New investigational drugs for the treatment of neuropathic pain

Introduction: Neuropathic pain (NP) is a chronic condition that arises from a lesion or dysfunction of the somatosensory nervous system. However, there are several new targets and novel technologies in the pipeline to address this unmet medical need.

Areas covered: In this review, the authors briefly discuss a direction of the development of agents that could be potentially used in NP treatment. Special attention is paid to 1.7-selective voltage-gated sodium channels, N-type voltage-gated calcium channels, angiotensin II (Ang II) AT₂ receptors and nerve growth factor (NGF) as promising targets for new drugs. Furthermore, the article also presents and discusses, in detail, the results of Phase II clinical studies with the AT₂ receptor antagonist ? EMA401 in NP (the results of Phase II clinical trials of other described compounds are not available, yet).

Expert opinion: There is a real hope that new drugs for NP may be available soon. This hope is based on advancing methods of genomics, developing new targets and more efficient drug screening. Some forms of direct influence on voltage-gated ion channels have a place in the treatment of NP, while the development of entirely novel Ang II AT₂ receptor antagonists or NGF inhibitors may be available for many chronic pain sufferers in the foreseeable future.     

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 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

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 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.     

Antiepileptic drugs for central post-stroke pain management

Antiepileptic drugs (AEDs) are commonly prescribed for a wide range of disorders other than epilepsy, including both neurological and psychiatric disorders. AEDs play also a role in pharmacological management of neuropathic pain. Central post-stroke pain (CPSP) is a disabling morbidity occurring in 35% of patients with stroke. The pathophysiology of CPSP is not well known but central disinhibition with increased neuronal excitability has been suggested. AEDs include many different drugs acting on pain through several mechanisms, such as reduction of neuronal hyperexcitability. To our knowledge conclusive evidence has not been published yet. The aim of this review is to delineate efficacy and safety of AEDs in CPSP.     

Antidepressants in the treatment of neuropathic pain

Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class--may among the antidepressants--favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.     

恩再适治疗神经病理性疼痛的临床应用

目的 评价恩再适治疗神经病理性疼痛的疗效.方法 选择25例神经病理性疼痛的患者,每个患者给予恩再适9ml加入0.9%生理盐水250ml中静脉滴注,1次/日,连续14天,在用药前,用药后第1天、第7天和第14天用VAS10分法检测神经病理性疼痛的缓解程度.结果 用药后第1天,疼痛改善不明显;第7天开始,恩再适明显缓解神经病理性疼痛;本次观察显效率68.85%,总有效率92.5%.有1例患者出现皮疹,停药后皮疹逐渐消失.结论 恩再适治疗神经病理性疼痛有效率较高,安全性较好.     

Drug treatment of neuropathic pain

Neuropathic pain results from damage to or dysfunction in the nervous system. The term usually refers to pain caused by a primary abnormality in the peripheral nervous system, while pain caused by damage to the central nervous system tends to be called central pain. Once established, neuropathic pain frequently runs a chronic course and can be severe and difficult to treat. Most doctors (but especially GPs, neurologists, neurosurgeons, oncologists and pain clinic specialists) will encounter patients with neuropathic pain. Management, ideally in a multidisciplinary pain-relief clinic, often involves the combined use of a range of pharmacological and non-drug approaches, the latter including transcutaneous electrical nerve stimulation, psychological treatments, and specialist procedures to stimulate, block or destroy discrete areas of the nervous system. Here, we review just the drug treatments for neuropathic pain.     

TDM-based imipramine treatment in neuropathic pain

Tricyclic antidepressants (TCA) are the best-documented treatment of neuropathic pain. TCAs have a pronounced interindividual pharmacokinetic variability and a narrow therapeutic index. The aim of this study was to characterize the plasma concentration-effect relationship of imipramine in neuropathic pain and to determine the usefulness of therapeutic drug monitoring (TDM) of TCA treatment in a population with noncancer chronic pain. To do this, 83 patients with chronic noncancer neuropathic pain were included. Information on previous use of TCA was collected, and patients were tested for the presence of hyperalgesia. Pain intensity and pain relief were recorded, and the Short Form McGill Pain Questionnaire and Major Depression Inventory were completed before and during a TDM-based imipramine treatment. Imipramine dose was increased in steps of 25 mg/d every second week, and blood samples were taken at every dose. Endpoints were best possible pain relief, unacceptable side effects, or insufficient pain relief despite plasma drug level > 500 nmol/L. Dose range used was 10-300 mg/d. The study showed that imipramine 75 mg/d caused a 36-fold interindividual variation in steady-state plasma drug concentrations. In 46 responders (global pain relief > 25%) the plasma drug concentration at which an individual maximal analgesic effect was obtained ranged from 50 to 1400 nmol/L, but for the majority it was below 400 nmol/L. The concentration-effect relationship was similar for patients with central versus peripheral neuropathic pain and independent of the presence of hyperalgesia. Previous treatment failure with non-TDM TCA treatment was not a predictor of poor response to TDM-based treatment. In conclusion, there is a pronounced interindividual variability in concentration-effect relationship for imipramine treatment in neuropathic pain, but the majority of patients obtain a maximal analgesic effect at drug levels below 400 nmol/L. The concentration-effect relationship is similar for patients with central and peripheral neuropathic pain. Further studies are needed to document if TDM improves pain relief; however, TDM reduces the risk for toxicity.     

