Safety and Efficacy of Single-Dose Ketorolac for Postoperative Pain Management After Primary Palatoplasty: A Prospective Cohort Study With Historical Controls.

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.

IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain.

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 of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-based 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 significantly affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing 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.

Sickle cell disease subjects and mouse models have elevated nitrite and cGMP levels in blood compartments.

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.

Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease.

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.

Association between Pain Sensitivity, Central Sensitization, and Functional Disability in Adolescents With Joint Hypermobility.

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.

Rapamycin increases fetal hemoglobin and ameliorates the nociception phenotype in sickle cell mice.

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 (Aß-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(Aß-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.

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 < 0.001) 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 a history of trauma-related chronic pain are more likely to benefit from this therapeutic modality.

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 (VOEs), which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients with SCD, increasing opioid use is associated with continued and increasing pain. Dexmedetomidine, an α2 -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 patients with SCD. Here, we present the hospital course of 3 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 3 to 6 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.

Prolonged perioperative infusion of low-dose ketamine does not alter opioid use after pediatric scoliosis surgery.

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.

Barriers to and facilitators of paediatric medical device innovation: a scoping review protocol.

INTRODUCTION: The development of paediatric medical devices continues to lag adult medical devices and contributes to issues of inequity, safety, quality and patient outcomes. New legislation and funding mechanisms have been introduced over the past two decades, but the gap remains. Clinical trials have been identified as a pain point, but components of effective clinical research infrastructure are poorly understood. As part of a multimodal research strategy, the Pediatric Device Consortia (PDC) will conduct a scoping review to better understand infrastructural barriers to and facilitators of paediatric medical device clinical research identified in the health sciences literature. METHODS AND ANALYSIS: The following databases will be included for this review: Medline, Embase, Cochrane CENTRAL, Web of Science and IEEE Xplore. Additional grey literature will be sought out through Google Scholar and reviewing the citations of included studies. Included studies will discuss medical devices according to the U.S. Food and Drug Administration classification, focus on the paediatric population (ages 0-21 years) and involve human premarket or postmarket research. All study types that were published in 2007-present in English, Spanish, French or Italian will be included. Using Covidence web-based software, two independent reviewers will screen the resulting titles, abstracts and the full text of potential studies. Conflicts will be resolved by the primary investigator during both phases. REDCap will be used for quantitative and qualitative data charting, generating data tables and narrative synthesis. ETHICS AND DISSEMINATION: This research did not require research ethics board consideration as it does not involve human participants and all data will be collected from published literature. We will share our findings through peer-reviewed manuscripts, clinical and research conference presentations and professional networks available to the PDC. STUDY REGISTRATION: Open Science Framework (https://osf.io/k72bn).

Dexmedetomidine for patients undergoing diagnostic cardiac procedures: a noninferiority study.

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.

The three isoforms of nitric oxide synthase distinctively affect mouse nocifensive behavior.

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 Aß 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.

The Challenges of Identifying Fibromyalgia in Adolescents.

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.

High-dose dexmedetomidine increases the opioid-free interval and decreases opioid requirement after tonsillectomy in children.

PURPOSE: 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. METHODS: 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. RESULTS: 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) (P < 0.001). 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). CONCLUSIONS: 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).

The effect of dexmedetomidine during myringotomy and pressure-equalizing tube placement in children.

BACKGROUND: Bilateral myringotomy (BMT) is a commonly performed otolaryngologic procedure in children. OBJECTIVES: To examine the effects of intranasal dexmedetomidine, an α(2)-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 < 0.0001) and proportion of patients having pain (P = 0.016) was significantly higher in one control group (rescue analgesia only) compared with fentanyl or dexmedetomidine groups. Importantly, length of stay in the PACU was significantly longer in dexmedetomidine-2 µg·kg(-1)-treated compared with dexmedetomidine-1 µg·kg(-1)-treated, fentanyl-treated, or the control group, P = 0.0037. CONCLUSIONS: In this trial, we were unable to answer the original question as to the role of dexmedetomidine on time-averaged pain and agitation scores after BMT. However, our findings clearly demonstrate that in children undergoing BMT, at higher doses, dexmedetomidine significantly prolongs length of stay in the PACU.

Trigger point injections for axial back pain in adolescents.

Adolescents who participate in athletics or have abnormal musculoskeletal anatomy have higher incidences of back pain than non-athletic peers with normal anatomy. Significant time and money spent in diagnostic evaluations for axial back pain can result in treatment delay causing a subsequent decrease in quality of life. Myofascial trigger points are a commonly overlooked reason for axial back pain. They develop due to an abnormal myoneural connection in the setting of muscle overuse. Trigger point injections are a technically simple intervention that is both diagnostic and therapeutic in alleviating trigger point-mediated back pain. There are few complications from these injections, and they should be considered prior to surgical referral or fluoroscopic-guided interventions.

Molecular Biology of Opioid Analgesia and Its Clinical Considerations.

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.

First evaluation of tapentadol oral solution for the treatment of moderate to severe acute pain in children aged 6 to <18.

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 <18 years experiencing moderate to severe acute pain after surgery. Efficacy (change in pain intensity after tapentadol intake) was assessed in an exploratory manner using the McGrath Color Analog Scale and Faces Pain Scale-Revised. Adverse events were monitored throughout the trial. RESULTS: Forty-four patients who received a single dose of 1 mg/kg tapentadol OS were included in this investigation. Maximum serum concentrations of tapentadol (111 ng/mL) and tapentadol-O-glucuronide (2,400 ng/mL) observed in this trial were within the range of individual maximum concentrations observed in healthy adults administered a comparable dose (range for tapentadol 23.2-129 ng/mL, for tapentadol-O-glucuronide 1,040-4,070 ng/mL). Following tapentadol administration, pain intensity scores improved from baseline at all timepoints. Treatment-emergent adverse events, none of which were serious, were experienced by 45.5% of the patients; the most commonly reported were vomiting (29.5%) and nausea (9.1%). CONCLUSIONS: Tapentadol OS administered as a single dose of 1 mg/kg in children aged 6 to <18 years was generally well tolerated and produced similar serum concentrations as administration of 50-100 mg tapentadol immediate-release tablets in adults. A decrease in postsurgical pain was observed using exploratory subject-reported pain assessments. Tapentadol OS may provide a new treatment option in the management of moderate to severe acute pain in children and adolescents.

Ketamine as an adjuvant for treatment of cancer pain in children and adolescents.

UNLABELLED: 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.

Hypothermia-induced bradycardia in a neonate receiving dexmedetomidine.

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.