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Aim. Fibromyalgia (FM) is a noninflammatory disorder of the nervous system characterized by widespread musculoskeletal pain and somatic complaints of at least 3 months duration. There are no current diagnostic criteria for fibromyalgia in children to guide clinicians in recognition, thus leading to many subspecialty referrals and extensive imaging and tests. The purpose of this retrospective review is to compare two diagnostic criteria for juvenile fibromyalgia. Methods. A retrospective chart review of 20 children diagnosed with juvenile fibromyalgia from a singular pain physician practice was performed. Both the Yunus diagnostic criteria and the 2016 American College of Rheumatology (ACR) diagnostic criteria were applied and compared. Results. 85% of patients met criteria for fibromyalgia under both criteria. 15% of patients met only ACR criteria as the Yunus criteria excluded those with underlying conditions. Of the children who fulfilled criteria with use of both diagnostic tools, this cohort reported a high somatic symptom burden as demonstrated by the ACR symptom severity scales of 12 and satisfaction of at least 4 Yunus and Masi minor criteria on average. Widespread pain was noted with an ACR Widespread Pain Index (WPI) of 7, and tender points were 4.8 on average across the cohort. Effective therapeutic regimens among patients varied widely from medical monotherapy to multimodal treatment. Patients presented with pain for 1.8 yrs on average prior to a diagnosis. All of the cohort had a normal laboratory evaluation; half the cohort received additional imaging and testing. Conclusion. This case series suggests the need for an updated diagnostic tool for pediatric fibromyalgia to facilitate recognition and treatment.

Background This is the first clinical trial in the global pediatric clinical development program for the use of the analgesic tapentadol in children and adolescents. Patients and methods This multicenter, open-label clinical trial investigated pharmacokinetics, safety and tolerability, and efficacy of tapentadol and its major metabolite tapentadol-O-glucuronide after administration of a single dose of tapentadol oral solution (OS) in pediatric patients aged 6 to

Objective: To analyze safety and efficacy of single-dose ketorolac after primary palatoplasty (PP). Design: Consecutive cohort of patients undergoing PP, comparing to historical controls. Setting: A large academic children’s hospital. Patients, Participants: A consecutive cohort of 111 patients undergoing PP (study n = 47) compared to historical controls (n = 64). Interventions: All patients received intraoperative acetaminophen, dexmedetomidine, and opioids while the study group received an additional single dose of ketorolac (0.5 mg/kg) at the conclusion of PP. Main Outcome Measures: Safety of ketorolac was measured by significant bleeding complications and need for supplementary oxygen. Efficacy was assessed through bleeding, Face Legs Activity Cry Consolability (FLACC) scale, and opioid dose. Results: Length of stay was similar for both groups (control group 38.5 hours [95% CI: 3.6-43.3] versus study group 37.6 hours [95% CI: 31.3-44.0], P = .84). There were no significant differences in all postoperative FLACC scales. The mean dose of opioid rescue medication measured as morphine milligram equivalents did not differ between groups ( P = .56). Significant postoperative hemorrhage was not observed. Conclusions: This is the first prospective study to evaluate the safety and efficacy of single-dose ketorolac after PP. Although lack of standardization between study and historical control groups may have precluded observation of an analgesic benefit, analysis demonstrated a single dose of ketorolac after PP is safe. Further investigations with more patients and different postoperative regimens may clarify the role of ketorolac in improving pain after PP.

The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle ofSchistosoma mansonieggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE’s analgesic effect. In contrast, IPSE’s analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes.In vitrotesting of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE’s nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

Purpose The purpose of this study was to examine the association between pain sensitivity, central sensitization, and functional disability in adolescents with joint hypermobility. Design and Methods A cross-sectional descriptive design was utilized for this study. A sample of 40 adolescents being evaluated for chronic pain and autonomic nervous system dysfunction were recruited. Subjects were evaluated for pain, function, central sensitization, and sensitivity on pain and touch sensory nerve fiber types. Data were analyzed to detect associations between variables. Results Joint hypermobility had a moderately significant correlation with central sensitization measured by the Central Sensitization Inventory, as well as increased pain sensitivity as evidenced by hypersensitivity of Aδ sensory nerve fibers. The presence of central sensitization was also positively associated with level of functional disability. Conclusions Findings implicate joint hypermobility as a possible antecedent to pain hypersensitivity and central sensitization syndromes that when recognized and addressed effectively may reduce functional disability in those affected. Practice Implications It is important for pediatric nurses that work with adolescents that have chronic pain to understand variables that may impact pain and functional disability in order to develop methods to increase function, reduce pain, and increase perceived quality of life.

BackgroundN-methyl-D-aspartate receptor activation has been implicated in the pathobiology of inflammatory, nociceptive and neuropathic pain, opioid tolerance, opioid-induced hyperalgesia, and central sensitization. Some of those mechanisms underlie sickle cell disease(SCD)-associated pain.MethodsWe conducted an exploratory cohort study of SCD patients who during vaso-occlusive episodes (VOEs) received subanesthetic doses of the N-methyl-D-aspartate receptor antagonist, ketamine, as an adjunct to opioids. We sought to identify predictors of changes in pain scores and of the percentage of ketamine infusions associated with meaningful changes (≥20% reduction) in pain and opioid consumption.ResultsEight-five patients received 181 ketamine infusions for VOE-associated pain. Combined with opioids, ketamine yielded significant decrease in pain scores and opioid consumption. Ketamine administered to males and to younger patients yielded greater pain score decrease compared with females (P=0.013) and older patients (P=0.018). Fifty-four percent of infusions yielded meaningful reductions in pain scores, and in multivariate analysis, sex, age group, pain location, and infusion duration independently predicted pain score changes.ConclusionThis study suggests that in SCD patients admitted with VOE-associated pain, ketamine has age- and sex-dependent effects. These data can inform sample and effect size calculations for controlled trials to determine which SCD patients would benefit most from ketamine.

