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.

Cutaneous endothelin-A receptors elevate post-incisional pain.

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET(A)), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ET(A) was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4h after surgery and lasting at least 24h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24h, but that of secondary hyperesthesia remained strong for at least 24h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ET(A) in the immediate peri-operative period prevents the later development of central sensitization.

Symptomatic management of calciphylaxis: a case series and review of the literature.

Calciphylaxis, or calcific uremic arteriopathy, is a rare complication of end-stage renal impairment. It is characterized by the development of small vessel vasculopathy with subcutaneous necrosis and ulceration. Intense pain and cutaneous hyperesthesia are prominent features. Mortality rates are high, and the resulting morbidity is significant. While symptomatic management is the mainstay of treatment, it can be challenging. We describe the symptomatic management of a series of three patients with calciphylaxis. Particular emphasis is placed on the use of multimodal analgesia with high-dose opioids, ketamine, and benzodiazepines and on the use of preemptive analgesia.

Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.

Activated glial cells (microglia and astroglia) in the spinal cord play a major role in mediating enhanced pain states by releasing proinflammatory cytokines and other substances thought to facilitate pain transmission. In the present study, we report that intrathecal administration of minocycline, a selective inhibitor of microglial cell activation, inhibits low threshold mechanical allodynia, as measured by the von Frey test, in two models of pain facilitation. In a rat model of neuropathic pain induced by sciatic nerve inflammation (sciatic inflammatory neuropathy, SIN), minocycline delayed the induction of allodynia in both acute and persistent paradigms. Moreover, minocycline was able to attenuate established SIN-induced allodynia 1 day, but not 1 week later, suggesting a limited role of microglial activation in more perseverative pain states. Our data are consistent with a crucial role for microglial cells in initiating, rather than maintaining, enhanced pain responses. In a model of spinal immune activation by intrathecal HIV-1 gp120, we show that the anti-allodynic effects of minocycline are associated with decreased microglial activation, attenuated mRNA expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-1beta-converting enzyme, TNF-alpha-converting enzyme, IL-1 receptor antagonist and IL-10 in lumbar dorsal spinal cord, and reduced IL-1beta and TNF-alpha levels in the CSF. In contrast, no significant effects of minocycline were observed on gp120-induced IL-6 and cyclooxygenase-2 expression in spinal cord or CSF IL-6 levels. Taken together these data highlight the importance of microglial activation in the development of exaggerated pain states.

Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model.

Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer chemotherapeutic agents, including the vinca alkaloids such as vincristine. The resulting symptoms, which frequently include moderate to severe pain, can often be disabling. The current study utilized a vincristine-induced neuropathic pain animal model [Pain 93 (2001) 69], in which rats were surgically implanted with mini-osmotic pumps set to deliver vincristine sulfate (30 microg kg(-1)day(-1), i.v.), to examine the time course of progression of various pain modalities and to compare the dose-response effects of clinically utilized drugs on mechanical allodynia to further validate the relevance of this model to clinical pathology. Vincristine infusion resulted in significant cold allodynia after 1 week post-infusion, however mechanical and thermal nociception showed little to no effect. In contrast, marked mechanical allodynia occurred by 1 week of vincristine infusion and returned nearly to pre-infusion levels by the 4th week after infusion pump implantation. ED(50) values (micromol/kg, p.o.) were determined in the mechanical allodynia assay for lamotrigine (82), dextromethorphan (94), gabapentin (400), acetaminophen (1100) and carbamazepine (3600); however, aspirin and ibuprofen had no effects up to 300 and 1000 micromol/kg, respectively. Additionally, ED(50) values (micromol/kg, i.p.) were determined in the mechanical allodynia assay for clonidine (0.35) and morphine (0.62), but desipramine and celecoxib had no effects up to 66 and 260 micromol/kg, respectively. Findings from the current, preclinical study further validate this model as clinically relevant for chemotherapy-induced pain. The surprisingly good effects observed with acetaminophen warrant further investigation of its mechanism(s) of action in neuropathic pain.

Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain.

Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.

