Sensory profiles in women with neuropathic pain after breast cancer surgery.

PURPOSE: We performed a detailed analysis of sensory function in patients with chronic post-surgical neuropathic pain (NP) after breast cancer treatments by quantitative sensory testing (QST) with DFNS (German Research Network on Neuropathic Pain) protocol and bed side examination (BE). The nature of sensory changes in peripheral NP may reflect distinct pathophysiological backgrounds that can guide the treatment choices. NP with sensory gain (i.e., hyperesthesia, hyperalgesia, allodynia) has been shown to respond to Na+-channel blockers (e.g., oxcarbazepine). METHODS: 104 patients with at least "probable" NP in the surgical area were included. All patients had been treated for breast cancer 4-9 years ago and the handling of the intercostobrachial nerve (ICBN) was verified by the surgeon. QST was conducted at the site of NP in the surgical or nearby area and the corresponding contralateral area. BE covered the upper body and sensory abnormalities were marked on body maps and digitalized for area calculation. The outcomes of BE and QST were compared to assess the value of QST in the sensory examination of this patient group. RESULTS: Loss of function in both small and large fibers was a prominent feature in QST in the area of post-surgical NP. QST profiles did not differ between spared and resected ICBN. In BE, hypoesthesia on multiple modalities was highly prevalent. The presence of sensory gain in BE was associated with more intense pain. CONCLUSIONS: Extensive sensory loss is characteristic for chronic post-surgical NP several years after treatment for breast cancer. These patients are unlikely to respond to Na+-channel blockers.

Severe CNS angiostrongyliasis in a young marine: a case report and literature review.

Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis worldwide. Infection typically occurs through ingestion of undercooked molluscs or vegetables contaminated by infective larvae. Endemic regions were previously limited to southeast Asia and the Pacific basin; however, this parasite is seeing an alarming increase in global distribution with reported cases in more than 30 countries, including several states in the USA. Although infection typically results in meningitis, a broad spectrum of CNS involvement and severity is emerging as diagnostic methods (such as real-time PCR) continue to improve diagnosis. In this Grand Round, we report a case of a 20-year-old active duty US marine serving in Okinawa, Japan, afflicted with severe CNS angiostrongyliasis marked by radiculomyelitis with quadriparesis, hyperaesthesia, and urinary retention. We present this case to highlight that no clear guidelines exist for the treatment of severe CNS angiostrongyliasis and provide our consensus recommendation that treatment algorithms include use of dual corticosteroids plus anthelmintics when radicular symptoms are present. In this Grand Round we review the clinical features, epidemiology, advances to diagnostic techniques, and available data on current treatment options for CNS angiostrongyliasis. This diagnosis should be highly considered in the differential diagnosis of a patient presenting with meningeal symptoms, paraesthesia or hyperaesthesia, and CSF eosinophilia so that treatment can be started early, which is particularly important in children, because of their increased risk of severe disease and mortality. We recommend combined therapy with albendazole and prednisolone, with consideration for increased steroid dosing in severe cases.

Eficacia de un gel bioadhesivo dental con dióxido de silicio obliterante, nitrato potásico y monofluorofosfato sódico en pacientes con hiperestesia dentinaria / Efficacy of a bioadhesive dental gel containing precipitated silica particles, potassium nitrate, and sodium monofluorophosphate in patients with dentin hyperesthesia

