Topics of Interest

Systematic Non-Opioid Analgesia for Postoperative Pediatric Pain

By Bobbie L Riley, MD

While working to overcome the barriers of effective pain management, consideration of interventions that have been evaluated in adult literature can lead to more effective pediatric patient care.  Enhanced Recovery After Surgery (ERAS) is a multimodal perioperative care plan delivered to surgical patients and serves as an example of using evidence-based best practice to establish a standardized approach to the surgical patient allowing for ongoing adaptation and collaboration by multiple disciplines.1-2

In adults, this targeted approach has resulted in improved patient outcome by reducing length of stay and reducing complication rates.3 Improvement in care is shown to be an upshot of multimodal efforts by minimizing the surgically induced stress response.3 Evidence of the impact from an enhanced recovery approach in the pediatric literature is limited by confounding variables such as the heterogenic surgical population (surgical types and acuity), as well as the amount of ERAS society recommendations incorporated in these evaluated approaches. 

Similar in concept, a bundled approach has shown that structured intervention for management of pain in children following day surgery is effective. Walther-Larsen et al, recently found that a “surgery-specific regime” improved pain management in children after ambulatory surgery. Furthermore, available studies evaluating ERAS in the pediatric population conclude thus far it appears safe and potentially effective.4

Moderate to severe pain is poorly managed in approximately 30% of postoperative pediatric patients32 Previously, opioids were the first line rescue medication for this type of pain; however, opioids are associated with significant adverse effects.31 Multimodal pain management achieves analgesia through the effects of different classes of analgesics working through different mechanisms of action, allowing for an overall reduction in each of the individual drugs with equivalent or improved pain control.28 Through these diverse modes of action, multimodal analgesic strategies continue to evolve with shown efficacy in adult literature. As a result, non-opioid analgesia has transitioned to the first line approach to managing perioperative pain, allowing for opioids to be reserved as rescue analgesia.  With reduced opioid consumption for pain control there is a reduced incidence of opioid-related adverse effects; nausea, vomiting, sedation, pruritis, GI dysmotility, and respiratory depression, all of which can limit rapid recovery and rehabilitation.5-6 Early use of non-opioid analgesia is also associated with reduced odds of serious postoperative adverse events and the need for rescue medication in pediatrics.7

Below is a review of systemic, non-opioid analgesia for consideration in optimizing the quality of perioperative pain control and therefore the quality of postoperative recovery.5,6 Systemic, non-opioid analgesics include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) and other adjuvants such as gabapentinoids, NMDA antagonists, glucocorticoids, a-2 agonists and local anesthetics.  Each of these differ in mechanism of action (anti-nociceptive, anti-inflammatory or anti-hyperalgesic) and act at various locations within the pain pathway.  

