In order to study the participation of histamine in pain perception, histamine-related gene knockout (KO) mice were examined for pain threshold by means of several nociceptive tasks. H₁ receptor KO (H₁RKO) mice showed significantly fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, formalin, capsaicin, and abdominal constriction tests. Sensitivity to noxious stimuli in H₁RKO mice were significantly decreased when compared to wild-type mice. The antinociceptive phenotypes of H₂ receptor KO (H₂RKO) were similar to H₁RKO mice. We also examined the antinociceptive effects of morphine in H₁RKO and H₂RKO mice. In the nociceptive assays, the antinociceptive effects produced by morphine were more enhanced in both H₁RKO and H₂RKO mice. The effects of histamine H₁ and H₂ receptor antagonists on morphine-induced antinociception were studied in ICR mice. The co-administrations of d-chlorpheniramine or cimetidine enhanced the effects of morphine in all nociceptive assays examined. The histidine decarboxylase gene knockout mice showed similar phenotypes of H₁RKO and H₂RKO mice. These results suggest that histamine play a suppressive role in morphine-induced antinociception in the spinal and supra-spinal levels through H₁ and H₂ receptors.

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This review attempts to summarize some of the mechanisms underlying the suppression of the morphine-induced rewarding effect and reduced sensitivity to morphine-induced antinociceptive action under a chronic pain-like state. It is of interest to note that animals with sciatic nerve ligation exhibited long-lasting thermal hyperalgesia and a significant increase in the levels of protein kinase Cγ (PKCγ)-, phosphorylated-conventional PKC (p-cPKC)-, brain-derived neurotrophic factor (BDNF)- and TrkB-like immunoreactivities (IR) on the ipsilateral side in the dorsal horn of the spinal cord, indicating a substantial increase in BDNF/PKC pathway under a neuropathic pain-like state. Intrathecal administration of inhibitors of PKC and a Trk-dependent tyrosine kinase and antibody to BDNF produced significant suppression of the thermal hyperalgesia evoked by sciatic nerve ligation. Astroglial hypertrophy/proliferation in the dorsal horn was also noted in sciatic nerve-ligated mice. As in nerve injury, animals tolerant to morphine-induced antinocicep-tion exhibited these changes. These findings suggest that the increase in the activity of spinal cPKC and the release of BDNF, or the spinal astrocytic response to under a neuropathic pain-like state may cause the suppression of morphine-induced antinociception.
A growing body of clinical evidence suggests that when opioid analgesics are used to control pain in patients, psychological dependence is not a major concern. It should be mentioned that animals with sciatic nerve ligation failed to exhibit morphine-induced place preference. Nerve injury also caused a significant decrease in the activity of extracellular signal-regulated kinase (ERK) on tyrosine hydroxylase (TH)-positive cells and a significant suppression of μ-opioid receptor (MOR)-mediated G-protein activation associated with an increase in G-protein-coupled receptor kinase 2 (GRK2) in GABA-containing cells in the ventral tegmental area (VTA). Furthermore, the inhibition of the ERK cascade in the VTA by treatment with specific inhibitors suppressed the morphine-induced rewarding effect. Moreover, pre-microinjection of the MOR antagonist, naltrexone (NTX), into the VTA reversed the changes by sciatic nerve ligation, indicating that a robust increase in released endogenous μ-opioids may be induced by sciatic nerve ligation, leading to the down-regulation of the MOR function. It should be pointed out that an inflammatory pain-like state following formalin injection to the paw significantly suppressed the morphine-induced rewarding effect and the increase in dopamine (DA) turnover in the limbic forebrain. These effects were almost reversed by pretreatment with the κ-opioid receptor antagonist, nor-binaltorphimine (nor-BNI). In addition, the decrease in the morphine-induced increase in extracellular levels of DA and its metabolites in the nucleus accumbens (N. Acc.) following formalin injection was reversed by the microinjection of a specific dynorphin A antibody into the N. Acc. These findings provide direct evidence that the reduction in MOR function and the persistent decrease in ERK activity of dopaminergic neurons in the VTA may contribute to the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state. In contrast, the endogenous κ-opioid system may be activated by chronic inflammatory nociception. The activation of the κ-opioidergic system may, in turn, inhibit DA release in the N. Acc., resulting in the suppression of the development of rewarding effects produced by morphine.

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Opiates remain important drug treatment in severe pain. The opioid system consists of endogenous opioid peptides and mu, delta and kappa opioid receptors which are target molecules for analgesia, reward and many physiological functions of opiates. The powerful analgesic effects of morphine and related drugs focus attention on morphine-preferring mu opioid receptors. Analgesia, reward, respiratory depression, constipation, immunosuppression and physical dependence induced by morphine are absent in mice lacking the mu opioid receptor. These data show that the mu receptor is the critical molecular target for most effects of morphine, both therapeutic effects and side effects. Mice lacking the mu receptor which we and other groups generated will be a useful tool to study complex opioid systems. We have also analyzed individual differences of human mu receptor gene. We have been studying possible relationship between individual genetic variance and effects of opioids for development of custom-made individualized treatment on pain.