Introducción: La hiperestesia dentinaria se caracteriza por un dolor intenso, de corta duración, asociado a la exposición de la dentina en respuesta a estímulos térmicos, táctiles, osmóticos o químicos. De prevalencia creciente, reduce la calidad de vida del paciente. El objetivo principal fue evaluar la eficacia de un gel bioadhesivo dental con dióxido de silicio obliterante, nitrato potásico y monofluorofosfato sódico en pacientes con hiperestesia dentinaria. Como objetivo secundario se valoraron su aceptabilidad y tolerancia. Métodos: El producto se aplicó durante 14 días, 3 veces/día, después de la limpieza dental y se mantuvo sin aclarar 30 minutos (n=19). Se evaluó su eficacia mediante exploración odontológica por técnica táctil y de chorro de aire. Al finalizar el estudio los pacientes completaron un cuestionario de percepción del producto. Resultados: La evaluación odontológica mostró una reducción significativa de la hipersensibilidad dental en todos los puntos temporales del estudio (p<0,05) mediante técnica táctil y de chorro de aire. Esta mejoría fue sostenida y aumentó a medida que avanzó el tratamiento. Todas las preguntas sobre la eficacia del producto y sus características organolépticas percibidas tuvieron una respuesta positiva. Los resultados del tratamiento fueron considerados muy satisfactorios/satisfactorios por un 95% de los pacientes. No se observó ninguna reacción adversa significativa derivada del uso del producto. Conclusiones: El gel bioadhesivo dental con dióxido de silicio obliterante, nitrato potásico y monofluorofosfato sódico, administrado 3 veces/día, consiguió una reducción significativa de la hipersensibilidad dental, mejoría que fue aumentando con el tiempo. El producto presentó muy buena aceptabilidad y tolerancia (AU)

Introduction: Dentin hypersensitivity is characterized by an acute pain of short duration associated with exposure of dentin to thermal, tactile, osmotic or chemical stimuli. It shows increasing prevalence and reduces the quality of life of patients. The main objective was to evaluate the effectiveness of a dental bio-adhesive gel with precipitated amorphous silica, potassium nitrate, and sodium monofluorophosphate in patients with dentin hypersensitivity. The secondary objective was to evaluate acceptability and tolerance of the product. Methods: The product was applied for 14 days, 3 times / day after habitual cleanliness routine and was not rinsed for 30 minutes. Its efficacy was evaluated by sensitive touch and air jet techniques. At the end of the study the patients filled a subjective questionnaire about the perception of the product. Results: The dental evaluation showed a significant reduction of dental hypersensitivity at all time points of the study (p<0.05) according to the sensitive touch and air jet technique results. This improvement increased as the treatment progressed. All questions about the effectiveness of the product and its organoleptic characteristics received a positive answer. Treatment results were considered very satisfactory or satisfactory by 95% of patients. No significant adverse reactions associated to the product were observed. Conclusions: Dental bio-adhesive gel with precipitated amorphous silica, potassium nitrate, and sodium monofluorophosphate, administered 3 times / day resulted in a significant reduction of dental hypersensitivity, and this improvement increased with time. The product showed very good acceptability and tolerance (AU)

Low-Dose Tricyclics for Esophageal Hypersensitivity: Is it all Placebo Effect?

Limsrivilai et al. report on a randomized control trial (RCT) testing the efficacy of imipramine for treating esophageal hypersensitivity and functional heartburn, the first RCT to test this therapy in this indication. Among 43 functional heartburn and esophageal hypersensitivity patients randomized to treatment with 25 mg qhs imipramine and 40 randomized to matched placebo, the response rates, judged by a 50% reduction in gastroesophageal reflux disease symptoms, were 37.2% and 37.5%, respectively, with no observed difference between patients with hypersensitivity and those with functional heartburn. On the positive side, imipramine treatment was associated with improvement in quality of life as assessed by total SF-36 score. Although negative at first glance, there are several important lessons from this study: (i) low-dose tricyclic is sufficient in these patients; (ii) proton pump inhibitors can (and should) be discontinued when they are ineffective; and (iii) distinguishing between functional heartburn and esophageal hypersensitivity is of unclear clinical relevance.

Imipramine for Treatment of Esophageal Hypersensitivity and Functional Heartburn: A Randomized Placebo-Controlled Trial.

