Prävalenz und Charakteristik neuropathischer Schmerzen bei malignen Erkrankungen

Neuropathic pain is one of the problem areas in the management of cancer pain. In a retrospective study, prevalence and characteristics of neuropathic pain in 1318 cancer patients attending a pain clinic were examined. Of the patients, 135 suffered from neuropathic, 285 from neuropathic and nociceptive, 890 from nociceptive and 8 from unknown pain conditions. Among the patients with neuropathic pain 62% rated the pain intensity as very sincere; this was so in 48% of those with nociceptive pain. Neuropathic pain was caused by direct tumour involvement (nerve compression or infiltration) in 71%, by oncological treatment (surgery, chemotherapy, radiation) in 15%, by debilitating disease (e.g. herpes zoster) in 6% and by factors unrelated to cancer or its treatment in 8% of the patients. Of 110 clinically analysed neuropathic pain conditions, 44% were neuralgic, 31% radicular, 13% sympathically maintained, and 10% caused by deafferentiation, while in 3% the nature was unknown. To evaluate the efficacy of cancer pain treatment, nocicepetive pain has to be differentiated from neuropathic pain. In addition to this, neuropathic pain has to be divided into subgroups.     

鼠神经生长因子联合加巴喷丁治疗外周神经损伤后神经病理性疼痛

目的:观察鼠神经生长因子联合加巴喷丁治疗外周神经损伤性神经病理性疼痛的疗效。方法:16例外周神经损伤术后神经病理性疼痛患者,经非甾体类药物和或阿片类药物治疗后疼痛无明显缓解甚至加重。应用鼠神经生长因子联合加巴喷丁进行治疗,观察疼痛视觉模拟评分(visual analoguescale,VAS)、疼痛种类及睡眠时间变化情况。结果:所有患者疼痛评分、疼痛性质的种类明显减少,睡眠时间增加。结论:早期使用鼠神经生长因子联合加巴喷丁治疗神经损伤后神经病理性疼痛患者,可以很好缓解疼痛,改善睡眠质量。     

Mechanism-based pharmacotherapy for cancer pain

Cancer pain is usually treated by 1) pharmacotherapy, 2) nerve block, 3) radiation therapy, 4) cognitive therapy and 5) alternative medicine. Among these methods, pharmacotherapy is the simplest way to relieve cancer pain without special equipment or special settings. WHO cancer treatment guideline shows morphine is effective to most cancer pain. However, 10-20% of the patients' pain is refractory to morphine. A majority of such refractory pain is due to nerve injury caused by cancer itself or by treatment. Recently, many biological processes involved in the mechanism of neuropathic pain have been elucidated. Pharmacological treatment aimed at blocking such processes should produce specific effects on the pain. Such mechanism-based pharmacotherapy is the most effective way to treat difficult pain.     

Acute neuropathic pain after surgery: Are we treating them early/late?

Acute neuropathic pain (ANP) is now recognised as a cause of post surgical pain. We describe an 80 year old female who presented with sciatic nerve injury following a total hip replacement surgery. Clinical presentation included acute neuropathic pain, numbness, paraesthesia and foot drop. Symptoms and signs of nerve injury and pain were confirmed by neurophysiological studies to be due to a proximal sciatic nerve lesion. Its aetiology, pathogenesis, diagnosis and pharmacotherapy is discussed.In conclusion, we had a patient who demonstrated acute post operative neuropathic pain in combination with post surgical nociceptive pain after hip surgery. ANP responded well to Amitriptyline and Gabapentin. Early diagnosis and treatment with antineuralgics is recommended to prevent progression to chronic post operative neuropathic pain.However, clinical trials are required to confirm efficacy of these treatments in acute neuropathic pain.     

The evidence for pharmacological treatment of neuropathic pain

Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.     

