Neobook — clinical reference

Stepwise treatment of paediatric pain

Opioid switching

Breakthrough pain

Discontinuing opioids in children and opioid-withdrawal syndrome

Opioid overdose

Starting doses of analgesics in children

Analgesic doses in renal and hepatic impairment

Bisphosphonates

Other analgesics

Stepwise treatment of paediatric pain

As for adults, the WHO approach to pain management applies to children.

However, there are some differences in the step-wise approach to pain management that apply to paediatric patients.

STEP 1

Paracetamol alone or with ibuprofen are the drugs of choice at step 1 for children older than 3 months.
Paracetamol is the only choice for children younger than 3 months.
In children not able to take orally (e.g., vomiting, postoperative), paracetamol suppositories or IV paracetamol (especially in the postoperative paediatric patient) provide valuable alternatives.
Other NSAIDs and COXIBs are not recommended for use in children.
Aspirin should not be used in children or teenagers, because of the risk of Reye’s syndrome.⁸⁰
Children may be at an increased risk of paracetamol-induced liver damage if they are malnourished, obese, suffering from a febrile illness, taking a prolonged course of treatment, have poor oral intake (nutrition and hydration), or are taking liver enzyme-inducing drugs.
Inadvertent paracetamol poisoning may occur with the concomitant use of combination drugs (prescription or over-the-counter), most of which contain paracetamol.
Acetylcysteine is the antidote in the case of paracetamol overdose.
Age-appropriate doses of ibuprofen and paracetamol are listed in Table 1.

STEP 2

Low-dose morphine is the opioid of choice at step 2.
Tilidine drops are also used at step 2 in South Africa and provide the convenience of being concentrated and easy to administer even in children who cannot swallow.
Codeine and tramadol are not recommended for use in children, but tramadol may be used in adolescent patients.
There is anecdotal evidence that tricyclic antidepressants may be useful, especially in pain associated with HIV infection. Ideally, administration of tricyclic antidepressants in children should be preceded by ECG testing (contraindicated if QT is prolonged).

STEP 3

Morphine is the opioid of choice at step 3.
Persistent pain may be managed with prolonged-release oral morphine formulations administered every 8 to 12 hours. Unfortunately available tablet strength and inability of the young child to swallow tablets preclude their use in very young children. MST must not be crushed. The smallest prolonged-release tablet is a 10 mg tablet, which when given twice daily is equivalent to 3.3 mg of morphine given 4 hourly (the starting dose for a 16 kg child).

By the clock administration of analgesia

Children should receive regular analgesia with supplemental doses for breakthrough pain (taking care not to exceed the maximal daily dose of paracetamol).

Analgesia should be administered by the appropriate route

Medication should be administered by the simplest, most effective and least painful route.
The oral route of analgesic administration is preferred (liquid or, when the child is old enough, solid forms).
IM injections should not be used.
Alternative routes of administration should be chosen based on clinical judgement and patient preference and include IV, SC, rectal and transdermal. Rectal administration results in unreliable blood concentrations and is not a preferred route of administration.

Individualised treatment

There is no maximum dose of opioid analgesic for progressive malignant pain and dose should be titrated according to the child’s level of pain and tolerability.
Age-appropriate starting doses of opioids are listed in Tables 2 to 4.

Opioid switching

Switching to an alternative opioid or route of administration is recommended when adequate titration of the initial choice fails to achieve adequate analgesia and side effects are intolerable.
In children with persistent pain, alternatives to morphine include fentanyl and oxycodone.
When switching opioids, dose conversions must be age-appropriate and consideration should be given to the bioavailability of the formulation, potential interactions with other medicines, renal and hepatic clearance, and the opioid analgesics that have previously been used to relieve the child’s pain.
Dose equivalents for opioid switching are listed in Table 5.

Breakthrough pain

Breakthrough pain must be distinguished from end of dose pain and incident pain related to movement or another precipitating factor.
Immediate-release and IV morphine are recommended for breakthrough pain in children at a dose of 5% to 10% of the total daily dose of morphine (50%-100% of the regular 4 hourly dose).
When converting from oral to IV morphine, care must be taken to observe correct dose conversions.
Morphine takes up to 30 minutes to become fully effective, so another breakthrough dose should not be administered before 30 minutes.
If breakthrough doses are required, the regular morphine doses should be adjusted (see below).