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Our aim in this study was to compare the postoperative pain-relieving effects and side effects of epidural infusions with higher concentrations of ropivacaine and dosage of fentanyl. The subjects were 45 patients who underwent upper abdominal surgery under general anesthesia with propofol and a low dose of fentanyl (less than 10μg/kg) combined with epidural anesthesia. At the end of the surgery, continuous epidural infusion of 0.2mg fentanyl in 92ml 0.2% ropivacaine (Group B, n=15), or 0.3mg fentanyl in 90ml 0.2% ropivacaine (Group F, n=15) or 0.2mg fentanyl in 92ml 0.3% ropivacaine (Group R, n=15) was started at a rate of 4ml/h for 24hrs. Postoperative analgesic effects were evaluated by the number of demands for supplemental analgesic, VAS at rest and on coughing at 4, 12 and 24hrs postoperatively, and patients' attitudes to postoperative pain relief. VAS on coughing in Groups F and R were significantly less than that of Group B at 12 and 24hrs after the operation. Hypotension occurred in 4 patients in both the F and R groups, while there was no incidence, of hypotension in the B group. We concluded that the change from 0.2% to 0.3% epidural ropivacaine, and the increased dosage of epidural fentanyl from 0.2mg/day to 0.3mg/day, were similarly effective for postoperative analgesia.

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Background: The existence of regional differences in the number of medical doctors in Japan has been known. However, the geographical distribution of pain clinicians in Japan has not been unknown. Therefore, this study was aimed at investigating the numbers of pain clinicians regionally.
Methods: We compared the numbers of members and diplomats of the Board of the Japan Society of Pain Clinicians (JSPC) in the regular population and medical doctors among the 47 prefectures and the 11 district Societies of the JSPC.
Results: There were significant correlation coefficients between each of the general population, the number of medical doctors, members of the JSPC, and diplomats of the Board of the JSPC in all prefectures. The average number of members of the JSPC per 100, 000 population was 3.2, and the maximum difference among all prefectures (MDAP) was 3.6 times. The Tokyo District Society of the JSPC had the largest number (5.3), and the Tokai District Society had the smallest (2.2), of members per 100, 000 population. The average number of diplomats of the Board of the JSPC per 100, 000 population was 1.0, and the MDAP was 6.4 times. The Tokyo District Society of the JSPC had the largest number (1.7), and the Tokai District Society had the smallest (0.7), of diplomats of the Board per 100, 000 population. The average percentage of members of the JSPC in medical doctors was 1.6%, and the MDAP was 3.3 times. The Tokyo District Society of the JSPC had the highest percentage (2.1%), and the Tokai District Society had the lowest (1.3%), of members of the JSPC in medical doctors. The average percentage of diplomats of the Board of the JSPC in medical doctors was 0.52%, and the MDAP was 5.8 times. The Hokuriku District Society of the JSPC had the highest percentage (0.76%), and the Kyushu District Society had the lowest (0.36%), of diplomats of the Board of the JSPC in medical doctors. The average percentage of diplomats of the Board of the JSPC per members of JSPC was 32%, and the MDAP was 3.3 times. The Hokuriku District Society of the JSPC had the highest percentage (44%), and the Kyushu District Society had the lowest (25%), of diplomats of the Board of the JSPC per members of the JSPC.
Conclusion: There were remarkable regional differences in the numbers of members of the JSPC and diplomats of the Board of the JSPC in the regular population and medical doctors, in terms of the MDAP in this study. These results suggest that there is a regional discrepancy in the number of pain clinicians in Japan.

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We report 3 cases of intractable lower limb pain, in which pain relief was hardly obtained by conventional pain treatments and the involvement of psychogenic factors was strongly suspected.
The common clinical features consisted of swelling, coldness, severe continuous pain, and movement disability in the lower limb. In case 1, the limb pain developed after Chiari osteotomy. However, we could not detect organic disorders that would explain the complaints in any of these cases. While we mainly performed nerve block therapy including drug therapy for these patients, the patients never indicated any pain reduction. Because psychogenetic factors were considered to be involved in each complaint based on interviews with the patients, we performed Minnesota Multiphasic Personality Inventory (MMPI) test as a psychological examination. The results were highly indicative of a psychogenic disorder contributing to the pain complaint in each case.
Since the clinical features of chronic pain arose in each patient after a modified psychogenic process, we concluded that a psychological approach in addition to conventional pain treatment is indispensable for the treatment of chronic pain.

