Postoperative Pediatric Pain Practice Post the Codeine Era: Peri-Operative...
hosted by Dr. Todd Ponsky · StayCurrentMD
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What the experts said
The real revolution in pediatric pain management started in the 1990s.
The blood-brain barrier in neonates and infants is immature and reaches relative maturity at approximately 9 months of age; full barrier function comparable to adults is achieved around 2 years.
Fentanyl, being highly lipophilic, crosses the blood-brain barrier equally in adults and pediatric patients regardless of barrier maturity.
Morphine dosing (0.1 mg/kg) is calculated based on the blood-brain barrier preventing some morphine from reaching the brain; in neonates with immature barriers, more morphine crosses, requiring dose adjustment.
Pharmaceutically, 100 mcg of fentanyl is equivalent to 10 mg of morphine because fentanyl is 100 times more potent than morphine, but this equivalence does not apply in the first year of life due to immature blood-brain barrier.
Hepatic metabolism in neonates is immature and cannot adequately handle phase 1 and phase 2 drug metabolism; liver function matures by approximately one year of age.
Protein binding is reduced in neonates due to insufficient albumin and alpha-1 acid glycoprotein production; the unbound (free) portion of drugs is responsible for pharmacodynamic effects.
Renal function in neonates is immature until approximately one year of age; kidneys cannot concentrate urine, handle protein load, or manage sodium load effectively.
Volume of distribution differs significantly in neonates compared to adults: neonates are 'born bags of water' with higher total body water, affecting hydrophilic drug distribution, while adults have higher fat content affecting lipophilic drugs.
Preemptive analgesia, including regional blocks, reduces pain signals reaching the CNS and also reduces the stress response (aldosterone, epinephrine, norepinephrine, glucagon, neuropeptide Y), which can later act as pain modulators.
NSAIDs exhibit a ceiling effect: increasing the dose beyond a certain point does not increase analgesic efficacy but does increase side effects.
The recommended dose of ketorolac in pediatrics is 0.2 to 0.3 mg/kg per dose, maximum 15 mg per dose, given no more frequently than every 8 hours.
Studies have shown that ketorolac doses exceeding 15 mg per dose or more than 3 doses per day result in increased side effects without additional analgesic benefit.
Ketorolac-induced kidney damage can be both cumulative and idiosyncratic; at Akron Children's Hospital, one case of kidney damage occurred after a single high dose.
At Akron Children's Hospital, IV ketorolac is limited to a maximum of 15 mg every 8 hours for no more than 2 days; a third day requires clinical reassessment.
Dr. Joshi's practice uses ketorolac 15 mg three times daily, combined with 1 g acetaminophen three to four times daily, which decreases opioid consumption by approximately 50%.
For adult patients, Dr. Joshi loads with 30 mg ketorolac intraoperatively, then continues 15 mg every 8 hours postoperatively.
Tramadol is a weak mu-opioid receptor agonist and a weak norepinephrine and serotonin reuptake inhibitor, providing an alternative mechanism of action when opioid receptors show resistance.
Tramadol is particularly effective for muscular pain, making it an excellent choice for patients with congenital scoliosis and similar conditions.
Tramadol is classified as a Schedule 4 drug in the US (as of the recording date), though it is considered an opioid elsewhere; it has addiction potential.
Codeine has an unfavorable side effect profile with high incidence of nausea, vomiting, and constipation—more than stronger narcotics like hydrocodone or oxycodone.
Codeine is not a preferred drug of addiction due to unfavorable side effects, minimal tolerance development (especially to constipation), and less euphoria compared to other opioids.
Codeine conversion to morphine occurs in the liver via the cytochrome P450 enzyme CYP2D6; approximately 10% of Caucasians lack this enzyme and are poor metabolizers.
10 to 29% of North African and Ethiopian populations have multiple copies of the CYP2D6 gene, making them ultra-rapid metabolizers who convert codeine to extremely high serum levels of morphine after normal codeine doses.
Codeine dosing is 10 times the morphine dose (e.g., 1 mg/kg codeine vs. 0.1 mg/kg morphine) because only a small portion converts to morphine; ultra-rapid metabolizers effectively receive 10 times the intended morphine dose.
CYP2D6 polymorphism has been implicated in neonatal toxicity and death when codeine is administered to lactating mothers, particularly those with increased CYP2D6 activity; two infant deaths have been reported.
90% of pediatric hospitals surveyed across the US have already removed codeine from their formularies.
As of November 1st (year of recording), Akron Children's Hospital removed all codeine formulations from the pharmacy and order sets.
Oxycodone is 10 times more potent than codeine and is dosed at 0.05 to 0.1 mg/kg, which can be problematic for very small children requiring precise measurement with TB syringes.
Boston Children's Hospital discharges mothers with pre-filled TB syringes of oxycodone (6–10 syringes for 2 days, every 4–6 hours) to avoid dosing errors.
No hydrocodone preparation exists without acetaminophen in the US; Lortab elixir (hydrocodone with acetaminophen) is widely available.
