Analgesics in Kids: FAQs

How does pain assessment in children differ from adults?

Not all children can competently describe their pain.³¹

• When assessing pain, consider patient behavior, physiologic measures, facial expressions, parental assessment, and patient self-report. However, keep in mind that pain expression can be affected by physical, emotional, and cultural factors. Children with special needs may be difficult to assess.³¹

Pain assessment tools specifically for use in children are available:

• For infants, consider the NIPS (Neonatal Infant Pain Scale), or the PIPP (Premature Infant Pain Profile) available at https://txpeds.org/sites/txpeds.org/files/documents/pipp-scale.pdf.^32,33
• For children older than one year who cannot self-report, consider the FLACC-R (Faces, Legs, Activity, Cry and Consolability-Revised).³²
• For children four and up, consider the FPS-R (Faces Pain Scale-Revised).³²
• For children over eight years of age, a 100 mm visual analog scale or the 10-point Numeric Rating Scale (NRS) might be appropriate.³²
• NIPS, FLACC-R, FPS-R, and NRS are available at https://www.uwhealth.org/healthfacts/pain/7590.pdf. This link also provides information for parents on assessing pain and providing nondrug pain interventions.

Do infants feel pain?

It is a myth that infants do not feel pain the way adults do, or that there are no adverse effects of untreated pain in infants.³¹

Opioids can be used in children of all ages when dosed appropriately for the patient’s age.³⁸ Some are more appropriate than others (this point is covered in detail below).

How does the efficacy and safety of acetaminophen and ibuprofen compare?

Most evidence suggests that short-term, ibuprofen and acetaminophen are equally safe and effective for pain in children (e.g., dental pain, sore throat, post-tonsillectomy pain, fracture).^{25-27 But} other studies or analyses suggest that ibuprofen is more effective (e.g., as a pre-medication for primary tooth extraction, migraine, otitis media).^40-42

Is it rational to combine or alternate acetaminophen and ibuprofen?

Acetaminophen and ibuprofen are often alternated for treatment of pain.³⁴ It has been suggested that an alternating schedule might reduce bleeding risk (as opposed to ibuprofen monotherapy) post-op, or provide a synergistic analgesic effect.^16,34 However, there is no data showing that alternating acetaminophen and ibuprofen is more effective or safer than monotherapy for pain.³⁴

The results of a qualitative systematic review suggest that combining acetaminophen and an NSAID is more effective than monotherapy for acute post-op pain. Studies were performed in orthopedic, gynecologic, and dental surgery, inguinal hernia repair, and tonsillectomy. Few of the studies included children.³⁵ A subsequent study in children did not show the combination to be more effective than either drug alone for tonsillectomy pain in chidren.²⁶

How does the efficacy and safety of non-opioid analgesics compare to those of opioids?

Several studies have shown that ibuprofen is at least as effective as, and safer than, opioids for pediatric orthopedic injuries.²⁸

Ibuprofen plus acetaminophen seems to be as effective as morphine plus acetaminophen in children (n=91) after tonsillectomy/adenoidectomy [Evidence level B-1].²⁴ The pain associated with this procedure is considered moderate to severe.²⁴ Ibuprofen did not increase bleeding events, and morphine was associated with a higher risk of oxygen desaturation.²⁴

NSAID-associated bleeding is of concern post-op. However, review of 14 randomized controlled trials that included over 1,000 children found that NSAIDs did not significantly increase the odds of postoperative bleeding requiring surgical intervention vs placebo or other analgesics (OR 1.69; 95% CI, 0.71 to 4.01).¹⁴ Excluding ketorolac, the OR was 0.89 (95% CI 0.28 to 2.83). In an analysis of ten trials involving 7,455 children, the odds ratio for bleeding requiring nonsurgical intervention was 0.99 (95% CI 0.41 to 2.4). Another meta-analysis looked at 36 studies including over 3,000 adults and children.¹⁵ Among children, there was no association between NSAIDs and severe bleeding (OR 1.06, 95% CI 0.65 to 1.74), reoperation (OR 1.80, 95% CI 0.54 to 5.99), readmission (OR 1.11, 95% CI 0.31 to 3.98), or bleeding managed conservatively (OR 1.35, 95% CI 0.70 to 2.60). Among patients (adults and children) who received NSAIDs only postoperatively (not pre- or peri-operatively), there was an increased risk of bleeding (OR 2.02, 95% CI 1.25 to 3.27). This may be a result of multi-comparisons. A small increased bleeding risk associated with NSAID use in this setting cannot be excluded, but the benefits of using an NSAID may outweigh the risk post-tonsillectomy.^12,14

When is it appropriate to use an opioid in a child?