  • Acetaminophen is one of the most commonly used non-opioid analgesic medications.  It acts predominately as an antipyretic.  Although not entirely clear, it’s mechanism of action appears to inhibit cyclooxygenase centrally and activate descending serotonergic pathways.8 Acetaminophen has been shown to reduce postoperative pain intensity and in doing so has an opioid sparing effect.9-11,28 Various routes of administration are available.  Preliminary comparison of intravenous administration to oral administration suggest there is no difference in the impact of opioid consumption between the two.34,35
  • NSAIDs’ primary mechanism of action is anti-inflammatory by inhibiting prostaglandins, both centrally and peripherally.  There is strong evidence to support that they reduce postoperative pain intensity, opioid consumption and, as a result, adverse opioid side effects.10-12, 28 Many postoperative pain control studies for children in an ambulatory setting are carried out following tonsillectomy because of the associated moderate to severe postoperative pain. Associated risk for bleeding with NSAIDS due to their impact of platelet aggregation has resulted in a concern for use in this population. Yet, the most recent literature does not support a significant risk for bleeding with their use for tonsillectomy pain.36,37
    Combining NSAIDs with acetaminophen may afford more effective pain relief than either independently. The additive effect of the combination of NSAIDs and acetaminophen is commonly used for postoperative pain relief.  Some evidence suggests that combining these medications may also have a synergistic effect.9,10 When they are not contraindicated, NSAIDs and acetaminophen should be administered around the clock to the postsurgical patient.28
  • Gabapentinoids, such as gabapentin, act on the alpha-2-delta subunit of voltage gated calcium channels in the central nervous system. Gabapentinoids may be an effective part of a multimodal approach in managing postoperative pain. They reduce pain intensity and reduce opioid consumption, thereby decreasing the adverse effects of opioids.21,22 Muhly et al incorporated gabapentin in a multimodal clinical pathway for rapid recovery following scoliosis surgery allowing for shorter length of stay without an increase in reported pain scores or readmission rates. Gabapentin may also effectively reduce the incidence of chronic postsurgical pain.23
  • Ketamine, a N-methyl-D-aspartate antagonist, has known analgesic and anesthesia properties.8 It is safely used in children.17,18 Concern for adverse drug effect occurs at higher dosing rates than those required for analgesic effect.39 Ketamine at analgesic dosing decreases pain intensity intraoperatively, although evidence of a postoperative opioid sparing effect is unclear.38 Loftus et al found an opioid sparing effect with the intraoperative use of low dose Ketamine in adult chronic back pain patients undergoing back surgery.40 This may reflect the role of low dose Ketamine as an antihyperalgesic and partly why adding low dose Ketamine to morphine PCA/NCA improves analgesia in children for mucositis pain.41,42
  • Glucocorticoids are primarily anti-inflammatory and may also affect anti-nociceptor receptors.  Dexamethasone, is frequently used to reduce perioperative nausea and vomiting.8 De Oliveira et al found that a single dose of systemic dexamethasone of more than 0.1 mg/kg can be an effective adjunct in a multimodal strategy for reducing postoperative pain and opioid consumption after surgery.43 Systemic administration of dexamethasone as an adjunct to peripheral nerve blockade prolongs analgesic duration.45 Comparing systemic to perineural administration of dexamethasone in adults suggests perineural administration may further extend this analgesic effect.44 The safety profile and mechanism of this effect are unclear in children, but suggest a future potential.
  • Alpha-2 adrenergic agonists, such as clonidine and dexmedetomidine, act on the alpha-2 adrenergic receptors which are densely located in the substanstia gelatinosa, a site believed to be responsible for reducing pain.8 Alpha-2 adrenergic agonists possess many advantageous properties to make them an attractive systemic and regional adjunct for perioperative pain control.  Clonidine and dexmedetomidine are both used safely in the pediatric population.  Literature supports the addition of clonidine to epidural solutions in children showing fewer associated side effects compared to epidural solutions containing opioids and without compromising the analgesic efficacy.46-48  When administered systemically, side effects such as hypotension, bradycardia and sedation allow for dexmedetomidine to be better tolerated compared to clonidine.19,20,49 Intraoperative use of dexmedetomidine is reported to reduce opioid consumption; however, the mechanism of an opioid-sparing effect is not established in children.50-51
  • Local anesthetics through regional and systemic routes of administration have multiple physiological advantages such as improvement of perfusion, attenuating the stress and inflammatory responses (peripheral and central), as well as an opioid-sparing effect, all of which makes them a valuable part of a multimodal management strategy.2,25-27 Although beyond the scope of this discussion, techniques and the implementation of regional analgesia in pediatrics continues to evolve with established safety.26,53 Newer in concept is the administration of low dose systemic lidocaine for perioperative pain management.  Lidocaine, acts to block sodium channels, producing analgesia from pain due to hyperalgesia.8,54 McCarty et al found that intravenous administration in adult patients undergoing abdominal surgery was well tolerated and advantageous for postoperative pain control.25 The opioid-sparing effect has not been consistently demonstrated by local anesthetics.  Although, while limited, systematic follow up to these initial findings suggest iv lidocaine may be a useful adjuvant during general anesthesia and could prove to be a promising adjuvant in the pediatric population.25,53