A mouse model of neuropathic cancer pain

We developed a mouse model of neuropathic cancer pain by inoculating Meth A sarcoma cells to the immediate proximity of the sciatic nerve in BALB/c mice. The tumor grows predictably with time and gradually compresses the nerve, thereby causing nerve injury. Time courses of thermal hyperalgesia and mechanical sensitivity to von Frey hairs were determined and signs of spontaneous pain were evaluated. We compared this model with the chronic constriction injury (CCI) model, which is a neuropathic pain model widely utilized in the rat. Furthermore, to characterize the difference in nerve injury between the two models, we performed histological examination of the nerve of the two models by light and electron microscopy. Progressive compression of the sciatic nerve by growth of a tumor mass resulted in a gradual development of thermal hyperalgesia and mechanical allodynia in the ipsilateral hind paw. Signs of spontaneous pain, such as lifting of the paw, were also observed. However, further growth of the tumor reversed the mechanical hypersensitivity and produced mechanical hyposensitivity, while thermal hyperalgesia and signs of spontaneous pain still persisted. Histologically, gradual compression by the tumor resulted in a progressive damage to both myelinated and unmyelinated fibers. However, the severity of damage to the myelinated fibers was considerably less compared to that of the CCI mice. In the CCI mice, severe damage to myelinated fibers, especially large fibers, was observed and unmyelinated fibers were damaged to a lesser degree. These results suggest that gradual compression of a nerve by a malignant tumor results in nerve damage with a profile considerably different from that of chronic constriction injury produced by loose ligation of the nerve. Our new tumor model may be useful in studies of neuropathic cancer pain due to nerve compression by malignant tumors.     

Neural Modulation by Blocks and Infusions

Abstract:   Neural blockade is widely used in clinical practice to alleviate acute or chronic pain, including neuropathic pain. However, to date there is little controlled evidence to confirm the efficacy of nerve blocks in neuropathic pain. The most common indication for nerve blocks, especially sympathetic blockade, is complex regional pain syndrome, in which success rates of up to 38% have been achieved, depending on the type of the block used. Greater efficacy has been achieved by combining a nerve block with patient-controlled analgesia. Sympathectomy is recommended for the treatment of neuropathic pain only after careful consideration of its usefulness, effectiveness, and risk of adverse effects. Current evidence and clinical experience suggest that neural blockade could be a useful adjunct in the management of refractory neuropathic pain, but further well-controlled studies would be of great benefit to support this type of therapy.     

Chronic blockade of interleukin‐1 (IL‐1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury

Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL‐1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL‐1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL‐1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle‐treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1±1.1% of the axons); whereas IL‐1ra‐treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8±0.4% of the axons). To test whether IL‐1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL‐1ra four days following SNT, after the allodynic response was already manifested. Whereas saline‐treated mice displayed robust allodynia, acute IL‐1ra treatment induced long‐lasting attenuation of the allodynic response. The results support our hypothesis that IL‐1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.     

Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: A potential biomarker of efficacy

Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms.     

我国癌症病人的疼痛和生活质量的初步调查

１９９２年我们对我国癌症病人疼痛和生活质量组织了三省市１１单位的前瞻性调查。在１５４３例各类癌症患者中，有７８９例（５１．１％）伴有不同程度的疼前。早、中晚期患者伴有疼痛分别为３０％，５０．６％和６６．４％。在所有伴有疼痛的患者中直接由肿瘤本身引起的占７８．６％，其它原因仅占２０％左右，其中伴有两种以上原因的为６．７％。对癌症类型、疼痛性质和部位也作了分析。在３８６例有远处转移的病人中伴有疼痛的为     

The role of tramadol in cancer pain treatment—a review

In most cancer patients pain can be successfully treated with pharmacological measures using opioid analgesics alone or in combination with adjuvant analgesics (coanalgesics). Weak opioids are usually recommended in the treatment of moderate cancer pain. There is still a debate as to whether the second step of the WHO analgesic ladder comprising opioid analgesics such as tramadol, codeine, dihydrocodeine, and dextropropoxyphene is still needed for the treatment of cancer pain. On the basis of our experience and review of the literature we think that there is definitely a place for weak opioids in the treatment of moderate cancer pain. One of the most interesting and useful weak opioids is tramadol (Adolonta, Contramal, Nobligan, Top-Algic, Tramal, Tramal Long, Tramal Retard, Tramundin, Trodon, Ultram, Zydol). Its unique mechanism of action, analgesic efficacy and profile of adverse reactions have been the reason of performing many experimental and clinical studies with tramadol. In this article we summarize data on pharmacology, mechanisms of action, pharmacokinetics, side effects and clinical experience assessing analgesic efficacy, adverse reactions and safety of tramadol in cancer pain.     

