A variety of different isoforms of voltage-gated Na⁺ channels have now been cloned. The recent three-dimensional analysis of Na⁺ channels has unveiled a unique and unexpected structure of the Na⁺ channel protein. Na⁺ channels can be classified into two major categories, Na_v1 isoforms currently comprising nine highly homologous clones, and Na_x that has structure diverging from Na_v1. Although Na_x has not been successfully expressed in an exogenous system, recent studies using gene-targeting have unveiled their unique “concentration”-sensitive but not voltage-sensitive role. The functional role of Na_v1 isoforms is primarily to carry action potential generation in excitable cells. However, some of the Na_v1 isoforms can also influence subthreshold electrical activity through a persistent type of Na⁺ current. Na_v1.8 and Na_v1.9 contain an amino acid sequence common to tetrodotoxin (TTX)-resistant Na⁺ channels and are localized in small primary sensory neurons that mediate pain sensation. Our patch-clamp recordings from DRG neurons of Na_v1.8-null mutant mice disclosed a novel TTX-insensitive Na⁺ current. The demonstration of its dependence on Na_v1.9 transcripts provided evidence for a specialized role of Na_v1.9, together with Na_v1.8, in pain sensation. In this article, these emerging views of novel functions mediated by multiple types of Na⁺ channels are summarized, to give a perspective for the expanding Na⁺ channel mutigene family.

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Since nerve blocks in conjunction with local anesthetics have dramatic pain relieving effects in the treatment of acute pain, they also have been used for treatment of chronic persistent pain. In most cases of intractable pain, the original pain relapses after the short period of relief afforded by nerve blocks. Because nerve block is an invasive technique, it should not be used frequently to obtain temporary effects, but should be avoided as much as possible by using other analgesic measures. Alternatively, it might be beneficial if physical and psychosocial functions in chronic pain patients can be restored through its pain relieving effects.
Although nerve blocks have been used for diagnosis and prognosis in patients with persistent pain, simple interpretation of the results might be misleading in determination of follow-up treatment. Therefore, the results should be interpreted in consideration of various factors affecting the sensitivity and specificity of nerve block. It is unclear wether or not they prevent the transition of acute pain to chronic persistent pain, though they have been empirically used.
In this article, I describe mainly the roles of sympathetic nerve block in complex regional pain syndrome and postherpetic neuralgia which are well-known diseases associated with persisitent pain.

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Objectives: We investigated 25 peripheral nerve biopsy specimens obtained from amputated lower extremities in 20 patients suffering from diabetic foot (DF), which was the final advanced stage of severe diabetic lower extremity lesions. Histopathological observation of the fine structures of peripheral nerves was performed mainly by electron microscope. Methods: During operation, we identified the nerve trunk at two sites such as the proximal stump and peripheral part of the amputated section. The nerve was dissected at these sites and nerve specimens were obtained. Specimens were then immediately soaked in a 2% glutaraldehyde solution. Following a process of dehydration and staining with toluidine, entire images were examined by light microscope. Thereafter, ultrathin sections stained with lead citrate were observed by electron microscopy. Results: The peripheral nerve lesions in the DF were histopathologically classified into three types: diabetic neuropathy, ischemic neuropathy and mixed type. The characteristic finding was a combination of retrograde Wallerian degeneration and severe ischemic nerve lesion at the proximal side in patients with multiple amputations. Conclusion: In conclusion, the ultrastructural study of peripheral nerve lesions in severe DF may be very useful in finding an effective way to prevent the progress of nerve ischemia and diabetic neuropathy, and may be helpful in understanding the pathogenesis of this problematic disease.

