Development of novel strategies for the treatment of pain in children

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Abstract

Acute and chronic pain are common in children and adolescents and are 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. We are examining new strategies to effectively treat pain in children, which are based on mechanistic approaches and non-opioid based. One such approach is the use of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, which has been used as an adjuvant to opioids in adult chronic pain and has been shown, in some instances, to decrease pain and minimize opioid-requirement. The use of sub anesthetic ketamine as an analgesic is supported by evidence, both from animal and human studies, implicating the activation of NMDA receptors in the pathobiology of nociceptive, inflammatory, and neuropathic pain and in central sensitization. In addition, activation of NMDA receptors has also been shown in animals and in human experimental studies to play a role in settings where acute or chronic use of opioids is associated with tolerance or opioid-induced hyperalgesia. Therefore, based on these preclinical findings, ketamine has been examined clinically as an adjuvant to opioids for the treatment of acute and chronic pain and in settings of opioid-induced hyperalgesia. We examined the effects of sub-anesthetic ketamine on pain intensity and opioid use in children and adolescents with acute and chronic pain syndromes treated both in inpatient and outpatient settings. We have shown that subanesthetic doses of ketamine can be safely administered to children and adolescents both on inpatient and outpatient settings, and in low doses it has an acceptable side-effect profile. Overall, in children with chronic pain, ketamine significantly reduces pain intensity, especially in the setting of complex regional pain syndrome. However, in patients admitted to the hospital, the effect of ketamine on pain scores varied according to clinical diagnosis, infusion duration, and pain location and greater reductions in pain scores are observed in patients with cancer pain. We have also examined a large cohort of patients with sickle cell disease (SCD), who during admissions for acute pain crises were treated with sub-anesthetic doses of ketamine. In patients with SCD, sub-anesthetic doses of ketamine in combination with opioids were associated with an overall decrease in pain intensity and in opioid consumption. We also showed in multivariate analyses that sex, age, pain location, and ketamine treatment duration were independent predictors of decreases in pain. Specifically, male sex, younger age, and longer infusions were independent predictors of greater reductions in pain scores. Additionally, the presence of chest pain predicted lesser reductions in pain scores compared with pain that was generalized. It is noteworthy that, while predictive of pain score reductions, no patient (age, sex, and pain location) or infusion characteristics (duration), were predictors of reductions in opioid consumption. Moreover, we showed in a small cohort of patients with SCD who were treated with opioids and ketamine and did not have improvement in pain scores or decreases in opioid consumption during pain crises, the addition of dexmedetomidine, an 2 agonist, can be beneficial. Those results are in keeping with our findings that dexmedetomidine ameliorates the nocifensive phenotype in SCD mice. Together, our findings suggest that in patients with SCD during the course of acute pain crises, the effects of ketamine on pain scores and opioid consumption can vary according to age, sex, and pain location. Another approach we are also exploring for the management of acute pain during the perioperative setting is the use of dexmedetomidine, an alpha2-adrenoreceptor agonist with sedative and analgesic properties. A number of animal studies support the hypothesis that dexmedetomidine may have a role in the treatment of pain. For example, in neuropathic pain models, the antinociceptive effect of dexmedetomidine appears to be opioid independent and is associated with supraspinal facilitation of inhibitory postsynaptic currents as well as inhibition of sensory neurons from the substance gelatinosa. In models of visceral pain, dexmedetomidine has antinociceptive effects unrelated to opioid receptor activation and are associated with increased nitric oxide availability. We have previously shown that in children undergoing tonsillectomies, dexmedetomidine improves pain management and prolongs opioid-free intervals during the immediate post-operative period. Additionally, in obese adolescents undergoing bariatric surgery, the intraoperative administration of dexmedetomidine decreases opioid utilization during the perioperative period. This past year after studying the effect of dexmedetomidine on regional rates of cerebral protein synthesis (rCPS), we showed that there were no differences between rCPS measured during dexmedetomidine-sedation and the awake state in ten healthy controls. In the comparison of rCPS in dexmedetomidine-sedated fragile X participants (n = 9) and healthy controls (n = 14) we found no statistically significant differences. These results from in vivo measurements in human brain do not support the hypothesis that rCPS are elevated due to the absence of Fragile X mental retardation protein. Another setting associated with acute and chronic pain in children is that of sickle cell disease. In the laboratory, we had previously shown that dexmedetomidine ameliorates the altered nociception phenotype in mouse models of sickle cell disease. We are now examining the role for dexmedetomidine in pain management during vaso-occlusive episodes in sickle cell patients. We have preliminary findings suggesting possible beneficial effects of dexmedetomidine in decreasing opioid requirements and supporting the hypothesis that dexmedetomidine may have a role as a possible analgesic adjuvant to mitigate vaso-occlusive-episodes-associated pain in patients with sickle cell disease. Overall, we have collected data on the feasibility and safety of new approaches to treat pain in children, such as the administration of sub anesthetic ketamine or the use of an alpha2 agonist, such as dexmedetomidine. These data will inform the design, sample and effect sizes calculations for the conduct of larger randomized clinical trials to identify pediatric patients who could benefit from those strategies.