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The analgesic effect of orally administered pentazocine in 32 patients with cancer pain was studied retrospectively. Analyzed data included the daily dosage of pentazocine, the change in pain score during the administration, the administration period, and side effects. The average initial dose and maintenance dose of pentazocine were 92.2mg/day and 135.2mg/day, respectively. The pain scores before, during and at the end of the administration of pentazocine were 76.3mm, 23.0mm, and 41.6mm respectively. The average administration period of pentazocine was 32.0 days. Although 11 of the 32 patients had their pain controlled sufficiently by pentazocine alone, 16 patients were changed from pentazocine to morphine, and the remaining patients were changed to other therapy including oral codeine, splanchnic ganglion block or surgery, because of the insufficient analgesic effect of pentazocine. Side effects including nausea, vertigo and drowsiness were seen in 12 patients, but these were controlled by decreasing the dose of pentazocine. These data suggest that oral pentazocine can be a useful therapeutic method for the management of cancer pain.

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Intrathecal injection of prednisolone sodium succinate is approved in Japan for treatment of such diseases as encephalomyelitis, central nervous system leukemia and malignant lymphoma. We gave a total of 16 intrathecal prednisolone sodium succinate injections (each, 40mg dissolved in 2-3ml of 3% lidocaine) to six patients with intractable postherpetic neuralgia, and reviewed the therapeutic utility and complications. The median visual analogue scale pain-intensity score decreased significantly, from 55mm to 35mm, after the treatment (p<0.05). Ephedrine hydrochloride was necessary in 14 of the 16 injections, to treat hypotension. In addition, respiratory depression from a high level of spinal anesthesia and sedation occurred 11 times and required assisted ventilation, while diazepam was given 9 times for treatment and prevention of local anesthetic adverse effects on the central nervous system. We conclude that intrathecal prednisolone sodium succinate injection therapy is useful for intractable postherpetic neuralgia patients, however, side effects caused by the solvent lidocaine occurred frequently. Therefore, we consider it important to perform this method with careful monitoring.

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Muscle cramps in the lower extremities are one of the major complications of hemodialysis, and cause severe refractory pain. Four patients who were suffering from pain due to muscle cramps during and after hemodialysis were treated with 0.2ml physiological saline injections at acupoints before the start of hemodialysis.
The muscle cramps of all four patients were decreased by the acupoint injection therapy. Although minor subcutaneous hemorrhage was sometimes seen after injections in some patients, no severe side effects were observed. Physiological saline injections at acupoints resulted in decreased muscle cramps in the lower extremities as a complication of hemodialysis.

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Patients with severe spinal spasticity have difficulty in their daily activities, such as moving from a bed to a wheelchair, and ambulation, especially when leg spasticity is accompanied by pain and discomfort. From the standpoint of care providers, severe spasms prevent a successful rehabilitation course from being implemented.
Treatment modalities presently available are oral antispasmodic drugs, spinal cord stimulation, intrathecal baclofen, and intrathecal phenol block (ITPB). In this study, ITPB was administered to 6 spastic para paresis patients (27-64 years old, 11 injections). The blocks successfully reduced spasticity of the legs in all of the patients. No patients experienced reduction of leg muscle tone after ITPB. In this summary, ITPB markedly reduces muscle hyperactivity of the leg, and thereby facilitates sitting on a bed or chair. The effective duration of the procedure was shorter in younger patients. Every patient was satisfied with the results obtained.

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Complex regional pain syndrome type I (CRPS I) is a syndrome with pain and signs of autonomic dysfunction after trauma or immobilization. The pathophysiological mechanisms of CRPS I remain unknown. However, signs of autonomic dysfunction and abnormal pain sensation were recently reported after artificial immobilization in a study using human volunteers and animals. Immobilization is one of the contributing factors for development of signs of CRPS I. We report 3 patients who had a history of physician-imposed immobilization following surgery or trauma. All patients were evaluated by the current IASP diagnostic criteria for CRPS. Two of the 3 patients were fixed with a cast or a splint. The duration of immobilization was 8 to 12 weeks. Physicians and patients need to be educated on the importance of early mobilization following surgery or trauma.

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We performed simultaneous alcohol blocks of the celiac and inferior mesenteric plexus for abdominal cancer pain. In ten patients suffering from cancer pain, the effectiveness of pain relief, and the side effects of a wide-range block and of alcohol were examined. The simultaneous block of the celiac and inferior mesenteric plexus was a safe and useful method for cancer patients suffering from abdominal pain.
Successful simultaneous blocks could avoid repeated blocks for exhausted cancer patients.

