Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral ϩ mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirrorimage SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.

Context Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients. Objective To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer. Design, Setting, and Patients Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death. Intervention Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment. Main Outcome Measures Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer. Results Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, PՅ.01 for both groups; QOL, PϽ.001 for both groups), with a larger decrease in pain for the NCPB group (P = .005). From repeated measures analysis, pain was also lower for NCPB over time (P = .01). However, opioid consumption (P = .93), frequency of opioid adverse effects (all PϾ.10), and QOL (P=.46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of Ն5/10) vs opioid-only patients (14% vs 40%, P=.005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P=.26, proportional hazards regression). Conclusion Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival.

Calcimimetic compounds, which activate the parathyroid cell Ca 2ϩ receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca 2ϩ ([Ca 2ϩ ] i ) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC 50 ϭ 51 nM) in the presence of 0.5 mM extracellular Ca 2ϩ elicited increases in [Ca 2ϩ ] i in a dose-and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca 2ϩ , cinacalcet HCl (IC 50 ϭ 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC 50 ϭ 34 nM) produced a concentrationdependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca 2ϩ levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.

Herpes zoster (HZ), commonly called shingles, is a distinctive syndrome caused by reactivation of varicella zoster virus (VZV). This reactivation occurs when immunity to VZV declines because of aging or immunosuppression. Herpes zoster can occur at any age but most commonly affects the elderly population. Postherpetic neuralgia (PHN), defined as pain persisting more than 3 months after the rash has healed, is a debilitating and difficult to manage consequence of HZ. The diagnosis of HZ is usually made clinically on the basis of the characteristic appearance of the rash. Early recognition and treatment can reduce acute symptoms and may also reduce PHN. A live, attenuated vaccine aimed at boosting immunity to VZV and reducing the risk of HZ is now available and is recommended for adults older than 60 years. The vaccine has been shown to reduce significantly the incidence of both HZ and PHN. The vaccine is well tolerated, with minor local injection site reactions being the most common adverse event. This review focuses on the clinical manifestations and treatment of HZ and PHN, as well as the appropriate use of the HZ vaccine. © 2009 Mayo Foundation for Medical Education and ResearchOn completion of this article, you should be able to (1) recognize the common presentation of herpes zoster, (2) summarize appropriate treatment for acute herpes zoster and postherpetic neuralgia, and (3) select patients for whom herpes zoster vaccine is appropriate.H erpes zoster (HZ), commonly called shingles from the Latin cingulum, meaning belt, 1 is a distinctive syndrome caused by reactivation of varicella zoster virus (VZV). The risk of HZ increases with age; approximately half of all cases occur in persons older than 60 years. One of the most common and debilitating sequelae of HZ is postherpetic neuralgia (PHN), defined as pain persisting more than 3 months after the rash has healed. CLINICAL MANIFESTATIONS AND DIAGNOSISHerpes zoster is a painful, blistering skin eruption in a dermatomal distribution. After primary infection with varicella (ie, chicken pox), the virus persists asymptomatically in the ganglia of sensory cranial nerves and spinal dorsal root ganglia. As cellular immunity to VZV decreases with age or because of immunosuppression, the virus reactivates and travels along the sensory nerves to the skin, causing the distinctive prodromal pain followed by eruption of the rash. It is estimated that approximately 1 in 3 people will develop HZ during their lifetime, resulting in an estimated 1 million episodes in the United States annually. 2 Herpes zoster can occur at any age but is generally less severe in children and young adults, with the greatest morbidity and mortality seen in older adults and in immunocompromised patients. A recent population-based study in Olmsted County, Minnesota, found that the incidence of HZ was 3.6 per 1000 patientyears. 3 In that study, the incidence of HZ and the rate of HZassociated complications increased with age, with 68% of cases occurring in those aged 50 years and older. Prodromal...

These results demonstrate that: (i) VSMCs express a functional CaR; (ii) a reduction in CaR expression is associated with increased mineralization in vivo and in vitro; (iii) calcimimetics decrease mineral deposition by VSMC. These data suggest that calcimimetics may inhibit the development of VC in CKD patients.