Retigabine: chemical synthesis to clinical application

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.     

The mechanism of action of gabapentin in neuropathic pain

Neuropathic pain is a common and potentially treatable cause of considerable lifelong morbidity. Effective pharmacological treatments are scarce, but one group of drugs that has shown promise is the antiepileptics. Gabapentin has become popular as a first-line treatment for neuropathic pain because of its efficacy as an antineuropathic agent and relatively benign side-effect profile. However, its mechanism of action is far from clear. This review discusses the available evidence for the postulated mechanisms of action of gabapentin. Understanding the mechanism of action of this agent may well lead to the development of safer and more effective antineuropathic drugs.     

Current management of pain associated with multiple sclerosis

While pain is a common problem in patients with multiple sclerosis (MS), it is not frequently mentioned by patients and a more direct approach is required in order to obtain information about pain from patients. Many patients with MS experience more than one pain syndrome; combinations of dysaesthesia, headaches and/or back or muscle and joint pain are frequent. For each pain syndrome a clear diagnosis and therapeutic concept needs to be established. Pain in MS can be classified into four diagnostically and therapeutically relevant categories: (i) neuropathic pain due to MS (pain directly related to MS); (ii) pain indirectly related to MS; (iii) MS treatment-related pain; and (iv) pain unrelated to MS. Painful paroxysmal symptoms such as trigeminal neuralgia (TN), or painful tonic spasms are treated with antiepileptics as first choice, e.g. carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin, etc. Painful 'burning' dysaesthesias, the most frequent chronic pain syndrome, are treated with TCAs such as amitriptyline, or antiepileptics such as gabapentin, pregabalin, lamotrigine, etc. Combinations of drugs with different modes of action can be particularly useful for reducing adverse effects. While escalation therapy may require opioids, there are encouraging results from studies regarding cannabinoids, but their future role in the treatment of MS-related pain has still to be determined. Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents such as baclofen or tizanidine and in patients with phasic spasticity, gabapentin or levetiracetam are administered. In patients with severe spasticity, botulinum toxin injections or intrathecal baclofen merit consideration. While physiotherapy may ameliorate malposition-induced joint and muscle pain, additional drug treatment with paracetamol (acetaminophen) or NSAIDs may be useful. Moreover, painful pressure lesions should be avoided by using optimally adjusted aids. Treatment-related pain associated with MS can occur with subcutaneous injections of interferon-beta or glatiramer acetate, and may be reduced by optimizing the injection technique and by local cooling. Systemic (particularly 'flu-like') adverse effects of interferons, e.g. myalgias, can be reduced by administering paracetamol, ibuprofen or naproxen. A potential increase in the frequency of pre-existing headaches after starting treatment with interferons may require optimization of headache attack therapy or even prophylactic treatment. Pain unrelated to MS, such as back pain or headache, is common in patients with MS and may deteriorate as a result of the disease. In summary, a careful analysis of each pain syndrome will allow the design of the appropriate treatment plan using various medical and nonmedical options (multimodal therapy), and will thus help to improve the quality of life (QOL) of the patients.     

中枢性卒中后疼痛治疗药物的研究进展

目的 探讨注射用丹参多酚酸联合阿托伐他汀治疗缺血性脑卒中合并冠心病的疗效及对患者血脂、血管内皮功能和炎症因子的影响。方法 回顾性纳入2018年6月—2020年6月于濮阳市安阳地区医院心内科收治的缺血性脑卒中合并冠心病患者124例,根据治疗方法不同将患者分为对照组和观察组,每组各62例。两组患者入院均采取抗血小板聚集、调脂、扩张冠状动脉、吸氧、控制脑水肿、降颅内压、改善微循环、维持水电解质平衡及保护脑神经等常规治疗。对照组在常规治疗基础上给予阿托伐他汀钙片,20 mg/次,每日1次;观察组在对照组基础上给予注射用丹参多酚酸0.13 g溶于250 mL0.9%氯化钠注射液中,静脉滴注,每日1次。两组治疗疗程均为14 d。比较两组临床疗效;对比治疗前与治疗14 d后两组患者日常生活能力（ADL）评分和美国国立卫生研究院卒中量表（NIHSS）评分、血脂、血管内皮功能相关指标和炎症因子的变化。结果 观察组总有效率（93.55%）显著高于对照组（70.97%）,组间差异显著（P<0.05）。治疗后两组ADL评分、高密度脂蛋白-胆固醇（HDL-C）水平、血清一氧化氮（NO）和血管内皮生长因子（VEGF）水平均较治疗前显著升高（P<0.05）,而NIHSS评分、低密度脂蛋白-胆固醇（LDL-C）、三酰甘油（TG）和总胆固醇（TC）水平、内皮素-1（ET-1）水平、肿瘤坏死因子α（TNF-α）、高敏C-反应蛋白（hs-CRP）和白细胞介素-6（IL-6）水平较治疗前显著降低（P<0.05）;观察组治疗14 d后ADL评分、HDL-C水平显著高于对照组（P<0.05）,而NIHSS评分、LDL-C、TG和TC水平均显著低于对照组（P<0.05）;观察组治疗14 d后血清NO和VEGF水平显著高于对照组（P<0.05）,而ET-1水平显著低于对照组（P<0.05）;观察组治疗14 d后血清TNF-α、hs-CRP和IL-6水平显著低于对照组（P<0.05）。结论 注射用多酚酸联合阿托伐他汀治疗缺血性脑卒中合并冠心病疗效良好,且可改善患者血脂紊乱及血管内皮功能紊乱状态,并减轻炎症反应。     