Increased HCN Channel Activity in the Gasserian Ganglion Contributes to Trigeminal Neuropathic Pain

Orofacial neuropathic pain caused by trigeminal nerve injury is a debilitating condition with limited therapeutic options. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are involved in the development and maintenance of chronic pain. However, the effect of HCN channel activity in the Gasserian ganglion on trigeminal neuropathic pain has not been examined. We evaluated nociceptive behaviors after microinjection of the HCN channel blockers ZD7288 or ivabradine into the Gasserian ganglion in rats with trigeminal nerve injury. Both blockers dose-dependently ameliorated evoked and spontaneous nociceptive behavior in rats with trigeminal neuropathic pain. Moreover, the clinically available HCN channel blocker ivabradine showed a prolonged antinociceptive effect. In the Gasserian ganglion, HCN1 and HCN2 are major HCN isoforms. After trigeminal nerve injury, the counts of HCN1 as well as HCN2 immuno-positive punctae were increased in the ipsilateral Gasserian ganglions. These results indicate that the increased HCN channel activity in the Gasserian ganglion directly contributes to neuropathic pain resulting from trigeminal nerve injury.

Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review

Pain in cancer patients remains common and is often associated with insufficient prescribing of targeted analgesia. An explanation for undertreatment could be the failure to identify neuropathic pain mechanisms, which require additional prescribing strategies. We wanted to identify the prevalence of neuropathic mechanisms in patients with cancer pain to highlight the need for detailed assessment and to support the development of an international classification system for cancer pain. We searched for studies that included adult and teenage patients (age above 12 years), with active cancer and who reported pain, and in which a clinical assessment of their pain had been made. We found 22 eligible studies that reported on 13,683 patients. Clinical assessment methods varied, and only 14 studies reported confirmatory testing for either sensory abnormality or diagnostic lesion to corroborate a diagnosis of neuropathic pain. We calculated that the prevalence of patients with neuropathic pain (95% confidence interval) varied from a conservative estimate of 19% (9.4% to 28.4%) to a liberal estimate of 39.1% (28.9% to 49.5%) when patients with mixed pain were included. The prevalence of pain with a neuropathic mechanism (95% confidence interval) ranged from a conservative estimate of 18.7% (15.3% to 22.1%) to a liberal estimate of 21.4% (15.2% to 27.6%) of all recorded cancer pains. The proportion of pain caused by cancer treatment was higher in neuropathic pain compared with all types of cancer pain. A standardised approach or taxonomy used for assessing neuropathic pain in patients with cancer is needed to improve treatment outcomes.     

Topical analgesics for neuropathic pain: Preclinical exploration,clinical validation,future development

Topical analgesics applied locally to skin or to specialized compartments modify pain by actions on sensory nerve endings and/or adjacent cellular elements. With this approach, there are low systemic drug levels, good tolerability and few drug interactions, and combination with oral formulations is feasible. The goal of this review is to provide an overview of the potential for topical analgesics to contribute to improved management of neuropathic pain. Mechanistic and preclinical studies indicate much potential for development of novel topical analgesics for neuropathic pain. In humans, two topical analgesics are approved for use in post‐herpetic neuralgia (lidocaine 5% medicated plaster, capsaicin 8% patch), and there is evidence for efficacy in other neuropathic pain conditions. Comparative trials indicate similar efficacy between topical and oral analgesics. Not all individuals respond to topical analgesics, and there is interest in determining factors (patient factors, sensory characteristics) which might predict responsiveness to topical analgesics. There is a growing number of controlled trials and case reports of investigational agents (vasodilators, glutamate receptor antagonists, α2‐adrenoreceptor agonists, antidepressants, centrally acting drugs), including combinations of several agents, indicating these produce pain relief in neuropathic pain. There is interest in compounding topical analgesics for neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of neuropathic pain.     

The evaluation of neuropathic components in low back pain

Chronic low back pain is highly prevalent in Western societies. Large epidemiological studies show that 20% to 35% of patients with back pain suffer from a neuropathic pain component. Presently, chronic lumbar radicular pain is the most common neuropathic pain syndrome. The pathophysiology of back pain is complex and nociceptive, and neuropathic pain-generating mechanisms are thought to be involved, which established the term mixed pain syndrome. Neuropathic pain may be caused by lesions of nociceptive sprouts within the degenerated disc (local neuropathic), mechanical compression of the nerve root (mechanical neuropathic root pain), or by action of inflammatory mediators (inflammatory neuropathic root pain) originating from the degenerative disc even without any mechanical compression. Its diagnosis and management remain an enigma, mainly because there is no gold standard for either. Accuracy of diagnostic tests used to identify the source of back pain and their usefulness in clinical practice, particularly for guiding treatment selection, is unclear. In connection with the specific instance of back pain (one of the single most costly disorders in many industrialized nations), neuropathic pain components are a significant cost factor.     

