Emerging therapies for neuropathic pain

Neuropathic pain develops as a result of damage to either the peripheral or central nervous system. It is characterised by spontaneous burning pain and/or ongoing pain with accompanying hyperalgesia and allodynia. Neuropathic pain is difficult to treat as it is often refractory to conventional analgesic treatments, with most patients obtaining only partial relief. At present, there are four major medication categories that are considered first-line treatment for neuropathic pain: antidepressants, anticonvulsants, local anaesthetic/topical agents and opioids. The efficacy of these treatments in neuropathic pain, excepting opioids, has been discovered serendipitously. However, responder rates and overall efficacy is poor with these agents and tolerability or side effects are often limiting. This update will review existing treatment options for neuropathic pain, and highlight more recent advances in the development of novel analgesics to treat this chronic disorder.     

Emerging drugs for neuropathic pain

Importance of the field: Atopic eczema (AE) is a chronic relapsing inflammatory skin condition and one of the most common, potentially debilitating diseases with increasing incidence.

Areas covered in this review: The complex etiology of AE with multiple systemic and local immunologic and inflammatory responses and interactions between susceptibility genes and environmental factors leading to defects in skin barrier function and eczematous skin lesions is presented. Knowledge of pathogenesis is important for understanding the more innovative treatment approaches discussed.

What the reader will gain: Basic therapy consists of hydrating topical treatment and avoidance of specific and unspecific provocation factors. For acute eczematous skin lesions, anti-inflammatory treatment consists mainly of topical glucocorticoids and topical calcineurin inhibitors (tacrolimus and pimecrolimus). Microbial colonization and superinfection may induce skin exacerbation, which can be treated by either topical or systemic antimicrobial treatment. Systemic anti-inflammatory therapy is limited to severe cases and consists of systemic steroids, cyclosporine A or mycophenolate mofetil. Novel anti-inflammatory concepts that go beyond corticosteroids are in the early phases of development. There are targeted therapeutic approaches, such as cytokine and chemokine modulators and it remains to be investigated how effective they will be and what side effects they may carry.

Take home message: Existing treatment modalities such as barrier repair therapy, topical immunosuppressive agents, antiseptic treatment as well as systemic treatment options are discussed. The review aims to summarize the most recent findings of more innovative treatment approaches such as modulation of cytokines or chemokines, modulation of T-cell responses or anti-IgE therapy.     

Emerging drugs for neuropathic pain

Introduction: Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation.

Areas covered: A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, α-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor.

Expert opinion: Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain.     

Emerging drugs for neuropathic pain

Although there are many analgesics on the market for the treatment of nociceptive pain, there are none with FDA approval for the treatment of neuropathic pain. With a better understanding of the anatomy and physiology of pain, there is a significant effort in developing new drugs that interact specifically with pain pathways. This higher drug specificity is likely to result in drugs that are more efficacious with fewer side effects. This has led to the development of many drugs for the treatment of neuropathic pain. These drugs are divided into the following therapeutic classes: 1) N-methyl-D-aspartate (NMDA) receptor antagonists, 2) ion channel antagonists, 3) alpha2-agonists, 4) nicotinic receptor agonists, 5) prostaglandin receptor antagonists, 6) adenosine agonists and adenosine kinase inhibitors, 7) neuropeptide antagonists, and 8) prosaposins. The results of preclinical and clinical trials are promising for these new agents. Whether these agents will be efficacious as single agents is yet to be determined; however, preliminary results show that combination therapy may be more beneficial with fewer side effects.     

Emerging drugs in neuropathic pain

Neuropathic pain is a personally devastating and costly condition affecting 3-8% of the population. Existing treatments have limited effectiveness and produce relatively frequent adverse effects. Preclinical research has identified many promising pharmacological targets; however, reliable predictors of success in humans remain elusive. At least 50 new molecular entities have reached clinical development including: glutamate antagonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, opioids, cannabinoids, COX inhibitors, acteylcholine modulators, adenosine receptor agonists and several miscellaneous drugs. Eight drugs are in Phase III trials at present. Strategies that may show promise over existing treatments include topical therapies, analgesic combinations and, in future, gene-related therapies. Recent years have heralded an explosion of pharmaceutical development in neuropathic pain, reflecting advanced knowledge of neurobiology and a heightened perception of the commercial value of neuropathic pain therapeutics. In the interest of improving patient care, the authors recommend implementing comparative studies throughout the development process in order to demonstrate the increased value of novel agents.     