Increasing the dose of morphine

If pain is not controlled by regular morphine, the dose may be increased in one of two ways:

Increase the regular dose by 30%-50% (e.g., increase 5 mg q4h to 6.5-7.5 mg q4h).
Add up all the breakthrough doses and divide by 6, then add this total to the current daily maintenance dose; e.g., in a child with maintenance dose 5 mg q4h requiring 4 breakthrough doses of 2.5 mg each in a 24 hour period:

Total breakthrough dose = 4 x 2.5 mg = 10 mg
10 mg ÷ 6 = 1.67 mg
5 mg + 1.67 mg = 6.67 mg; round up to 7 mg
New dose = 7 mg po q4h with 3.5-7 mg for breakthrough pain

Discontinuing opioids in children and opioid-withdrawal syndrome

In children who have received significant doses of an opioid, sudden discontinuation of opioids may be associated with symptoms, including:

Irritability
Anxiety
Insomnia
Agitation
Increased muscle tone
Abnormal tremors
Nausea
Vomiting
Abdominal cramps
Diarrhoea
Poor appetite
Tachypnea
Tachycardia
Fever
Sweating
Hypertension

If the opioid needs to be discontinued, it should be withdrawn slowly, tapering the dose as follows:

For short-term therapy (7-14 days): the original dose can be decreased by 10- 20% of the original dose every 8 hours, gradually increasing the time interval.
For long-term therapy: the dose should be reduced not more than 10-20% per week.
These pharmacological approaches should be accompanied by measurement of withdrawal symptoms using a scoring system.

Opioid overdose

Opioid overdose may be associated with respiratory depression, pinpoint pupils and coma.
Naloxone is a specific antidote, starting at doses of 1 mcg/kg titrated over time (e.g., every 3 minutes) until the necessary dose is found. If necessary, this may be followed by a low dose infusion to maintain wakefulness until symptoms of opioid overdose resolve.
Assisted ventilation should be provided where necessary and the child should be carefully monitored.
Naloxone should be used with extreme caution so as not to precipitate acute pain or withdrawal symptoms.
Where necessary, the opioid should be restarted at a lower dose.

Starting doses of analgesics in children

Starting doses of analgesics for children are listed in Tables 1 to 4.

Table 1: Nonopioid and Weak Opioid Analgesic Doses (Oral Route)¹³
Nonopioid Analgesics
	Paracetamol	Ibuprofen
Neonates (age 0-29 days)	5-10 mg/kg q6-8h^a	Not indicated
Infants (age 30 days to 3 months)	10 mg/kg q4-6h^a
Infants (age 3-12 months) and Children 1-12 years	10-15 mg/kg q4-6h^a,b	5-10 mg/kg q6-8h
Maximum daily dose	4 doses/day	40 mg/kg/day
Weak Opioids
Tilidine
Children	1 mg/kg/dose q6h (approximately equivalent to 1 drop per 2.5 kg/dose q6h) Do not exceed a single dose of 1 mg/kg 3-4 times daily (q6h)
Tramadol
Adolescents (age >12 years)	< 50kg: 1-2 mg/kg/dose 3-6 hourly (max 8 mg/kg/day) >50kg: 50-100 mg 3-6 hourly (max 400 mg/day)
^a Children who are malnourished or in a poor nutritional state are more likely to be susceptible to toxicity at standard dose regimens due to reduced natural detoxifying glutathione enzyme. ^b Maximum 1 gram at a time.

Table 2: Starting Doses for Opioid Analgesics for Opioid-naive Neonates¹³
Medicine	Route of Administration	Starting Dose
Morphine	IV injection^a	25-50 mcg/kg every 6 hrs
	SC injection
	IV infusion	Initial IV dose^a 25-50 mcg/kg, then 5-10 mcg/kg/hr 100 mcg/kg every 6 or 4 hrs
Fentanyl	IV injection^b	1-2 mcg/kg every 2-4 hrs^c
	IV infusion^b	Initial IV dose^c 1-2 mcg/kg, then 0.5-1 mcg/kg/hr
IV: intravenous; SC: subcutaneous ^a Administer IV morphine slowly over at least 5 minutes ^b The intravenous doses for neonates are based on acute pain management and sedation dosing information. Lower doses are required for non-ventilated neonates. ^cAdminister IV fentanyl slowly over 3-5 minutes