To evaluate the effect of dexmedetomidine infusions in patients with advanced malignancies, advanced heart disease, or after stem cell transplantation (SCT), who during end-of-life care had pain and/or agitation unresponsive to conventional therapies.Pediatric patients with intractable advanced malignancies, end-stage congenital heart diseases, or after SCT can suffer a great deal during end of life. Pain, drowsiness, fatigue, irritability, and worrying are experienced frequently, considered distressing, and are strongly associated with reductions in health-related quality-of-life scores. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use can be ineffective and can be associated with increasing pain during end of life. Dexmedetomidine, a αObservational cohort study of consecutive patients treated with dexmedetomidine during end of life in a pediatric hospital. Primary outcomes included pain scores and morphine-equivalent intake.We identified nine patients [median age 8 (interquartile range; IQR 0.55-17 years)] who during end of life had received dexmedetomidine infusions. In these patients, dexmedetomidine infusions had a median duration of two days (IQR 1.5-12 days) and were associated with significant (p 0.001) reductions in pain scores and a trend toward decreasing morphine-equivalent intake. There were no hemodynamic changes requiring vasoactive or anticholinergic agents.These preliminary findings of beneficial effects of dexmedetomidine support the hypothesis that dexmedetomidine has a role in palliative care of children and adolescents during end of life.

Kathy A Sheehy,1,* Caroline Lippold,1,* Amy L Rice,1 Raissa Nobrega,1 Julia C Finkel,1 Zenaide MN Quezado1,2 1Division of Anesthesiology, Pain, and Perioperative Medicine, The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s Research Institute, Children’s National Health System, George Washington University School of Medicine and Health Sciences, 2Center for Neuroscience Research, Children’s Research Institute, Children’s National Health System, Washington, DC, USA *These authors contributed equally to this work Background: Subanesthetic doses of ketamine, an N-methyl-D-aspartate receptor antagonist used as an adjuvant to opioid for the treatment of pain in adults with acute and chronic pain, have been shown, in some instances, to improve pain intensity and to decrease opioid intake. However, less is known about the role of ketamine in pain management in children, adolescents, and young adults. Purpose: We examined the effects of subanesthetic ketamine on pain intensity and opioid intake in children, adolescents, and young adults with acute and chronic pain syndromes treated in an inpatient setting. Methods: This is a longitudinal cohort study of patients treated with subanesthetic ketamine infusions in regular patient care units in a tertiary pediatric hospital. Primary outcomes included changes in pain scores and morphine-equivalent intake. Results: The study cohort included 230 different patients who during 360 separate hospital admissions received subanesthetic ketamine infusions for pain management. Overall, ketamine infusions were associated with significant reductions in mean pain scores from baseline (mean pain scores 6.64 [95% CI: 6.38–6.90]) to those recorded on the day after discontinuation of ketamine (mean pain scores 4.38 [95% CI: 4.06–4.69]), p

The hypothesis of decreased nitric oxide (NO) bioavailability in sickle cell disease (SCD) proposes that multiple factors leading to decreased NO production and increased consumption contributes to vaso-occlusion, pulmonary hypertension, and pain. The anion nitrite is central to NO physiology as it is an end product of NO metabolism and serves as a reservoir for NO formation. However, there is little data on nitrite levels in SCD patients and its relationship to pain phenotype. We measured nitrite in SCD subjects and examined its relationship to SCD pain. In SCD subjects, median whole blood, red blood cell and plasma nitrite levels were higher than in controls, and were not associated with pain burden. Similarly, Townes and BERK homozygous SCD mice had elevated blood nitrite. Additionally, in red blood cells and plasma from SCD subjects and in blood and kidney from Townes homozygous mice, levels of cyclic guanosine monophosphate (cGMP) were higher compared to controls. In vitro, hemoglobin concentration, rather than sickle hemoglobin, was responsible for nitrite metabolism rate. In vivo, inhibition of NO synthases and xanthine oxidoreductase decreased nitrite levels in homozygotes but not in control mice. Long-term nitrite treatment in SCD mice further elevated blood nitrite and cGMP, worsened anemia, decreased platelets, and did not change pain response. These data suggest that SCD in humans and animals is associated with increased nitrite/NO availability, which is unrelated to pain phenotype. These findings might explain why multiple clinical trials aimed at increasing NO availability in SCD patients failed to improve pain outcomes.

Understanding the molecular biology of opioid analgesia is essential for its proper implementation and mechanistic approach to its modulation in order to maximize analgesia and minimize undesired effects. By appreciating the molecular mechanisms intrinsic to opioid analgesia, one can manipulate a molecular target to augment or diminish a specific effect using adjuvant drugs, select an appropriate opioid for opioid rotation or define a molecular target for new opioid drug development. In this review, we present the cellular and molecular mechanisms of opioid analgesia and that of the associated phenomena of tolerance, dependence, and hyperalgesia. The specific mechanisms highlighted are those that presently can be clinically addressed.

Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickling, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickling and control mice as it decreased wakefulness scores compared with vehicle (all P

Summary Background Opioid consumption after posterior spinal fusion is known to be high and often exceeds those reported in other major surgical procedures. A number of clinical trials provide evidence that the perioperative use of subanesthetic doses of ketamine reduces pain and opioid requirements in some surgical procedures, but the effect of prolonged perioperative low-dose ketamine infusion in patients undergoing posterior spinal fusion for pediatric scoliosis surgery is unknown. Objective To test the hypothesis that a 72-h perioperative low-dose ketamine infusion would decrease opioid use in pediatric patients undergoing posterior spinal fusion. Methods In a double-blind prospective controlled trial, patients undergoing posterior spinal fusion for scoliosis were randomized to receive perioperative low-dose ketamine or placebo control. Patients received general anesthesia, intraoperative remifentanil, and morphine patient-controlled analgesia postoperatively. Daily opioid consumption, self-reported pain scores, and sedation scores were measured. Results Fifty-four patients were enrolled and 50 completed the study. Contrary to our hypothesis, ketamine– and control-treated patients had similar postoperative opioid use, pain scores, and sedation scores measurements. In contrast, ketamine-treated patients required less intraoperative remifentanil compared with control (mean 2.9 mg vs. 4 mg, P = 0.0415). Number of vertebrae instrumented, time between end-of-surgery and 24 h assessment, or remifentanil doses did not impact on postoperative opioid use. Over 96-h postoperatively, morphine-equivalent consumption was lower (−0.40, P = 0.006) and sedation score was higher (0.47, P = 0.0211) in male patients, compared with female patients. Conclusions These findings do not support the use of perioperative low-dose ketamine to decrease opioid use in children with scoliosis undergoing posterior spinal fusion.

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

Nitric oxide synthases (NOSs) have been shown to modulate thermal hyperalgesia and mechanical hypersensitivity in inflammatory and neuropathic pain. However, little is known about the effect of NOSs on baseline function of sensory nerve fibers. Using genetic deficiency and pharmacologic inhibition of NOSs, we examined the impact of the three isoforms NOS1, NOS2, and NOS3 on baseline nocifensive behavior by measuring current vocalization threshold in response to electrical stimulation at 5, 250, 2000 Hz that preferentially stimulate C, Aδ, and Aβ fibers. In response to 5, 250 and 2000 Hz, NOS1-deficient animals had significantly higher current vocalization thresholds compared with wild-type. Genetic deficiency of NOS2 was associated with higher current vocalization thresholds in response to 5 Hz (C-fiber) stimulation. In contrast, NOS3-deficient animals had an overall weak trend toward lower current vocalization thresholds at 5 Hz and significantly lower current vocalization threshold compared with wild-type animals at 250 and 2000 Hz. Therefore, NOSs distinctively affect baseline mouse current vocalization threshold and appear to play a role on nocifensive response to electrical stimulation of sensory nerve fibers.

Summary Background: Bilateral myringotomy (BMT) is a commonly performed otolaryngologic procedure in children. Objectives: To examine the effects of intranasal dexmedetomidine, an α2-adrenoceptor agonist, on time-averaged pain scores, pain control, need for rescue analgesia, and agitation scores in children undergoing BMT. Methods: We designed a trial to enroll 160 children randomized to one of four groups: two study groups, dexmedetomidine (1 or 2 μg·kg−1), or two control groups representing our institutional standards of practice (intranasal fentanyl-2 μg·kg−1 or acetaminophen as needed postoperatively). Results: After 101 children were enrolled, patient caregivers observed that some enrollees were excessively sedated and required prolonged postanesthesia care unit (PACU) stay. This observation led to an unplanned interim analysis and early trial termination. After data were collected, severe nonnormality of pain and agitation scores necessitated a switch of the outcome to assess repeated measurements of the proportion of patients with pain, severe pain, and agitation. Demographics, time to emergence, and agitation were similar among all groups. The risk of requiring acetaminophen rescue (P

Dexmedetomidine, a selective α(2) adrenoreceptor agonist, has analgesic and sedative properties, minimal impact on respiratory parameters, and reportedly decreases analgesic requirements after surgery. Given its pharmacodynamic profile, dexmedetomidine might have a role for postoperative pain control in children undergoing tonsillectomy. In this study, we hypothesized that dexmedetomidine would delay and decrease opioid requirements after tonsillectomy.In a double-blind controlled trial, participants undergoing tonsillectomy were randomized to receive one intravenous dose of fentanyl (1 μg·kg(-1) or 2 μg·kg(-1)) or dexmedetomidine (2 μg·kg(-1) or 4 μg·kg(-1)) immediately after endotracheal intubation. Primary outcomes included requirement for rescue morphine in the initial postoperative period.One hundred and one children were enrolled. During the postoperative period, dexmedetomidine (2 and 4 μg·kg(-1) groups combined) significantly prolonged the opioid-free interval of children who underwent tonsillectomy compared with fentanyl (1 and 2 μg·kg(-1) groups combined) (P0.001). Children treated with dexmedetomidine 2 μg·kg(-1) vs dexmedetomidine 4 μg·kg(-1) had similar cumulative incidence curves for time to morphine rescue, whereas there was a small difference in time to first morphine rescue administration when comparing fentanyl 1 μg·kg(-1) vs fentanyl 2 μg·kg(-1). Furthermore, length of stay in the postanesthesia care unit was significantly longer for children treated with dexmedetomidine vs children treated with fentanyl (P = 0.0016).High-dose dexmedetomidine decreases opioid requirements, prolongs the opioid-free interval after tonsillectomy, and prolongs length of stay in the postanesthesia care unit. It is conceivable that these early opioid-sparing effects could benefit patients at risk for respiratory complications early in the postoperative course after tonsillectomy (e.g., patients with obstructive sleep apnea). (ClinicalTrials.gov number, NCT00654511).