As multimodal strategies continue to develop, adaptations will likely be necessary to accommodate the pediatric population.  When considering various medications, knowledge of their mechanism and location of action within the pain pathway and familiarity of evidence supporting their use helps balance associated risk and benefit of each medication, patient and surgical type. Recognizing this balance is the premise behind PROSPECT, an initiative with the aim to provide evidence based procedure specific postoperative pain management guidelines for the adult population.33 These efforts are validated by the ability to improve care and positively impact postoperative pain control.  Furthermore, this is an opportunity to positively influence the associated known risks that contribute to developing persistent postsurgical pain.6,9,28-30

References

  1. Kehlet H, Multimodal approach to control postoperative pathophysiology and rehabilitation. BJA. 1997; 78: 606-617
  2. Kehlet H, Dahl J.  Anesthesia, surgery, and challenges in postoperative recovery. The Lancet. 2003; 362 (9399): 1921-1928
  3. Ljungvist O, Scott M, Fearon K. Enhanced Recovery After Surgery A Review. JAMA Surgery. 2017;152(3):292-298.
  4. Shinnick J, Short H, Heiss K, Santore M, Blakely M, Raval M. Enhancing recovery in pediatric surgery: a review of the literature. Journal of Surgical Research 202. 2016A: 165-176.
  5. Walther-Larsen S, Aagaard G, Friis S, Petersen T, Moller-Sonnergaard J, Romsing J. Structured intervention for management of pain following day surgery in children. Pediatr Anesth 2016; 26: 151-157.
  6. Berde C.  Bundled analgesia interventions for day-stay surgery. Pediatr Anesth 2016; 26: 120-121.
  7. Voepel-Lewis, T., Wagner, D., Burke, C., Tait, A.R., et al. Early adjuvant use of nonopioids associated with reduced odds of serious postoperative opioid adverse events and need for rescue in children. Pediatric Anestheisa. 2013;23:162-169.
  8. Dahl J, Nielsen R, Wetterslev J, Nikolajsen L, Hamunen K, Kontinen V, Hansen M, Kjeer J, Mathiesen O. Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review. Acta Anaesthesiol Scand 2014; 58: 1165-1181.
  9. Walther-Larsen S., Aagaard, GB., Friis, SM. Et al.  Structured intervention for manamgement of pain following day surgery in children.  Paediatr Anaesth. 2016;26(2):151-7.
  10. Hannam J, Anderson B, Mahadevan M, Holford N. Postoperative analgesia using diclofenac and acetaminophen in children. Pediatr Anesth 2014; 24: 953-961.
  11. Wong I, St John-Green C, Walker S. Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children. Pediatr Anesth 2013; 23: 475-495.
  12. Michelet D, Andreu-Gallien J, Bensalah T, Hilly J, Wood C, Nivoche Y, Mantz J, Dahmani S. A meta-analysis of the use of nonsteroidal anti-inflammatory drugs for pediatric postoperative pain. Anesth Anal 2012;114 (2):393-406.
  13. Steward D, Grisel J, Menzen-Derr J. Steroids for improving recovery following tonsillectomy in children. Cochrane Database Syst Rev. 2011 (8) CD003997.
  14. Dorkham M, Chalkiadis G, Sternberg B, Davidson A. Effective postoperative pain management in children after ambulatory surgery, with a focus on tonsillectomy: barriers and possible solutions. 2014; 24: 239-248.
  15. Chong M, Berbenetz N, Lin C, Singh S. Perineural versus intravenous dexamethasone as a adjuvant for peripheral nerve blocks: a systematic review and meta-analysis. Reg Anesth Pain Med. 2011; 36(1): 63-71.