Emerging drugs in neuropathic pain

Neuropathic pain is a personally devastating and costly condition affecting 3 – 8% of the population. Existing treatments have limited effectiveness and produce relatively frequent adverse effects. Preclinical research has identified many promising pharmacological targets; however, reliable predictors of success in humans remain elusive. At least 50 new molecular entities have reached clinical development including: glutamate antagonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, opioids, cannabinoids, COX inhibitors, acteylcholine modulators, adenosine receptor agonists and several miscellaneous drugs. Eight drugs are in Phase III trials at present. Strategies that may show promise over existing treatments include topical therapies, analgesic combinations and, in future, gene-related therapies. Recent years have heralded an explosion of pharmaceutical development in neuropathic pain, reflecting advanced knowledge of neurobiology and a heightened perception of the commercial value of neuropathic pain therapeutics. In the interest of improving patient care, the authors recommend implementing comparative studies throughout the development process in order to demonstrate the increased value of novel agents.     

Emerging drugs for diabetic peripheral neuropathy and neuropathic pain

Introduction: Diabetic sensorimotor polyneuropathy (DSPN) is a common complication of diabetes.

Areas covered: In this review, the authors discuss the emerging drugs for DSPN, which aim either at improving alleviation of neuropathic pain or addressing the putative mechanisms underlying diabetic neuropathy.

Expert Opinion: Current treatment does not address the sensory deficits and pathogenesis underlying DSPN, so there is an unmet need for treatment options targeting the natural history of the condition. Some of these pathogenetic therapies have demonstrated clinically relevant improvements in neuropathic endpoints in recent randomised controlled trials. Since any effective analgesic monotherapy is known to induce a clinically meaningful response in only some 50% of the patients, there remains a substantial unmet need in patients with neuropathic pain. Advanced knowledge in the neurobiology of neuropathic pain and improved phenotypic profiling have led to a burst of research into novel pharmaceutical approaches. An array of promising molecular entities have reached the clinical stage of development, which should improve our therapeutic armamentarium in the fight against DSPN and neuropathic pain in the foreseeable future.     

Emerging therapies in metastatic bone pain

Introduction: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain.

Areas covered: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the ‘vicious cycle’ of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors.

Expert opinion: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile.     

Emerging therapies in metastatic bone pain

Introduction: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain. Areas covered: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the 'vicious cycle' of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors. Expert opinion: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile.     

Emerging pharmacologic therapies for osteoporosis

Osteoporotic fractures are an important public health problem, contributing substantially to morbidity and mortality in an ageing world population and consuming considerable health resources. Presently available pharmacologic therapies for prevention of fragility fractures are limited in scope, efficacy and acceptability to patients. Considerable efforts are being made to develop new, more effective treatments for osteoporosis, and to refine/optimize existing therapies. These novel treatments include an expanding array of drugs that primarily inhibit osteoclastic bone resorption: estrogenic compounds, bisphosphonates, inhibitors of receptor activator of NF-kappaB ligand signaling, cathepsin K inhibitors, c-src kinase inhibitors, integrin inhibitors and chloride channel inhibitors. The advent of intermittent parathyroid hormone (PTH) therapy has provided proof-of-principle that osteoblast-targeted (anabolic) agents can effectively prevent osteoporotic fractures, and is likely to be followed by the introduction of other therapies based on PTH (orally active PTH analogs, antagonists of the calcium sensing receptor, PTH-related peptide analogs) and/or agents that induce osteoblast anabolism by means of pathways involving key, recently identified, molecular targets (wnt-low-density lipoprotein receptor-related protein 5 signaling, sclerostin and matrix extracellular phosphoglycoprotein).     

Emerging therapies for multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM.     

Emerging pharmacological therapies for fibromyalgia

Fibromyalgia is a chronic pain disorder for which pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness and significant tolerability. To date, no drugs have been officially approved for the indication of fibromyalgia, and randomized, controlled clinical trials with fibromyalgia patients are taking place to identify potential therapeutic approaches. Although emerging therapies, such as the antidepressants duloxetine and milnacipran and the antiepileptic pregabalin, offer certain efficacy, randomized controlled trials are generally difficult due to factors such as a lack of understanding of the pathophysiology and a heterogenous fibromyalgia patient population. For a significant advance in the drug treatment of fibromyalgia, novel clues are still awaited that may offer an effective therapeutic approach.     

