Opioids in chronic pain.

The advance in our understanding of the biogenesis of various endogenous opioid peptides, their anatomical distribution, and the characteristics of the multiple receptors with which they interact open a new avenue for understanding the role of opioid peptide systems in chronic pain. The main groups of opioid peptides: enkephalins, dynorphins and beta-endorphin derive from proenkephalin, prodynorphin and proopiomelanocortin, respectively. Recently, a novel group of peptides has been discovered in the brain and named endomorphins, endomorphin-1 and -2. They are unique in comparison with other opioid peptides by atypical structure and high selectivity towards the mu-opioid receptor. Another group, which joined the endogenous opioid peptide family in the last few years is the pronociceptin system comprising the peptides derived from this prohormone, acting at ORL1 receptors. Three members of the opioid receptor family were cloned in the early 1990s, beginning with the mouse delta-opioid receptor (DOR1) and followed by cloning of mu-opioid receptor (MOR1) and kappa-opioid receptor (KOR1). These three receptors belong to the family of seven transmembrane G-protein coupled receptors, and share extensive structural homologies. These opioid receptor and peptide systems are significantly implicated in antinociceptive processes. They were found to be represented in the regions involved in nociception and pain. The effects of opioids in animal models of inflammatory pain have been studied in great detail. Inflammation in the periphery influences the central sites and changes the opioid action. Inflammation increased spinal potency of various opioid receptor agonists. In general, the antinociceptive potency of opioids is greater against various noxious stimuli in animals with peripheral inflammation than in control animals. Inflammation-induced enhancement of opioid antinociceptive potency is characteristic predominantly for mu opioid receptors, since morphine elicits a greater increase in spinal potency of mu- than of delta- and kappa-opioid receptor agonists. Enhancement of the potency of mu-opioid receptor agonists during inflammation could arise from the changes occurring in opioid receptors, predominantly in affinity or number of the mu-opioid receptors. Inflammation has been shown to alter the expression of several genes in the spinal cord dorsal horn. Several studies have demonstrated profound alterations in the spinal PDYN system when there is peripheral inflammation or chronic arthritis. Endogenous dynorphin biosynthesis also increases under various conditions associated with neuropathic pain following damage to the spinal cord and injury of peripheral nerves. Interestingly, morphine lacks potent analgesic efficacy in neuropathic pain. A vast body of clinical evidence suggests that neuropathic pain is not opioid-resistant but only that reduced sensitivity to systemic opioids is observed in this condition, and an increase in their dose is necessary in order to obtain adequate analgesia. Reduction of morphine antinociceptive potency was postulated to be due to the fact that nerve injury reduced the activity of spinal opioid receptors or opioid signal transduction. Our recent study with endogenous ligands of the mu-opioid receptor, endomorphins, further complicates the issue, since endomorphins appear to be effective in neuropathic pain. Identification of the involved differences may be of importance to the understanding of the molecular mechanism of opioid action in neuropathic pain, as well as to the development of better and more effective drugs for the treatment of neuropathic pain in humans.     

Oxcarbazepine in neuropathic pain

Neuropathic pain is a frequent condition that can result from a variety of underlying conditions and is frequently chronic and difficult to treat. A number of drugs are used to treat neuropathic pain, including anticonvulsants and antidepressants. Oxcarbazepine, a recently introduced antiepileptic drug, was found to possess antineuralgic properties in animal models of neuropathic pain. Several double-blind, placebo-controlled trials have evaluated oxcarbazepine in painful diabetic neuropathy and trigeminal neuralgia. There is good evidence that oxcarbazepine is effective in relieving the pain associated with trigeminal neuralgia. Its efficacy in treating painful diabetic neuropathy is less clear; however, it seems to be useful when tolerated at doses of 1800 mg/day.     

Topical analgesics in neuropathic pain

Neuropathic pain can be difficult to treat clinically, as current therapies involve partial effectiveness and significant adverse effects. Following the development of preclinical models for neuropathic pain, significant advances have been made in understanding the neurobiology of neuropathic pain. This includes an appreciation of the molecular entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and the contribution of inflammation. Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available for treating neuropathic pain in humans. Preclinical studies provide evidence that peripheral applications of opioids, alpha-adrenergic agents, and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide support for topical applications of such agents. An appreciation of the ability of drug application, to sites remote from the site of injury, to alleviate aspects of neuropathic pain will provide a significant impetus for the further development of novel topical analgesics for this condition.     