  16. Naja Z, Kanawati S, Khatib R, Ziade F, Naja Z, Naja AS, Rajab M. The effect of IV dexamethasone versus local anesthetic infiltration in postoperative nausea and vomiting after tonsillectomy in children: A randomized double-blind clinical trial. Int J Pediatr Otorhinolaryngology. 2017; 92:21-26
  17. Dahmani S, Michelet D, Abback P-S, Wood C, Brasher C, Nivoche Y, Mantz J. Ketamine for perioperative pain management in children: a meta-analysis of published studies. Pediatr Anesth 2011; 21: 636-652.
  18. Carstensen M, Moller A. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials. BJA 2010; 104 (4): 401-4-6.
  19. El-Hennaway AM, Avd-Elwahab AM, Avd-Elmaksoud AM, El-Ozairy HS, Voulis SR,. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. BJA 2009; 103:268-74.
  20. Neogi M, Bhattacharjee DP, Dawn S, Chatterjee N. A comparative study between clonidine and dexmedetomidine used as adjuncts to ropivacaine for caudal analgesia in pediatric patients.  J Anaesthesiol Clini Pharmacol 2010; 26: 149-153.
  21. Rusy L, Hainsworth , Nelson T, Czarnecki M, Tassone C, Thometz J, Luon R, Berens R, Weisman S. Gabapentin use in pediatric spinal fusion patients: a randomize, double-blind. Controlled trial. Anesth Analg. 2010; 110(5):1393-1398.
  22. Muhly W, Sankar W, Ryan K, Norton A, Maxwell L, DiMaggio T, Farrell S, Hughes R, et al. Rapid recovery pathway after spinal fusion for idiopathic scoliosis. Pediatrics. 2016:137(4): e2-e9.
  23. Clarke H, Bonin R, Orser B, Englesakis M, Wijeysundera D, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. Anesth Anal 2012:112(2)428-442
  24. Tippana E, Hamunen K, Kontinen V, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Anal 2007:104(6) 1545-1556.
  25. McCarthy G, Megalla S, Habib A. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery. Drugs 2010; 70 (9): 1149-1163.
  26. Visoiu M, Joy L, Grudziak J, Chelly J. The effectiveness of ambulatory continuous peripheral nerve blocks for postoperative pain management in children and adolescents. Pediatr Anesth 2014; 24: 1141-1148.
  27. Carli F, Kehlet H, Baldini G, Steel A, McRae K, Slinger P, Hemmerline T, Salinas F, Neal J. Evidence basis for regional anesthesia in multidisciplinary fast-track surgical care pathways. Reg Anesth Pain Med. 2011; 36(1): 63-71.
  28. Kossowsky J, Donado C, Berde C. Immediate rescue designs in pediatric analgesic trials A systematic review and meta-analysis. Anesthesiology. 2015;122(1): 150-171.
  29. Wu CL, Jensen T, Woolf C. Persistent postsurgical pain: risks factors and prevention. Lancet 2006; 367:1618-1625.
  30. Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet. 2011; 377(9784):2215-25.
  31. Morton NS, Errera A. APA national audit of pediatric opioid infusions. Pediatr Anesth 2010; 20:119-125.
  32. Groenwald CB, Rabbitts JA, Schroeder DR, et al.  Prevalence of moderate-severe pain in hospitalized children. Paediatr Anaesth 2012;22:661-668.
  33. Kehlet H, Wilkinson RC, Fischer HB, Camu F. PROSPECT: evidence-based, procedure-specific postoperative pain management. Best Practice & Research Clinical Anaesthesiology. 2007;21:149–159.
  34. Fenlon S, Collyer J, Giles J, Bidd H, Lees M, Nicholson J et al.  Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior? Br J Anaesth 2013;110(3):432-7.
  35. Jibril F, Sharby S, Mohamed A, Wilby KJ. Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical Decision-Making. Can J Hosp Pharm 2015;68(3):238-47.
  36. Lewis SR, Nicholson A, Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2013 Jul 18;(7):CD003591
