A 10-Year-Old Boy With Acute Postoperative Pain: A Rational Approach to Opioid Prescribing

Johanne Lynch, MD; Fiona Campbell, MD; Jason Hayes, MD

Disclosures

August 17, 2010

Opioids

Opioids are the drug of choice for the management of moderate to severe pain in children. The most commonly used routes of administration are oral and intravenous. The intramuscular route is avoided because of excessive pain associated with the injection. Patient-controlled analgesia pumps may be used in children older than 5 years.[7,8,9] Continuous intravenous infusions or intermittent intravenous bolus can be used in younger children; however, nurses may underestimate the severity of patients' pain and underdose relative to patient-controlled analgesia.[10]

Opioid Types

Morphine. Morphine is the most commonly used opioid in children. It may be given orally, rectally, or intravenously. Of note, the oral bioavailability is relatively poor (25%-40%), necessitating larger doses by this route. By age 6 months, the clearance of morphine metabolites is 80% that of adults. There is considerable individual variability in morphine requirements, and morphine doses should be titrated to effect. A typical bolus dose is 50-100 μg/kg (25 μg/kg in neonates), and infusion rates range from 5-40 μg/kg/hr.

Hydromorphone. Hydromorphone is 5 times more potent than morphine. It has no active metabolites and may be given intravenously or orally. Hydromorphone is generally viewed as a second-line alternative to morphine and is often used as part of an opioid rotation in an attempt to improve analgesia and reduce opioid-related adverse effects.[11]

Oxycodone. Oxycodone is a semisynthetic opioid available as a single agent or combined with acetaminophen or a nonsteroidal anti-inflammatory drug (eg, ibuprofen) or as a sustained-release preparation. Oxycodone is 1.5 to 2 times more powerful than morphine when administered orally. However, unlike morphine and hydromorphone, oxycodone undergoes metabolism by cytochrome P450 in the liver, making drug interactions more likely.[12]

Fentanyl. Fentanyl is a synthetic lipid-soluble opioid with higher potency, more rapid onset, and shorter duration of action than morphine. It is usually administered to children by the intravenous route in perioperative and intensive care settings.

Meperidine. Meperidine has one-tenth the analgesic potency of morphine. It is no longer recommended because of undesirable adverse effects (hallucinations, agitation, and seizures) related to its metabolite normeperidine.

Codeine. Codeine is generally not regarded as a first-line analgesic because of its unpredictable analgesic effect, which is dependent on metabolism to morphine by cytochrome P450 2D6. Younger children may be particularly susceptible because this enzyme is inactive at birth and is only 25% active by age 5 years. Slow metabolizers experience limited analgesia, whereas ultrarapid metabolizers may have toxic effects because of excessive metabolism to morphine.[13]

Opioid Dosing

Although all opioid agonists produce similar analgesic effects at equipotent doses, there is large interindividual variability in opioid requirements and equianalgesic dose ratios between opioids, which can vary depending on patient comorbidities, treatment duration, and dose of opioid before switching from one drug to another. Although equianalgesic dose ratio guidelines exist (see Table 2), they are an oversimplification of a complex process, and exact doses should be guided by appropriate patient assessment and clinical evaluation.

Criteria for conversion from intravenous to oral opioids should include (1) tolerance of oral intake, (2) stable pain of mild to moderate severity, and (3) no interventions planned in the immediate future that will alter the first 2 criteria.

Table 2. Opioid Equianalgesic/Conversions Table

Drug Equipotent IV Dose (mg/kg) Ratio of Potency to Morphine IV IV to PO Conversion Ratio Equipotent PO Dose (mg/kg) Ratio of Potency to Morphine PO Reference
Morphine 0.1 1 1:2-3 0.2-0.3 1 [14]
Hydromorphone 0.02-0.03a 3.5-5a 1:5b 0.04-0.08 3.5-5a [14,15]
Oxycodone 0.1 0.7-1 0.5-0.8:1 0.1 15-2 [16-18]
Fentanyl 0.01-0.0125 80-100 1:1 c Minimum 12.5 µg/hrc 70-00 [14,15,19]
Meperidine 0.5-1 0.1-0.14 1:3 1-3 0.1-0.14  

IV = intravenous; PO = by mouth
Note: Equianalgesic dose ratios apply to patients taking stable doses of opioids and should be used as guidelines only. Appropriate patient evaluation and clinical judgment are necessary before the use of equianalgesic dose ratios. Ranges reflect the high degree of interpatient variability.
a If converting morphine → hydromorphone, use lower dose; if converting hydromorphone → morphine, use higher dose.
b Data from bioavailability studies with high variability are reported (1:1-5).
c Conversion to transdermal fentanyl patch is based on average hourly consumption of IV fentanyl. Transition from fentanyl IV should be done in a stepwise fashion.

Opioid-Related Adverse Effects

Incidence. Vigilant monitoring and prompt management can reduce the incidence and severity of opioid-related adverse effects. The most common adverse effects observed in children receiving opioids are nausea and vomiting, itching, respiratory depression, and sedation.[20] The incidence of serious adverse events resulting in permanent harm is reported to be approximately 1 in 10,000, thus reinforcing the safety of opioid use in children.[21] Risk factors for adverse events include concurrent use of sedatives or opioids by different routes; excessive dosing in infants; and neurodevelopmental, respiratory, or cardiac comorbidities. Other commonly observed adverse effects include urinary retention and decreased gastrointestinal tract motility.

Management of adverse effects. Respiratory depression is the most serious adverse effect. It is dose dependent and is most pronounced with opioids that have a high affinity for μ-opioid receptors located in the brainstem, such as morphine, fentanyl, alfentanil, remifentanil, and sufentanil. Small doses of opioids reduce respiratory rate and disrupt the rhythm of breathing. With increasing doses, the tidal volume is reduced as well; however, the dose-response for respiratory depression is extremely variable among patients.[22] Mild respiratory depression can be managed by stimulating the patient, administering oxygen, and withholding further doses until the effects subside. Severe respiratory depression may require assisted ventilation and repeated administration of naloxone 2-4 μg/kg.

All opioids can cause nausea and vomiting by binding to μ- and δ-opioid receptors in the chemoreceptor trigger zone[23] and peripherally in the bowel.

Opioid-induced pruritus is mediated primarily by μ-opioid receptors located in multiple sites in the brain and spinal cord.[24] Degranulation of mast cells and release of histamine by systemically administered opioids, particularly morphine, are also thought to play a role.

Opioid antagonists, such as naloxone, and mixed agonist-antagonists, such as nalbuphine, can be used to counteract opioid-related adverse effects. Studies in adults and children have shown that the incidence and severity of nausea and pruritus can be reduced without affecting analgesia.[25]

Although the severity of opioid-induced adverse effects is generally dose dependent, the potential for adverse effects varies among patients. Therefore, it may be possible to reduce the severity of adverse effects by switching to a different opioid instead of reducing the dose. Opioid rotation may also improve analgesia in patients in whom tolerance to a specific opioid has developed. Tolerance rarely develops before 72 hours of continuous administration, whereas tolerance develops in the majority of children after 10 days of continuous administration.[26] Therefore, opioids should be discontinued gradually according to severity of pain and duration of administration. In general, infusions of less than 10 days' duration can be weaned by 20% every 8 hours, and infusions of greater than 10 days can be weaned by 10% of the original dose per day.

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