In children with advanced stages of cancer, pain control remains inadequate in many patients and a solution to this problem is sorely lacking. Factors related to progression of the primary disease and side-effects of high doses of opioids, the mainstay of pain therapy, contribute to the inadequacy of pain control. In addition, few studies suggest that opioids, by inducing tolerance, having pronociceptive effects and producing hyperalgesia in some patients, can also contribute to inadequacy of pain control. Researchers have shown that N-methyl-D-aspartate (NMDA) receptor antagonists may have a role in mitigating opioid-induced tolerance and hyperalgesia in adults. However, literature on NMDA antagonists to treat cancer pain in children and adolescents is scarce. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and yet had uncontrolled cancer pain. A low-dose ketamine infusion was administered to all patients to modulate the need for rapidly escalating opioid therapy. We found that in 8 of 11 patients, ketamine infusions used as an adjuvant to opioid analgesia was associated with opioid-sparing effects and apparent improvement in pain control and in the children’s ability to interact with their family. This study suggests that infusions of ketamine may offer a promising therapeutic option in the treatment of appropriately selected children and adolescents with intractable cancer pain. Perspective In many children with advanced stages of cancer, pain control remains inadequate. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and had uncontrolled cancer pain. In the majority of patients, ketamine appeared to improve pain control and to have an opioid-sparing effect.

Fetal hemoglobin-inducing therapies are disease-modifying and ameliorate the pain phenotype in sickle cell disease (SCD). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, increases HbF in erythroid precursor cells in vitro. We hypothesized that rapamycin would increase HbF levels and improve nociception phenotype in SCD mice. We used sine-wave electrical stimulation to examine nocifensive phenotype and evaluate myelinated [2000Hz (Aβ-fiber) and 250Hz (Aδ-fiber)] and unmyelinated (5Hz C-fibers)] sensory fiber function. Rapamycin significantly increased γ-globin mRNA and HbF levels [+2.3% (0.7, 3.9), mean increase (95% confidence interval, CI), p=0.006]. In homozygous (sickling) mice, long- (16 weeks), but not short-term (6 weeks), rapamycin treatment increased 2000Hz and 250Hz current thresholds in a pattern that varied according to sex. In male, but not female mice, rapamycin (compared with vehicle) was associated with increases in 2000Hz [21Units (7, 35), mean difference (95% CI), p=0.009 for sex∗treatment interaction] and 250Hz [9Units (1, 16), p=0.01] current thresholds. In rapamycin-treated homozygotes, HbF levels directly correlated with myelinated [2000Hz(Aβ-fiber, r=0.58, p=0.01) and 250Hz(Aδ-fiber, r=0.6, p=0.01)] but not unmyelinated sensory fiber current thresholds. These findings suggest that in SCD mice, rapamycin increases HbF and modulates current thresholds of myelinated fibers. Therefore, mTOR signaling might be implicated in the pathobiology of SCD.

AGE-RELATED changes in nociception has been an area of significant clinical and scientific interest over the past decades.1–6 One reason for such interest is that in the growing elderly population, pain is often associated with chronic illnesses and is one of the most common reasons prompting the need for medical care. However, it is unclear whether age-related physiologic changes in nociception contribute to increased prevalence of pain in the elderly.1,6 Another reason to study age-related changes in nociception is that when pain occurs at younger ages, it can lead to long-term changes in pain perception, processing, and development.7–11 Therefore, a better understanding of age-related changes in nociception would enable the development and delivery of age-appropriate therapy. Although the effects of aging are incompletely understood, there is evidence from human and animal studies suggesting that age-related changes in nociception have a curvilinear pattern. For example, population-based studies indicate that prevalence rates of chronic pain peak in midlife12,13 and that middle-aged individuals report larger number of pain locations, higher prevalence of fibromyalgia, and higher rates of undiagnosed causes of pain.14 In animals, age-related changes in sensitivity to longer-lasting and tonic pain peak during midlife.15 In a study evaluating pain behavior after formalin injection (a model of tissue injury and inflammation), rats displayed an age-related curvilinear pattern of sensitivity to tonic pain. Middle-aged rats showed the greatest sensitivity, whereas young and older animals displayed similar and lower sensitivity to the formalin test.15 Therefore, although the pattern of age-related changes in nociception is incompletely understood, there is growing evidence showing that it may be curvilinear. Similarly, the effects of aging in each of the individual sensory nerve fibers—Aβ (pressure sensation), Aδ (well-localized sharp pain), and C (diffuse burning pain)—are also incompletely understood. Some investigations in humans suggest that aging might differentially affect sensory nerves. Researchers have suggested that in the elderly, there is impairment of Aδ16 –18 and Aβ fibers2 manifested by abnormalities in thermal and pressure nociception. Therefore, the development of a method that allows for longitudinal studies of the effects of aging on each sensory nerve fiber is needed and could contribute to the understanding of age-related changes in nociception and to the development of age-specific therapy. In this study, we developed an assay to evaluate pain thresholds using electrical stimuli at 2,000, 250, and 5 Hz to preferentially stimulate Aβ, Aδ, and C sensory nerve fibers, respectively. In addition, contrary to most studies of nociception using methods that measure simple reflexive behavior in response to phasic nociceptive stimulation (tail-flick test, hot plate), we developed a technique that allows for the longitudinal study of complex pain-avoiding behavior in response to noxious stimulation. We defined vocalization as the pain-avoiding behavior to electrical stimuli and measured current vocalization threshold in 36 mice starting at the age of 10 weeks through their life span or 104 weeks.

