Non-Opioid Pharmacology in Pediatric Pain Management
Utilizing Ketamine in Pediatric Pain Management
By Kaitlyn Pellegrino, MD and Amy Beethe, MD
Department of Anesthesiology
Children’s Hospital & Medical Center
University of Nebraska Medical Center
Background and Mechanism
Pediatric perioperative pain is an ever-evolving topic, with continued increasing emphasis on opioid sparing, multimodal techniques. Our practices and knowledge are constantly advancing as we take care of more complex patients for more complicated surgeries. One area of investigation in pediatric perioperative pain is the use of N-methyl-D-aspartate (NMDA) antagonists such as ketamine. Ketamine and other NMDA antagonists have been shown in adults to mitigate the central nociceptive response decreasing both acute pain and opioid tolerance.1 Furthermore, ketamine has anti-inflammatory effects. A systematic review concluded that intraoperative ketamine reduces the postoperative IL-6 inflammatory response in surgical patients.2 Ketamine is a sympathomimetic and therefore does not significantly alter hemodynamics but can cause hypertension and tachycardia. The potency of NMDA receptor antagonists is directly related to their affinity for the NMDA receptor.3-4 Ketamine is unique in that it can be delivered by the intravenous, intranasal, oral, rectal, or intramuscular routes.
Safety and Toxicity
NMDA receptor antagonists have been shown to induce neuronal apoptosis in animal models but the impact in humans is undetermined. It is known that ketamine’s preservative, chlorobutanol, is neurotoxic so ketamine cannot be used in its normal formulation for subarachnoid or epidural injection. The S (+) enantiomer of ketamine is available as a preservative free solution and therefore is used in mainly caudal administration in the pediatric population.1 Ketamine has also been shown to cause hepatic and renal toxicity; however, this is seen primarily with recreational use or long term chronic pain use and not with the sub-anesthetic doses used in perioperative acute pain management.5-6 The most commonly reported adverse effects are hallucinations and agitation. The safety profile of ketamine is significantly increased by the lack of respiratory depression or decreased airway reflexes that are associated with other analgesics.7
Important Kinetic Differences Between Adults and Pediatrics
Ketamine is highly lipid soluble which leads to rapid onset. The half-life of ketamine is approximately 45 minutes, and its action is terminated by redistribution.8 It is metabolized by the liver, largely by the cytochrome P450 system. The differences in pharmacokinetics and pharmacodynamics between pediatric and adult patients could be the key to understanding the varied impacts of ketamine between the two populations. First, pediatric patients seem to be less sensitive to ketamine than adults, with ketamine concentrations at arousal measured at 0.9-3.8 mg L-1 in pediatrics compared to adult levels of 0.5mg L-1.9-10 Similarly, ketamine also has a shorter context-sensitive half-time in pediatrics than adults after 1.5 hours of infusion. The context-sensitive half-time after five hours of ketamine infusion was 60 mins in children and 83 mins in adults.11 Given these differences, one could hypothesize that further research on ketamine use in pediatrics at higher doses, could lead to success rates of reducing opioid consumption paralleling the adult literature.
Usage of Ketamine in Adult Population
In adults, ketamine use in the perioperative setting is well supported in the literature. A systematic review of 37 articles on the perioperative use of ketamine for acute post-operative pain by Bell et. al reported that 27 studies found that ketamine decreased overall pain intensity or postoperative analgesic requirements or both, particularly in surgeries associated with high pain scores.12 Further analysis showed that ketamine in the first 24 hours after surgery reduced morphine requirements and decreased the incidence of postoperative nausea and vomiting.12 Ten trials found no benefit of ketamine over placebo.12
However, further research is needed for consensus on not only optimal ketamine dose but also if bolus or bolus plus infusion leads is the most advantageous for treatment of pain. For chronic pain, there is a paucity of data to support prolonged benefits from the use of ketamine for either cancer and non-cancer related chronic pain.13 That said, despite limited data to suggest benefit, a trial of low-dose ketamine in conjunction with opiate therapy is recommended in chronic cancer pain unresponsive to opiates.14 Though ketamine is widely accepted as beneficial in the perioperative setting, Maheshwari et al. out of the Cleveland Clinic examined the benefits of a multimodal analgesic strategy including ketamine for 299 adults at high risk for pain undergoing multilevel posterior spine surgery.15 That study was ended early for futility when they found no clinically significant decrease in Quality of Recovery outcomes or in 48 hour post-op opioid use.15 While ketamine was only one aspect of the multimodal pathway of this multimodal protocol, it suggests that there is still more to learn about ketamine’s role in adult perioperative pain management.