Pregabalin: new drug. Very similar to gabapentin

(1) The first-line treatment for partial epilepsy is carbamazepine monotherapy; gabapentin monotherapy is an alternative, given its lower risk of drug-drug interactions. (2) The standard treatment for neuropathic pain associated with diabetes or post-herpetic neuralgia is a tricyclic antidepressant, with gabapentin as an alternative. Few drugs are available in this setting, and their efficacy is often modest. (3) Pregabalin is a GABA analogue closely related to gabapentin. Both drugs are marketed by Pfizer. Pregabalin has been approved for use in two indications: refractory partial epilepsy and neuropathic pain. (4) In patients with partial epilepsy inadequately controlled by a combination of two or possibly three antiepileptics, three placebo-controlled double-blind trials lasting 12 weeks suggest that adjunctive pregabalin treatment, at a dose of 600 mg/day divided in two or three doses, at least halves the frequency of seizures in 50% of patients. Pregabalin has not been compared with other second-line antiepileptics. (5) In neuropathic pain, there are 12 double-blind placebo-controlled trials involving patients with diabetes or post-herpetic neuralgia. Depending on the trial, between one-third and one-half of patients treated with pregabalin at a dose of 600 mg/day given in two or three doses had at least a 50% reduction in their pain score. In the only trial that included a group treated with amitriptyline (75 mg/day), the latter was significantly more effective than placebo, while pregabalin was not. (6) There are no comparative trials of pregabalin after amitriptyline and gabapentin failure. (7) The adverse effects profile of pregabalin is similar to that of gabapentin, and includes mainly neuropsychological reactions (dizziness and drowsiness). (8) Pregabalin, like gabapentin, can lead to weight gain and peripheral oedema especially in elderly patients. (9) Cases of visual field restriction have been reported with pregabalin in clinical trials. Animal studies suggest a possible risk of haemangiosarcoma, although no human cases have yet been described. (10) Pregabalin, like gabapentin, is eliminated unchanged in urine, implying a limited risk of interactions involving cytochrome P450, and suggesting that the dose should be reduced in patients with even moderate renal failure (creatinine clearance below 60 ml/min). (11) In practice, pregabalin offers nothing new for patients with partial epilepsy, for whom several other antiepileptics are available. The few available treatments for neuropathic pain have limited efficacy, and pregabalin may therefore be tried when both tricyclics and gabapentin fail. However, it is in no way certain that pregabalin is effective in such patients, and comparative trials are lacking.     

Pharmacological management of neuropathic pain following spinal cord injury

Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain.     

Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy

Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. This property of the nervous system to adapt morphologically and functionally to external stimuli is known as neuroplasticity and plays a crucial role in the onset and maintenance of pain symptoms. Many similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the rational for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. The availability of newer anticonvulsants tested in higher quality clinical trials has marked a new era in the treatment of neuropathic pain. Gabapentin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. Based on the positive results of these studies and its favourable adverse effect profile, gabapentin should be considered the first choice of therapy for neuropathic pain. Evidence for the efficacy of phenytoin as an antinociceptive agent is, at best, weak to modest. Lamotrigine has good potential to modulate and control neuropathic pain, as shown in 2 controlled clinical trials, although another randomised trial showed no effect. There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.     