  37. Moss JR, Watcha MF, Bendel LP, McCarthy DL, Witham SL, Glover CD. A multicenter, randomized, double-blind placebo-controlled, single dose trial of the safety and efficacy of intravenous ibuprofen for treatment of pain in pediatric patients undergoing tonsillectomy. Pediatric Anesthesia 2014 May;24(5): 483-9
  38. Michelet D, Hilly J, Skhiri A, Abdat R, Diallo T, Brasher D, Dahmani S. Opioid-Sparing Effect of Ketamine in Children: A Meta-Analysis and Trial Sequential Analysis of Published Studies. Pediatric Drugs. 2016;16(6):421-433
  39. Schwenk ES, Goldberg SF, Patel R et al. Adverse drug effects and preoperative medication factors related to perioperative low-dose ketamine infusions. Reg Anesth Pain Med. 2016;41:481-487.
  40. Loftus RW, Yeager MP, Clark JA, Brown JR, Abdu WA, Sengupta DK et al. Intraoperative Ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113(3):639-646.
  41. Visser E, Schug SA. The role of ketamine in pain management. 2006;60(7):341-348.
  42. James P, Howard RF, Williams DG. The additional of ketamine to a morphine nurse- or patient –controlled analgesia infusion (PCA/NCA) increases analgesic efficacy in children with mucositis pain. Pediatr Anesth 2010;20:805-811.
  43. De Oliveira G, Almeida MD, Benzon HT, McCarthy RJ. Perioperative Single Dose Systemic Dexamethasone for Postoperative Pain A Meta-analysis of Randomized Controlled Trials Anesthesiology. 2011;115(3):575-588.
  44. Chong MA, Berbenetz NM, Lin C, Singh S.  Perineural versus intravenous dexamethasone as an adjuvant for peripheral nerve blocks.  Regional Anesthesia & Pain Medicine. 2017;42(3):319-326
  45. Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systemic review and meta-analysis of randomized trials.  Br J Anaesth. 2014;112(3):427-439.
  46. Chalkiadis Sommerfield D, Low J, Orsini F, Dowden SJ, Tay M et al. Comparison of lumbar epidural bupivacaine with fentanyl or clonidine for postoperative analgesia in children with cerebral palsy after single-event multilevel surgery.  Dev Med Child Neurol. 2016;58(4):402-408.
  47. Cucchiaro et al. A comparison of epidural bupivacaine-fentanyl and bupivacaine-clonidine in children undergoing the Nuss procedure.  Anesth Analg. 2006 Aug;103(2):322-7.
  48. Engelman E1, Marsala C. Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis. Br J Anaesth. 2013 Jan;110(1):21-7.
  49. Mahmoud M, Mason KP. Dexmedetomidine: review, update, and future considerations of paediatric perioperative and periprocedural applications and limitations.  BJA. 2015, 171-182. Doi:10.1093/bja/aev226
  50. Schnabel A, Meyer-Friessem CH, Reichl SU, Zahn PK, Pogatzki-Zahn EM. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain 2013;154:1140-1149.
  51. Schnabel A, Rejchl SU, Poepping DM, Kranke P, Pogatzki-Zahnn EM, Zahn PK. Efficacy and safety of intraoperative dexmedetomindine for acute postoperative pain in children: a meta-analysis of randomized controlled trials. Peadiatr Anasth 2013;23:170-179.
  52. Polaner DM, Taenzer AH, Walker BJ et al. Pediatric Regional Anesthesia Network (PRAN): a multiinstitutional study of the use and incidence of complications of pediatric regional anesthesia. Anesth Anal 2012;115:1353-1364.
  53. Weibel S, Jokinen J, Pace NL, Schnabel A, Hollmann MW, Hahnenkamp K et al. Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis.  BJA. 2016;116(6):770-783.
  54. Wolfgang K, Ostermeier N, Sittl R, Weidner C, Schmelz M.  Low-dose lidocaine reduces secondary hyperalgesia by a central mode of action.  Pain 2000;85:217-224.

Back to top