Morphine

Generic name
Morphine
Brand name
ATC Code
N02AA01
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Morphine is predominantly eliminated through glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 2B7, thus morphine clearance directly reflects the formation of its two major metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The metabolites are cleared through renal elimination.

Morphine metabolism (glucuronidation) appears to increase exponentially with bodyweight in the first 3 years of life, with a major increase 10 days after birth (Knibbe 2009). It is hypothesized that the lack of uridine diphosphate glucuronic acid may explain the reduced morphine metabolism during the first week of life (Liu 2019). The age at which 50% abundance is achieved for UGT2B7 is calculated to be 2.8 years of age (Bhatt 2019). Morphine clearance shows substantial variability in neonates, infants and children (Euteneuer 2020, Krekels 2012, Altamini 2015, Elkomy 2016 ). Uniformity between values for volume of distribution is reported irrespective of age of the neonates and children (mean value 2.8±2.6 l/kg) (Kart 1997). 

Age

Bioavailability (%)

Distribution (L/kg)

Metabolism

Half-life (h)

Elimination (mL/min/kg)

Preterm

-

1.82-5.2 (Allegaert 2007, Pacifici 2016)

Glucuronidation primarily to M3G (Anand 2008)

6.6-11.1 (Allegaert 2007, Pacifici 2016)

2.3-7.8 (Allegaert 2007, Cote 2009)

Term neonates 

(0-30 days)

Oral 44.3 (Liu 2016)

5.15±2.6 (Liu 2016)

Glucuronidation to M3G, M6G (Anand 2008)

3.91±1 (Kart 1997)

6.5±2.8 (Cote 2009) 

9.2 (Kart 1997)
8.1±3.2 (Cote 2009)

6.78-17.1* (Krekels 2012)
0.58-16 (Krekels 2012)

Infants 
 (1 month-1 year)

Rectal 35 (Lundeberg 1996)

2 (Bouwmeester 2003)

2.8±2.6 (Bouwmeester 2003)

-

1.15±2.4 (Olkkola 1988)

5.2 (Simons 2006)

7.8-69.4 (Krekels 2012)
16.3-28.7* (Krekels 2012)
25.8-75.6 (Bouwmeester 2003)
25.3-48.9 (Cote 2009)

Children 

(1-18 years)

Oral 29.8 (Liu 2016)

3.17-3.76 (Bouwmeester 2003)

-

0.76±1 (Simons 2006)
2.0±1.8 (Kart 1997)

1-3 years 25.6-32.2* (Krekels 2012)

12-60 (Krekels 2012) 

23.6±8.5 (Cote 2009)
 

Adults  

Oral 19-74 (Lugo 2002)

2.1-4.0 (Lugo 2002)

-

2-4 (Lugo 2002)

20-30 (Lugo 2002)

Thigpen 2019
* Determined with popPK models

Oral and rectal bioavailability is unreliable (15-50%). Bioavailability of retard tablet is 40-70%. Bioavailability decreases with increasing strength.

If retard tablet is broken, morphine is released 20-25% faster. The duration of action is then about 8 hours.

Special populations
Mechanical ventilation appears to be of influence of morphine metabolite formation and elimination, with a reported decrease up to 30% in patients requiring mechanical ventilation with a duration greater than or equal to 10 days (Thigpen 2019). Morphine clearance may be reduced in neonates treated with therapeutic hypothermia (Favie 2020, Favie 2019, Frymoyer 2017, Roka 2008).

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Severe pain
  • Oral
    • Normal preparation (immediate release)
      • Term neonate
        [3]
        • 0.3 - 0.6 mg/kg/day in 6 doses.
      • 1 month up to 18 years
        [3] [52] [54]
        • 0.6 - 1.8 mg/kg/day in 6 doses.
    • Slow (modified or delayed) release
      • 6 years up to 18 years
        [3] [21]
        • 0.4 - 1.6 mg/kg/day in 2 doses. Initial dose in opoid naive patients max 60 mg/day. Increase gradually in case of insufficient effect.
  • Rectal
    • Term neonate
      [3]
      • 0.6 - 1.2 mg/kg/day in 6 doses.
    • 1 month up to 18 years
      [3] [53]
      • 1.2 - 1.8 mg/kg/day in 6 doses.
  • Intravenous
    • Preterm neonates Gestational age < 37 weeks
      [4]
      • Initial dose: 50 - 100 microg./kg/dose in 60 min.
      • Maintenance dose: 3 - 20 microg./kg/hour, continuous infusion.

      • Administer under monitoring.
        If there is insufficient effect, the hourly dose can be given as a bolus injection; increase step by step.

    • Term neonate
      [3] [4] [5]
      • Initial dose: 50 - 100 microg./kg/dose in 60 min.
      • Maintenance dose: 3 - 20 microg./kg/hour, continuous infusion.

      • Administer under monitoring.
        If there is insufficient effect, the hourly dose can be given as a bolus injection; increase step by step.

    • 1 month up to 3 years
      [13] [19] [22] [23] [24] [25] [48] [51]

      • VENTILATED PATIENTS

        Starting dose (BOLUS): 100 microgram/kg/dose
        Maintenance dose (CONTINUOUS INFUSION)

        4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour
        10-15 kg: 15-20 microgram/kg/hour, titrated up to 40 microgram/kg/hour
        In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous dose

        NON VENTILATED PATIENTS

        Starting dose (BOLUS):
        PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion.
        PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.
        Maintenance dose,(CONTINUOUS INFUSION):
        4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour
        10-15 kg: 15-20  microgram/kg/hour, titrated up to 40 microgram/kg/hour

      • Administer under monitoring.
        If there is insufficient effect, the hourly dose can be given as a bolus injection; increase step by step.