Modality of hyperalgesia tested,not type of nerve damage,predicts pharmacological sensitivity in rat models of neuropathic pain

Although many types of nerve damage can cause neuropathic pain, there are substantial commonalities in neuropathic pain symptoms, and patients can be divided into sub‐groups based on their symptom profile rather than etiology. Mechanism‐based treatment suggests that pharmacotherapy should be chosen be based shared commonalities of symptoms rather than etiology. The aim of the present study was to determine whether type of injury (etiology) or behavioral endpoint (symptom) is a better predictor of pharmacological responsivity in the most commonly used rodent models of neuropathic pain. We used the chronic constriction injury (CCI) model to directly compare the temporal and pharmacological characteristics of four different types of evoked stimuli; heat, pressure, acetone cooling and punctate mechanical. We then compared heat hyperalgesia and mechanical allodynia endpoints across etiologies using the spinal nerve ligation (SNL) model. Evoked pain responses in both models had strikingly different temporal characteristics. We then tested three standard therapies for neuropathic pain from different drug classes, oxycodone, gabapentin, and amitriptyline. Notably, regardless of the model tested, or the time of onset, common endpoints showed near‐identical pharmacological responses, and not all endpoints were equally sensitive to drug intervention within one model. Hypersensitivity to heat and pressure were highly responsive to oxycodone, gabapentin, and amitriptyline; whereas cold and mechanical allodynia were more difficult to reverse. Moreover, CCI‐ and SNL‐induced mechanical allodynia was completely insensitive to amitriptyline treatment. We conclude that regardless of model and time course of presentation, different symptoms of peripheral neuropathy have unique pharmacological responses.     

Continuous intravenous infusion of ketamine and lidocaine as adjuvant analgesics in a 5-year-old patient with neuropathic cancer pain

For difficult to treat neuropathic pain from cancer, adjuvant analgesics are often used with opioids. We present the case of a 5-year-old girl who was diagnosed with meningitis caused by malignant T-cell lymphoma. She had severe neuropathic pain not relieved by increasing doses of a fentanyl infusion. Intravenous administration of ketamine and lidocaine in combination with fentanyl provided excellent analgesia without significant side effects. Ketamine and lidocaine can be safely infused together with concomitant opioids for the treatment of refractory neuropathic pain caused by cancer.     

Pharmacological Treatment of Neuropathic Cancer Pain: A Comprehensive Review of the Current Literature

Abstract: Neuropathic cancer pain (NCP), commonly encountered in clinical practice, may be cancer‐related, namely resulting from nervous system tumor invasion, surgical nerve damage during tumor removal, radiation‐induced nerve damage and chemotherapy‐related neuropathy, or may be of benign origin, unrelated to cancer. A neuropathic component is evident in about 1/3 of cancer pain cases. Although from a pathophysiological perspective NCP may differ from chronic neuropathic pain (NP), such as noncancer‐related pain, clinical practice, and limited publications have shown that these two pain entities may share some treatment modalities. For example, co‐analgesics have been well integrated into cancer pain‐management strategies and are often used as First‐Line options for the treatment of NCP. These drugs, including antidepressants and anticonvulsants, are recommended by evidence‐based guidelines, whereas, others such as lidocaine patch 5%, are supported by randomized, controlled, clinical data and are included in guidelines for restricted conditions treatment. The vast majority of these drugs have already been proven useful in the management of benign NP syndromes. Treatment decisions for patients with NP can be difficult. The intrinsic difficulties in performing randomized controlled trials in cancer pain have traditionally justified the acceptance of drugs already known to be effective in benign NP for the management of malignant NP, despite the lack of relevant high quality data. Interest in NCP mechanisms and pharmacotherapy has increased, resulting in significant mechanism‐based treatment advances for the future. In this comprehensive review, we present the latest knowledge regarding NCP pharmacological management.