Strong opioids (e.g., morphine) are appropriate when non-opioids are not enough (e.g., severe pain).^31,32

Consider using a non-opioid with an opioid to reduce the amount of opioid needed.^31,32

What is the clinical concern with codeine in children?

There are case reports of children dying or nearly dying from respiratory depression after receiving codeine after surgery to remove their tonsils and/or adenoids.

In 2009, a case of a toddler dying after receiving codeine post-adenotonsillectomy was published.⁴ Three more cases were described in a 2012 publication.⁵ All four patients had undergone adenotonsillectomy for treatment of sleep apnea. In the three more recent cases, the children were three, four, and five years of age, weighing 14.4 kg to 29 kg. All were discharged home on codeine at an age-appropriate dose. All achieved supratherapeutic morphine levels after just four to six doses of codeine. In two patients for whom codeine levels were reported, they were within normal limits. Two of the three children in the 2012 report died. The other required mechanical ventilation, but recovered.

As part of their safety reviews, the FDA and Health Canada found that prescription codeine has been possibly linked to serious breathing problems in seven published international cases in patients under 18 years of age in whom it was used for the treatment of pain.^22,30 Six of the seven cases occurred in children under 12 years of age, including four deaths. Five of the seven cases occurred in children after surgery to remove tonsils or adenoids. However, it was also noted that these children had other medical conditions that could have contributed to the breathing problems.²²

In total, sixty-four cases of serious breathing problems (including 24 deaths) in children taking codeine have been reported to the FDA.⁴⁴ Most cases were in children less than 12 years of age, and in some cases occurred after just one dose of codeine.⁴⁴

At the time of their safety review activities, Health Canada had received a total of eight Canadian cases of breathing problems in patients under 18 years of age that were possibly linked to prescription codeine for the treatment of pain. Six of these cases occurred in children under 12 years of age, including three who died. Four of the eight cases occurred in children after surgery to remove tonsils or adenoids. It was also noted that other medications that were taken at the same time as the codeine-containing product could have contributed to the breathing problems.²²

Why might codeine be particularly problematic compared to most other opioids?

Codeine is metabolized to the active metabolite morphine by the CYP2D6 hepatic enzymes.³⁰

Ultrarapid CYP2D6 metabolism occurs in up to 10% of Caucasians; about 5% of African Americans; 1% to 2% of Chinese, Japanese, and Koreans; >20% in some Arab populations, and almost 30% in some African populations.^{7,30 In} patients who are not ultrarapid metabolizers, about 10% of codeine is converted to morphine. But ultrarapid metabolizers make up to 75% more morphine than normal.⁵ Patients who are ultrarapid 2D6 metabolizers may be especially sensitive to the respiratory depressant effects of codeine because they tend to produce large amounts of morphine from codeine.¹

In the 2009 case described above, genotyping showed that the child was an ultrarapid metabolizer, while the other two patients in the 2012 report had codeine/morphine levels consistent with ultrarapid metabolism.^{4,5 There} is at least one case of an adult ultrarapid metabolizer who required noninvasive ventilation after receiving oral codeine at a dose of only 25 mg three times daily for four days for cough.¹¹

Toxicity has occurred in breastfed infants whose mothers were taking codeine, including a fatality in the newborn of an ultrarapid metabolizer.^9,10,44

Another issue with codeine is that it may provide inadequate analgesia in poor CYP2D6 metabolizers due to its dependence on morphine for its analgesic effect.¹²

Should kids be genotyped to determine CYP2D6 metabolizer status before opioid use?

Routine CYP2D6 genotype testing is not recommended prior to the initiation of codeine therapy because patients with normal metabolism may, in some cases, convert codeine to morphine at levels similar to ultrarapid metabolizers.³⁰

Would it be ok to use codeine in a child who does not have risk factors?

Although all of the reported deaths in the case reports presented above occurred in children with sleep apnea, in the U.S., codeine-containing cough meds are no longer approved for kids <18 years of age and all prescription codeine products are contraindicated in children <12 years of age.^1,44

Likewise, Canadian labeling restrictions (see below) are not limited to patients with sleep apnea.^{3,21 The} American Academy of Pediatrics also points out that considering the prevalence of obesity in children, even many presenting for non-ear/nose/throat surgeries will have undiagnosed sleep apnea.³⁰

What does the product labeling say about codeine use in kids?