OBJECTIVES: Tricyclic antidepressants could be effective in the treatment of symptoms related to hypersensitive esophagus through their pain-modulating effect. We therefore assessed the benefit of imipramine in patients with esophageal hypersensitivity and functional heartburn. METHODS: Patients with normal endoscopy findings and typical reflux symptoms despite standard-dose proton-pump inhibitor therapy underwent 24-h pH-impedance monitoring. Patients with established esophageal hypersensitivity or functional heartburn were randomly assigned to receive 8 weeks of either once-daily imipramine 25 mg (n=43) or placebo (n=40). The primary end point was satisfactory relief of reflux symptoms, defined as a >50% reduction in the gastroesophageal reflux disease score. The secondary end point was improvement in quality-of-life (QoL) as assessed by the 36-Item Short Form Health Survey score. RESULTS: Patients receiving imipramine did not achieve a higher rate of satisfactory relief of reflux symptoms than did patients receiving placebo (intention-to-treat (ITT) analysis: 37.2 vs. 37.5%, respectively; odds ratio (OR), 0.99; 95% confidence interval (CI), 0.41-2.41; per-protocol (PP) analysis: 45.5 vs. 41.2%, respectively; OR, 1.19; 95% CI, 0.45-3.13). Subgroup analysis to assess the efficacy of imipramine for either esophageal hypersensitivity or functional heartburn yielded similar results. Treatment with imipramine provided significant improvement of QoL by PP analysis (72±17 and 61±19, respectively; P=0.048), but ITT analysis did not reveal any differences between imipramine and placebo (68±19 and 61±19, respectively; P=0.26). Adverse events were similar in both groups; however, constipation was more common with imipramine than placebo (51.2 vs. 22.5%, respectively; P=0.01). CONCLUSIONS: Although low-dose imipramine shows potential QoL benefits, it does not relieve symptoms more effectively than does placebo in patients with either esophageal hypersensitivity or functional heartburn.

Burning pain from chest to back · allodynia and hyperesthesia · extreme sensitivity at the left T5 dermatome · Dx?

A 27-year-old woman in the 21st week of her first pregnancy came to our clinic complaining of a constant burning pain that spread around her left chest wall to her back. She graded the pain as a 10 on a 0 to 10 visual analog scale. The pain, which began 3 months earlier, became worse when she took a deep breath, ate, or walked, but was alleviated by applying warm compresses. Our patient hadn't slept well since the pain began. Her medical history was noteworthy for chickenpox at age 5.

[Infiltration of enamel erosions as a part of combined dental care in gastroesophageal reflux disease].

The paper presents the results of evaluation of clinical efficacy of the Icon infiltration method for the treatment of tooth enamel erosion associated with gastroesophageal reflux disease (GERD). The study was performed in 10 volunteers. Twenty-seven teeth were treated, and the degree of dental hard tissues hyperesthesia reduction as well as the dynamics of erosions size was estimated. It was proved that in most part of cases hyperesthesia deceased significantly and there were no increase in the erosions area during the follow-up period.

The antinociceptive effect of (-)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice.

UNLABELLED: We used multiple pain models to investigate the effects of (-)-linalool, a monoterpene alcohol present in the essential oil of plants, on chronic inflammatory and neuropathic hypersensitivity in adult Swiss mice. Inflammatory or neuropathic hypersensitivity was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) or partial sciatic nerve ligation (PSNL), respectively. Twenty-four hours after CFA injection, we used Von Frey filaments and acetone-evoked cooling to evaluate tactile and thermal hypersensitivity, respectively. A single i.p. injection of (-)-linalool (50 or 200 mg/kg) administered 30 minutes before testing reduced CFA-induced mechanical hypersensitivity. Similarly, (-)-linalool reduced acetone-evoked hypersensitivity up to 4 hours after treatment. Compared with vehicle, (-)-linalool produced a marked reduction in CFA-induced paw edema. (-)-Linalool also reduced mechanical hypersensitivity induced by PSNL 7 days after injury. Multiple (-)-linalool treatments given chronically (twice a day for 10 days; 50 mg/kg, i.p.) significantly reduced mechanical hypersensitivity induced by CFA and PSNL. This multidose strategy did not cause tolerance. We also reasoned that (-)-linalool might reduce nociceptive behavior in response to direct administration of inflammatory mediators. Therefore, we injected the cytokines IL-1ß (.1 pg/site) and TNF-α (1 pg/site) intrathecally. (-)-Linalool inhibited the biting response induced by IL-1ß and TNF-α. PERSPECTIVE: The article adds information about antinociceptive properties of (-)-linalool in chronic inflammatory and neuropathic hypersensitivity. It also indicates that (-)-linalool might be potentially interesting in the development of new clinically relevant drugs for the management of persistent pain.

[Pachymeningitis associated with probable Horton's disease: a case report]. / Pachyméningite associée à une probable maladie de Horton : étude d'une observation.