Usage of Ketamine in Pediatric Perioperative Care and Pain Management
Ketamine is also used to treat pediatric pain. However, the opioid sparing effect is not clear.16 Dahmani et al. conducted a meta-analysis of 35 randomized, blinded, and controlled studies in the pediatric use of ketamine. Eighteen studies involved the use of systemic ketamine, four studies utilized topical or local ketamine during tonsillectomy, and thirteen studies involved the use of ketamine as an adjuvant to local anesthetics or opioid during caudal analgesia.17
This analysis found that use of systemic ketamine led to a reduction in post-operative care unit (PACU) pain scores and analgesic use; however, there was no post-operative analgesic sparing from hours 6-24 in pediatric patients.17 This data was supported by Michelet et al. who did a meta-analysis on 11 studies on the effect of systemic ketamine on postoperative opiate requirements. This meta-analysis found that ketamine did not decrease the use of opiate use in the first 24 hours postoperatively.18
Similarly, in a randomized, controlled trial of 29 patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis, patients were given a bolus of 0.5 mg/kg prior to surgical incision, an intraoperative infusion at 0.25mg/kg/h, and a postoperative infusion of 0.1mg/kg/h for 72 hours where there was no difference in total morphine consumption and pain scores compared to those in the placebo (saline) group for 96 hours postoperatively.19 Pediatric patients undergoing tonsillectomy have a high incidence of obstructive sleep apnea and are sensitive to opioids.20 Thus, the lack of respiratory depression associated with ketamine makes this a very attractive analgesic.
Elshamma et. al found patients undergoing tonsillectomy that received ketamine 0.5 mg/kg with or without fentanyl had superior analgesia on arrival to the PACU without the side-effects that would typically accompany increase in opioid doses.21 Ketamine administered locally during tonsillectomy has shown more promising results with decreased PACU and early (6-24 h) pain scoring; however, early analgesic requirements were not decreased.17 Finally, it has been shown that if ketamine is used as a caudal adjuvant, it increased the duration of the block with improved pain relief at emergence; however, pain scores in PACU were not shown to be affected.17
Lastly, a single center cohort study examined 280 pediatric patients who received sub-anesthetic ketamine infusions for effects on pain intensity and hospital opiate use. Twenty-two percent of these patients had acute pain and 78% of patients had chronic pain. Perioperative patients accounted for 17% of all patients.22 Patients affected by cancer related pain and inflammatory processes (pancreatitis and Crohn’s disease) showed the greatest reduction of pain scores.22 Conversely, patients with acute postoperative pain were found to have minimal opioid sparing effects by a ketamine infusion. Of note there was no standardization of ketamine dosing or titration of other narcotics in this study. More research is needed on the benefit of ketamine for pediatric chronic pain to draw definitive conclusions.
There are significant differences between the adult and pediatric literature with regards to the beneficial use of ketamine for perioperative care and pain management. While there is strong evidence to suggest the use of perioperative ketamine decreases morphine requirements 24 hours after surgery while reducing PONV in adults, the pediatric literature is not as convincing. This could be due to the pharmacokinetics and pharmacodynamics properties of ketamine in children. However, more research is needed to draw definitive conclusions.
- Hurley, R. W., Murphy, J. D., & Wu, C. L. (2015). Acute Postoperative Pain. Miller's Anesthesia (8th ed., Vol. 2, pp. 2974–2998). Philadelphia, PA: Elsevier.
- Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg 2012; 115: 934–43.
- Anis, N. A., Berry, S. C., Burton, N. R., & Lodge, D. (1983). The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate. British journal of pharmacology, 79(2), 565-575.
- Luethi, D., & Liechti, M. E. (2020). Designer drugs: mechanism of action and adverse effects. Archives of toxicology.
- Mendelson AM, Kohan L, Okai J, et al Adverse drug effects related to multiday ketamine infusions: multicenter study Regional Anesthesia & Pain Medicine Published Online First: 12 February 2020.
- Noppers, I. M., Niesters, M., Aarts, L. P., Bauer, M. C., Drewes, A. M., Dahan, A., & Sarton, E. Y. (2011). Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain, 152(9), 2173-2178.
- Thangathurai D, Roffey P. Postoperative pain relief with ketamine in patients with central sleep apnea. J Clin Sleep Med 2009; 5: 480.
- Rosenbaum SB, Gupta V, Palacios JL. Ketamine. Updated 2020 Feb 16. StatPearls. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Available from: https://www.ncgi.nlm.nih.gov/book/NBK470357.
- Indvall J, Ahlgren I, Aronsen KR, Stenberg P. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth. 1979; 51(12): 1167-73.
- Grant IS, Nimmo WS, McNicol LR, Clements JA. Ketamine disposition in children and adults. Br J Anaesth. 1983; 55(11): 1107-11.
- Dallimore D, Anderson BJ, Short TG, Herd DW. Ketamine anesthesia in children-exploring infusion regimens. Paediatr Anaesth. 2009; 18(8): 708-14.
- Bell R, Dahl J, Moore R, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005; 49: 1405-1428.
- Hocking G, Cousins M. Ketamine in chronic pain management: an evidence-based review. Anesth Anal 2003; 97: 1730-1739.
- Bredlau A, Rajbala T, Korones D, Dworkin R, Ketamine for pain in adults and children: a systematic review and synthesis of the literature. Pain Medicine 2013; 10 1505-1517.
- Maheshwari, K., Avitsian, R., Sessler, D. I., Makarova, N., Tanios, M., Raza, & Krishnaney, A. (2020). Multimodal Analgesic Regimen for Spine Surgery A Randomized Placebo-controlled Trial. Anesthesiology: The Journal of the American Society of Anesthesiologists.
- Russell, P., von Ungern-Sternberg, B. S., & Schug, S. A. (2013). Perioperative analgesia in pediatric surgery. Current Opinion in Anesthesiology, 26(4), 420-427.
- Dahmani S, Michelet D, Abback PS, Wood C, Brasher C, Nivoche Y, Mantz J. Ketamine for perioperative pain management in children: a meta-analysis of published studies. Paediatr Anaesth. 2011; 21(6): 636–652.
- Michelet D, Hilly J, Skhiri A, Abdat R, Diallo T, et al. Opioid-sparing effect of ketamine in children: A meta-analysis and trial sequential analysis of published studies. Pediatr Drugs. 2016; 18: 421-433.
- Seki, H., Ideno, S., Ishihara, T., Watanabe, K., Matsumoto, M., Morisaki, H. (2018). Postoperative pain management in patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis: a narrative review. Scoliosis and spinal disorders, 13, 17. https://doi-org.library1.unmc.edu/10.1186/s13013-018-0165-z
- Schwengel D, Sterni L, Tunkel D, Heitmiller E. Perioperative management of children with obstructive sleep apnea. Anesth Analg 2009; 109: 60-75.
- Elshammaa, N., Chidambaran, V., Housny, W., Thomas, J., Zhang, X., & Michael, R. (2011). Ketamine as an adjunct to fentanyl improves postoperative analgesia and hastens discharge in children following tonsillectomy - a prospective, double-blinded, randomized study. Paediatric anaesthesia, 21(10), 1009–1014.
- Sheehy KA, Lippold C, Rice AL, Nobrega R, Finkel JC, Quezado ZMN. (2017). Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study. J Pain Res. 10, 787-795.