抗抑郁药用于疼痛治疗的研究进展

慢性痛或神经痛是一种临床综合征,常伴有抑郁障碍,严重影响患者生活质量.对于神经痛,常规镇痛药物、甚至麻醉性镇痛药经常无效,而抗抑郁药、抗精神病药和抗癫痫药物等则有效.本文综述了抗抑郁药用于镇痛的作用机制和不同类型的抗抑郁药在疼痛治疗中的应用,旨在为疼痛的临床治疗提供参考.     

Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models

BACKGROUND AND OBJECTIVE: Treatment of neuropathic pain remains a challenge and the role of various analgesics in this setting is still debated. The effects of tramadol, an atypically acting analgesic with a combined opioid and monoaminergic mechanism of action, and morphine, a prototypical opioid, were tested in rat models of neuropathic and nociceptive pain. METHODS: Cold allodynia and mechanical hypersensitivity, symptoms of neuropathic pain, were studied in rat models of mononeuropathic pain. Cold allodynia was analyzed in the chronic constriction injury (CCI) model and mechanical hypersensitivity was analyzed in the spinal nerve ligation (SNL) model. Heat-induced rat tail-flick latencies were determined as measure for nociceptive pain. RESULTS: Cold allodynia and mechanical hypersensitivity were strongly attenuated with similar absolute potency after intravenous administration of tramadol and morphine. The doses of drug that were calculated to result in 50% pain inhibition (ED(50)) for tramadol and morphine were 2.1 and 0.9 mg/kg, respectively, in CCI rats and 4.3 and 3.7 mg/kg, respectively, in SNL rats. In the tail-flick assay of acute nociception, the potency of the two drugs differed markedly, as seen by ED(50) values of 5.5 and 0.7 mg/kg intravenously for tramadol and morphine, respectively. Accordingly, the analgesic potency ratio (ED(50) tramadol/ED(50) morphine) of both compounds differed in neuropathic (potency ratio 2.3 in CCI and 1.2 in SNL) and nociceptive pain models (potency ratio 7.8), suggesting a relative increase in potency of tramadol in neuropathic pain compared with nociceptive pain. CONCLUSION: The results of this study are consistent with clinical data supporting the efficacy of opioids in neuropathic pain conditions, and furthermore suggest an additional contribution of the monoaminergic mechanism of tramadol in the treatment of neuropathic pain states.     

Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development

INTRODUCTION: Pain is a major burden for affected individuals and society, and controlling neuropathic pain is especially challenging. The number of drugs available is limited and treatments are often marginally effective and burdened by side effects. Voltage-gated calcium channels (VGCC) play a major role in the development and maintenance of neuropathic pain and are thus prime targets for its treatment. AREAS COVERED: Currently available drugs that target the calcium channel include ziconotide, gabapentin and pregabalin. While there are no VGCC blockers currently in clinical trials, there are many in development. Recently, orally available, use-dependent compounds have been reported. We will review, in detail, compounds currently in development and include a brief review of VGCC and the drugs currently in use. EXPERT OPINION: There is real hope that new drugs targeting calcium channels will soon be available. This hope is based on advancing technologies for peptide synthesis, more efficient drug screening and orally available, use-dependent compounds. Some form of direct VGCC blockade or modulation will always have a place in the treatment of neuropathic pain, but given the complexity and neuroplasticity of pain transmission, polypharmacy will likely be required for many chronic pain sufferers for the foreseeable future.     

Cardiovascular effects of chronic treatment with a β2-adrenoceptor agonist relieving neuropathic pain in mice

Neuropathic pain is often a chronic condition, disabling and difficult to treat. Using a murine model of neuropathic pain induced by placing a polyethylene cuff around the main branch of the sciatic nerve, we?have shown that chronic treatment with β-AR agonists is effective against neuropathic allodynia. β-mimetics are widely used against asthma and chronic obstructive pulmonary disease and may offer an interesting option for neuropathic pain management. The most prominent adverse effects of chronic treatment with β-mimetics are cardiovascular. In this study, we compared the action of low doses of the selective β(2)-AR agonist terbutaline and of a high dose of the mixed β(1)/β(2)-AR agonist isoproterenol on cardiovascular parameters in a neuropathic pain context. Isoproterenol was used as a positive control for some heart-related changes. Cardiac functions were studied by echocardiography, hemodynamic measurements, histological analysis of fibrosis and cardiac hypertrophy, and by quantitative real time PCR analysis of atrial natriuretic peptide (Nppa), periostin (Postn), connective tissue growth factor (Ctgf) and β-myosin heavy chain (Myh7). Our data show that a chronic treatment with the β(2)-AR agonist terbutaline at low antiallodynic dose does not affect cardiovascular parameters, whereas the mixed β(1)/β(2)-AR agonist isoproterenol induces cardiac hypertrophy. These data suggest that low doses of β(2)-AR agonists may provide a suitable treatment with rare side effects in neuropathic pain management. This study conducted in an animal model requires clinical confirmation in humans.     

Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes

The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood-brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.     

Ibudilast (AV-411)

The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood–brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.     

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

The large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 h without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA(B)-dependent mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunit-selective conotoxins are therefore promising tools for the effective treatment of neuropathic pain.     

CNS response to a thermal stressor in human volunteers and rats may predict the clinical utility of analgesics

fMRI was used to test the hypothesis that global brain activation following a stressor (a thermal stimulus) that activates multiple brain circuits in healthy subjects can predict which drugs have higher potential for clinical utility for neuropathic pain. The rationale is that a drug will modulate multiple neural circuits that are activated by the system‐specific stressor (e.g., pain). In neuropathic pain, some brain circuits have altered function, but most brain systems are “normal.” Thus, the manner in which a drug effect on neural circuits is modulated by the stressor may provide insight into the clinical utility based on the readout of brain activation in response to the stimulus. Six drugs with known clinical efficacy (or lack thereof) in treating neuropathic pain were selected and the CNS response to each drug in the presence or absence of a pain stimulus was examined. The present results suggest that it is possible to identify potentially effective drugs based on patterns of brain activation in healthy human subjects and indicate that CNS activity is a more sensitive measure of drug action than standard psychophysical measures of pain intensity. This approach was repeated in rats and showed that a similar fMRI paradigm segregates these drugs in a similar manner suggesting a potential “translational tool” in evaluating drug efficacy for neuropathic pain. The sensitivity of this paradigm using fMRI allows clinical screening in small groups of healthy subjects, suggesting it could become a useful tool for drug development as well as for elucidating the mechanisms of neuropathic disease and therapy. Drug Dev. Res. 68:23–41, 2007. © 2007 Wiley‐Liss, Inc.     

Ziconotide infusion for severe chronic pain: case series of patients with neuropathic pain

Ziconotide intrathecal infusion was recently approved by the United States Food and Drug Administration for the treatment of intractable severe chronic pain. Patients with neuropathic pain make up a significant population among those who experience chronic pain for which there are less than optimal pharmacotherapeutic options. Published clinical trials provide a global view of ziconotide efficacy and safety. A subset of patients in clinical trials obtained complete pain relief, a remarkable finding given the history of drug treatment for neuropathic pain. To provide more information regarding those who respond to ziconotide therapy, we discuss three patients with neuropathic pain who received ziconotide infusion. Two patients with longstanding neuropathic pain, one with complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) of the leg and one with lumbar radiculitis, achieved temporary but complete pain relief from single 5- and 10-microg epidural test doses. In the third case, a patient with longstanding bilateral leg and foot neuropathic pain from acquired immunodeficiency syndrome and antiretroviral drug therapy achieved considerable pain relief from a long-term continuous intrathecal infusion. The patients who received a single dose had mild central nervous system adverse effects such as sedation, somnolence, nausea, headache, and lightheadedness. The patient who received the intrathecal infusion experienced mild-to-severe adverse effects depending on the rate of infusion; these effects included sedation, confusion, memory impairment, slurred speech, and double vision. This patient could sense impending adverse effects and made rate adjustments or suspended infusion to avert untoward symptoms. In all three cases, patients achieved considerable pain relief that was long-lasting and persisted well after dose administration or suspension of infusion.     

