TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1(-/-) mice. The electrophilic metabolites N-acetyl-p-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-p-benzoquinoneimine metabolite L-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1(-/-) mice. Intrathecal injection of a non-electrophilic cannabinoid, Δ(9)-tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. Our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.
BACKGROUND:: Intrathecal baclofen (ITB) is an effective therapy for spasticity and dystonia in pediatric populations; however, there are associated infectious complications. METHODS:: Patients who had an initial ITB device implanted at our center were followed to determine the proportion of patients with infectious and non-infectious complications, identify risk factors for infection and describe the clinical presentations, treatment and outcomes of infectious complications. RESULTS:: Over the 15 year study period, 139 patients had an initial ITB device placed. The mean age at placement was 13.6 years (range- 6 months to 41 years). In the first year of follow-up, 83% had no complications or secondary procedures, 17% had at least one secondary procedure and 5% had an infectious complication. The median time until infection was 14 days (mean 33 ± 42 days). Patients with secondary spasticity or dystonia were more likely to have infections than patients with cerebral palsy (86% vs.14%; p<0.0001). In the 94 patients with a first secondary procedure, 29% had at least one other procedure and 8% had an infection in the one year follow-up. Overall, 24 patients had 27 infections; 22% superficial, 33% deep and 45% organ space. Staphylococcus aureus was isolated in 50% of those with cultures obtained. Explantation was required in 59% of patients with an infection and differed by infection type: superficial (17%), deep (44%) and organ space (92%) (p=0.004). CONCLUSIONS:: Infectious complications were relatively uncommon; however, when present, frequently led to the explantation of the ITB pump device.
Dexmedetomidine, a selective alpha 2-adrenoceptor (α2AR) agonist, has provided significant analgesia in neuropathic pain. However, its underlying molecular mechanism has not been fully elucidated. In the present study, we found that intrathecal administration of dexmedetomidine alleviated mechanical allodynia induced by chronic constriction injury (CCI), and pretreatment with BRL44408 significantly reversed the dexmedetomidine-induced anti-nociceptive effect. Western blotting revealed that dexmedetomidine reduced the activation of microglia and the upregulation of interleukin-18 (IL-18) protein expression in the ipsilateral lumbar spinal dorsal horn, while BRL44408 pretreatment significantly blocked these effects of dexmedetomidine. Immunocytochemistry/immunohistochemistry indicated that the α2A-adrenoceptor was localised to microglia in primary culture, and IL-18 predominantly colocalised with the microglial marker Iba-1 in the dorsal horn of the spinal cord. These results suggest that the IL-18 signalling pathway in microglia may be involved in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI.
Stress induced cardiomyopathy (SIC) is becoming increasingly described as an underdiagnosed complication during common medical procedures. Reverse Takotsubo cardiomyopathy (RTC) is a variant of SIC that involves the basal and mid-ventricular segments and spares the apical segments. The authors present a rare case of RTC, following an inadvertent intrathecal injection during percutaneous epidural neuroplasty. Although the precise mechanism involved remains unclear, the direct neurohumoral effects of the hyperbaric anaesthetics and adhesiolytics appear to have resulted in a catecholamine surge and myocardial stunning that precipitated the SIC.
Effective pain control during local anesthetic injection is the cornerstone of behavior guidance in pediatric dentistry. The aim of this study was to evaluate the practical efficacy of a 2-stage injection technique in reducing injection pain in children. This was a split-mouth, randomized controlled crossover trial. One hundred cooperative children aged 7 to 13 years in need of bilateral local anesthetic injections (inferior alveolar nerve block, posterior superior alveolar nerve block, or maxillary and mandibular buccal infiltrations) for restorative, endodontic, and extraction treatments were recruited for the study. Children were randomly allocated to receive either the 2-stage injection technique or conventional technique at the first appointment. The other technique was used at the successive visit after 1 week. Subjective and objective evaluation of pain was done using the Wong-Baker FACES Pain Rating Scale (FPS) and Sound Eye Motor (SEM) scale, respectively. The comparison of pain scores was done by Wilcoxon sign-rank test. Both FPS and SEM scores were significantly lower when the 2-stage injection technique of local anesthetic nerve block/infiltration was used compared with the conventional technique. The 2-stage injection technique is a simple and effective means of reducing injection pain in children.
There is limited information on body composition, energy balance and fitness among childhood ALL survivors, especially those treated without cranial radiation (CRT). This analysis compares these metrics among 365 ALL survivors with a mean age of 28.6±5.9 years (149 treated with and 216 without CRT) and 365 age-, sex-, and race-matched peers. We also report risk factors for outcomes among survivors treated without CRT. Male survivors not exposed to CRT had abnormal body composition when compared to peers (%body fat 26.2±8.2 vs. 22.7±7.1). Survivors without CRT had similar energy balance, but had significantly impaired quadriceps strength (-21.9±6.0 Nm/kg, 60°/s) and endurance (-11.4±4.6 Nm/kg, 300°/s), exercise capacity (-2.0±2.1 ml/kg/min), low-back and hamstring flexibility (-4.7±1.6 cm), and dorsiflexion range of motion (-3.1±0.9°), and higher modified total neuropathy scores (+1.6±1.1) than peers. Cumulative asparaginase dose ≥120,000 IU/m(2) was associated with impaired flexibility, vincristine dose ≥39 mg/m(2) with peripheral neuropathy, glucocorticoid (prednisone equivalent) dose ≥8000 mg/m(2) with hand weakness, and intrathecal methotrexate dose ≥225 mg with dorsiflexion weakness. Physical inactivity was associated with hand weakness and decreased exercise capacity. Smoking was associated with peripheral neuropathy. Elimination of CRT from ALL therapy has improved, but not eliminated, body composition outcomes. Survivors remain at risk for impaired fitness.