Current treatment options in neuropathic pain

Neuropathic pain results from damage to the nervous system due to many diverse processes. It causes persistent, distressing pain that is reputedly unresponsive to conventional analgesics. Treatment is best managed in a multi-therapy pain clinic setting and pharmacotherapy is one facet of this treatment. There is no single effective drug treatment and patients have been empirically treated with antidepressants and antiepileptics in the past. This review focuses on evidence from randomized controlled trials to assess the efficacy of the currently available drug treatments.     

Zucapsaicin for the treatment of neuropathic pain

Introduction: Neuropathic pain (NP) is a chronic disease that stems from a primary lesion or dysfunction of the central or peripheral nervous system. Zucapsaicin is a synthetic cis isomer of natural capsaicin that has shown therapeutic efficacy in pain accompanying osteoarthritis of the knee. It is also currently under investigation for the relief of severe pain in adults suffering from NP.

Areas covered: The authors provide an overview of the pharmacological properties of zucapsaicin based on available data from both preclinical and clinical trials. They also discuss its mechanism of action.

Expert opinion: The mechanism of action and clinical indications of zucapsaicin are similar to that of its naturally occurring isomer, capsaicin. However, in contrast to capsaicin, zucapsaicin is better tolerated. In the future, zucapsaicin could become a valuable drug for treating pain relief. Indeed, it is possible, in addition to providing NP relief, that it may have a use in treating osteoarthritic pain, headaches and pain that accompany intestinal diseases.     

神经病理性疼痛的药物治疗研究进展

神经病理性疼痛是一种神经系统损伤引起的慢性疼痛,严重影响患者的生活质量。药物治疗仍是现用治疗神经病理性疼痛的主要方法。本文综述了现用于治疗神经病理性疼痛主要药物的分子药理机制及其临床运用特点,并在总结疼痛的发生机制的基础上对靶向治疗药物的研发进行了展望。     

Pharmacological treatment of diabetic neuropathic pain

Neuropathic pain continues to be a difficult and challenging clinical issue to deal with effectively. Painful diabetic polyneuropathy is a complex pain condition that occurs with reasonable frequency in the population and it may be extremely difficult for clinicians to provide patients with effective analgesia. Chronic neuropathic pain may occur in approximately one of every four diabetic patients. The pain may be described as burning or a deep-seated ache with sporadic paroxysms of lancinating painful exacerbations. The pain is often constant, moderate to severe in intensity, usually primarily involves the feet and generally tends to worsen at night. Treatment may be multimodal but largely involves pharmacological approaches. Pharmacological therapeutic options include antidepressants (tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), α2δ ligands and topical (5%) lidocaine patch. Other agents may be different antiepileptic drugs (carbamazepine, lamotrigine, topiramate), topical capsaicin, tramadol and other opioids. Progress continues with respect to understanding various mechanisms that may contribute to painful diabetic neuropathy. Agents that may hold some promise include neurotrophic factors, growth factors, immunomodulators, gene therapy and poly (adenosine diphosphate-ribose) polymerase inhibitors. It is hoped that in the future clinicians will be able to assess patient pathophysiology, which may help them to match optimal therapeutic agents to target individual patient aberrant mechanisms.     

Antiepileptic drugs in neuroprotection

Antiepileptic drugs (AEDs) are designed to prevent and suppress seizure activity. Their effects on calcium influx and molecular cascades contributing to necrotic and apoptotic neuronal death, however, suggests that they have functions other than just suppression of excitability. The neuroprotective effects of 20 AEDs currently in use or being investigated in Phase II - III clinical trials for treatment of epilepsy are reviewed. Data analyses is complicated by several factors. Firstly, the available data on the neuroprotective effects of different AEDs varies largely. Secondly, most of the evidence demonstrating neuroprotective effects comes from stroke models and it is uncertain whether these data can be extrapolated to other conditions, such as status epilepticus (SE) or traumatic brain injury. Thirdly, data obtained in adult animals cannot be extrapolated to young animals without caution. For example, AEDs protecting adult brain from stroke or SE-induced injury can cause apoptosis in immature brain. Finally, data comparison is complicated by the variability in study designs and methodologies between studies. With these caveats in mind, an analysis of the available data suggests that AEDs with different mechanisms of action can have mild-to-moderate neuroprotective effects. It is difficult, however, to associate the neuroprotective effects with a favourable functional outcome. For example, it is difficult to conclude that administration of AEDs during the latency phase would have an effect on the molecular cascades underlying epileptogenesis. The few favourable data demonstrating a decrease in the incidence of epilepsy after SE are probably related to the administration of AEDs during SE, which resulted in modification/alleviation of the insult itself and consequently, reduced its epileptogenecity. These experimental data, however, are clinically important because they show that early intervention of SE has an effect on long-term functional outcome. These observations emphasise the need to use additional outcome measures, such as markers of normal development or cognitive performance, when the benefits of neuroprotection achieved by the use of neuroprotective AEDs are assessed.     