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We report on 2 patients with chronic pain and drug dependence who were treated successfully.
A 38-year-old male who sustained a finger injury in a workplace accident suffered from stump pain and attacks of pain in the right hand associated with convulsions. After he was referred to this city hospital from the special hand surgery section of a university hospital, the pain attacks at night became more frequent. He was treated with injections of pentazosin by the doctors on night duty, and rapidly became dependent on analgesics. He was admitted to the hospital, and sympathetic nerve block was administered to control the chronic pain. Following the results of a drug challenge test, ketamine injection was used.
A 56-year-old male suffering from pain in the back and both lower limbs caused by failed back surgery had severe pain attacks associated with generalized convulsions. He frequently visited the hospital at night and received analgesic injections to stop the convulsions, and had remained dependent on drugs for over ten years. His past history indicated that he had sustained a whiplash injury in a traffic accident several years ago. Total spinal block was administered, and the pain caused by the whiplash injury was relieved.
While the sympathetic nerve block was continued, we also introduced psychotherapy for the treatment of drug-dependence condition. The cognitive behavioral approach employed was effective, in that it not only allowed the patients to accept their chronic pain condition, but also helped them to withdraw from the drug-dependent condition.
We conclude that a cognitive behavioral approach is important to help patients withdraw from a drug-dependence.

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Recently, epiduroscopy (EDS) has been increasingly applied in several countries for treatment of patients with refractory low back pain. However, there is no clear-cut indication to apply this procedure in patients with or without former surgical interventions for low back pain. We report 3 successful cases in which patients responded well to EDS even though these patients had shown poor outcome from epidural block in the past. It appears that if the symptoms are significant despite unremarkable imaging studies, EDS can be applied for the treatment of refractory low back pain.

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We report a case of Pancoast tumor found during treatment of postoperative pain. A 37-year-old male patient underwent thoracoscopic bulla resection of the left lung. He suffered from prolonged pain in his left chest and back after the operation, and had been treated with various kinds of nerve blocks and medication at several hospitals. He then visited our pain clinic because of prolonged intractable pain. Chest X-ray study showed the pleural thickening of the apex of the left lung. His pain was temporarily relieved with selective serotonin reuptake inhibitor, however, he gradually complained of pain and numbness in his left arm. We performed additional chest X-rays and MRI and found a Pancoast tumor with invasion of the left second rib. He received radiation therapy, chemotherapy and upper lobectomy of the left lung with chest wall resection, but metastasis in the kidney and adrenal gland were found, and he died nine months after the operation. This case suggested that we have to consider malignant disease when we examine patients with intractable pain.

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Departmention (SCS) has been used for cases resistant to non-interventional pain management and nerve blocks such as failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS). Only a few reports of SCS for an upper limb pain associated with cervical vertebral surgery have involved patients suffering from CRPS type I, however. A 64-year-old man was referred to our pain clinic because of severe upper limb pain after cervical vertebral surgery. Several types of medication including morphine and repeated nerve blocks both failed to relieve his pain. Continuous epidural block was at least partially effective, suggesting his epidural space was not totally occluded with adhesions. However, infection of the epidural tubing site necessitated removal of the tube. Based on these findings, we chose SCS treatment for this patient. SCS treatment was performed and immediately relieved his upper limb pain and allodynia. We conclude that SCS may be a useful option for the treatment of CRPS type I in upper limb associated with cervical vertebral surgery.

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We demonstrated the anatomical area of cerebral activation triggered by non-nociceptive stimulation in a single patient with allodynia using functional MRI evaluations, The patient presented with swelling, allodynia and a rise in skin temperature in her right foot after 3 weeks in a cast due to a fracture in the metatarsal bone. Cerebral activation with non-nociceptive stimulus was measured for both the painful right foot and the healthy left foot. The same measurements were carried out 3 months later, after confirming that the allodynia in the patient's right foot had disappeared. Non-nociceptive stimulation to the area with allodynia triggered an increase in activity in the primary and second somatosensory area, inferior parietal lobe, insula, medial prefrontal cortex, anterior cingulate cortex and supplementary motor area, whereas stimulation to the healthy side only resulted in activity in the primary somatosensory area and inferior parietal lobe. Three months later, after the symptoms of allodynia had disappeared, the same stimuli to the right foot showed a decrease in activation of only the primary and second somatosensory area.
Allodynia is secondary to nerve injury or tissue damage. The mechanism of how allodynia is perceived is essentially unknown. In our case the patient presented signs which fit the criteria for CRPS type I. Although these symptoms ceased naturally, the allodynia seen in our patient was common to that of CRPS type I. We believe that our findings are significant for understanding the pathophysiology of allodynia seen in CRPS type I.