Background: Intrathecal analgesia and radiofrequency techniques for tumor ablation are employed for palliation of symptoms. These interventions are efficacious in a select number of patients for controlling pain and improving quality of life. Careful selection of an appropriate candidate must be performed to prevent needless, invasive, and costly interventions, as interventional pain management alone will not treat total pain in cancer patients. We describe here a patient who experienced intractable pain and unsuccessfully underwent cordotomy but responded to the interdisciplinary (IDT) palliative care approach in an acute palliative care unit (APCU). Case: A middle-aged female with ovarian cancer metastatic to the left psoas muscle and the supraclavicular and retroperitoneal lymph nodes was admitted with severe left thigh and flank pain. She had been unsuccessfully treated with different opioid regimens, hypogastric nerve block, epidural steroid injection, and cordotomy. The palliative care team was consulted while awaiting placement of an intrathecal pump. The patient was subsequently transferred to the APCU for symptom management and transition to hospice. On admission, her morphine equivalent daily dose (MEDD) was 660 mg. Our IDT-composed of a physician, fellow, nurse practitioner, counselor, chaplain, social worker, and physical and occupational therapists-was able to identify several sources of distress that likely contributed to her expression of pain. Our IDT focused on frequent counseling, improving her function, provided medication education, discussed goals of care, and educated about hospice. She was discharged to hospice care with good pain control and an 85% reduction in her MEDD. Conclusion: An APCU approach involving an IDT alleviated the need for invasive interventions by diagnosing and treating the psychosocial, emotional, and spiritual distress contributing to the patient’s total pain expression. Successful management must be reflective of rigorous assessment of the physical, psychological, spiritual, social, and practical aspects before consideration of more invasive treatments.
BACKGROUND:The epidural test dose, used to identify unintended intrathecal placement, should reliably produce a spinal block without posing a threat to the patient. Most anesthesiologists administer a dose of local anesthetic, commonly lidocaine 45 mg. Pregnant patients are more sensitive to local anesthetics; high and total spinal anesthesia have been reported in the pregnant population with this dose. We hypothesized that lidocaine 30 mg was as effective as lidocaine 45 mg in creating rapid objective evidence of a sensory or motor block.METHODS:In this prospective, randomized, double-blind trial, patients scheduled for cesarean delivery were assigned to 1 of 4 groups: lidocaine 30 mg in the spinal or epidural space, or lidocaine 45 mg by the same routes. A blinded observer assessed the degree of sensory and motor block. The ability to identify intrathecal injection of each dose was compared. Sensory block above T6 dermatome and hypotension were recorded as side effects.RESULTS:Intrathecal administration of lidocaine 30 mg produced rapid subjective and objective signs of neuroblockade within 3 minutes (100%, 95% confidence interval CI, 85%-100% for each). Lidocaine 45 mg produced similar results. All patients in both groups described their legs as warm or heavy after 3 minutes and had a motor block by 5 minutes. On the basis of an intrathecal catheter rate of 1:380, the observed negative predictive value for intrathecal placement if the patient described no sensory changes at 3 minutes was 100% (95% CI, 99.95%-100%) for 30 mg and 100% (95% CI, 99.93%-100%) for 45 mg. We did not identify a decrease in the rate of side effects with the lower dose.CONCLUSIONS:Our results suggest that there is unlikely to be a large difference in the ability of these doses to detect unintentional intrathecal catheter placement. While the negative predictive value for intrathecal injection is very high for both doses, the 95% CI for the sensitivity of either dose is too wide to demonstrate clinical safety to identify all intrathecal catheters. A much larger study is warranted to assess whether there is a lower sensitivity with the 30-mg dose, or a propensity toward high cephalad motor block levels with the 45-mg dose.
Intrathecal chemotherapy with methotrexate, a folate antagonist, is widely used to treat central nervous system malignancies. The mechanisms underlying methotrexate-induced neurotoxicity are unclear but may be related to increased homocysteine levels. Intrathecal methotrexate-induced myelopathy mimicking sub-acute combined degeneration, with normal B12 levels, has been documented. We examined treatment and magnetic resonance imaging (MRI) characteristics of 13 patients with leukemia who received intrathecal methotrexate and developed urinary and bowel incontinence, ascending motor weakness, and sensory loss with dorsal column hyper-intensity on MRI between 2000 and 2016. Cerebrospinal fluid evaluation was negative for leukemia in all patients and positive for elevated protein in 12 patients. Seven of 8 patients with available data had reduced serum folate, increased serum homocysteine, or both, implicating methotrexate as the cause of neurotoxicity. Autopsy of one patient revealed loss of myelinated axons in the posterior columns. These findings suggest that methotrexate neurotoxicity may be mediated by folate antagonism. Awareness and a high index of suspicion of these characteristic clinical and radiographic features in patients who develop myelopathy after intrathecal methotrexate may help to avoid additional neurotoxic therapy in such patients. This article is protected by copyright. All rights reserved.
Substance P-saporin (SP-SAP), a chemical conjugate of substance P and a recombinant version of the ribosome-inactivating protein, saporin, when administered intrathecally, acts as a targeted neurotoxin producing selective destruction of superficial neurokinin-1 receptor-bearing cells in the spinal dorsal horn. The goal of this study was to provide proof-of-concept data that a single intrathecal injection of SP-SAP could safely provide effective pain relief in spontaneous bone cancer pain in companion (pet) dogs.