What are the recommendations for opioid use in children?


Introduction/Background

When treating pain in children in the era of the opioid epidemic, judicious pain management is required in order to alleviate pain while minimizing adverse events, opioid dependence, opioid misuse, and addiction.1-4 Neonates with prenatal opioid exposure may present with opioid withdrawal and developmental issues.5 In addition to the fact that children’s bodies are still developing, genetic and phenotypic variability are factors that do not make all opioids therapeutically viable options for pain management in children.6-9 Pain management also varies depending on the cause, severity, and anticipated duration of pain.1,10

Answer

Pain management in children should incorporate validated age-specific pain assessment scales before and after each dose to assess efficacy. 1 Observational tools are used for infants and toddlers, while children age 5 years and older may use scales that incorporate self-reporting. Special scales also exist to evaluate pain in children with cognitive impairment who cannot self-report and have certain baseline behavior patterns with limited physical movements.

At the start of pharmacotherapy, pain relief expectations and when pain medications should be used should be discussed with the patient and caregiver.1 Nonpharmacologic treatments (eg, heat/ice application, massage) may supplement medications for pain management. Pediatric pain treatment has been based on the World Health Organization (WHO) 2-step ladder and WHO guidelines for persisting pain in children, which are currently under revision.1,4,9,10 The WHO two-step methodology, scheduled dosing frequencies, appropriate dosage forms and administration routes, and individualized treatment based on the child’s pain severity are the standard for treating chronic, non-cancer pain in children.1,10

Step 1 of the WHO 2-step ladder addresses mild pain.10 Nonopioid medications such as acetaminophen and ibuprofen are recommended depending on the child’s age. Acetaminophen may be used from birth.1,10 In the United States ibuprofen may be started at 6 months of age and older.1

Step 2 of the WHO 2-step ladder recommends strong opioids for moderate to severe pain.10 The drug of choice is immediate-release morphine. Gradual titration to an effective dose with an acceptable level of side effects is recommended. 1,10 An effective dose produces pain relief between two doses via the lowest effective dose. Frequent assessment facilitates dose adjustment. Doses should be based on the child’s assessment of pain severity.10

Oral dosage forms are preferred in children because of ease of administration and this route is usually the least painful.1,10 If more immediate pain relief is needed, the intravenous, not intramuscular, route should be used.1 Oral solutions should be used until a child can swallow tablets.10 Patient-controlled analgesia may be used in children from about 5-7 years of age.1,10 Breakthrough (rescue) doses consist of immediate-release oral or intravenous morphine.10

Opioids are dosed based on weight for children.1 Maximum initial doses for opioid-naïve patients should not be exceeded. Appropriate dosing decreases the risk of developing adverse effects such as respiratory depression and sedation. Lower doses should be used in nonventilated newborns under 3 months of age along with increased respiration monitoring. Weight-based dosing in children weighing more than 40 kg may be used as long as the dose does not exceed the adult dose. Doses should be increased by a maximum of 50% over 24 hours in ambulatory settings. 10 Rescue doses for breakthrough pain are usually 5-10% of the required total daily opioid dose. If rescue doses are needed often, the total daily dose of scheduled morphine may need to be adjusted.

For persisting, chronic pain, medications should be given on a scheduled basis, not as needed (prn). However, as needed use may be necessary in the case of intermittent, unpredictable occurrences of pain.10 Besides scheduled doses, children may receive rescue doses when intermittent breakthrough pain occurs. Morphine dose frequency is every 4-6 hours in term opioid-naïve neonates, every 3-4 hours in opioid-naïve infants and older children and adults and can be every 8-12 hours for extended-release products.1,10

Duration of therapy for acute pain should be limited to 3-5 days.1 Conditions such as sickle cell disease, limb pain, complex regional pain syndrome, and cancer often need long-term analgesia. Treatment-related constipation caused by long-term opioid use can be managed with a stimulant laxative and stool softener.10

If after optimal titration, analgesia is not achieved and intolerable side effects occur, morphine may be switched to oxycodone, hydromorphone, methadone, or fentanyl.10 Fentanyl may be better than morphine for pediatric patients with cardiovascular dysfunction and persistent pulmonary hypertension because fentanyl will not cause hemodynamic changes and decreases pulmonary vascular resistance.1 Fentanyl boluses must be administered over 3-5 minutes in children to prevent chest wall rigidity that could compromise breathing. Intranasal fentanyl has been used for immediate pain relief in infants and children. Transdermal fentanyl should not be used in neonates and infants due to faster and greater absorption that can lead to toxicity. It can be used in older children and adolescents to manage persistent, chronic pain.

