Acute Pediatric Pain Management

Analgesics for the Treatment of Postoperative Pain for Children

By Samantha L. Brackett, MD and Sophie R. Pestieau, MD
Children's National Hospital
Washington, DC

Postoperative pain management in the pediatric population remains challenging due to difficulties in accurately assessing pain, as well as concerns for adverse drug effects. Pediatric postoperative pain management should be individualized and multimodal in its approach in order to optimize pain control while minimizing adverse effects.1 Multimodal analgesia may include opioids, non-opioid analgesics, regional or neuraxial anesthesia, as well as non-pharmacologic therapies such as relaxation techniques and distraction.

The World Health Organization (WHO) pain ladder has been expanded to guide the management of acute and chronic pain, although it was initially intended for patients with cancer pain.2,3 The WHO pain ladder recommends non-opioid medications such as acetaminophen or a non-steroidal anti-inflammatory drug (NSAID) for the initial management of pain.4 If non-opioid medications do not adequately control pain, the next step in the ladder recommends considering a weak opioid with or without a non-opioid.4 If such opioids combined with acetaminophen or NSAIDs are unable to control moderate to severe pain, then stronger, full opioid agonists are recommended.4 Non-opioid adjuvant medications such as gabapentin, dexamethasone, ketamine, and dexmedetomidine can be incorporated at any step in the WHO pain ladder.4

The co-administration of opioids with acetaminophen, NSAIDs, or other non-opioids have been found to be more effective than opioids alone.4 Specifically, the co-administration of opioids and NSAIDs during the perioperative period has shown to decrease postoperative pain, opioid requirements, and opioid side effects such as nausea and vomiting.5 In addition, pain intensity is further decreased when acetaminophen was administered in combination with NSAIDs, suggesting a synergistic effect.5

Here we summarize the pharmacologic management of post-operative pediatric pain, with an emphasis on multimodal analgesia. Effective post-operative pain management includes an appropriate individualized pre-operative assessment, which may involve the pre-op administration of anxiolytics, gabapentinoids, or other medications that may improve clinical outcome and overall patient comfort.6 Regional or neuraxial techniques should also be utilized whenever appropriate.

Non-Opioid Analgesics
Ibuprofen, naproxen, and ketorolac are a group of NSAIDs that have analgesic and anti-inflammatory effects by inhibiting cyclooxygenase (COX) types 1 and 2, blocking prostaglandin and thromboxane production.1 Cyclooxygenase metabolites result in peripheral nerve sensitization and vasodilation which leads to inflammation and pain.1 Therefore, NSAIDS are helpful in treating inflammatory or bony pain.1

Due to the reversible antiplatelet effects of inhibiting thromboxane synthesis, NSAIDS may increase bleeding times, however the literature has been equivocal.1 NSAIDs can also be associated with indigestion, nausea, gastrointestinal bleeding, and renal insufficiency.4 Therefore, their use should be limited in patients at risk for such adverse effects. They should not be used in children less than six months of age.7

Acetaminophen is a non-opioid analgesic that is a selective central COX-3 inhibitor which prevents prostaglandin synthesis in the hypothalamus.1,7 It also reduces substance P and nitric oxide mediated hyperalgesia.7 Acetaminophen acts as an anti-pyretic, without anti-inflammatory or antiplatelet activity.1 Overall, it is well tolerated with few interactions and a favorable side effect profile.4 Due to its association with hepatic necrosis, the maximum daily dose in a preterm infant, full-term infant, and older child are 60, 80, and 90 mg/kg, respectively.1 Acetaminophen is usually the first-line treatment for mild to moderate acute pain.4

The use of acetaminophen and NSAIDs in the perioperative period has opioid-sparing effects of 30-40%, reduced opioid-related side effects, and cost benefits.1,7 In addition, the co-administration of acetaminophen and an NSAID has an additive effect on pain control, and is associated with improved post-operative pain scores and patient satisfaction.1,2

Non-opioid analgesics as a single-agent therapy should be reserved for the treatment of mild to moderate pain due to their ceiling effect.1,4 Therefore, acetaminophen and NSAIDs are often administered in combination with opioids to treat severe pain, as demonstrated in the WHO pain ladder.1 However, due to their opioid sparing effects and benefit as adjuncts in the management of moderate to severe pain, they should be used whenever possible in the perioperative setting to mitigate postoperative pain control.2 Scheduled, rather than pro re nata (PRN), dosing of acetaminophen and NSAIDs allows for more consistent drug levels and therefore more effective pain control.4

Opioids
Opioid medications are recommended by the WHO in combination with non-opioid analgesics and adjuvants for the management of moderate to severe pain.2,4 Opioids are associated with side effects such as nausea, urinary retention, constipation, ileus, respiratory depression, sedation, and pruritus.2 Neonates are at a particularly increased risk of central respiratory depression due to immature hepatic and renal systems, as well as a decreased hypoxic respiratory drive.2 Opioid-induced nausea and vomiting are histamine mediated and can be treated with antihistamines or selective serotonin antagonists such as ondansetron.4 Oral opioids and acetaminophen should be administered in separate formulations, to allow scheduled or regular dosing of acetaminophen, while reserving opioids for PRN administration.2

