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

Sheehy et al. BMC Pediatrics (2015) 15:198 DOI 10.1186/s12887-015-0515-4 RESEARCH ARTICLE Open Access Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study Kathy A. Sheehy1†, Elena A. Muller1†, Caroline Lippold1, Mehdi Nouraie2, Julia C. Finkel1 and Zenaide M N Quezado1,3* Abstract 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. * Correspondence: † Equal contributors 1 Divisions of Anesthesiology and Pain 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, Washington, USA 3 Center for Neuroscience Research, Children’s Research Institute, Children’s National Health System, Washington, USA Full list of author information is available at the end of the article © 2015 Sheehy et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sheehy et al. BMC Pediatrics (2015) 15:198 Background Chronic pain, defined as pain lasting for more than 3 months, is common in children and adolescents and its prevalence varies according to pain location and associated primary disease [1–4]. Clinicians treating children and adolescents with chronic pain recognize that it can pose diagnostic and therapeutic challenges and children with chronic pain can have significant physical disabilities, decreased mobility, sleep disturbances, and mood disorders [5–8]. Furthermore, pain-related interference with school attendance and daily activities and pain-related emotional disturbances can be associated with increased risks of developmental stagnation and suicidal ideation [6, 7, 9, 10]. Given the biological, psychological, and social consequences of chronic pain in children and adolescents, its clinical evaluation requires exploration of these various domains and its therapy a multidisciplinary approach [11, 12]. In many children and adolescents, the pharmacologic treatment of chronic pain requires a combination of opioids, anticonvulsants, and antidepressants [13]. However, despite administration of drugs with various mechanisms of action, the treatment of chronic pain in children and adolescents can remain ineffective [13, 14]. Further, the choice of pharmacological agents to treat children and adolescents with chronic pain is predominately based on expert opinions, studies showing efficacy of given therapies in adults, and on practitioner’s consensus [15–17]. Further, as randomized clinical trials of effective therapies are lacking, the approach to treat pain in children and adolescents often involves trial and error. Therefore, it is imperative that effective therapies are developed to improve the health outcomes of children and adolescents with chronic pain. Researchers have shown that activation of the Nmethyl-D-aspartate (NMDA) receptor increases excitatory transmission in afferent pathways, contributes to sensitization of nociceptive neurons, and is involved in induction and maintenance of central sensitization, thus playing a role in the development of chronic pain [18, 19]. For this reason, ketamine, an NMDA receptor antagonist, has been investigated as an adjuvant for the treatment of chronic pain syndromes. There is some evidence, albeit not from large randomized clinical trials, suggesting that ketamine decreases pain intensity and reduces opioid requirements when used as an adjuvant to therapy of chronic and acute pain in adults [20–32]. In small clinical trials and case-series of adult patients with complex regional pain syndrome (CRPS), ketamine yields analgesia, which in some cases is reported to last for up to 11 weeks after treatment [29, 30, 32, 33]. While the use of ketamine for chronic pain has been studied much less frequently in children than in Page 2 of 8 adults, its use has shown some promise in controlling pain in pediatric patients with cancer [34]. In a phase I trial, five out of 12 adolescents with chronic pain had significant improvement in pain scores and two had resolution of pain after a 2-week oral ketamine treatment [23]. Therefore, while large randomized clinical trials are lacking, there is some evidence to suggest that ketamine might have a role in the treatment of chronic pain in children and (...truncated)