Antidepressants in chronic neuropathic pain

This review presents available clinical studies and new insights into mechanisms of analgesic effect and possible new routes of administration of antidepressant drugs. Older TCAs continue to be superior treatments. We focused on recent findings on newer antidepressants as analgesics. Their use should be supported by further controlled trials.     

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.     

Antiepileptic drugs in the treatment of neuropathic pain

Antiepileptic drugs are an effective treatment for various forms of neuropathic pain of peripheral origin, although they rarely provide complete pain relief. Multiple multicentre randomised controlled trials have shown clear efficacy of gabapentin and pregabalin for postherpetic neuralgia and painful diabetic neuropathy. Theses drugs can be rapidly titrated and are well tolerated. Topiramate, lamotrigine, carbamazepine and oxcarbazepine are alternatives for the treatment of painful diabetic neuropathy, but should be titrated slowly. Carbamazepine remains the drug of choice for trigeminal neuralgia; however, oxcarbazepine and lamotrigine are potential alternatives.There is an apparent need for large-scale randomised controlled trials on the efficacy of antiepileptic drugs in neuropathic pain in general, and in cancer-related neuropathic pain and neuropathic pain of central origin in particular. Trials with long-term follow-up are required to establish the long-term efficacy of antiepileptic drugs in neuropathic pain. There is only limited scientific evidence to support the idea that drug combinations are likely to be more efficacious and safer than each drug alone; further studies are warranted in this area.     

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.     

Antidepressants in pain management

Antidepressants exhibit a number of pharmacological mechanisms, including norepinephrine and serotonin modulation, direct and indirect effects on opioid receptors, inhibition of histamine, cholinergic and N-methyl-D-aspartate receptors, and inhibition of ion channel activity. Although it is not entirely clear which mechanisms produce analgesia and to what extent, the available animal and clinical trials data indicates that tricyclic antidepressants are effective in treating many types of pain. The newer selective serotonin reuptake inhibitors also appear to be effective for chronic headache and other non-neuropathic forms of chronic pain but are not as well studied. This article reviews the current basic and clinical research on antidepressants in pain management.     

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.     

Antidepressants and pain

Tricyclic antidepressants, together with anticonvulsants, are considered to be first-line drugs for the treatment of neuropathic pain. Antidepressants are analgesic in patients with chronic pain and no concomitant depression, indicating that the analgesic and antidepressant effects occur independently. The analgesia induced by these drugs seems to be centrally mediated but consistent evidence also indicates a peripheral site of action. Several pharmacological mechanisms account for their antinociceptive effect but the inhibition of monoamine transporters (and, consequently, the facilitation of descending inhibition pain systems) is implicated on the basis of mechanistic and knockout-mouse studies. However, pain is a common symptom of depression, and depression is frequent in chronic pain patients, supporting the hypothesis that pain and depression share some common biochemical mechanisms. We suggest that antidepressants have a genuine analgesic effect and that research into their mechanisms of action will help to facilitate the development of new drugs.     

Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes

Irritable bowel syndrome (IBS) is characterized by abdominal pain associated with disordered defecation, which may include urgency and altered stool frequency. Visceral pain syndromes, including IBS, may be effectively treated by a variety of therapies that modulate the interactions between the central and enteric nervous systems. Clinical observations and preliminary data suggest that antidepressants may be efficacious for the treatment of these syndromes. The tricyclic antidepressants (TCAs) have been utilized most extensively in this area, but there is a need for more rigorous efficacy data. Serotonin, an important neurotransmitter in both the central and enteric nervous systems, modifies both motility and sensation in the gut. Recognition of the importance of serotonin in digestive motility and sensation has sparked interest in the use of agents that modify serotonergic transmission in visceral pain syndromes. Pharmacological therapeutics that modulate the biological amines (serotonin, norepinephrine, dopamine and catecholamines) both peripherally and within the central nervous system may offer more effective therapies for these disorders. The selective serotonin reuptake inhibitors are commonly used in clinical practice, but more rigorous, controlled studies are needed to determine their effects beyond the treatment of psychiatric comorbidity. The newer generation antidepressants may provide additional insight into the pathophysiology of the brain-gut interactions and their relationship to functional bowel disorders, providing new therapeutic interventions.     

Novel sodium channel antagonists in the treatment of neuropathic pain

Introduction: Effective and safe drugs for the treatment of neuropathic pain are still an unmet clinical need. Neuropathic pain, caused by a lesion or disease that affects the somatosensory system, is a debilitating and hampering condition that has a great economic cost and, above all, a tremendous impact on the quality of life. Sodium channels are one of the major players in generating and propagating action potentials. They represent an appealing target for researchers involved in the development of new and safer drugs useful in the treatment of neuropathic pain. The actual goal for researchers is to target sodium channels selectively to stop the abnormal signaling that characterizes neuropathic pain while leaving normal somatosensory functions intact.

