of these results reached statistical significance. Patients treated with tanezumab did report a statistically significant decrease in the numbers of episodes of urinary urgency per 24-hours. Conversely, scores on other secondary outcomes, including the Interstitial Cystitis Symptom Index, number of micturitions per 24-hours, and mean volume voided per micturition did not separate from placebo. Tanezumab was generally well tolerated in this study, and the rate of treatment emergent adverse events (TEAEs) was similar between those receiving active drug and those receiving placebo. Headache was the most commonly reported adverse event in the tanezumab group. A number of patients in the tanezumab group experienced new, peripheral neurologic symptoms, such as paresthesia and hyperesthesia, although these were reported to be generally mild or moderate, and resolved by the end of the study.

Tanezumab has also been tested for the treatment of diabetic neuropathy [3]. In a trial that was initially designed as a 24-week randomized, double-blind, placebo-controlled, parallel group study, patients were scheduled to receive 20 mg of subcutaneous tanezumab every eight weeks. Due to safety concerns with the molecule, this trial was terminated early. Seventy-three patients with diabetic neuropathy had entered the trial and received at least one dose of medication at the time of discontinuation, their efficacy data was analyzed at the eight week time point. There was a significant difference between the tanezumab and placebo groups in mean change from baseline in average pain score and percentage of patients reporting improvement from baseline of 30%, 50%, and 70%. There was a non-statistically significant trend towards patients reporting a 90% improvement in pain and the patients’ global improvement scores. There was no apparent effect on quantitative sensory testing thresholds or intra-epidermal nerve fiber density on distal thigh and leg biopsies. The most common treatment-emergent adverse events were other pain syndromes (e.g. arthralgia, pain in extremity, myalgia) and abnormal peripheral sensations.

Fulranumab is another NGF antibody currently undergoing clinical development. The first randomized, controlled trial results were recently published for this compound, for the treatment of patients with osteoarthritis pain [21]. The compound is also being evaluated for the treatment of various neuropathic pain indications, including BPS/IC, PHN, DN, post-trauma pain and cancer pain (www.clinicaltrials.gov). A third NGF antibody, fasinumab (RGN475), is also in development, although no clinical data have yet been published (Regeneron Pharmaceuticals website, accessed Aug 8, 2013).

The FDA suspended NGF clinical trials in 2010 due to suspected cases of osteonecrosis in patients using NGF antibody alone or with NSAIDs. A review of findings suggested a dose response relationship between NGF antibody and rapidly progressing osteoarthritis (OA), which was greater in combination with NSAIDs [22]. In 2012, the FDA recommended reinitiating clinical trials with a greater attention to abnormal joint side effects, including baseline imaging and continuous clinical evaluations [22].

Nav1.7

Regulation of voltage-gated sodium channels (Nav) is believed to play a role in neuropathic pain, and selective blockage of specific channels is currently being explored as a possible route to effective pain treatment. Sodium channels are involved in membrane excitability and the generation and propagation of action potentials that contribute to the transmission of peripheral nociceptor signaling to the central nervous system [25]. Moreover, sodium channel expression is regulated in pathological pain conditions and some of them are selectively expressed in nociceptors [6,23]. These aspects make targeting sodium channels a viable and appealing approach to treat pain, and in fact, several sodium channel blockers are analgesic including lamotrigine, carbamazepine, and lidocaine. However, these agents are non-selective sodium channel blockers and thus clinically express adverse events which limit their dosing and efficacy. The current approach being taken by many groups is to identify and develop subtype-selective sodium channel blockers, specifically those selective for nociceptive neurons and thus involved in pathological pain. One of the most highly pursued subtypes is the Nav1.7 sodium channel. Genetic changes in the SCN9A gene, which encodes for the Nav1.7 voltage-gated sodium channel, has been linked to multiple rare pain syndromes, such as congenital indifference to pain (loss of function mutations) and inherited erythromelalgia (IEM) (gain of function mutations) [11].

Patients suffering from IEM were tested in a small, four-patient, exploratory trial of Xenon Pharmaceuticals Nav1.7 voltage-gated sodium channel antagonist, XEN402 [11]. This rare autosomal dominant condition is characterized by attacks of severe, debilitating, symmetrical burning pain of the distal extremities, often associated with elevated skin temperatures and erythema [11]. The attacks can be spontaneous or evoked, with exercise, prolonged standing, exposure to heat, and changes in humidity believed to be common inciting factors. Adequate pain treatment is challenging, and often inadequate. It is theorized that hyperactivity of the Nav1.7 voltage-gated sodium channel may be the underlying pathophysiologic mechanism of the spontaneous attacks of pain, thus antagonism of this channel could lead to a decreased incidence or severity of these episodes.

The clinical trial of XEN402 had a four-patient, randomized, double-blind, placebo-controlled cross-over design. Each patient received XEN402 twice daily for two 2-day treatment periods, which were separated by a 2-day washout period. Three patients presented with episodic, spontaneous pain episodes, and six pain induction procedures were used during each two day study period in order to facilitate efficacy measurements. Pain was induced with either exposure of the distal extremities to heat or through exercise. The fourth subject presented with severe, chronic pain of her hands and feet, with episodes of acute worsening of symptoms. Due to her chronic pain, no episodes of pain induction were necessary. All four subjects reported a decrease in their pain symptoms with XEN402. The three subjects who underwent pain induction reported significant reduction in pain scores, with a reported statistically significant decrease in induced pain of 42% while treated with XEN402 compared to treatment with placebo. The fourth patient, who was in chronic pain also reported decreased chronic pain scores with XEN402 compared to placebo, although not statistically significant. Two patients experienced dizziness and somnolence with XEN402 treatment, which led to reduction of their final administered dose. No subjects discontinued from the study and no serious adverse events were reported.

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