Antiepileptic drugs in the treatment of anxiety disorders: role in therapy

Pharmacotherapy for anxiety disorders is an active area of research. A variety of drug groups have been shown to be effective in treating many of the anxiety disorders, with selective serotonin reuptake inhibitors (SSRIs) being considered first-line agents for virtually all anxiety disorders. There is a clinical need for alternative drug treatments, as many patients do not achieve a complete response and experience significant adverse effects. The successful use of antiepileptic drugs in mood disorders has led clinicians and researchers to investigate their potential efficacy in other psychiatric disorders, particularly in anxiety disorders. There have been a number of investigations conducted in the form of case reports, case series and open-label trials, suggesting the potential usefulness of antiepileptic drug treatment in a variety of anxiety disorders. More reliable evidence for the use of antiepileptic drugs in anxiety disorders can be gleaned from recent placebo-controlled trials. Thus far, the strongest placebo-controlled evidence has demonstrated the efficacy of pregabalin in treating social phobia and generalised anxiety disorder, while smaller or less robust controlled trials have suggested the potential efficacy of gabapentin in social phobia, lamotrigine in post-traumatic stress disorder, and valproic acid in panic disorder. Antiepileptic drugs may have a place in the treatment of anxiety disorders; however, further investigation is warranted to determine in what circumstances they should be used as monotherapy or as augmenting agents in individuals who are partially or non-responsive to conventional therapy.     

Antiepileptic drugs in neuroprotection

Antiepileptic drugs (AEDs) are designed to prevent and suppress seizure activity. Their effects on calcium influx and molecular cascades contributing to necrotic and apoptotic neuronal death, however, suggests that they have functions other than just suppression of excitability. The neuroprotective effects of 20 AEDs currently in use or being investigated in Phase II – III clinical trials for treatment of epilepsy are reviewed. Data analyses is complicated by several factors. Firstly, the available data on the neuroprotective effects of different AEDs varies largely. Secondly, most of the evidence demonstrating neuroprotective effects comes from stroke models and it is uncertain whether these data can be extrapolated to other conditions, such as status epilepticus (SE) or traumatic brain injury. Thirdly, data obtained in adult animals cannot be extrapolated to young animals without caution. For example, AEDs protecting adult brain from stroke or SE-induced injury can cause apoptosis in immature brain. Finally, data comparison is complicated by the variability in study designs and methodologies between studies. With these caveats in mind, an analysis of the available data suggests that AEDs with different mechanisms of action can have mild-to-moderate neuroprotective effects. It is difficult, however, to associate the neuroprotective effects with a favourable functional outcome. For example, it is difficult to conclude that administration of AEDs during the latency phase would have an effect on the molecular cascades underlying epileptogenesis. The few favourable data demonstrating a decrease in the incidence of epilepsy after SE are probably related to the administration of AEDs during SE, which resulted in modification/alleviation of the insult itself and consequently, reduced its epileptogenecity. These experimental data, however, are clinically important because they show that early intervention of SE has an effect on long-term functional outcome. These observations emphasise the need to use additional outcome measures, such as markers of normal development or cognitive performance, when the benefits of neuroprotection achieved by the use of neuroprotective AEDs are assessed.     

Molecular approaches for neuropathic pain treatment

Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. It is estimated that 75-150 million people in the United States have a chronic pain disorder. Neuropathic pain has a great impact on the quality of life. It is debilitating and often has an associated degree of depression that contributes to decreasing human wellbeing. Moreover, the management of chronic pain is costly to the health care system. The United States Congress has declared the present decade (2001-2010) as the "Decade of Pain Control and Research", making pain a national healthcare priority. In Europe, statistics provided by the International Association on the Study of Pain (IASP) and the European Federation of the IASP Chapters (EFIC) indicate that one in five people suffer from moderate to severe chronic pain, and that one in three are unable or less able to maintain an independent lifestyle due to their pain. Between one-half and two-thirds of people with chronic pain are less able or unable to exercise, enjoy normal sleep, perform household chores, attend social activities, drive a car, walk or have sexual relations. The effect of pain means that one in four reports that relationships with family and friends are strained or broken, according to the IASP/EFIC data. Neuropathic pain treatment is extremely difficult. Neuropathic pain is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury. Current available drugs are usually not acting on the several mechanisms underlying the generation and propagation of pain. Nowadays, pain research is directing on new molecular methods, such as gene therapy, stem cell therapy and viral vectors for delivery of biologic antinociceptive molecules. These methods could provide a new therapeutic approach to neuropathic pain relief.     

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.