In the U.S., all prescription codeine-containing products are contraindicated in children younger than 12 years of age.⁴⁴ Codeine-containing cough meds are no longer indicated for kids <18 years of age.¹ Codeine is contraindicated for post-operative management in children <18 years who have undergone removal of the tonsils and/or adenoids.⁴⁴ Labeling recommends against codeine use in children between 12 and 18 years of age who are obese or who have conditions that may predispose them to respiratory risk, such as obstructive sleep apnea or severe lung disease.⁴⁴ These contraindications/warnings also apply to dihydrocodeine (found in Synalgos-DC).⁴⁴ The FDA is considering additional regulatory action for OTC codeine products, where available.⁴⁴

In Canada, codeine is only for use in patients 12 years and older.³ It is also contraindicated in patients less than
18 years of age to treat pain after tonsillectomy and/or adenoidectomy, as these patients are more susceptible to the risk of serious breathing problems.²¹

What do professional societies say about codeine use in kids?

The American Academy of Pediatrics is urging prescribers and parents to stop giving codeine to children <18 years old, for any reason.³⁰

Can codeine or tramadol be taken by breastfeeding moms?

The FDA found several published cases of excess sleepiness, serious breathing problems, and one death in breastfed infants whose mothers were taking codeine.⁴⁴

U.S. labeling now states that breastfeeding is not recommended when taking codeine or tramadol.⁴⁴ The FDA did not find any reports of adverse events in infants related to tramadol use by breastfeeding moms, but because tramadol and its active metabolite are found in breast milk, and tramadol has the same risks associated with ultrarapid metabolism as codeine, the FDA is requiring this warning for tramadol.⁴⁴

If a codeine- or tramadol-containing product is selected, use the lowest dose for the shortest period of time. Inform mothers using codeine or tramadol to seek immediate medical care in the event of signs and symptoms of neonatal toxicity (e.g., unusual sleepiness; difficulty breastfeeding or breathing; slow, shallow, or noisy breathing; limpness).^{43,44 Nursing} mothers who are ultrarapid metabolizers may also experience toxicity symptoms (e.g., extreme sleepiness, confusion, or shallow breathing).⁴³

What are some non-opioid options for cough in kids?

Fluids, humidity (from a shower or humidifier), and for children one year and older only, honey up to two teaspoons at bedtime to thin secrections.^{29,46 A} cool-mist humidifier may be preferred as warm-mist humidifiers/vaporizers can pose a burn hazard.³⁶

Cough in kids less than four years, or lasting more than seven days without improvement, should be evaluated.³⁶

Do not use cough and cold medicines in children <6 years of age. The risk of side effects or overdose outweighs benefit.³⁹ Consider benzonatate (Tessalon Perles; U.S. only) if pharmacologic treatment is necessary in older kids.¹

What are some safer opioid alternatives to codeine for pain when a non-opioid is not enough?

Like codeine, oxycodone has an active metabolite (oxymorphone) formed through CYP2D6 that could theoretically accumulate in ultrarapid metabolizers.¹⁷ However, oxycodone is metabolized mainly by CYP3A4 to a weak metabolite (noroxycodone), and there is not a good correlation between clinical response to oxycodone and CYP2D6 activity.^18-20

• In the U.S., OxyContin (extended-release oxycodone) is FDA approved for children 11 years and older who have been taking and tolerating opioids for at least five consecutive days, AND at a total daily dose of at least 20 mg of oxycodone or its equivalent for at least two days immediately preceding OxyContin dosing, and for whom non-opioids are ineffective, not tolerated, or inadequate.³⁷

Opioid analgesics that are not metabolized by the CYP2D6 enzyme system to active metabolites include morphine, hydromorphone, oxymorphone, buprenorphine, and fentanyl.^{17,18 Therefore}, they should be safer choices in ultrarapid CYP2D6 metabolizers.¹⁷ However, safety is a concern with any opioid in children with obstructive sleep apnea.^12,18

• Although morphine is the most commonly used opioid in pediatric palliative care, there is little information on at-home use of morphine (or hydromorphone) in other pediatric populations, and it has a bitter taste.¹⁸ Nevertheless, experts at the Hospital for Sick Children in Toronto consider morphine the opioid of choice in children.³²
• Consider an oral morphine dose of 0.2 mg/kg/dose, up to 5 mg/dose max, or 10 mg/dose max for larger adolescents, every four hours as needed.²⁰

When an opioid is needed, use the lowest effective weight-based dose, with monitoring for signs of overdose.^12,13

Is hydrocodone a good codeine alternative?

