Clinical pharmacology of analgesics in infants and the pharmacologic management of pain in neonates

Pacifici, Gian Maria

doi:10.5935/MedicalExpress.2014.03.03

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Sumário

REVIEWS • MedicalExpress (São Paulo, online) 1 (3) • June 2014 • https://doi.org/10.5935/MedicalExpress.2014.03.03 copy

Clinical pharmacology of analgesics in infants and the pharmacologic management of pain in neonates

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVES:

The objectives of this study are to describe (1) the clinical pharmacology of analgesics in infants and (2) the pharmacologic management of pain in neonates.

METHODS:

The bibliographic search was performed using PubMed and EMBASE databases as search engines.

RESULTS:

Opioid analgesics are the most commonly used analgesics for acute pain and they include intravenous morphine (50 to 200 µg/kg), oral methadone (50 to 200 µg/kg), intravenous fentanyl (0.5 to 4 µg/kg), alfentanyl (10 to 20 µg/kg), sufentanil (10 to 15 µg/kg), and remifentanil (5 µg/kg). Fentanyl, alfentanyl, sufentanil and remifentanil are short-action opioid analgesics. Non-opioid analgesics can be used for moderate pain; they include oral paracetamol (acetaminophen, 12 to 15mg/kg), the intravenous benzodiazepine midazolam (50 to 150 µg/kg) which is not recommended in neonates, intravenous propofol (2.5 mg/kg) which is used for induction of general anaesthesia, and ketamine, (2 mg/kg intravenously or 4 mg/kg intramuscularly) which produces a short-lasting, trance-like state with profound analgesia and amnesia.

CONCLUSION:

The use of non-opioid analgesics has increased in the last years for the management of non-acute pain. If prevention or elimination of pain is not possible, a more realistic goal may be to aggressively intervene to minimize pain and its effects.

KEYWORDS:
analgesia; analgesics; management of pain; neonate; pain; pharmacokinetics.

Development stage	Number of infants	Dose (µg/kg)	t_1/2 (hours)	Cl (ml/kg/min)	Vd (l/kg)	Reference
Preterm and term	19	10 to 100	2.2 ± 1.6	2.1 ± 1.2	2.0 ± 1.0	29
Preterm	10	100	10 ± 3.7	3.4 + 3.3	1.8 + 0.8	32
Preterm	26	Note A	8.9 ± 3.3	3.6 ± 0.9	2.7 ± 1.0	33
Term	10	100	8.1 ± 8.1	8.7 ± 5.8	1.3 ± 0.4	31
Term	20	Note B	6.6 ± 2.9	5.5 ± 12.4	5.0 ± 6.8	22
Term	3	100	6.7 ± 4.6	15.5 ± 10.0	2.9 ± 2.1	32
Adults	-	-	1.9 ± 0.5	24 ± 10	3.3 ± 0.9	34

Drug	Development stage	Number of infants	Dose (μg/kg)	t_1/2 (hours)	Cl (ml/kg/min)	Vd (l/kg)	Reference
Fentanyl	Preterm	6	30	8.7 ± 5.1	2.2 ± 2.4	1.0 ± 0.4	56
Fentanyl	Preterm	5	25	7.6 ± 1.8	1.3 ± 0.7	0.8 ± 0.5	57
Fentanyl	Term	5	25	5.5 ± 0.8	1.7 ± 0.5	0.8 ± 0.3	57
Fentanyl	Preterm	7	25	9.5 ± 2.6	19.2 ± 8.2	17.2 ± 9.0	59
Fentanyl	1 to 71 days	14	Note A	3.1 to 13.5	9.0 to 32.8	5.4 to 11.9	58
Fentanyl	Adults	-	-	3.7 ± 0.4	13.0 ± 2.0	4.0 ± 0.4	34
Alfentanyl	Preterm	13	Note B	4.1 ± 2.6	3.2 ± 2.2	0.5 ± 0.2	69
Alfentanyl	Preterm	5	25	7.6 ± 1.8	1.3 ± 0.7	0.8 ± 0.5	57
Alfentanyl	Term	5	25	5.5 ± 0.8	1.7 ± 0.5	0.8 ± 0.3	57
Alfentanyl	Preterm	22	20	5.3	0.9	0.8	70
Alfentanyl	Adult	-	-	1.6 ± 0.2	6.7 ± 2.4	0.8 ± 0.3	34
Sufentanil	0 days to 1 month	9	10 to 15	13.0 ± 5.8	6.7 ± 6.1	4.1 ± 1.0	74
Sufentanil	1 to 7 days	3	10	10.5 ± 7.4	4.3 ± 2.5	2.7 ± 0.1	115
Sufentanil	20 to 28 days	3	10	4.0 ± 1.3	17.0 ± 3.5	3.4 ± 0.2	115
Sufentanil	Adults	-	-	2.7 ± 0.4	12.7 ± 0.8	1.7 ± 0.2	116
Remifentanil	0 to 2 months	8	5	5.4 ± 1.8 (min)	90.5 ± 36.8	0.4 ± 0.3	79
Remifentanil	Adult	-	-	18 to 24 (min)	40 to 60	0.3 to 0.4	34