Transient neurologic symptoms after epidural analgesia in a five-year-old child.

Transient neurologic symptoms occurred in a five-year-old child after discontinuation of epidural analgesia with bupivacaine and morphine, which had been established for two days after thoracotomy. The symptoms resolved within 12 hours with acetaminophen.

Efeito de agentes anti-hiperestésicos à base de oxalato de potássio na permeabilidade da dentina humana: estudo in vitro / Effect of potassium oxalate based dessensitizing agents on human dentin permeability: in vitro study

O oxalato de potássio tem sido utilizado no tratamento da hiperestesia dentinária através da precipitaçäo de cristais de oxalato de cálcio intra e extracanaliculares, obstruindo os túbulos dentinários e reduzindo o deslocamento de fluido. O objetivo desse estudo foi analisar in vitro quantitativa e qualitativamente a permeabilidade da dentina tratada com três diferentes formulaçöes à base de oxalato de potássio e um gel fluoretado, sob cinco diferentes pré-tratamentos superficiais. O grau de oclusäo dos túbulos dentinários foi avaliado por meio de microscopia eletrônica de varredura, observando a precipitaçäo cristalina, e pela mediçäo da conditividade hidráulica da dentina após a aplicaçäo dos agentes anti-hiperestésicos. A natureza dos elementos químicos que compöem os cristais e os compostos formados foram identificados por meio da microanálise de raios X e da difraçäo de raios X, respectivamente. Para o ensaio de condutividade hidráulica, realizado por meio de um dispositivo específico, foram preparados 200 discos de dentina com 1 mm de espessura, obtidos de terceiros molares humanos extraídos. Os espécimes foram divididos em 20 grupos de dez espécimes, correspondentes a três géis derivados do oxalato de potássio: Oxa-Gel, pH 4,10; Experimental 1, pH 4,02; Experimental 2, pH 2,52, e um gel de fluoreto de sódio acidulado a 1,23 por cento - Nupro (Dentsply) - pH 3,6 a 3,9. Esses materiais foram aplicados na dentina sob as seguintes condiçöes de pré-tratamento: seca com ar; seca com papel absorvente; mantida molhada; acidificada e seca com ar; acidificada e seca com papel. Os ensaios foram realizados na seguinte sequência experimental: na presença de smear layer, após condicionamento com EDTA 0,5 M, por um minuto; após a aplicaçäo dos materiais-teste e após o desafio com ácido cítrico a 6 por cento, por um minuto...

Notalgia paraesthetica--report of three cases and their treatment.

Notalgia paraesthetica is a rare entity which involves the posterior primary rami of thoracic nerves T2-T6. Patients present with a localized discomfort or pruritus on the back. The condition runs a benign course and usually resolves spontaneously. However, whilst present the symptoms can be relentless and disturbing to patients. We report three patients with notalgia paraesthetica, all of whom were helped symptomatically by the topical application of the local anaesthetic cream, EMLA (2.5% lignocaine and 2.5% prilocaine).

Mode of analgesic action of dipyrone: direct antagonism of inflammatory hyperalgesia.

Dipyrone blocked carrageenin-induced oedema and hyperalgesia in a dose-dependent manner. In contrast with indomethacin, paracetamol and acetyl salicylic acid, much lower doses of dipyrone were necessary for blocking hyperalgesia (ED50 = 19 mg/kg, i.p.) than oedema (180 mg/kg, i.p.) Dipyrone administered intraperitonially or intraplantarly was able to antagonise PGE2-, isoprenaline- and calcium chloride-induced hyperalgesia, effects which are not observed with non-steroid anti-inflammatory drugs. Systemic or local administration of dipyrone had no effect upon Db-cAMP-induced hyperalgesia while a centrally acting analgesic, morphine, given systemically, was highly effective. These results support our suggestion that the mechanism of action of dipyrone is different from that of classical non-steroidal anti-inflammatory drugs. Although the site of action is peripheral its analgesic effect does not derive from inhibition of the synthesis of prostaglandins but is exerted via direct blockade of the inflammatory hyperalgesia.