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.     

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.     

Mechanisms of neuropathic pain

Neuropathic pain is a disease of global burden. Its symptoms include spontaneous and stimulus-evoked painful sensations. Several maladaptive mechanisms underlying these symptoms have been elucidated in recent years: peripheral sensitization of nociception, abnormal excitability of afferent neurons, central sensitization comprising pronociceptive facilitation, disinhibition of nociception and central reorganization processes, and sympathetically maintained pain. This review aims to illustrate these pathophysiological principles, focussing on molecular and neurophysiological findings. Finally therapeutic options based on these findings are discussed.     

Cannabinoids and neuropathic pain

After a brief overview of the endocannabinoid system (CB receptors, and endocannabinoids) and of the cannabinergic ligands, some general issues related to cannabinoids and pain are commented. Finally, the most important findings regarding cannabinoids and neuropathic pain are discussed in detail.     

Focus on topiramate in neuropathic pain

Topiramate is a drug that has shown efficacy in the treatment of epilepsy. A survey of MEDLINE, EMBASE and the American Academy of Neurology Abstracts reveals there is now evidence that topiramate is also effective in the treatment of neuropathic pain. The dose that has been studied ranges from 25 mg to 800 mg with a suggested dose of 400 mg daily. However, further randomized, double blind studies are needed to confirm this new use of topiramate and explore the proper dose and mechanism of action. Topiramate is conspicuous amongst the antiepileptic drugs for being well tolerated and having fewer drug interactions. Thus, it might offer an advantage over such drugs.     

Pharmacological strategies in relieving neuropathic pain

The pharmacological treatment of neuropathic pain relies, to a large extent, on drugs belonging to a small number of defined classes. Opioids, tricyclic antidepressants, antiepileptic drugs and membrane stabilisers form the current basis of treatment. Varying levels of evidence support the use of individual members of these classes and overall show no indication that one class of drug, or individual drug has universal effectiveness. More refined knowledge of the modes of action of these agents used to treat neuropathic pain should lead to a more logical approach to the management of this difficult series of conditions. A number of drugs currently licensed for a different indication have recently had an analgesic effect in neuropathic pain attributed to them. In addition, a number of novel compounds are undergoing investigation and provide hope of dicovering more efficacious treatment options in the future.     

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.     

Pharmacological strategies in relieving neuropathic pain

The pharmacological treatment of neuropathic pain relies, to a large extent, on drugs belonging to a small number of defined classes. Opioids, tricyclic antidepressants, antiepileptic drugs and membrane stabilisers form the current basis of treatment. Varying levels of evidence support the use of individual members of these classes and overall show no indication that one class of drug, or individual drug has universal effectiveness. More refined knowledge of the modes of action of these agents used to treat neuropathic pain should lead to a more logical approach to the management of this difficult series of conditions. A number of drugs currently licensed for a different indication have recently had an analgesic effect in neuropathic pain attributed to them. In addition, a number of novel compounds are undergoing investigation and provide hope of dicovering more efficacious treatment options in the future.     

Sodium channel blockers in neuropathic pain

Subtypes of tetrodotoxin resistant voltage-gated sodium channels are involved in the development of certain types of neuropathic pains. After nerve injury hyperexcitability and spontaneous firing develop at the site of injury and also in the dorsal root ganglion cell bodies. This hyperexcitability results at least partly from accumulation of sodium channels at the site of injury. The facts that these sodium channels seem to exist in peripheral nerves only and that they can be blocked at the resting state (use-dependent block) offer the possibility to develop drugs, which selectively block these damaged, overexcited nerves. At the moment no such drugs are available. However, some of the most potent drugs that are currently used to manage neuropathic pain e.g. amitriptyline and other tricyclic antidepressants, also block these channels in addition to having several other mechanisms of action. Also most anticonvulsants that are used to alleviate neuropathic pain are sodium channel blockers. Lidocaine, the prototype drug, has been shown to be effective in peripheral neuropathic pain. Its use is limited by the fact that it cannot be administered orally. An oral local anesthetic type sodium channel blocker, mexiletine is an antiarrhythmic agent that is effective in neuropathic pain. However, effective doses may be difficult to achieve because of adverse effects.     

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.     

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.