Combination therapy for neuropathic pain: a review of current evidence

Neuropathic pain is a debilitating chronic condition that remains very difficult to treat. Recently, a number of clinical studies have compared the effectiveness of combination drug therapy with monotherapy for neuropathic pain treatment. In this article, we summarize up-to-date clinical studies of combination therapy for the treatment of both cancer- and non-cancer-related neuropathic pain. Despite a relatively small number of clinical studies on this topic, several positive indications have emerged. First, clinical studies using gabapentin (five positive trials) and pregabalin (five positive trials and one negative trial) in combination with an opioid, cyclo-oxygenase-2 inhibitor or antidepressant have shown positive responses greater than the respective monotherapies for pain related to diabetic neuropathy and postherpetic neuropathy. Second, high-concentration (8%) topical capsaicin and a 5% lidocaine patch seem to be effective add-on therapies (a modality of combination therapy) for various neuropathic pain conditions. Third, combination therapy for cancer-related neuropathic pain has yielded only limited success based on a number of small-scale clinical studies. While there are benefits of using combination therapy for neuropathic pain treatment, including better pain relief and reduced adverse effects, more clinical studies are required in order to (i) make head-to-head comparisons between combination and single-drug therapies, (ii) identify symptom-specific combination therapies for distinctive clinical neuropathic pain conditions, (iii) explore combination therapies that include non-drug modalities such as physical therapy, psychological coping and biofeedback to facilitate functional restoration and (iv) develop new and objective evaluation tools for clinical outcome assessment.     

Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation

Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP) results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in itself. The prevalence of NP is estimated to be between 6.9% and 10% in the general population. This condition can complicate the recovery from stroke, multiple sclerosis, spinal cord lesions, and several neuropathies promoting persistent disability and poor quality of life. Subjects suffering from NP describe it as burning, itching, lancing, and numbness, but hyperalgesia and allodynia represent the most bothersome symptoms. The management of NP is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits. Botulinum toxin (BTX) as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people. Although BTX-A is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP. The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization. Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment. This paper addresses the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and painful diabetic neuropathy, which are commonly managed in a rehabilitation setting. Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders including post-traumatic neuralgia, phantom limb, and complex regional pain syndrome with focal dystonia. The use of BTX-A could represent a novel therapeutic strategy in caring for neuropathic pain whenever common pharmacological tools have been ineffective. However, large and well-designed clinical trials are needed to recommend BTX-A use in the relief of neuropathic pain.     

Pharmacological management of neuropathic pain

In health, the nervous system exists in a balance between inhibitory and excitatory influences. This balance may be upset if neural tissue is damaged or irritated and may give rise to neuropathic pain. Such neuropathic pain does not respond consistently to opioid analgesics or NSAIDs and it may therefore be necessary to utilise other therapeutic agents with known activity on either the excitatory or inhibitory components of the pain pathway. These other agents are traditionally considered with reference to their original uses; we still refer to tricyclic antidepressants (TCAs) and anticonvulsant drugs when a consideration of their modes of action may allow more rational use. For example, carbamazepine is related to the TCAs by virtue of its chemical structure and proposed mode of action and yet is still classified as an anticonvulsant drug. With respect to the opioids, increasing evidence points to an analgesic effect in neuropathic pain, although concerns regarding tolerance and dependence still prevent more widespread use. The anticonvulsants comprise a group of compounds possessing anticonvulsant and analgesic properties, but each possesses differing modes of action and so several members of the class should be tried before a conclusion is reached that they, as a whole, are ineffective. TCAs may also have a role in the treatment of neuropathic pain. As with all drugs, if their use is not associated with pain relief in a defined period of time, their use should be terminated. Topical TCAs may also have a role where the area of neuropathic pain is small. Other options, such as SSRIs, membrane stabilisers, capsaicin, baclofen and clonidine may have potential in treating neuropathic pain. The available evidence regarding the efficacy of currently available agents for the treatment of neuropathic pain is sparse. With the knowledge of achieving analgesia, according to the modes of actions of various agents it is hoped that the treatment of this difficult condition may be more logical and successful.     

HCN2 ion channels: an emerging role as the pacemakers of pain

Acute nociceptive pain is caused by the direct action of a noxious stimulus on pain-sensitive nerve endings, whereas inflammatory pain (both acute and chronic) arises from the actions of a wide range of inflammatory mediators released following tissue injury. Neuropathic pain, which is triggered by nerve damage, is often considered to be very different in its origins, and is particularly difficult to treat effectively. Here we review recent evidence showing that members of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channel family - better known for their role in the pacemaker potential of the heart - play important roles in both inflammatory and neuropathic pain. Deletion of the HCN2 isoform from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, but acute pain sensation is unaffected. This work shows that inflammatory and neuropathic pain have much in common, and suggests that selective blockers of HCN2 may have value as analgesics in the treatment of pain.