Summary Background : Propofol is frequently used for the induction and maintenance of anaesthesia in children aged 3 years and older. The present study compared the clinical and chemical effects of propofol containing disodium edetate (Diprivan®) with that of sevoflurane in children younger than 3 years of age. Methods : This was an open-label, comparative, parallel-group study. Fifty-six healthy children were randomly assigned to receive either propofol (n = 28; mean age 14.7 months) or sevoflurane (n = 28; mean age 13.2 months) for ambulatory surgical procedures. Anaesthesia was induced with nitrous oxide (60%), oxygen and sevoflurane (8%). In the propofol group, it was followed by an intravenous infusion of propofol at a rate of 200 μg·kg−1·min−1. For the sevoflurane group, anaesthesia was maintained with sevoflurane (1.5–2.5%). Haemodynamic measurements, recovery time and side-effects were recorded. Ionized calcium and magnesium concentrations in blood were measured. Statistical analysis was performed using ancova and the Fisher's exact test. Results : The effects of propofol were similar to those of sevoflurane with respect to haemodynamic profile, recovery times (20 min vs 19.4 min) and side-effects (i.e. vomiting 10.7% vs 7.1%). Throughout the study, there were no significant differences between the mean ionized calcium and ionized magnesium concentrations in the two groups. Conclusions : In children younger than 3 years of age, propofol containing ethylenediaminetetraacetic acid has a similar profile to sevoflurane with respect to haemodynamic effects, recovery times, side-effects, ionized calcium and ionized magnesium levels.

IMPLICATIONS This open-label, multicenter trial was designed to determine the safety profile and analgesic efficacy of tramadol for the treatment of painful conditions lasting 7-30 days in 7-16-yr-old children. We found that tramadol 1-2 mg/kg per os every 4-6 h (maximal dose = 8 mg x kg(-1). d(-1), not to exceed 400 mg/d) is a safe and effective analgesic in this patient population.

In this double-blinded, randomized, multicenter study, we examined analgesic efficacy and tolerability of tramadol in postoperative pediatric patients. Eighty-one postsurgical ASA physical status I and II patients ages 7-16 yr received oral tramadol (approximately 1 or 2 mg/kg) for postoperative analgesia when they were ready to transition from morphine patient-controlled analgesia to oral analgesics. Rescue analgesia consisted of morphine patient-controlled analgesia or an oral equivalent dose of oxycodone. Patients rated their pain just before the administration of tramadol and at regular intervals for 8 h afterwards using the Wong-Baker Faces Pain Rating Scale. The 2-mg/kg group required approximately half as much rescue analgesia as the 1-mg/kg group (P = 0.006). Parents rated the larger dose more favorably. Adverse events were generally mild to moderate in severity (vomiting [10%], nausea [9%], pruritus [7%], rash [4%]) and similar between the two treatment groups. There were no significant changes in hemodynamic variables, respiratory rate, or SpO(2) percentages between the two treatment groups or in all patients compared with pretreatment values.Oral tramadol 1-2 mg/kg is well tolerated and effective in postoperative children ready to transition from morphine patient-controlled analgesia. The group receiving 2 mg/kg required less rescue analgesic compared with those receiving 1 mg/kg.

Background: This prospective, randomized study examined the effect of baricity of intrathecal preservative-free morphine on the duration of postoperative analgesia and incidence of side-effects in infants and children receiving high spinal anaesthesia with hyperbaric tetracaine in combination with a light general anaesthetic. Methods: Fourteen infants and children, aged 7–91 months, undergoing repair of either uncomplicated atrial or ventricular septal defects, were randomized to receive either 10 μg·kg–1 of intrathecal morphine in combination with 0.5% tetracaine D10 (hyperbaric morphine group) or intrathecal morphine mixed with saline and injected sequentially after the administration of 0.5% tetracaine D10 (hypobaric morphine group). After spinal injection, patients were positioned in 30° of Trendelenburg for a minimum of 10 min. Postoperatively, patients were monitored for a minimum of 12 h. Pain scores and the incidence and severity of side-effects were recorded every 1 h. Results: All patients were extubated at the conclusion of surgery without any incidence of respiratory depression. There was a decreased incidence of vomiting in the hypobaric morphine group and no significant difference in the duration of analgesia. Conclusions: When intrathecal morphine is administered in conjunction with a hyperbaric tetracaine spinal to paediatric cardiac patients in the head down position, sequential administration of the hypobaric solution may mitigate side-effects.

Desflurane and sevoflurane anesthesia are associated with emergence agitation in children. In this study, we examined the effect of a single intraoperative dose of fentanyl on emergence characteristics in children undergoing adenoidectomy. One hundred children, 2-7 yr old, were randomly assigned to receive desflurane or sevoflurane for maintenance of general anesthesia after an inhaled induction with sevoflurane and a 2.5 microg/kg dose of fentanyl. An observer blind-ed to the anesthetic technique assessed the times to achieve emergence, extubation and recovery criteria, as well as emergence behaviors. The results showed a similar incidence of severe emergence agitation after general anesthesia with desflurane (24%) and sevoflurane (18%). Times to achieve extubation and postanesthesia care unit discharge criteria were shorter with desflurane than with sevoflurane. With this technique, desflurane allows for a more rapid emergence and recovery than sevoflurane. In children receiving desflurane or sevoflurane, the concurrent use of fentanyl in a dose of 2.5 microg/kg results in a small incidence of emergence agitation.The concurrent use of fentanyl in a dose of 2.5 microg/kg in children receiving desflurane or sevoflurane results in a low incidence of emergence agitation. Desflurane allows for a more rapid emergence and recovery than sevoflurane.