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A 66 year-old woman was referred to our clinic with a complaint of severe tongue pain resulting from dental treatment 9 years earlier. First she received stellate ganglion block, oral am itriptylin and etizolam. After observation of the effectiveness of lidocaine and ketamine hydrochloride by drug challenge test, she also started oral mexiletine, and finally intravenous ketamine infusion therapy successfully reduced her pain. However, she had skin eruption 69 days after her first visit. Although we discontinued every medication, skin eruption deteriorated and she experienced transient liver dysfunction and significant increase of HHV-6 IgG Ab. Her clinical features, clinical course and the positive result on a patch test for mexiletine indicated that she had hypersensitivity syndrome. Mexiletine is effective in the treatment of pain, but we should be aware of its potential adverse side effects.

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The authors describe a case of opioid withdrawal syndrome encountered when an analgesic regime was converted from epidural morphine to transdermal fentanyl patch in which the patient's chief symptom was sudden onset of severe watery diarrhea A 46-year-old woman suffering from advanced uterine cancer consulted our clinic for right groin pain and leg edema The analgesic effect of 200mg daily of oral morphine, prescribed at the previous hospital, was quite insufficient. Permanent alcohol blockade of the right lumbar sympathetic ganglia significantly reduced her leg edema but not her pain. Continuous epidural analgesia with increment dose of morphine, up to 300mg daily, was required to relieve her pain. Two months later, we converted continuous epidural analgesia with morphine to transdermal fentanyl patch therapy due to the patient's request and the potential risk of epidural abscess or bacterial meningitis.
On the first day of drug replacement, 30mg of fentanyl patch and the reduced dose of epidural morphine, 100mg daily, were administered. After confirming that her pain had been controlled sufficiently during the following 24 hours, epidural infusion of morphine was discontinued. A few hours later, sudden onset of abdominal discomfort followed by severe watery diarrhea appeared. 20mg of oral morphine dramatically resolved the symptoms.
In Japan, reports of fentanyl patch-associated opioid withdrawal syndrome has been very rare, however, it will likely become more frequent because the potent and prolonged analgesic effect and the ease of administration of fentanyl patch will soon increase its clinical use both as a primary and a replacement analgesic. When using a fentanyl patch as a replacement analgesic, meticulous observation of a patient and early diagnosis following prompt and proper treatment of withdrawal symptom is required.

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We encountered two patients with intractable perineal pain who were successfully treated with anticonvulsants.
Case 1: A 70-year-old woman had undergone osteotomy of her knee for osteoarthritis under spinal anesthesia in September 1999. One month after the operation, she suffered from perineal shooting pain with a visual analog score of 10/10. Nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants and caudal epidural block did not relieve the severe pain. In June 2000, she was admitted to our hospital and received carbamazepine for 2 weeks. Although pain was completely cured, she developed Stevens-Johnson syndrome and then stopped taking carbamazepine. One month later, she again suffered from the perineal pain. Other anticonvulsants, phenytoin, sodium valproate, clonazepam and zonisamide were administered as a trial, and of these clonazepam and zonisamide were effective in controlling the pain. Currently, her visual analog score is 3 to 4/10 while taking zonisamide and amitriptyline hydrochloride.
Case 2: A 52-year-old man was hospitalized for chronic pancreatitis. During hospitalization he had perineal shooting pain with visual analog score of 10/10. Pain could not be controlled with NSAIDs or opioids. In December 2001, he visited our pain clinic and was treated with carbamazepine and amitriptyline for 2 weeks. Although the pain was completely disappeared, he developed syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Three days after discontinuation the drugs, he recovered from SIADH, but again had perineal pain. Zonisamide was then administered. One month after the start of medication, his pain diminished. Currently, he is free of pain under zonisamide.
The efficacy of anticonvulsants for perineal pain has not been reported, but perineal pain in our two patients was successfully treated with carbamazepine. However, our patients had to discontinue carbamazepine because of severe side effects, and other anticonvulsants showed efficacy. We consider that anticonvulsants are effective for intractable perineal shooting pain.

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