INTRODUCTION: Horton's disease is the most common vasculitis of elder people. Several neurological complications are reported, but pachymeningitis is exceptional. OBSERVATION: A 71-year-old patient who presented headache, hyperesthesia of the scalp, weight loss with a biological inflammatory syndrome and meningeal thickening on MRI. The diagnosis of pachymeningitis related to Horton's disease was retained. The patient was treated by corticosteroids with a good clinical, biological and radiological course after 22 months. CONCLUSION: Horton's disease is a potential diagnosis in elderly persons with pachymeningitis and inflammatory syndrome.

Allodynia-associated symptoms, pain intensity and time to treatment: predicting treatment response in acute migraine intervention.

OBJECTIVE: To evaluate the relationship between treatment outcomes and allodynia-associated symptoms (AAS) at the time of treatment with almotriptan. METHODS: Analyses were performed with data collected prospectively from patients in 2 recently completed early intervention trials, AXERT Early miGraine Intervention Study (AEGIS) and AXERT 12.5 mg time vs Intensity Migraine Study (AIMS): 2-hour pain free, 2-hour pain relief (AEGIS only), sustained pain free (SPF), use of rescue medication, and median headache duration (AIMS only), in the presence and absence of pretreatment AAS, which was determined by responses to a questionnaire. Analyses were conducted to evaluate possible prognostic variables. RESULTS: The presence of pretreatment AAS did not have a significant effect on 2-hour pain-free, 2-hour pain-relief or SPF rates, use of rescue medication, or headache duration. Significant factors for most favorable outcomes (greater 2-hour pain-free, 2-hour pain-relief and SPF rates, less use of rescue medication, and shorter headache duration) included treatment with almotriptan 12.5 mg, treatment of mild or moderate headache pain, and treatment within 1 hour of headache onset. CONCLUSION: Almotriptan 12.5 mg was efficacious in providing 2-hour pain free, 2-hour pain relief, SPF, and reducing rescue medication use irrespective of the presence of AAS at the time of treatment. The most optimal efficacy outcomes occurred when patients treated migraine attacks early and before the onset of severe pain. The presence of AAS, which may indicate an early phase of allodynia, did not influence the efficacy of almotriptan therapy.

Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury.

The activation of glial cells in the CNS has been suggested to be involved in abnormal pain sensation after peripheral nerve injury. Previous studies demonstrated phosphorylation of p38 mitogen-activated protein kinase (MAPK) in spinal cord glial cells after peripheral nerve injury, and such phosphorylation has been suggested to be involved in the development of neuropathic pain. The aim of this study was to examine the dorsal column nuclei for phosphorylation of p38 MAPK following peripheral nerve injury and to explore a possibility of its contribution to neuropathic pain. Immunohistochemical labeling for phosphorylated p38 (p-p38) MAPK was performed in histological sections of the rat spinal cord and medulla oblongata after the fifth lumbar (L5) spinal nerve ligation (SNL). The number of p-p38 MAPK-immunoreactive (IR) cells was significantly increased in the L5 dorsal horn and the gracile nucleus ipsilateral to the injury at days 3-21 after SNL. Double immunofluorescence labeling with cell-specific markers revealed that p-p38 MAPK-IR cells co-expressed OX-42, suggesting their microglial identity. Increased immunofluorescence labeling for OX-42 indicated that microglial cells were activated by SNL in the L5 dorsal horn and the gracile nucleus ipsilateral to the injury. Continuous infusion of a p38 MAPK inhibitor into the cisterna magna for 14 days beginning on the day of SNL suppressed the development of tactile allodynia, but not thermal hyperalgesia induced by nerve injury. These results demonstrate that SNL activates p38 MAPK pathway in microglia in the gracile nucleus as well as in the spinal cord dorsal horn. Activation of p38 MAPK in medullary microglia may contribute to the pathogenesis of neuropathic pain.

The effect of menthol on cold allodynia in patients with neuropathic pain.