Areas covered: This review covers the most recent publications regarding sodium channel blockers and their development as new treatments for neuropathic pain. The main areas discussed are the natural sources of new blockers, such as venom extracts and the recent efforts from many pharmaceutical companies in the field.

Expert opinion: There have been serious efforts by both the pharmaceutical industry and academia to develop new and safer therapeutic options for neuropathic pain. A number of different strategies have been undertaken; the main efforts directed towards the identification of selective blockers starting from both natural products or screening chemical libraries. At this time, researchers have identified and characterized selective compounds against Na_V1.7 or Na_V1.8 voltage-gated sodium channels but only time will tell if they reach the market.     

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.     

Management strategies for the treatment of neuropathic pain in the elderly

Pain caused by dysfunction or damage to the peripheral or central nervous system is typified by the symptoms described by patients with painful diabetic neuropathy, post-herpetic neuralgia and central poststroke pain. All these conditions are more common in the elderly. Neuropathic pain has long been recognised as one of the more difficult types of pain to treat; however, with the current emphasis on providing a multidisciplinary assessment and approach to management, more patients will be offered relief of their symptoms and an improved quality of life. Despite the use of combination drug therapy, adequate pain relief in the elderly is difficult to achieve without adverse effects. In an attempt to minimise these it is important to include non-drug treatment options in the management plan. Lifestyle changes and environmental modification, together with encouragement to adopt an appropriate exercise programme and an emphasis on maintaining mobility and independence should always be considered. Interventional therapy ranging from simple nerve blocks to intrathecal drug delivery can be of value. Drug treatment remains the mainstay of therapy. Tricyclic antidepressants such as amitriptyline, while having significant adverse effects in the elderly, have a number needed to treat (NNT) of 3.5 for 50% pain relief in diabetic neuropathy and 2.1 for 50% pain relief in postherpetic neuralgia. The newer antiepileptic drugs, such as gabapentin, appear to have a better adverse effect profile and provide similar efficacy with the NNT for treating painful diabetic neuropathy being 3.7 and 3.2 for treating pain in postherpetic neuralgia. As our understanding of the complexities of the pain processes increases, we are becoming more able to appropriately combine treatments to achieve not only improved pain relief but also improved function.     

Mechanism-based treatment in chronic neuropathic pain: the role of antidepressants

Antidepressant drugs have been widely used for many years to treat neuropathic pain, despite the rationale for their use was still unclear. We review recent insights into their mechanism of action, focusing on central and peripheral analgesic actions. Beside the traditional monoaminergic hypothesis, other pharmacological actions have been studied: antidepressants interfere with the opioid system, interact with the NMDA receptors, and inhibit ion channel activity. Firm evidence from randomised controlled trials demonstrated that TCAs are the most effective drugs for treatment of different neuropathic pain conditions. They exhibit the lowest number needed to treat compare with all other drugs investigated. SSRIs failed to provide an adequate analgesia, due to their high selectivity. SSRIs are clearly less effective than TCAs (NNT: 6.7 vs 2.4) supporting the hypothesis that a balanced inhibition of noradrenaline and serotonin reuptake is more effective in relieving pain. On the basis of initial results Venlafaxine seems to be the most promising of the newer antidepressants as analgesic. Newer antidepressants show a better side effects profile, but further investigation are warranted to clarify their potential role in management of pain. Neuropathic pain remains a challenging condition to treat, as all currently available drugs fail to achieve adequate pain relief in a significant proportion of patients. TCAs should be currently considered the first choice in treatment of neuropathic pain and the gold standard against which to compare other potential new treatments.     

Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain

Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-D-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects.     

Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain

Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-d-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects.     

Antidepressants in the management of chronic pain syndromes

Conditions in which antidepressants have been used include diabetic neuropathy, postherpetic neuralgia, headaches, arthritis, chronic back pain, cancer, thalamic pain, facial pain, and phantom limb pain. Although much of the available information is derived from inadequately controlled trials, it seems that antidepressants provide analgesia in many of these disorders. The analgesic effects tend to be independent of antidepressant effects, and doses of heterocyclic antidepressants used for analgesia seem to be lower than those considered effective in the treatment of depression. Doses should be started low and gradually increased until the patient reaches the highest tolerable dose. Onset of analgesia is variable, ranging from 1 day to 10 weeks. Common side effects include dry mouth, drowsiness, urinary retention, orthostatic hypotension, and constipation. Optimum dosages and schedules have not been established.