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Concept: Intrathecal


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.

Concepts: Neuron, Pain, Sensory system, Paracetamol, Rat, Rodent, Mouse, Intrathecal


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.

Concepts: Staphylococcus aureus, Infection, Median, Transmission and infection of H5N1, Intrathecal, Spastic diplegia, Intrathecal pump, Baclofen


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.

Concepts: Present, Molecular biology, Signal transduction, Effect, Pain, Agonist, Intrathecal, Functional selectivity


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.

Concepts: Childbirth, Randomized controlled trial, Anesthesia, Epidural, Catheter, Intrathecal, Local anesthetic, Spinal anaesthesia


BACKGROUND: Shivering during regional anesthesia is a common complication and is related to a decrease in the patient’s core body temperature. Previous studies have shown that acupuncture on specific acupoints can preserve core body temperature. The present study evaluated the effect of electroacupuncture in preventing the shivering caused by regional anesthesia. METHODS: This prospective and randomized controlled study analyzed the data from 80 patients undergoing urological surgery, who were classified as ASA I or II. Spinal anesthesia was performed in all patients using 15 mg of bupivacaine. The patients were randomly allocated to receive either placebo acupuncture (Group P, n = 40) or electroacupuncture (Group A, n = 40) for 30 min before administration of spinal anesthesia. Shivering score was recorded at 5 min intervals, with 0 representing no shivering and 4 representing the most severe shivering possible. Heart rate, blood pressure, and tympanic temperature were recorded before the intrathecal injection, and again every 5 min thereafter until 30 min. RESULTS: After spinal anesthesia, the decrease in tympanic temperature was less for Group A patients than Group P, with the difference being statistically significant. After 15 min, 13 patients in Group P attained a shivering score of 3 or more, compared with 3 patients in Group A. Significantly more patients in Group P attained a shivering score of at least 1. CONCLUSIONS: The prophylactic use of electroacupuncture might maintain core body temperature, and may effectively prevent the shivering that commonly develops during regional anesthesia.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12612000096853.

Concepts: Clinical trial, Randomized controlled trial, Statistical significance, Pharmaceutical industry, Clinical research, Acupuncture, Intrathecal, Spinal anaesthesia


The endogenous tetrapeptide endomorphin-2 (EM2) participates in pain modulation by binding to pre- and/or post-synaptic μ opioid receptor (MOR). In the present study, pathological expression and antinociceptive effects of EM2 at the spinal level were investigated in a rat model of bone cancer pain. The model was established by introducing Walker 256 mammary gland carcinoma cells into the tibia medullary cavity. Immunohistochemical staining for EM2 showed a markedly reduced EM2-immunoreactivity in the ipsilateral spinal dorsal horn on days 6, 12 and 18 post Walker 256 inoculation (p < 0.05). Intrathecal injection (i.t.) of EM2 significantly attenuated cancer-induced mechanical allodynia (p < 0.05) which could be blocked by β-funaltrexamine (β-FNA), the μ receptor antagonist (p < 0.05). Furthermore, topical application of EM2 dose-dependently inhibited the electrically evoked C-fiber responses and postdischarge of wide dynamic range (WDR) neurons within the spinal cord (p < 0.05), and pretreatment with β-FNA abolished the hyperactivity of these neurons. Compared with the antinociception of morphine which took effect from 40 min to 100 min post application, the analgesic action of EM2 was characterized by quick onset and short-lived efficacy (p < 0.05), being most potent at 10 min and lasting about 20 min. These findings indicate that the down-regulated spinal EM2 is an important contributor to the neuropathological process of bone cancer pain and enhancing activation of EM2/μ receptor signaling might provide a therapeutic alternative to optimizing the treatment of cancer-induced bone pain.

Concepts: Receptor, Opioid, Pain, Morphine, Opioid receptor, Buprenorphine, Pain management, Intrathecal


Advances in intrathecal analgesia and intrathecal drug delivery systems have allowed for a range of medications to be used in the control of pain and spasticity. This technique allows for reduced medication doses that can decrease the side effects typically associated with oral or parenteral drug delivery. Recent expert panel consensus guidelines have provided care paths in the treatment of nociceptive, neuropathic, and mixed pain syndromes. While the data for pain relief, adverse effect reduction, and cost-effectiveness with cancer pain control are compelling, the evidence is less clear for noncancer pain, other than spasticity. Physicians should be aware of mechanical, pharmacological, surgical, and patient-specific complications, including possible granuloma formation. Newer intrathecal drug delivery systems may allow for better safety and quality of life outcomes.

Concepts: Pharmacology, Medicine, Chemotherapy, Drug, Pain, Pharmaceutical drug, Pain management, Intrathecal


Intrathecal catheter placement into the lumbar cistern has varied indications, including drug delivery and CSF diversion. These Silastic catheters are elastic and durable; however, catheter-associated malfunctions are well reported in the literature. Fractured catheters are managed with some variability, but entirely intradural retained fragments are often managed conservatively with observation. The authors describe a case of a 70-year-old man with an implanted intrathecal morphine pump for failed back surgery syndrome who presented to an outside hospital with a history of headache, neck pain, nausea, and photophobia of 3 days' duration. He also described mild weakness and intermittent numbness of both legs. Unenhanced head CT demonstrated subarachnoid hemorrhage (SAH). A right C-5 hemilaminectomy was performed. This case is unique in that there was no indication that the lumbar intrathecal catheter had fractured prior to the patient’s presentation with SAH. This case demonstrates that intrathecal catheter fragments are mobile and can precipitate intracranial morbidity. Extrication of known fragments is safe and should be attempted to prevent further neurosurgical morbidity.

Concepts: Intracranial pressure, Pain, Subarachnoid hemorrhage, Cerebrospinal fluid, Neurosurgery, Catheter, Intrathecal, Intrathecal pump


Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.

Concepts: Time, Chemotherapy, Neurology, Leukemia, Methotrexate, Acute lymphoblastic leukemia, Nitrous oxide, Intrathecal


Background: The simultaneous presentation of systemic diffuse large B cell lymphoma (DLBCL) with central nervous system (CNS) disease is not well controlled by either R-CHOP or systemic methotrexate (MTX) alone. Methods: We conducted a pilot trial with 6 patients who were initially diagnosed with systemic DLBCL with CNS involvement. Patients were treated with a systemic MTX plus R-CHOP regimen. Results: The overall response rate was 4/6 (66.7%). The CNS response rate and systemic response rate were 4/6 (66.7%) and 5/6 (83.3%), respectively. The median response duration of the 4 patients with complete remission at completion was 25.5 months, and the median survival of all patients was 25.1 months. CNS lesions progressed in all relapsed and refractory patients, while systemic disease progression was observed in 1 patient. No fatal hematologic adverse effects, hepatotoxicity or nephrotoxicity were observed. Conclusions: The dose of systemic MTX (1∼1.5 g/m(2)) or dose intensity (4-week interval in 4 patients) used in this trial was considered insufficient. Therefore, the dose of MTX or interval of each chemotherapy cycle should be modified in future trials to control CNS disease involved with DLBCL. © 2014 S. Karger AG, Basel.

Concepts: Central nervous system, Nervous system, Brain, Chemotherapy, Lymphoma, Chemotherapy regimens, Intrathecal, Central nervous system disease