The most common oral opioids are oxycodone, morphine, hydrocodone, and codeine.2 Morphine and oxycodone do not require biotransformation to produce analgesic effects, while codeine and hydrocodone are prodrugs that require biotransformation by CYP hepatic enzymes to become active.2 There is an FDA black box warning for codeine following tonsillectomy and adenoidectomy in the pediatric population due to increased deaths from respiratory depression in this population.2 Due to individual variability in CYP2D6 expression, children may have variable rates of codeine metabolism into its active form, morphine.2 Ultra-rapid metabolizers are at risk of respiratory depression from increased morphine blood levels, while slow metabolizers may not achieve adequate analgesia.2 Hydrocodone is a prodrug similar to codeine that is metabolized by the CYP2D6 enzyme to produce its active form, hydromorphone, and its formulations usually contain other drugs such as acetaminophen.2

Oxycodone is more active than its main metabolite, noroxycodone; metabolism of oxycodone is done by the CYP3A4/5. Oxymorphone and noroxymorphone metabolites are formed by the CYP2D6 enzymes.2 Ultra-rapid metabolizers may not achieve adequate analgesia, while slow metabolizers are at risk for increased side effects.2 Other medications such as macrolides, antifungal, and antiviral agents are CYP3A4 inhibitors, enhancing oxycodone-induced side effects.2

Common intravenous opioids used in the pediatric population include morphine, fentanyl, and hydromorphone. Morphine has well studied pharmacokinetics in the pediatric population. Its volume of distribution is similar across age groups, while its half-life decreases with age.6 Despite the familiarity and cost benefit associated with morphine, it may not have superior analgesic properties or side effect profiles compared with other opioids.6 Fentanyl has less central respiratory depression and hemodynamic instability than morphine.6 However fentanyl and other synthetic opioids have been associated with chest wall rigidity.6

Intravenous opioids may be administered via bolus dosing or patient or nurse controlled analgesia (PCA or NCA).2 PCA use is often reserved for postoperative patients with severe pain that requires frequent analgesia. Patients using PCAs should be monitored with continuous pulse oximetry.2

Adjuvant Analgesics
Ketamine is an NMDA receptor antagonist and anesthetic agent with analgesic properties. It has been shown to reduce postoperative pain, nausea, and opioid requirements.1,7 Low dose ketamine infusions of 0.05-0.2 mg/kg/hr may be useful in treating neuropathic and postoperative pain, as well as pain poorly responsive to opioids in opioid-tolerant patients.1 Due to its sympathetic stimulation, it may produce tachycardia and hypertension.2 Ketamine will not produce respiratory depression, unlike opioids, but may increase oral secretions.2 Ketamine is available in per os (po) form, but its oral bioavailability is poor.8 Because of this and the potential for side effects it’s rarely used orally for postoperative pain management.

Dexmedetomidine is an α 2-adrenergic agonist with sedative, analgesic and opioid sparing properties.1 In addition, its administration does not result in respiratory depression, and therefore it may be beneficial in children with obstructive sleep apnea.1 Dexmedetomidine administered at 1-2 mcg/kg is approximately equivalent to intravenous fentanyl of 1-2 mcg/kg.1 Side effects include bradycardia or rebound hypertension with bolus dosing.

Anticonvulsants such as gabapentin and pregabalin may be helpful in the treatment of neuropathic pain, complex regional pain syndromes, paresthesia and allodynia.1 Their mechanism of action involves the inhibition of voltage-gated calcium channels, reducing calcium influx and preventing the release of excitatory neurotransmitters.1 Their use in the perioperative period as part of a multimodal analgesic regimen has resulted in decreased opioid consumption and improved postoperative pain scores.1 Their main side effect is increased somnolence.1

In conclusion, pediatric post-operative pain management should be individualized and multimodal, in order to maximize analgesia and mitigate adverse effects.

References:

  1. Davis, P. J., & In Cladis, F. P. (2017). Smith's anesthesia for infants and children.
  2. O'Donnell FT, Rosen KR. Pediatric pain management: a review. Mo Med. 2014;111(3):231–237.
  3. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56:514–517.
  4. Blondell RD, Azadfard M, Wisniewski AM. Pharmacologic therapy for acute pain. Am Fam Physician. 2013. June 1;87(11):766–72.
  5. Michelet D, Andreu‐Gallien J, Bensalah T, Hilly J, Wood C, Nivoche Y, et al. A meta‐analysis of the use of nonsteroidal anti-inflammatory drugs for pediatric postoperative pain. Anesthesia & Analgesia 2012;114(2):393‐406.
  6. Lee JY, Jo YY. Attention to postoperative pain control in children. Korean J Anesthesiology. 2014;66(3):183–188. doi:10.4097/kjae.2014.66.3.183
  7. Lönnqvist, P.A., N. S. Morton, N.S. Postoperative analgesia in infants and children, BJA: British Journal of Anaesthesia, Volume 95, Issue 1, July 2005, Pages 59–68, https://doi.org/10.1093/bja/aei065
  8. Peltoniemi, M.A., Hagelberg, N.M., Olkkola, K.T. et al. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet 55, 1059–1077 (2016) doi:10.1007/s40262-016-0383-6

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