Physical dependence can occur within 7 days of continuous opioid use in children and is more likely as the dose and duration of treatment increases.1 Weaning should be done when discontinuing opioids to prevent withdrawal. Sudden discontinuation of opioids should be avoided so that children do not experience adverse effects with a withdrawal syndrome.1,10 The validated Neonatal Abstinence Score or Sophia Observation Withdrawal Symptoms Scale may be used to measure withdrawal in neonates and older children.1,10 Family members and caregivers should be taught symptoms of opioid withdrawal in children.1

Opioid medications that should not be used in children include codeine, hydrocodone, and tramadol.1,9,11-14 Genetic differences in metabolism via the cytochrome p-450 2D6 isoenzyme (CYP2D6) impact conversion of codeine to morphine, significantly varying morphine levels.1,9,11 Hydrocodone also undergoes CYP2D6 conversion to the active metabolite hydromorphone, and thus poses the same concerns regarding varying levels.1,9 Tramadol is metabolized primarily by CYP3A4 to an inactive metabolite and by CYP2D6 to an active metabolite, desmethyltramadol.1,9 Variable CYP2D6-based metabolism can result in subtherapeutic or supratherapeutic pain management and/or side effects, including serious breathing problems and death, even with only one dose.1,9, 11-13 Food and Drug Administration required boxed warnings note codeine and tramadol are now contraindicated for use in children.11-13 Codeine and tramadol are also not recommended for pain management in women who are breastfeeding due to the risk of serious adverse reactions in breastfed infants.12

References

  1. Shah P, Siu A. Considerations for neonatal and pediatric pain management. Am J Health Syst Pharm 2019;76(19):1511-1520. doi: doi.org/10.1093/ajhp/zxz166
  2. Krane EJ, Weisman SJ, Walco GA. The national opioid epidemic and the risk of outpatient opioids in children. Pediatrics. 2018; 142(2):e20181623. doi: doi.org/10.1542/peds.2018-1623
  3. Chung CP, Callahan ST, Cooper WO, et al. Outpatient opioid prescriptions for children and opioid-related adverse effects. Pediatrics. 2018;142(2):e20172156. doi: https://doi.org/10.1542/peds.2017-2156
  4. World Health Organization. Web statement on pain management guidance. June 20, 2019. Available at https://www.who.int/medicines/areas/quality_safety/guide_perspainchild/en/. Accessed November 26, 2019.
  5. Behnke M, Smith VC; Committee on Substance Abuse; Committee on Fetus and Newborn. Prenatal substance abuse: Short- and long-term effects on the exposed fetus. Pediatrics. 2013;131(3):e1009-e1024.doi: doi.org/10.1542/peds.2012-3931
  6. Lu Hong, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther. 2014;19(4):262–276. doi: 10.5863/1551-6776-19.4.262
  7. Chidambaran V, Sadhasivam S, Mahmoud M. Codeine and opioid metabolism - Implications and alternatives for pediatric pain management. Curr Opin Anaesthesiol. 2017;30(3):349-356. doi: 10.1097/ACO.0000000000000455.
  8. Allegaert K, Rochette A, Veyckemans F. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics, and elimination clearance. Pediatr Anesth. 2011;21(3):266–273. doi:10.1111/j.1460-9592.2010.03389.x
  9. Tobias JD, Green TP, Coté CJ; Section on Anesthesiology and Pain Medicine; Committee on Drugs. Codeine: Time to Say “No”. Pediatrics. 2016;138(4): e20162396. doi: 10.1542/peds.2016-2396
  10. World Health Organization. WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. Geneva, Switzerland: World Health Organization; 2012. https://www.ncbi.nlm.nih.gov/books/NBK138354/pdf/Bookshelf_NBK138354.pdf. Accessed November 26, 2019.
  11. Food and Drug Administration Center for Drug Evaluation and Research. Summary minutes of the Joint Pulmonary‐Allergy Drugs Committee and Drug Safety and Risk Management Advisory Committees Meeting. December 10, 2015. https://www.fda.gov/media/95855/download. Accessed November 26, 2019.
  12. Food and Drug Administration. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. 2017, Apr 20. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm. Accessed November 26, 2019.
  13. Food and Drug Administration. FDA Drug Safety Communication: Safety review updated of codeine use in children; new boxed warning and contraindication on use of tonsillectomy and/or adenoidectomy. February 20, 2013. http://wayback.archive-it.org/7993/20170722185707/https://www.fda.gov/Drugs/DrugSafety/ucm339112.htm. Accessed November 26, 2019.
  14. Food and Drug Administration. FDA Drug Safety Communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. January 11, 2018. https://www.fda.gov/Drugs/DrugSafety/ucm590435.htm. Accessed November 26, 2019.

Prepared by:
Christina Petrykiw, PharmD, CDE
Clinical Instructor
University of Illinois at Chicago College of Pharmacy

The information presented is current as of December 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.