The use of oral opioids to control children’s pain in the post-codeine era

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Untreated or undertreated pain is associated with severe adverse outcomes ^[1]-[3]. The undertreatment of pain in children has been identified as a problem for more than two decades, and there have been many initiatives to address this issue. Some approaches have included the use of oral medications as opposed to intravenous (IV) or intramuscular drug delivery. Although the treatment of pain in children has improved dramatically, many challenges remain. There has been a marked increase in the prescribing of analgesics – notably oral opioids – in adults, and a major opioid crisis has followed. Despite increased prescribing, pain is still not well managed for many patients ^[4].

In children, oral analgesia is administered most commonly in the form of oral ibuprofen or acetaminophen. More potent options include both opiates, which are drugs derived from the opium poppy (Papaver somniferum), and opioids, which is a larger group that includes opiates. Opioids may be either naturally sourced or synthetic, and they act via opioid receptors in the brain. Drugs such as morphine and codeine are opiates, while drugs such as oxycodone and oxymorphone are opioids.

When an oral opioid is indicated for a child, the one most commonly used historically has been codeine. Codeine is 3-methylmorphine, a pro-drug that – after being ingested orally – is metabolized by CYP2D6 to morphine. The demethylation of codeine to morphine is the principal mechanism of codeine’s analgesic activity. Without its metabolism, codeine is relatively ineffective as an analgesic.

The activation of codeine to morphine is polymorphic, meaning that in the general population, there are distinct phenotypes for activation. These include extensive metabolizers (the most common phenotype who, despite their name, are ‘normal’ metabolizers); poor metabolizers (up to 10% of patients, in whom codeine is converted to morphine more slowly, resulting in a less effective analgesic response); and ultrarapid metabolizers (in whom codeine changes to morphine very effectively and quickly) ^[5][6]. The ultrarapid metabolizer phenotype has been associated with risk for serious adverse outcomes, including death. While this phenotype is uncommon in Northern European populations (1% or less), ultrarapid metabolizers are very common in countries adjacent to the Mediterranean Sea, in the Horn of Africa, and southern India. The variation in metabolization is rarely an issue for a single dose of codeine but in the context of repeated doses, morphine can accumulate to potentially dangerous concentrations.

The risk for toxicity associated with polymorphism, along with concerns relating to the safety of codeine for postoperative pain management in children with conditions such as sleep apnea, led first to calls from drug regulatory agencies and professional organizations for more cautious use of codeine, followed by their recommendations to avoid codeine use in children. Many paediatric facilities in Canada and the United States have removed codeine from their formularies in light of these concerns ^[7].

Opioids

Opioids, including opiates, are drugs with morphine-like effects that they exert by interacting with opioid receptors. Opioids include both synthetic and semisynthetic drugs, and their effects and side effects depend on which receptor(s) the drug interacts with. The supraspinal analgesic effects of opioids lead to both their analgesic and euphoric effects. While there are several different opioid receptors, the analgesic effects of opioids are mediated primarily by the µ (mu) receptor.

Opioids are commonly used to manage moderate to severe pain. They are a crucial part of pain control strategies such as the World Health Organization (WHO) Pain Ladder ^[8], which describes pain control as an escalating strategy using increasingly potent analgesics. As part of such stepwise therapies, opioids have been commonly – and increasingly – used for analgesic therapy in children. Medical knowledge of and experience with IV opioid use in children far exceeds that for oral opioids.

Oral opioids in children

Codeine-related safety and efficacy issues led many hospitals to remove the drug from their formularies. Replacement oral agents have included morphine, oxycodone, hydrocodone, and tramadol ^[9]. Controversy remains regarding optimal strategies for oral opiate use, including morphine, for analgesia in children ^[10]. Furthermore, emerging evidence has demonstrated that for many conditions, oral opioids offer no advantage over appropriately dosed nonsteroidal anti-inflammatory drugs (NSAIDs).

Morphine

Morphine has been used parenterally in children for many years, and because codeine’s major route of action is via metabolism to morphine, the use of oral (PO) morphine in place of codeine appears logical. However, oral morphine use in children has been far from routine. Morphine is a prototypical opiate that was first isolated from opium in 1804 by Frederich Sertürner. It has been used clinically since 1817 for the treatment of pain and, in paediatric cases, is most commonly administered parenterally. In just the last decade, some studies have explored the use of oral morphine, and several interesting observations have been made ^[11]-[13].

First, like many opiates, morphine is subject to extensive first-pass metabolism, such that only 25% to 35% of the orally administered dose is available systemically for analgesic effects ^[12][13]. This mechanism is a crucial determinant for dose adjustment when switching from IV to oral administration and – especially – when switching the other way, from PO to IV. For example, when changing IV morphine to oral, it is necessary to multiply the dose by three to compensate for its relatively low bioavailability.

Secondly, and not surprisingly, IV morphine has a more rapid onset of analgesia, while oral morphine is more comfortable to administer, has a shorter administration time and, in particularly acute care circumstances, appears to be comparably efficacious ^[14]. Also, readily available liquid preparations for oral administration make oral morphine a feasible therapeutic option.