Table 3: Starting Doses for Opioid Analgesics in Opioid-naive Infants (Age 1 Month to 1 Year)¹³
Medicine	Route of Administration	Starting Dose
Morphine	Oral (immediate-release)	80-200 mcg/kg every 4 hrs
	IV injection^a	1-6 months: 100 mcg/kg every 6 hrs 6-12 months: 100 mcg/kg every 4 hrs (max 2.5 mg/dose)
	SC injection
	IV infusion^a	1-6 months: Initial IV dose: 50 mcg/kg, then: 10-30 mcg/kg/hr 6-12 months: Initial IV dose: 100-200 mcg/kg, then: 20-30 mcg/kg/hr
	SC infusion	1-3 months: 10 mcg/kg/hr 3-12 months: 20 mcg/kg/hr
Fentanyl^b	IV injection	1-2 mcg/kg every 2-4 hrs^c
Fentanyl^b	IV infusion	Initial IV dose 1-2 mcg/kg^c, then 0.5-1 mcg/kg/hr
Oxycodone	Oral (immediate-release)	50-125 mcg/kg every 4 hours
^a Administer IV morphine slowly over at least 5 minutes ^b The intravenous doses of fentanyl for infants are based on acute pain management and sedation dosing information. ^c Administer IV fentanyl slowly over 3-5 minutes

Table 4: Starting Doses for Opioid Analgesics in Opioid-naive Children (Age 1-12 Years) ¹³
Medicine	Route of Administration	Starting Dose
Morphine	Oral (immediate-release)	1-2 years: 200-400 mcg/kg every 4 hrs 2-12 years: 200-500 mcg/kg every 4 hrs (max 5 mg)
	Oral (prolonged-release)	200-800 mcg/kg every 12 hrs
	IV injection^a	1-2 years: 100 mcg/kg every 4 hrs 2-12 years: 100-200 mcg/kg every 4 hrs (max 2.5 mg)
	SC injection
	IV Infusion	Initial IV dose: 100-200 mcg/kg^a, then 20-30 mcg/kg/hr
	SC infusion	20 mcg/kg/hr
Fentanyl	IV injection	1-2 mcg/kg^b, repeated every 30-60 minutes
Fentanyl	IV infusion	Initial IV dose 1-2 mcg/kg^b, then 1 mcg/kg/hr
Oxycodone	Oral (immediate-release)	125-200 mcg/kg every 4 hours (max 5 mg/dose)
Oxycodone	Oral (prolonged-release)	5 mg every 12 hours
^a Administer IV morphine slowly over at least 5 minutes ^bAdminister IV fentanyl slowly over 3-5 minutes

Table 5: Dose Conversions for Opioid Switching
Dose Ratio (Parenteral : Oral) ¹³
Morphine	1:2-1:3	-
Equivalent Dose ⁸¹
Morphine oral	10 mg	-
Morphine subcutaneous	5 mg	-
Oxycodone oral	5 mg	-
Oral Morphine to Fentanyl Patch ¹³
Morphine salt daily dose	Fentanyl patch	This table represents a conservative conversion to fentanyl transdermal patch and should NOT be used to convert from transdermal fentanyl to other analgesic therapies; overestimation of the dose of the new agent and possibly overdose with the new analgesic agent may result. The dosing conversion from oral morphine to transdermal fentanyl is conservative to minimize the potential for overdosing patients with the first dose, and therefore approximately 50% of patients are likely to require a higher dose following the initial application.
45 mg daily	12.5 mcg
90 mg daily	25 mcg
180 mg daily	50 mcg
270 mg daily	75 mcg
360 mg daily	100 mcg

Note: As with adults, a 12 hour overlap period is required when switching from oral morphine to a fentanyl patch. Patch changes in children, however, may need to be made sooner than adults because of more rapid metabolism of fentanyl. In some instances patches may need to be changed every 48 hours rather than 72 hours. As with adults, provision needs to be made for breakthrough pain relief in patients on fentanyl patches.

One of the limitations with fentanyl patches in young children is their strength size and, where available, buprenorphine patches provide a good alternative for use in the smaller child or infant. See Conversion Ratios From Oral Morphine to Buprenorphine Patch.