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A 54-year-old woman developed neck pain, paresis and high-fever following epidural block. The epidural block was performed three times at a clinic within 2 weeks for treatment of low back pain attributable to a slipped 4th lumbar vertebral disc. Two hours after the last epidural block, neck stiffness was observed, and astasia-abasia appeared the next morning. On blood examination, an increase in WBC (13, 500/μl) and CRP (33.4mg/dl) was found, and spine MRI findings strongly suggested epidural abscess at the C2-L4 level. Emergency laminectomy and laminoplasty at cervical and lumbar spine, and drainage of an abscess were performed. An abscess was found in the epidural space, and a hematoma was found in the lumbar epidural space. In blood and epidural tissue cultures, Staphylococcus aureus was observed. This observation and the episode of neurological disorders after the epidural block suggested that the bolus of the epidural block was the cause of the epidural abscess. The hematoma found near the epidural injection site might have been due to the coagulation impairment caused by ticlopidine hydrochloride, and was a potential source of the bacterial infection.

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Primary palmar hyperhidrosis is a condition that can be defined as excessive perspiration beyond physiological needs, and the majority of sufferers notice their symptoms in early childhood. We examined the long-term outcome of thoracoscopic sympathectomy for palmar hyperhidrosis in children. Between 1994 and 2002, a total of 35 children aged 9 to 15 years with severe palmar hyperhidrosis underwent bilateral thoracoscopic sympathectomy on the 2nd and/or 3rd rib beds. A total of 24 patients (16 females and 8 males) were followed by postal questionnaire. The postoperative follow-up period ranged from 12 to 71 months. No perioperative complications such as pneumothorax, wound infection, hypesthesia, bleeding, or Horner's syndrome were encountered. Three patients had recurrence during the follow-up period because of incomplete resection due to anatomical difficulties. Twenty-one patients (87.5%) noted improvement of palmar hyperhidrosis and 22 patients (91.7%) had postoperative compensatory sweating. Nineteen patients (79.2%) were satisfied after the operation because of the improvement of the inconvenience in their school life. In conclusion, early surgical treatment for severe hyperhidrosis can improve social development and scholastic achievement in childhood. However, recurrence and compensatory sweating restricted postoperative satisfaction. Intensive preoperative patients and parent information, long-term follow-up, and reconsideration of surgical technique to avoid postoperative recurrence is needed.

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We report a rare case of severe bladder-referred pain and allodynia in the lower abdominal skin and perineum 12 weeks after intravesical bacillus Calmette-Guérin (BCG) therapy was performed for a patient's superficial bladder cancer. This is the first report of a prolonged complication after intravesical BCG therapy.
An 88-year-old woman was admitted with a complaint of pollakiuria. Her illness was diagnosed as superficial bladder cancer by cytodiagnosis, and transurethral electro-resection of the bladder tumor (TUR-Bt) was performed. She underwent intravesical BCG therapy for recurrent superficial bladder tumor twice a year. During the intravesical BCG therapies, she complained of severe bladder irritability, but non-steroidal anti-inflammatory drugs (NSAIDs) had some favorable effects. Twelve weeks after the second intravesical BCG therapy was finished, severe pain and allodynia occurred in her lower abdominal skin and perineum. At the time of our first examination, the regions of the pain and allodynia shaped an inverted triangle below the navel on her lower abdomen, constricting to the perineum. These regions coincided with regions at which bladder-and kidney-referred pain are known to occur. Oral administration of morphine was started and was quite effective. Currently, she is almost free of pain under morphine.

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[in Japanese]

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Epidural abscess and meningitis are rare but serious complications subsequent to epidural catheter placement. There are a number of different methods for preventing these infections.
After we experienced a case of epidural abscess related to epidural catheterization in September 2002, we changed procedures for preventing catheter infection during continuous epidural block. The modified procedures include scrubbing the site for insertion using chlorhexidine in ethanol and/or povidone iodine every 2 to 3 days, applying a small patch containing chlorhexidine (Biopatch^®), using patient-controlled analgesia (PCA) devices for all patients, and allowing only anesthetists or nurses in the pain management department to prepare the infusion solutions.
We evaluated the effectiveness of these procedures by comparing the incidence of catheter infection over the one-year period before implementing the modified procedures with that after implementing the modified procedures, retrospectively.
We also checked the patients' age, gender, duration of catheterization, the site of insertion, and the cause of cessation of catheterization during both periods.
Although 13 of the 65 patients who received the pre-modified infection-preventive procedures during epidural catheterization suffered catheter-related infection, none of the 35 patients who received the modified procedures suffered infection. The incidence of catheter-related infection was significantly lower using the modified procedures compared to that using the pre-modified procedures.
In conclusion, our modified infection-preventive procedures, which include using PCA devices, applying Biopatch^®, and preparing infusate only by the pain management department staff, minimize the risk of infection-related complications during epidural catheterization.

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