Children undergoing placement of bilateral myringotomy tubes (BMT) often exhibit pain-related behavior (agitation) in the postanesthesia care unit. We compared the emergence and recovery profiles of pediatric patients who received sevoflurane with or without supplementary intranasal fentanyl for BMT surgery. By using a prospective, double-blinded design, 150 children 6 mo to 5 yr of age, scheduled for routine BMT surgery, were anesthetized with sevoflurane (2%-3%) in a 60% N(2)O/O(2) gas mixture. Patients were randomized to receive equal volumes of intranasal saline (Control), 1 microg/kg fentanyl or 2 microg/kg fentanyl. A blinded observer evaluated each patient using a previously described 4-point agitation scale and the Steward recovery scale. Response to parental presence was observed after a score of six (full recovery) was achieved on the Steward recovery scale. There were no significant differences among the three groups regarding age, weight, surgeon, duration of anesthesia, or ear condition. Recovery times and emergence characteristic scores were not statistically different. Agitation scores were significantly reduced in the 2-microg/kg Fentanyl group as compared with the Control group (P = 0.012). Fentanyl 2 microg/kg is recommended to reduce the incidence of agitation seen in these patients.We examined the use of nasally administered fentanyl for the relief of agitation or discomfort after placement of bilateral myringotomy tubes in 150 children ages 6 mo to 5 yr using a prospective, double-blinded design. Fentanyl 2 microg/kg was found to reduce the incidence of agitation in these patients.

UNLABELLED We compared, in a double-blinded manner, the anesthetic maintenance and recovery properties of remifentanil with a clinically comparable fentanyl-based anesthetic technique in pediatric ambulatory surgical patients. Anesthesia was induced with either halothane or sevoflurane and nitrous oxide and oxygen. Patients were randomized (computer generated) to receive either remifentanil or fentanyl in a blinded syringe with nitrous oxide and oxygen in one of four possibilities: halothane/remifentanil, halothane/fentanyl, sevoflurane/remifentanil or sevoflurane/fentanyl. In patients receiving remifentanil, a placebo bolus was administered, and a continuous infusion (0.25 microg. kg(-1). min(-1)) was begun. In patients receiving fentanyl, a bolus (2 microg/kg) was administered followed by a placebo continuous infusion. The time from discontinuation of the anesthetic to extubation, discharge from the postanesthesia care unit (PACU), and discharge to home, as well as pain scores, were assessed by a blinded nurse observer. Systolic blood pressure and heart rate were noted at selected times, and adverse events were recorded. Remifentanil provided faster extubation times and higher pain-discomfort scores. PACU and hospital discharge times were similar. There were no statistical differences among the groups for adverse events. There were statistically, but not clinically, significant differences in hemodynamic variables. We noted that continuous infusions of remifentanil were intraoperatively as effective as bolus fentanyl. Although patients could be tracheally extubated earlier with remifentanil, this did not translate to earlier PACU or hospital discharge times. In addition, remifentanil was associated with higher postoperative pain scores. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanil's use as an anesthetic for children. IMPLICATIONS This is a study designed to examine the efficacy and safety of a short-acting opioid, remifentanil, when used in pediatric patients. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanil's use as an anesthetic for children.

Unilateral epidural anaesthesia occurring in an infant is reported. An epidurogram revealed the presence of a midline structure suggestive of the dorsomedian septum. Epidural anatomy is reviewed and implications for threading epidural catheters in infants are discussed.

Background: Opioids are the mainstay of therapy for painful vasoocclusive episodes (VOEs) in sickle cell disease (SCD). Based on limited studies, low-dose ketamine could be a useful adjuvant analgesic for refractory SCD pain, but its safety and efficacy has not been evaluated in pediatric SCD. Procedure: Using retrospective chart review we recorded and compared characteristics of hospitalizations of 33 children with SCD hospitalized with VOE who were treated with low-dose ketamine and opioid PCA vs. a paired hospitalization where the same patients received opioid PCA without ketamine. We seek to 1) describe a single center experience using adjuvant low-dose ketamine with opioid PCA for sickle cell related pain, 2) retrospectively explore the safety and efficacy of adjuvant low-dose ketamine for pain management, and 3) determine ketamine’s effect on opioid consumption in children and adolescents hospitalized with VOE. Results: During hospitalizations where patients received ketamine, pain scores and opioid use were higher (6.48 vs. 5.99; p=0.002 and 0.040 mg/kg/h vs. 0.032 mg/kg/h; p=0.004 respectively) compared to hospitalizations without ketamine. In 3 patients, ketamine was discontinued due to temporary and reversible psychotomimetic effects. There were no additional short term side effects of ketamine. Conclusions: Low-dose ketamine has an acceptable short-term safety profile for patients with SCD hospitalized for VOE. Lack of an opioid sparing effect of ketamine likely represents use of low-dose ketamine for patients presenting with more severe VOE pain. Prospective randomized studies of adjuvant low-dose ketamine for SCD pain are warranted to determine efficacy and long-term safety.

To report the use of dexmedetomidine to facilitate rapid opioid and benzodiazepine withdrawal in children with transplanted hearts and to review the receptor physiology and pharmacodynamic impact of dexmedetomidine on the denervated heart.Case series.Intensive care unit at a tertiary pediatric medical center.The series included a 6-month-old infant with pulmonary atresia who had a 3-month exposure to high-dose opioids and benzodiazepines and had undergone cardiac transplantation 4 wks before the use of dexmedetomidine and a 7-yr-old boy who had been sedated while undergoing extracorporeal membrane oxygenation for 3 wks before transplantation and started to receive dexmedetomidine 3 days after transplantation.Administration of dexmedetomidine to facilitate the discontinuation of opioids and benzodiazepine.Successful rapid withdrawal from opioids and benzodiazepines while maintaining hemodynamic stability.To our knowledge, this report describes the first use of dexmedetomidine to facilitate opioid withdrawal in children with a cardiac transplant. Dexmedetomidine allowed for the preservation of satisfactory hemodynamic parameters during acute withdrawal from opioids in children with denervated hearts.