OBJECTIVE: Cutaneous application of menthol in healthy subjects induces cold allodynia via sensitization of cold-sensitive nociceptors. We investigated the effects of menthol on preexisting cold allodynia in patients to test whether the allodynia was exacerbated. DESIGN: In eight neuropathic pain patients (six of peripheral, two of central origin), 40% menthol was applied topically to an area of preexisting cold allodynia. Mirror-image skin areas and aged-matched healthy subjects served as controls in patients with unilateral and bilateral neuropathic pain, respectively. Prior to and after menthol, cold pain thresholds were measured using a thermotest device. RESULTS: Menthol induced significant cold allodynia in control areas. However, in neuropathic areas, results were more heterogeneous. Overall, preexisting cold allodynia was not aggravated by topical menthol and was attenuated in 6/8 patients. CONCLUSIONS: These results suggest that, unlike in controls, menthol is not more hyperalgesic, but may be analgesic in some patients with peripheral and central neuropathic pain.

Attenuating phosphorylation of p38 MAPK in the activated microglia: a new mechanism for intrathecal lidocaine reversing tactile allodynia following chronic constriction injury in rats.

Increasing evidences approve the long-term analgesia effects of intrathecal lidocaine in patients with chronic pain and in animal peripheral nerve injury models, but the underlying mechanism remains elusive. Previous evidences suggest that the activation of the p38 MAPK signaling pathway in hyperactive microglia in the dorsal horn of spinal cord involves in nerve injury-induced neuropathic pain. In this study, we demonstrate that attenuating phosphorylation of p38 MAPK in the activated microglia of spinal cord, at least partly, is the mechanism of intrathecal lidocaine reversing established tactile allodynia in chronic constriction injury model of rats. This finding not only provides a new insight into the mechanisms underlying long-term therapeutic effects of lidocaine on neuropathic pain, but also reveals one more specific drug target for analgesia.

Tramadol and several anticonvulsants synergize in attenuating nerve injury-induced allodynia.

Neuropathic pain results from injury or dysfunction of the central or peripheral nervous system. The treatment of neuropathic pain is challenging, in part because of its multiple etiologies. The present study explores combinations of the analgesic tramadol and each of four anticonvulsants in the treatment of surgically induced (ligation of the L5 spinal nerve) allodynia in rats. Each of the five drugs studied exhibited a dose-dependent antiallodynic effect. When studied in combination, tramadol and each of two of the anticonvulsants (topiramate and RWJ-333369) interacted synergistically at all three ratios studied, whereas tramadol and each of the other two anticonvulsants (gabapentin and lamotrigine) exhibited a synergistic antiallodynic effect at only one of three ratios investigated. In addition, tramadol and topiramate were found to interact synergistically in a nociceptive pain model, the mouse hot-plate test. These studies suggest the benefit of using combinations of analgesics and anticonvulsants in the relief of neuropathic pain.

Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.

Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.

The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain.

Trigeminal neuralgia is a disorder of paroxysmal and severely disabling facial pain and continues to be a real therapeutic challenge. At present there are few effective drugs. Here we have evaluated the effects of the synthetic cannabinoid WIN 55,212-2 on mechanical allodynia and thermal hyperalgesia in a rat model of trigeminal neuropathic pain produced by a chronic constriction injury (CCI) of the infraorbital branch of the trigeminal nerve (ION). Relative to sham operation controls, rats with the CCI-ION consistently displayed hyperresponsiveness to von Frey filament and heat stimulation of the vibrissal pad. Both mechanical allodynia and thermal hyperalgesia are seen both ipsilateral and contralateral to the side of nerve injury, but is significantly more severe ipsilaterally. Administration of WIN 55,212-2 (0.3-5 mg/kg i.p.) dose-dependently increased the mechanical and heat withdrawal thresholds. WIN 55,212-2 (0.3-3 mg/kg i.p.) produced no significant motor deficits in animals using the rotarod test. The effect of WIN 55,212-2 was mimicked by cannabinoid CB1 receptor agonist HU 210 and was antagonized by CB1 receptor antagonist AM 251, but not by CB2 receptor antagonist AM 630 or vanilloid receptor 1 antagonist capsazepine, suggesting the involvement of CB1 receptors. CCI-ION also induced a time-dependent upregulation of CB1 receptors primarily within the ipsilateral superficial laminae of the trigeminal caudal nucleus revealed by both Western blot and immunohistochemistry. Taken together, these results suggest that cannabinoids may be a useful therapeutic approach for the clinical management of trigeminal neuropathic pain disorders.