Development stage	Number of infants	Dose (mg/kg)	t_1/2 (hours)	Cl (ml/kg/min)	Vd (l/kg)	Reference
Preterm	21	20 Rectally	11.0 ± 5.7	1.7 ± 0.7	na	4
Preterm	7	20 Rectally	4.8 ± 1.2	0.7 ± 11	na
Note A	283	Note B	6.1	3.0 (44%)^* * The values in brackets indicate the percent variability. t1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.	0.9 (20%)^* * The values in brackets indicate the percent variability. t1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.	90
Preterm	48	Note C	na	Note D	1.0 l/kg (30)^* * The values in brackets indicate the percent variability. t1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.	87
Preterm	50	Note E	na	1.2 (30.5)^* * The values in brackets indicate the percent variability. t1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.	1.1 l/kg (29.6)^* * The values in brackets indicate the percent variability. t1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.	91
Adults	-	^-	2.0 ± 0.4	5.0 ± 1.4 l/kg	0.9 ± 0.1 l/kg	34

Comments	Development stage	Number of infants	Dose (µg/kg)	t1/2(hours)	Cl (ml/kg/min)	Vd (l/kg)	Reference
Healthy neonates
Intravenous administration	Preterm	24	100	6.3	1.8	1.1	117
Population pharmacokinetics of midazolam in neonates and children
Note A	Preterm	187	Note B	9.9	1.2 ± 0.2	1.0 ± 0.2	118
Note C	Preterm	60	100	14.1	0.94	1.15	119
Age ranged from 2 days to 17 years	-	18	50 to 400 µg/kg/h Infusion	5.5 ±3.5	5.0 ± 3.9	1.7 ± 1.1	92
Adult subjects
Adults	-	-	^-	1.9 ±0.6	6.6 ± 1.8	1.1 ± 0.6	34

Development stage	Number of infants	Dose (µg/kg)	t_1/2 (hours)	Cl (ml/kg/min)	Vd (l/kg)	Reference
Preterm	9	3	12.8	13.6^a a the range was 3.7 to 78.2 ml/min/kg;	3.7^b b the range was 1.33 to 7.96 l/kg; t-]/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.	110
Preterm	25	3	na	28.0 ml/min (32)^* * The values in brackets indicate the percent variability;	1.3 l (19)^* * The values in brackets indicate the percent variability;	109
Preterm	25	3	na	29.0 ml/min	1.3 l	112
1 to 3 years	12	4	1.6 (0.01)^* * The values in brackets indicate the percent variability;	53.0 ± 13.0	9.5	120
4 to 7 years	10	2.5	na	30.0 ± 2.9	0.7 ± 0.1	121
1 week to 12 years	21	4 mg/kg/h	na	30.2	1.4	107
4 to 12 years	12	2.5	4.8 ± 0.5	40.0 ± 3.6	5.0 ± 2.7	108
Adults	-	-	3.5 ± 0.7	27.0 ± 5.0	1.7 ± 0.7	34

Drug	Sedation and analgesia	Infusion rate (µg/kg/h)	Anaesthesias	Monitoring	Reference
Morphine	50 to 200 (µg/kg)	10 to 20	Not applicable	Monitor respiratory and cardiovascular status closely. Observe for abdominal distension. Consider urine retention.	15
	IVor IM	IV
Methadone	50 to 200 (µg/kg	Not applicable	Not applicable	Monitor respiratory and cardiacstatus closely. A 12-lead ECG should be obtained. Assess forgastric residual, abdominal distension, and loss of bowel sounds.	15
	PO
Fentanyl	0.5 to 4 (µ/kg)	1 to 5	5 to 50 (µg/kg/dose	Monitor respiratory and cardiovascular status closely. Observe for abdominal distension, loss of bowel sounds, and muscle rigidity	15
	IV	IV	IV
Alfentanyl	10 to 20 (µ/kg	Loading dose of 8 (µg/kg, followed by an infusion of 2.5 to 10	400 ng/ml	High incidence of chest wall rigidity with doses above 20 (µg/kg	65, 66, 69, 76
	IV	IV	IV
Sufentanil	10 to 15 (µg/kg	0.41	No data available	No data available	74, 75
Remifentanil	5 (µg/kg	0.25 (µg/kg/min
	IV	IV	No data available	No data available	79, 122, 123
Paracetamol (Acetaminophen)	20 to 25 µg/kg Loading dose (PO)	Not applicable	Not applicable	Assess for signs of pain. Monitor temperature. Administration. Asses liver functions. Liver toxicity occurs with prolonged administration >48 hours.	15
	12 to 15 µg/kg
	Maintenance dose (PO)
Midazolam	It is not recommended in neonates 50 to 150 µg/kg IV or IM 200 µg/kg (PO) 200 to 300 µg/kg/dose intranasally.	10 to 60 µg/kg/h IV Maintenance infusion 60 to 400 µg/kg/h IV	Not applicable	Follow respiratory status and blood pressure closely, especially when used concurrently with narcotics. Assess hepatic function. Observe for signs of withdrawal after discontinuation ofprolonged therapy.
	For anticonvulsant activity, the loading dose is 150 µg/kg and the maintenance dose is 60 to 400 µg/kg/h.				15
Propofol	Use during neonatal intubation 2.5 mg/kg IV Do not use for prolonged period in children ,3 years	Prolonged sedation: used to provide sustained sedation for patients requiring intensive care. Do not use in children less than 3 years.	Maintenance anaesthesia: give IV less than 4 mg/kg/h in children less than 3 years	Must be supervised by an experienced intensivist and recovery monitored until it is complete. Can cause respiratory depression and hypotension.	9, 16
Ketamine	0.5 to 2 µg/kg (IV) 2 to 5 µg/kg PR	Sustained IV administration: 1 µg/kg loading dose followed by0.5 µg/kg/h. 4 µg/kg IM	2 µg/kg (IV) 4 µg/kg (IM)	Stridor and laryngospasm can be encountered. Prolonged apnea may be encountered. Increased production of salivary secretion.	9, 16

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