Microfluidic synthesis of small and nearly-monodisperse liposomes is used to investigate the size-dependent passive transdermal transport of nanoscale lipid vesicles. While large liposomes with diameters above 105 nm are found to be excluded from deeper skin layers past the stratum corneum, the primary barrier to nanoparticle transport, liposomes with mean diameters between 31-41 nm exhibit significantly enhanced penetration. Furthermore, multicolor fluorescence imaging reveals that the smaller liposomes pass rapidly through the stratum corneum without vesicle rupture. These findings reveal that nanoscale liposomes with well-controlled size and minimal size variance are excellent vehicles for transdermal delivery of functional nanoparticle drugs.

In this work, the established technique for microfluidic synthesis of nanoscale liposomes of tunable size has been exploited for preclinical studies investigating the ability of small liposomes to passively cross through dermal layers for transdermal drug delivery. Topical application of therapeutics provides an avenue for painless, noninvasive delivery of molecules aimed at a range of clinical conditions. Unlike traditional methods, which yield polydisperse liposomes too large to traverse dermal layers (typically >80 nm), the microfluidic method enables the first investigation of nearly-monodisperse liposomes which are within the size range of interest (approximately 40 nm and below) for passive transdermal drug delivery. Here, the microfluidic method for liposome production has been utilized to generate small, nearly-monodisperse liposomes and demonstrated size-dependent passive uptake into porcine dermal tissue.

When anesthetizing children with congenital heart disease for diagnostic cardiac catheterization, anesthesiologists and cardiologists seek to use anesthetic regimens that yield minimal hemodynamic changes and allow for spontaneous ventilations. Recently, dexmedetomidine has been used as an anesthesia adjunct because of its sedative and analgesic properties and minimal ventilatory depressive effects. We tested the hypothesis that the combination of sevoflurane and dexmedetomidine is non-inferior to sevoflurane alone as it refers to hemodynamic measurements during diagnostic cardiac catheterization in children with a transplanted heart, one ventricle (Fontan procedure), or normal cardiac physiology. Patients were anesthetized with inhalation of sevoflurane in nitrous oxide/oxygen and, after baseline hemodynamic measurements, successive boluses of dexmedetomidine followed by continuous infusion were administered. In this study, non-inferiority was shown when differences at steady-state (dexmedetomidine + sevoflurane) compared to baseline (sevoflurane alone) and its associated 95% confidence interval fell completely within the range of plus or minus 20%. Forty-one (26 normal physiology, 9 cardiac transplantation, and 6 Fontan) patients were enrolled. Non-inferiority of sevoflurane + dexmedetomidine compared with sevoflurane alone was shown for heart rate, but not for arterial blood pressure in patients with normal and cardiac transplant physiology. In patients with normal cardiac physiology, non-inferiority was demonstrated for bispectral index. Therefore, while the lack of depressive respiratory effects and non-inferiority for heart rate are desirable, the lack of non-inferiority of dexmedetomidine + sevoflurane combination for arterial blood pressure do not justify the routine use of this combination compared with sevoflurane alone for children with congenital heart disease undergoing cardiac catheterization.

Dexmedetomidine, an alpha(2)-adrenergic agonist, decreases lipolysis and thus prevents nonshivering thermogenesis in infants. We report the case of a two-day-old neonate who received dexmedetomidine for sedation and analgesia after undergoing primary repair of bladder exstrophy. After 9 hours, the patient developed bradycardia and profound hypothermia. The bradycardia was unresponsive to anticholinergics but resolved approximately two hours after radiant heat was applied. This report highlights the potential profound impact of dexmedetomidine on thermoregulation in neonates. Dexmedetomidine impacts thermoregulation in neonates and its use warrants careful attention to the control of temperature and to the routine use of exogenous heat.

BACKGROUND The current study was conducted to assess the safety and tolerability of a transdermal fentanyl delivery system for the relief of chronic pain in a pediatric population, and also to validate titration recommendations and conversion to transdermal fentanyl from oral opioid therapy. METHODS This 15-day (with 3-month extension), single-arm, open-label trial was conducted at 66 sites in 10 countries. A total of 199 pediatric patients (ages 2–16 years) with both malignant and nonmalignant conditions who were receiving oral or parenteral opioids for moderate to severe chronic pain were enrolled. Transdermal fentanyl doses were titrated upward according to the rescue medication consumed during the previous application period. Degree of pain was assessed by patients and parents/guardians using visual and numeric scales. Level of play and quality of life were assessed using the Play Performance Scale (PPS) and the Child Health Questionnaire (CHQ). Adverse events were monitored on Days 1–15. Hypoventilation and sedation were monitored every 4 hours during the first 72 hours of the study. RESULTS A total of 173 patients completed the primary treatment period and 130 entered the extension phase. The average daily pain intensity scores were reported to have decreased by Day 16 and improvements in the mean PPS scores were observed to the end of the extension period. The CHQ scores demonstrated improvements in 11 of 12 domains after Month 1 of the extension period. CONCLUSIONS Transdermal fentanyl was found to be a safe and well tolerated alternative to oral opioid treatment for children ages 2–16 years who were previously exposed to opioid therapy. Cancer 2005. © 2005 American Cancer Society.