Thirdly, there is great variability in the absorption and effects of oral morphine in children, with the pharmacokinetics of oral morphine being more complex than previously believeed ^[12]. This variability can, in some circumstances, be associated with risk for respiratory depression.

Oxycodone

Oxycodone is a semisynthetic opioid agonist that has been used to treat moderate to severe pain in adults since 1917. Over the last decade, however, oxycodone has been increasingly prescribed for children, especially since Health Canada and the Food and Drug Administration in the United States have cautioned against codeine use. In 2014, oxycodone, became the most commonly prescribed oral opiate for children in the U.S. ^[15].

Similar to morphine, an oral dose of oxycodone has reduced bioavailability compared with IV dosing. Approximately 37% of the orally administered dose is available systemically for analgesic effects in children ^[16][17]. This is very similar to scope of effect in adults. Oxycodone undergoes extensive metabolism, including partial metabolism by CYP2D6 to an active metabolite called oxymorphone ^[18][19]. Thus, the risks associated with ultrarapid metabolizers for codeine may very well exist for oxycodone ^[19]. The pharmacokinetics of oxycodone are also variable, especially in infants ^[18]. Therefore, oral morphine is preferable to oral oxycodone as an alternative to codeine.

Hydromorphone

Hydromorphone is a morphine derivative that is significantly more potent than morphine ^[11][20] and is believed to be somewhat easier to absorb. Hydromorphone also undergoes extensive metabolism, and one of its metabolites (hydromorphone-3-glucuronide) is active. The potency of hydromorphone suggests that there may be advantages to using oral hydromorphone versus oral morphine, but there is relatively little data supporting this and more research comparing use of the two opiates in children is needed ^[11][20].

Tramadol

Tramadol is a codeine analog that acts as an atypical opiate. Specifically, tramadol appears to exert analgesic effects via being both a weak agonist at the µ-opiate receptor and a weak inhibitor of norepinephrine and serotonin reuptake ^[21]. Tramadol has been associated with lower rates of certain opiate-related adverse effects, such as inhibition of gastrointestinal function and constipation. In contrast to other agents, tramadol is very well absorbed, with 70% bioavailability ^[22], and has a longer half-life than many other oral opiates.

Tramadol is primarily eliminated renally, but it also undergoes metabolism by both CYP2D6 and CYP3A4. Metabolism of tramadol by CYP2D6 produces an active metabolite with much greater affinity for the µ receptor than tramadol itself. Therefore, the same issues with ultrarapid metabolizers via CYP2D6 connected to codeine also apply to tramadol use ^[23]. Tramadol metabolism by CYP3A4 is inhibited by a number of drugs, including some anti-convulsants and selective serotonin reuptake inhibitors (SSRIs). Furthermore, there is considerable variability in tramadol metabolism in children, notably young children. This variability and risk for medication errors have made the most appropriate dosing form for tramadol in children a controversial issue ^[24][25]. While tramadol has some attractive features, the place of oral tramadol in therapy for children has yet to be defined.

Alternates to opioids

While opioids have historically been an essential part of the ‘Analgesic ladder’, emerging data suggest that there are conditions in children for which alternative therapies such as acetaminophen or NSAIDs are safe and effective ^[7][26][27]. Moreover, there is an emerging body of evidence suggesting that in certain circumstances, oral morphine offers no advantage over oral NSAIDs ^[26][27]. The use of NSAIDs or acetaminophen (or both) should be maximized before moving to opioids. Also, nonpharmacologic approaches to pain control have been demonstrated for some painful procedures and conditions in children and a multimodal approach to managing pain should be used, whenever and as much as possible.

Summary

In the post-codeine era, clinicians should carefully consider their options for oral analgesia. While there are several oral opioids available, oral morphine appears to be the option best supported by evidence of efficacy and safety. Clinicians should also consider alternatives to opioid use in pursuit of effective, safe pain control for children.

Recommendations

1. Effective and safe pain control should be a focus of treatment plans for children with acute or chronic conditions, based on best practice guidelines and current evidence.
2. Pain control should involve both pharmacologic and nonpharmacologic approaches and be appropriate for the case, setting, and nature of the pain.
3. Medication choice and administrations should be both commensurate with the nature and severity of the pain and demonstrated to be effective and safe for use in children. Analgesics should be used in a stepwise manner, beginning with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) before progressing to opioids.
4. While there are a number of oral opioid formulations available for analgesia for children, oral morphine is still the drug with the strongest evidence base for efficacy and safety. Other oral opioids appear promising, but more evidence is needed to establish their efficacy, safety, and role in therapy before using them routinely.
5. Research into pain management for children in both acute and chronic settings is urgently needed.

Acknowledgements

This position statement has been reviewed by the Acute Care, Bioethics, and Community Paediatrics Committees of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY DRUG THERAPY AND HAZARDOUS SUBSTANCES COMMITTEE

Members: Shinya Ito MD, Geert ‘t Jong MD (Chair), Jean-François Turcotte MD (Board Representative), Sunita Vohra MD
Liaisons: Michael J. Rieder MD (Canadian Society of Pharmacology and Therapeutics)
Principal authors: Michael J. Rieder MD, Geert ‘t Jong MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.