Hydromorphone is 7 to 8 times more potent than morphine and is recommended for resistant severe pain or when patients have multiple allergies or side effects to other narcotics.
Hydromorphone has a much better overall side effect profile than morphine and is the first choice for PCAs at Akron Children's Hospital; approximately 950 of 1000 annual PCAs use hydromorphone.
Ibuprofen 10 mg/kg every 6 to 8 hours has been shown in multiple studies to be equivalent or equipotent to codeine for mild to moderate pain.
After giving 1 g IV acetaminophen intraoperatively, only 2 g remains available for that day under the new 3 g/day maximum.
Hydrocodone is the recommended first-choice opioid alternative to codeine for pain rated 7 or above (or lower if not controlled by acetaminophen, NSAIDs, or tramadol).
Lortab (hydrocodone 7.5 mg in 15 mL, or 0.5 mg/mL) has a better side effect profile than codeine and is dosed like morphine (0.1 mg/kg).
Hydrocodone requires CYP2D6 to convert to hydromorphone, but because the dose is 1/10 that of codeine, even ultra-rapid metabolizers remain within a safe therapeutic range.
Hydromorphone achieves peak CSF levels faster than morphine; when optimal pain control is achieved in the recovery room with morphine, peak CSF levels occur later on the floor, increasing side effect risk including respiratory depression.
At Parkland Hospital (Dallas), hydromorphone is preferred over morphine due to better pharmacokinetics and because many patients (diabetics, Hispanics, African Americans) have renal dysfunction.
Fentanyl PCAs are used for patients with morphine or hydromorphone intolerance, for trauma patients with severe pain in the first 24 hours (to assess usage before converting to longer-acting agents), and for movement-related pain when patients are otherwise comfortable at rest.
For chronic opioid therapy patients, larger PCA doses with longer lockout intervals (e.g., 3–4 mg morphine every 20 minutes) reduce anxiety and provide better analgesia than frequent small doses.
PCA demand dose must always be equal to or greater than the continuous infusion rate to ensure patients feel the bolus effect.
Prescribing combination opioid-acetaminophen products (e.g., hydrocodone/acetaminophen) alongside separate acetaminophen creates high risk of acetaminophen overdose; instead, prescribe single-agent opioids (oxycodone or hydromorphone elixir) with scheduled ibuprofen.
At Akron Children's Hospital, PCA lockout intervals are: hydromorphone every 20 minutes, morphine every 10 minutes, fentanyl every 6 minutes.
In children, the maximum acetaminophen dose has been reduced from 100 mg/kg/day to 60 mg/kg/day for infants and young children up to age 2; for children over age 2, the maximum is 90 mg/kg/day.
Oxycodone has very high 'likability' among drug addicts and is strongly euphoria-inducing; it is probably the worst choice of opioids for patients with previous opioid addiction or alcoholism, worse than morphine or hydromorphone.
Acetaminophen and NSAID dosing must be calculated based on lean body weight, not actual or ideal body weight, especially in the 40% of US pediatric population that is obese; failure to do so can result in mortality.
Dr. Joshi's practice for opioid-naive adults: morphine 1 mg every 5–6 minutes or 2 mg every 10 minutes; hydromorphone 0.2 mg every 10 minutes.
At least three large studies (≥1000 patients each), including one from Cleveland Clinic, demonstrated efficacy and safety of NSAIDs (including ketorolac) after tonsillectomy without increased bleeding risk.
For opioid-tolerant patients, give at least half of their daily opioid dose preoperatively and consider adding a background infusion early, though not initially.
Similar literature from prostatectomy studies shows NSAIDs (ketorolac) do not increase bleeding risk in bloody surgical procedures.
A single dose of dexamethasone 4 to 8 mg given after induction of anesthesia provides significant antiemetic prophylaxis and postoperative pain relief and should be used in most patients unless contraindicated.
Dexamethasone 4 mg does increase blood sugar levels in diabetics but does not exceed treatment thresholds (140–180 mg/dL per American Diabetes Association and American College of Endocrinologists); it is safe in well-controlled diabetics.
The PROSPECT group reviewed data showing single-dose dexamethasone does not increase perioperative infection risk in high-risk patients.
Dexamethasone benefits are greater for outpatient procedures due to high incidence of postoperative nausea/vomiting and home opioid use.
MD Anderson Cancer Center routinely gives every surgical patient dexamethasone with induction.
Dexamethasone dosing varies by indication: 0.15 mg/kg for nausea/vomiting, 0.1 mg/kg for pain, 0.5 mg/kg (maximum 8 mg) for anti-inflammatory effect (airway edema).
IV lidocaine infusion (1 mg/kg bolus, then 1–2 mg/kg/hr) is called 'poor man's epidural analgesia' and has been compared to epidural analgesia in abdominal surgery, showing significant benefit for pain relief, return of bowel function, ambulation, and hospital stay.
The PROSPECT group recommends IV lidocaine infusion as second-line therapy (not first-line) when thoracic epidural is contraindicated or failed, or when NSAIDs/COX-2 inhibitors and acetaminophen are contraindicated due to renal or hepatic issues.