Emerging therapies for graft-versus-host disease

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: (i) recipient conditioning, (ii) donor T cell activation, and (iii) effector cells mediating GVHD. Standard agents and agents under development to prevent and treat GVHD are discussed. The various pharmacological agents impact on different phases of the GVHD cascade. Sirolimus is a new immunophilin binding agent that appears to be synergistic with tacrolimus and cyclosporin. It also seems to promote allograft tolerance. Mycophenolate mofetil (MMF) is an antimetabolite that is currently under study for prophylaxis and treatment of acute and chronic GVHD; results are encouraging. Other agents such as the purine analogue pentostatin and the monoclonal antibodies alemtuzumab, daclizumab and infliximab are discussed at length within the GVHD context. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for the treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

Emerging therapies for respiratory diseases

This Society for Medicines Research symposium, sponsored by UCB, was held on September 11, 2007, at the Wellcome Trust Conference Centre, Hinxton, Cambridge, United Kingdom. The meeting, organized by Ruth Lock, Steve Collingwood and Andrew Ratcliffe, reviewed current thinking in the area of airway drug delivery and the challenges and progress made in the discovery and development of novel medicines to treat respiratory diseases, such as chronic obstructive pulmonary disease, asthma, allergic rhinitis and cystic fibrosis.     

Emerging targeted therapies for glioma

Introduction: Gliomas are the most common malignant primary brain tumors in adults. Despite aggressive treatment with surgery, radiation and chemotherapy, these tumors are incurable and invariably recur. Molecular characterization of these tumors in recent years has advanced our understanding of gliomagenesis and offered an array of pathways that can be specifically targeted.

Areas covered: The most commonly dysregulated signaling pathways found in gliomas will be discussed, as well as the biologic importance of these disrupted pathways and how each may contribute to tumor development. Our knowledge regarding these pathways are most relevant to Grade IV glioma/glioblastoma, but we will also discuss genomic categorization of low grade glioma. Further, drugs targeting single pathways, which have undergone early phase clinical trials will be reviewed, followed by an in depth discussion of emerging treatments on the horizon, which will include inhibitors of Epidermal Growth Factor Receptor (EGFR) and receptor tyrosine kinases, Phosphoinositide-3-Kinase (PI3K), angiogenesis, cell cycle and mutant Isocitrate Dehydrogenase (IDH) mutations.

Expert opinion: Results from single agent targeted therapy trials have been modest. Lack of efficacy may stem from a combination of poor blood brain barrier penetration, the genetically heterogeneous make-up of the tumors and the emergence of resistance mechanisms. These factors can be overcome by rational drug design that capitalizes on ways to target critical pathways and limits upregulation of redundant pathways.     

Emerging therapies for colorectal cancer

Colorectal carcinoma is a leading cause of cancer mortality worldwide. Survival for patients with metastatic disease is approximately 2 years on average and there is an ongoing need for the identification of new therapeutic agents. As the cancer research community has appreciated, newly discovered pathways governing cancer cell growth, survival, apoptosis, invasion and angiogenesis--all a host of potential therapeutic targets--have come into view. Basic research, preclinical data and observations arising from early stage trials have pointed towards possible roles for many of these agents in the future treatment of colorectal cancer. In this review, the authors summarize agents in development, modulating several of the most promising molecules and pathways that are thought to be relevant to colorectal cancer.     

Emerging therapies for heart failure

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death. Additional molecular targets are being evaluated in preclinical and clinical settings including vasopeptidase inhibitors, endothelin-1 receptor antagonists, arginine vasopressin antagonists, selective aldosterone blockers, TNF-alpha blockers and matrix metalloproteinase inhibitors. Although these approaches hold promise as viable therapeutics, a thorough evaluation of clinical benefit from these agents requires additional trials. Future disease-modifying approaches will also undoubtedly include cell transplantation and gene therapy. It is likely that notable advances in HF treatment will come from agents that attenuate myocardial remodelling. Indeed, maintenance or improvement of cardiac structure can attenuate HF development and improve mortality.     

Emerging therapies for colorectal cancer

Colorectal carcinoma is a leading cause of cancer mortality worldwide. Survival for patients with metastatic disease is ～ 2 years on average and there is an ongoing need for the identification of new therapeutic agents. As the cancer research community has appreciated, newly discovered pathways governing cancer cell growth, survival, apoptosis, invasion and angiogenesis – all a host of potential therapeutic targets – have come into view. Basic research, preclinical data and observations arising from early stage trials have pointed towards possible roles for many of these agents in the future treatment of colorectal cancer. In this review, the authors summarize agents in development, modulating several of the most promising molecules and pathways that are thought to be relevant to colorectal cancer.