In the U.S., as for codeine, hydrocodone-containing cough meds are no longer indicated for kids <18 years of age.¹

Like codeine, hydrocodone has an active metabolite (hydromorphone) formed through CYP2D6 that could theoretically accumulate in ultrarapid metabolizers.^{17,18 Hydromorphone} levels are up to eight times higher in ultrarapid metabolizers, and poor metabolizers get minimal analgesia.³⁰

In Canada, hydrocodone (an ingredient of certain cough syrups) is no longer recommended in patients under six years of age. This recommendation is based on rare cases of serious breathing problems including deaths in children in this age group, usually involving higher-than-recommended doses.²¹

As part of their safety review, Health Canada assessed a total of seven reports, in children and adolescents, of hydrocodone use related to serious breathing problems or related to hydrocodone overdose. Two reports involved children that were seven and fifteen years old; one was considered related to the hydrocodone use but there was not enough information provided in the other report to assess it. There were five reports in children under six years of age, and upon further analysis, three were considered related to hydrocodone. Death was reported in two of these, involving a two-year-old and a five-year-old; one was considered related to hydrocodone, but there was not enough information provided in the other report to determine if the death was due to hydrocodone use.²³

Also as part of their safety review, Health Canada identified a published case of a three-year-old child that experienced serious breathing difficulties after use of hydrocodone and later died. Upon further review, the event was considered to be due to hydrocodone use.²³

In most of the cases, including the fatal cases, the children received more than the recommended dose for their age.²³

At this time, the evidence available in the side effect reports of hydrocodone does not present enough information to conclude that the rate in which it is metabolized is a factor, as is the case for codeine.²³

Is tramadol a good opioid alternative for kids?

Tramadol is metabolized to the active metabolite O-desmethyltramadol.² As with codeine, ultrarapid 2D6 metabolizers quickly achieve higher than normal levels of tramadol’s active metabolite.^2,8

A five-year-old child in France experienced severely slowed and difficult breathing requiring emergency intervention and hospitalization after taking a single prescribed dose of tramadol oral solution for pain relief following surgery to remove his tonsils and adenoids.² The patient was found to be an ultrarapid metabolizer and had high levels of O-desmethyltramadol.²

There is also a case report of tramadol-associated cardiac arrest in an adult ultrarapid metabolizer however, this patient had been abusing tramadol.⁸

Tramadol is not approved for use in children.² However, because it may be used off-label in the pediatric population, perhaps as a replacement for codeine, this case report prompted the FDA to investigate tramadol’s safety in children
17 years of age and younger.^2,6

As a result of this investigation, U.S. labeling now contraindicates tramadol for use in children less than 12 years of age, and in children younger than 18 years of age to treat pain after surgery to remove the tonsils and/or adenoids.⁴⁴ Tramadol is not recommended in children 12 to 18 years of age who are obese or have conditions such as obstructive sleep apnea or severe lung disease.⁴⁴

In Canada, tramadol is not recommended for use in children less than 18 years of age.⁴⁵ Health Canada has not received any Canadian reports of serious breathing problems related to the use of tramadol in children and adolescents, but is aware of the published case from France.⁴⁵ Labeling is being updated to further highlight the risk of serious breathing problems and explain that some patients have increased risk due to ultra-rapid metabolizer status.⁴⁵

Another issue with tramadol is that, as with codeine, tramadol may provide inadequate analgesia in poor CYP2D6 metabolizers.¹²

What are some caregiver counseling points regarding analgesics use in kids?

Parents/caregivers can help relieve pain by providing distractions (e.g., watch a movie or read a book together); repositioning, rocking, or stroking the child; or singing to them or providing soft music.³³

If an opioid is prescribed, educate parents to recognize signs of trouble that require emergency medical treatment (e.g., excessive sleepiness, confusion, difficult or noisy breathing, respiratory pauses during sleep, etc).^12,13

Ensure that parents understand the dosing instructions, including how to measure the dose of liquid medications, to reduce overdose risk.¹⁸