Analgesic doses in renal and hepatic impairment

Recommendations for dose adjustment in children with renal or hepatic impairment are described in Table 6.1 and 6.2.

Table 6.1: Dose Adjustment in Children With Renal Impairment
Drug	Renal Impairment^†
	Mild	Moderate	Severe
Paracetamol	-	10-15 mg/kg/dose; may administer q8h	10 mg/kg/dose; may administer q8h
Ibuprofen	Use lowest effective dose and monitor renal function. Sodium and water retention may occur, possibly leading to renal failure	Avoid
Morphine	Reduce dose by 25%. Increase dose interval to 6-8 hourly (titrate against pain)		Reduce dose by 50% or consider switching to an alternative opioid with less renal elimination, e.g., fentanyl. Increased and prolonged effect; increased risk of neurotoxicity
Naloxone	Opioids may accumulate in renal impairment so extended treatment with naloxone may be required to reverse the opioid effect
Oxycodone	Dose reduction may be required. Start with lowest dose and titrate according to response
^†Mild renal impairment: GFR 20-50 ml/min/1.73 m² or serum creatinine 150-300 micromol/L Moderate renal impairment: GFR 10-20 ml/min/1.73 m² or serum creatinine 300-700 micromol/L Severe renal impairment: GFR <10 ml/min/1.73 m² or serum creatinine >700 micromol/L

Table 6.2: Dose Adjustment in Children with Hepatic Impairment
Drug	Hepatic Impairment
Paracetamol	Dose-related toxicity; do not exceed daily recommended dose
Ibuprofen	Use with caution - there is increased risk of gastrointestinal bleeding; can cause fluid retention; avoid in severe liver disease
Morphine	Reduce dose. May precipitate coma
Naloxone	No dose adjustment necessary
Oxycodone	In moderate to severe hepatic dysfunction, avoid or reduce dose by 50%

Bisphosphonates are not recommended for the management of cancer pain in children

Other analgesics

There is insufficient evidence to make specific recommendations about the use of antidepressants and anti-epileptic drugs for the treatment of cancer pain.

Typical paediatric doses of drugs that have not been discussed in the previous sections are listed in Table 7.

Table 7: Typical Doses of Other Analgesics and Drugs ²⁵
Drug	Dose	Comments
Amitriptyline	2- 12 years: 0.1-0.2 mg/kg at night Increase to max 1-2 mg/kg at night over 1-2 weeks 12-18 years: 10-25 mg po at night, increase to 75 mg maximum	Do ECG before using. Contraindicated in patients with prolonged QT interval. Pain dose is lower than for depression. Takes up to 3 weeks for effect. No longer considered first line if other adjuvants are available.
Carbamazepine	5-20 mg/kg/day in 2 or 3 divided doses, increase gradually to avoid side effects	Induces cytochrome P450. Drug interactions with antiretroviral drugs Can cause pancytopenia
Gabapentin	2-12 years: 3-5 mg/kg/dose. Start nocte,then q12h then q8h. Increase to 10-20 mg/kg/dose 12-18 years: 300 mg on day 1; 300 mg q12h on day 2; 300 mg q8h on day 3. Max 1200 mg q8h	Avoid sudden withdrawal Do not use in patients with history of psychiatric illness.
Corticosteroids	Prednisone 1-2 mg/kg/day Dexamethasone: 0.1-1.5 mg/kg (max 10mg) increased to 0.1-0.25 mg/kg/dose q12h for 14 days	Useful for neuropathic pain, bone pain, IRIS
Clonidine	1-4 mcg/kg/dose q6-12h	Caution in renal failure, vascular disease, depression
Diazepam	1-6 years: 1 mg/day in divided doses (2-3). 6-14 years: 2-10 mg/day in divided doses (2-3).	Used for associated anxiety
Hyoscine butylbromide	1 month-2 years: 0.5 mg/kg/dose PO q8h 2-5 years: 5 mg po q8h 6-12 years: 10 mg po q8h	For colicky abdominal pain. Can cause nausea, dry mouth and constipation

IRIS: Immune Reconstitution Inflammatory Syndrome

Analgesic Medication for Children with Cancer Pain

Drugs mentioned