Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study

Background Chronic pain is common in children and adolescents and is often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been used as an adjuvant for treatment of adult chronic pain and has been shown, in some instances, to improve pain and decrease opioid-requirement. We examined the effects of subanesthetic ketamine infusions on pain intensity and opioid use in children and adolescents with chronic pain syndromes treated in an outpatient setting. Methods Longitudinal cohort study of consecutive pediatric patients treated with subanesthetic ketamine infusions in a tertiary outpatient center. Outcome measurements included self-reported pain scores (numeric rating scale) and morphine-equivalent intake. Results Over a 15-month period, 63 children and adolescents (median age 15, interquartile range 12–17 years) with chronic pain received 277 ketamine infusions. Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity (p \u3c0.001) and yielded greater pain reduction in patients with complex regional pain syndrome (CRPS) than in patients with other chronic pain syndromes (p = 0.029). Ketamine-associated reductions in pain scores were the largest in postural orthostatic tachycardia syndrome (POTS) and trauma patients and the smallest in patients with chronic headache (p = 0.007). In 37 % of infusions, patients had a greater than 20 % reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (p = 0.3). Conclusions These data suggest that subanesthetic ketamine infusion is feasible in an outpatient setting and may benefit children and adolescents with chronic pain. Further, patients with CRPS, POTS, and

In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is associated with brown adipose tissue and thermoregulation abnormalities

Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the disease, would recapitulate the thermoregulation impairment observed in children with INCL. We also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable to maintain body temperature as in mice thermogenesis requires upregulation of Pgc-1α and uncoupling protein 1 (Ucp-1) in brown adipose tissue. We found that the Ppt1-KO mice had lower basal body temperature as they aged and developed hypothermia during cold exposure. Surprisingly, this inability to maintain body temperature during cold exposure in Ppt1-KO mice was associated with an adequate upregulation of Pgc-1α and Ucp-1 but with lower levels of sympathetic neurotransmitters in brown adipose tissue. In addition, during baseline conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid droplets) compared to wild-type animals. After cold stress, wild-type animals had significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets compared with baseline measurements, thus suggesting that Ppt1-KO had less lipolysis in response to cold stress. These results uncover a previously unknown phenotype associated with PPT1 deficiency, that of altered thermoregulation, which is associated with impaired lipolysis and neurotransmitter release to brown adipose tissue during cold exposure. These findings suggest that INCL should be added to the list of neurodegenerative diseases that are linked to alterations in peripheral metabolic processes. In addition, extrapolating these findings clinically, impaired thermoregulation and hypothermia are potential risks in patients with INCL

Mouse current vocalization threshold measured with a neurospecific nociception assay: the effect of sex, morphine, and isoflurane.

Sine-wave electrical stimulation at frequencies 2000, 250, and 5 Hz to respectively evaluate Aβ, Aδ, and C sensory neurons has recently been added to the armamentarium used to evaluate sensory neurons. We developed an automated nociception assay using sine-wave stimulation methodology to determine current vocalization threshold in response to 2000, 250, and 5 Hz and examine the effects of sex, analgesics, and anesthetics in mice. At baseline, males had significantly higher mean current vocalization thresholds compared with female mice at 2000, 250, and 5 Hz (p ≤ 0.019). By 1 h after intrathecal injections of morphine there were significant increases in current vocalization threshold percent changes from baseline that varied with doses (p = 0.0001) and frequency used (p < 0.0001). Specifically, with increasing doses of morphine, there were significantly greater increases in current vocalization threshold percent changes from baseline in response to 5 Hz compared with 250 and 2000 Hz stimulation in a significantly ordered pattern: 5 Hz > 250 Hz (p < 0.0001) and 250 Hz > 2000 Hz (p = 0.0002). Forty-five minutes after exposure, there were no effects of isoflurane on current vocalization thresholds at any frequency. Therefore, our findings suggest that this automated nociception assay using sine-wave stimulation in mice, can be valuable for measurements of the effects of sex, opioids, and anesthetics on the response to electrical stimuli that preferentially stimulate Aβ, Aδ, and C-sensory fibers in vivo. This investigation suggests the validation of this assay and supports its use to examine mechanisms of nociception in mice

Dexmedetomidine as an Adjuvant to Analgesic Strategy During Vaso-Occlusive Episodes in Adolescents with Sickle-Cell Disease.

Patients with sickle cell disease (SCD) can experience recurrent vaso-occlusive episodes (VOE), which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some SCD patients, increasing opioid use is associated with continued and increasing pain. Dexmedetomidine, a α(2)-adrenoreceptor agonist with sedative and analgesic properties, has been increasingly used in the perioperative and intensive care settings and has been shown to reduce opioid requirement and to facilitate opioid weaning. Therefore, there might be a role for dexmedetomidine in pain management during VOEs in SCD patients. Here we present the hospital course of three patients who during the course of VOEs had severe pain unresponsive to opioids and ketamine and were treated with dexmedetomidine. Dexmedetomidine infusions that lasted for three to six days were associated with marked reduction in daily oral morphine-equivalent intake and decreases in pain scores (numeric rating scale). There were no hemodynamic changes that required treatment with vasoactive or anticholinergic agents. These preliminary findings of possible beneficial effects of dexmedetomidine in decreasing opioid requirements support the hypothesis that dexmedetomidine may have a role as a possible analgesic adjuvant to mitigate VOE-associated pain in patients with SCD

Modulation of social deficits and repetitive behaviors in a mouse model of autism: The role of the nicotinic cholinergic system

Rationale: Accumulating evidence implicates the nicotinic cholinergic system in autism spectrum disorder (ASD) pathobiology. Neuropathologic studies suggest that nicotinic acetylcholine (ACh) receptor (nAChR) subtypes are altered in brain of autistic individuals. In addition, strategies that increase ACh, the neurotransmitter for nicotinic and muscarinic receptors, appear to improve cognitive deficits in neuropsychiatric disorders and ASD. Objective: The aim of this study is to examine the role of the nicotinic cholinergic system on social and repetitive behavior abnormalities and exploratory physical activity in a well-studied model of autism, the BTBR T+ Itpr3 tf /J (BTBR) mouse. Methods: Using a protocol known to up-regulate expression of brain nAChR subtypes, we measured behavior outcomes before and after BTBR and C57BL/6J (B6) mice were treated (4 weeks) with vehicle or nicotine (50, 100, 200, or 400 μg/ml). Results: Increasing nicotine doses were associated with decreases in water intake, increases in plasma cotinine levels, and at the higher dose (400 μg/ml) with weight loss in BTBR mice. At lower (50, 100 μg/ml) but not higher (200, 400 μg/ml) doses, nicotine increased social interactions in BTBR and B6 mice and at higher, but not lower doses, it decreased repetitive behavior in BTBR. In the open-field test, nicotine at 200 and 400 μg/ml, but not 100 μg/ml compared with vehicle, decreased overall physical activity in BTBR mice. Conclusions: These findings support the hypotheses that the nicotinic cholinergic system modulates social and repetitive behaviors and may be a therapeutic target to treat behavior deficits in ASD. Further, the BTBR mouse may be valuable for investigations of the role of nAChRs in social deficits and repetitive behavior