    • 3 years up to 18 years and ≥ 15 kg
      [26] [29] [31] [33]

      • VENTILATED PATIENTS

        Starting dose (BOLUS): 100 microgram/kg/dose
        Maintenance dose (CONTINUOUS INFUSION):
         10-40 microgram/kg/hour.
        In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous dose

        NON VENTILATED PATIENTS

        Starting dose (BOLUS):
        PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion.
        PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.
        Maintenance dose (CONTINUOUS INFUSION):10-40 microgram/kg/hour

  • Subcutaneous
    • 1 month up to 3 years
      [13] [16] [19] [22] [23] [24] [25] [51]

      • VENTILATED PATIENTS

        Starting dose (BOLUS): 100 microgram/kg/dose
        Maintenance dose (CONTINUOUS INFUSION)

        4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour
        10-15 kg: 15-20 microgram/kg/hour, titrated up to 40 microgram/kg/hour
        In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous dose

        NON VENTILATED PATIENTS

        Starting dose (BOLUS):
        PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion.
        PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.
        Maintenance dose,(CONTINUOUS INFUSION):
        4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour
        10-15 kg: 15-20  microgram/kg/hour, titrated up to 40 microgram/kg/hour

      • Administer under monitoring.
        If there is insufficient effect, the hourly dose can be given as a bolus injection; increase step by step.

    • 3 years up to 18 years and ≥ 15 kg
      [26] [29] [31] [33] [51]

      • VENTILATED PATIENTS

        Starting dose (BOLUS): 100 microgram/kg/dose
        Maintenance dose (CONTINUOUS INFUSION):
         10-40 microgram/kg/hour.
        In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous dose

        NON VENTILATED PATIENTS

        Starting dose (BOLUS):
        PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion.
        PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.
        Maintenance dose (CONTINUOUS INFUSION):10-40 microgram/kg/hour
Severe pain: administration via PCA pump
  • Intravenous
  • Subcutaneous
    • 5 years up to 18 years
      [40] [51]

      • BOLUS: 15-20 microgram/kg, lockout interval 15-30 minutes,
        BACKGROUND INFUSION:  0-15 microgram/kg/hour, max 100 microgram/kg/hour
Respiratory Distress in Palliative Care
  • Oral
    • Normal preparation (immediate release)
      • Preterm (GA < 37 weeks) and Term neonate
        [57]
        • Initial dose: 0.3 mg/kg/day in 6 doses.

        • Adjust startingdose based on the patients needs and comfort. Incremental increases of 50% of the initial dose can serve as a guideline, but deviations may be needed.

      • 1 month up to 18 years
        [57]
        • Initial dose: 0.6 mg/kg/day in 6 doses.

        • Adjust startingdose based on the patients needs and comfort. Incremental increases of 50% of the initial dose can serve as a guideline, but deviations may be needed.

  • intravenous / subcutaneously
    • Preterm (GA < 37 weeks) and Term neonate
      [56]
      • Initial dose: 6 microg./kg/dose, once only.
      • Maintenance dose: 6 microg./kg/hour, continuous infusion.
        • Adjust the dose based on the patients needs and comfort. Incremental increases of 50% of the maintenance dose can serve as a guideline, but deviations may be needed.
        • Before each increase in the maintenance dose, administer a single bolus equal to the last continuous infusion dose
        .
    • 1 month up to 18 years
      [55] [56] [58]
      • Initial dose: 10 microg./kg/dose, once only.
      • Maintenance dose: 10 microg./kg/hour, continuous infusion.
        • Adjust the dose based on the patients needs and comfort. Incremental increases of 50% of the maintenancel dose can serve as a guideline, but deviations may be needed.
        • Before each increase in the maintenance dose, administer a single bolus equal to the last continuous infusion dose
        .

Renal impaiment in children > 3 months

In cases of reduced renal function, the active metabolite morphine-6-glucuronide accumulates. This is especially important when administering high doses and/or over a longer period.

  • GFR 50-80 ml/min/1.73 m2: no dose adjustment
  • GFR 30-50 ml/min/1.73 m2: 75% of normal dose, titrate according to response
  • GFR 10-30 ml/min/1.73 m2: 75% of normal dose, titrate according to response
  • GFR < 10 ml/min/1.73 m2: 50% of normal dose, titrate according to response

Source: Pediatric Drug Book – Kidney Disease Program. 

Clinical consequences

Symptoms of opioid toxicity include depression of the central nervous system with consciousness lowered to coma, respiratory depression or irregular breathing pattern, bradycardia, hypotension, hypothermia, hyporeflexia, miosis, urinary retention, nausea, vomiting, constipation, confusion, muscle spasms and convulsions.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Respiratory depression, hypotension, urinary retention, vomiting, obstipation, itching.

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

In children of 1 to 6 months (born full-term), premature babies up to the age of 1 year, monitoring of the respiration is needed if there are airway, kidney/liver or neuromuscular conditions or in concomitant use of sedatives.
For chronic pain treatment, always prescribe slow-release morphine together with a laxative.
Do not grind up the slow-release tablets.

Too rapid intravenous administration may increase the frequency of side effects. Administer very slowly in children (SmPC).

When postoperative respiratory depression occurs, naloxone IV can be administrated (see naloxone monograph ).

In children with obesity, ideal body weight is recommended instead of total body weight for morphine dosing ((Ross 2015, NHS 2021)). 

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

OPIOIDS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

References

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Changes

Therapeutic Drug Monitoring


Overdose