Prolonged use of opioids and benzodiazepines for the care of critically ill infants and children can generate physical dependence. We present a case of an 8-mo-old infant with Hunter’s syndrome who was maintained on very large doses of fentanyl and midazolam and who could not be weaned from these drugs by conventional taper. We used dexmedetomidine, an 2-adrenergic agonist, to facilitate opioid and benzodiazepine withdrawal. A processed electroencephalogram (Bispectral Index) was used to guide the titration of dexmedetomidine in this neurologically impaired infant. This is the first report of this drug being used in an infant to manage chemical dependence withdrawal. (Anesth Analg 2004;98:1658 –9) T he use of opioids and benzodiazepines for sedation is a mainstay of intensive care unit (ICU) patient care. The dependence that develops with long-term use of these drugs creates new problems for the patients and the ICU team directing their care. We present a case of an 8-mo-old infant with Hunter’s syndrome who was maintained on very large doses of fentanyl and midazolam. He could not be weaned from these drugs by a conventional withdrawal taper technique, and dexmedetomidine was used. Case Report A 13.3-kg boy with Hunter’s syndrome developed respiratory failure of unknown etiology that required mechanical ventilation from birth. In the neonatal ICU (NICU), he was intubated and mechanically ventilated over the next 6 mo while the cause for his respiratory failure was investigated. At age 7 mo, the diagnosis of Hunter’s syndrome was verified, and the patient underwent a tracheostomy. Fentanyl 3370 g/d and midazolam 270 mg/d were used to achieve adequate sedation. Attempts to slowly wean the sedatives by 5% yielded unacceptable agitation, tachycardia, and hypertension. To transfer the patient from the NICU, IV sedatives needed to be discontinued. The Anesthesia Pain Service was consulted for evaluation of alternative methods for weaning the infant from opioid and benzodiazepine dependence. Methadone was not considered because of the infant’s severely limited enteral intake. An acute detoxification was therefore attempted with dexmedetomidine to prevent an acute abstinence syndrome. The baseline neurological impairment of the infant made it difficult to evaluate the depth of sedation. The infant was both blind and deaf and manifested 10 –20 beats of clonus when touched. Because typical sedation scales implement auditory and tactile stimuli, a Bispectral Index score (BIS) (Aspect Systems, Newton, MA) was used to help guide the titration of the dexmedetomidine. The BIS monitor was placed 6 h before the midazolam and fentanyl infusions were stopped, to determine the baseline values occurring with adequately sedated behavior. On the basis of the observations made during this period, a target BIS value of 60 – 80 was used. Immediately after the fentanyl and midazolam infusions were discontinued, the dexmedetomidine infusion was initiated with an initial loading dose of 1 g/kg given over 10 min followed by a continuous rate of 0.2 to 0.7 g·k g 1 ·h 1 to keep the BIS within the targeted range. If the maximum rate of 0.7 g·k g 1 ·h 1 was reached and the BIS score was more than 80 or the arterial blood pressure was 20% of baseline, the initial dose could be repeated every 6 h. (This was needed on Days 2, 3, and 4 at least once a day.) The infusion was tapered off on Day 7. No rebound effects were noted hemodynamically or behaviorally during the taper. The patient manifested no agitation for the ensuing 2 wk and was transferred to a chronic care facility.

Summary Background: This prospective series examined the haemodynamic effects of high spinal anaesthesia in combination with light general anaesthesia in infants and children undergoing open heart surgery who were candidates for immediate or early postoperative extubation. Methods: After midazolam premedication and sevoflurane inhalation induction, 30 patients, aged 7 months to 13 years, who were undergoing open heart surgery, received spinal anaesthetics with 0.5% tetracaine D10 mixed with morphine. The spinal blocks were placed at the L2,3 or L3,4 interspace with cephalad spread being promoted by positioning the patient in 30° of Trendelenburg for a minimum of 10 min. Maintenance of anaesthesia was with isoflurane 0.2–0.5% in 70% nitrous oxide to maintain heart rate and blood pressure within 20% of postinduction baseline values. Haemodynamic values were recorded at predetermined timed intervals and intraoperative events up to and including aortic cannulation. For analysis of the data, patients were divided into four age groups ( 7 years). Results: Haemodynamic stability was demonstrated in all four age groups. Statistically significant slowing of the heart rate did occur in the groups older than 1 year at 25 min, although clinically significant bradycardia requiring treatment never occurred. Hypotension did occur during specific surgical manipulations but recovered spontaneously. Atropine, fluid boluses and vasopressors were never used. At the conclusion of surgery, all patients met extubation criteria and could move all four extremities. Conclusions: High spinal anaesthesia with hyperbaric tetracaine and morphine in combination with light general anaesthesia is well tolerated haemodynamically by the paediatric population studied.

UNLABELLED We used a neuroselective transcutaneous electrical stimulus to determine the onset time of cutaneous anesthesia with 4% liposomal lidocaine under occluded and nonoccluded conditions. The pain tolerance threshold (PTT) was used to atraumatically evaluate nociception. Twenty adult volunteers had liposomal lidocaine applied to the volar surface of each forearm for durations ranging from 0 through 30 min (at 5-min intervals) under occluded and nonoccluded conditions. The PTT was determined using three different frequencies (2000 Hz, 250 Hz, 5 Hz) stimulating A beta, A delta, and C fibers, respectively. The time to reach the maximum PTT achieved defined the anesthetic onset time for each frequency. A differential onset of cutaneous anesthesia among the three frequencies was clearly demonstrated, however there was no significant difference in onset time between occluded and nonoccluded conditions. Blockade of C fiber transmission occurred significantly earlier than that of A delta (P = 0.029), which occurred earlier than that of A beta (P = 0.001) as determined using the Wilcoxon's signed rank test. We conclude that a mean onset time of approximately 4 +/- 2 min for blockade of C fiber transmission and 6 +/- 4 min for A delta fiber transmission suggests that painful stimuli such as venipuncture may be attenuated as early as 7 min. IMPLICATIONS An average onset time of approximately 7 min for topical 4% liposomal lidocaine was determined using neuroselective neurostimulation. This suggests that procedural pain such as venipuncture may be attenuated in this time frame. This technique requires correlation with conventional sensory measurements.