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

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.

RESUMO

OBJETIVOS:

Os objetivos deste estudo são (1) descrever a farmacologia clínica de analgésicos em crianças e (2) o tratamento farmacológico da dor em recem-nascidos.

MÉTODOS:

A pesquisa bibliográfica foi realizada utilizando as bases de dados PubMed e EMBASE como ferramentas de busca.

RESULTADOS:

Os analgésicos opióides são os analgesicos mais utilizados para a dor aguda e incluem morfina por via intravenosa (50 a 200 ug/kg), metadona por via oral (50 a 200 ug/kg), fentanil (0,5 a 4 mg/kg), alfentanil (10 a 20 ug/kg), sufentanil (10 a 15 ug/kg), e remifentanil (5 ug/kg). Fentanil, alfentanil, sufentanil e remifentanil são opióides de curta ação analgésica. Os analgésicos não opióides podem ser utilizados para a dor moderada e incluem paracetamol oral (acetaminofeno, de 12 a 15 mg/kg), o midazolam benzodiazepina intravenosa (50 a 150 ug/kg) que porém não é recomendado em recém-nascidos, o propofol (2,5 mg/kg), que é utilizado para a indução da anestesia geral, e Ketamina (2 mg/kg por via intravenosa ou 4 mg/kg por via intramuscular), que produz transe de curta duração, com profunda analgesia e amnésia.

CONCLUSÃO:

O uso de analgésicos não-opióides aumentou nos últimos anos para o tratamento da dor não aguda. Se a prevenção ou eliminação da dor não é possível, uma meta mais realista podem ser intervir agressivamente para minimizar a dor e os seus efeitos.

INTRODUCTION

The mainstay of systematic analgesia for moderate to severe pain is the use of opioid therapy. Opioids provide both sedation and analgesia, have a wide therapeutic window, and decrease hemodynamic and moderate stress response. The opioids include: morphine, methadone, fentanyl, alfentanyl, sufentanil, and remifentanil. Morphine and fentanyl are the most commonly used analgesic opioids in the "neonatal intensive care unit" (NICU).¹

The non opioid analgesics comprise the non-steroidal antiinflammatory drug paracetamol (acetaminophen), the benzodiazepine midazolam, which is not recommended in neonates, and the anaesthetics propofol and ketamine. Ketamine produces a trance-like state with profound analgesia and amnesia. In recent years, the use of non-opioid analgesics for the management of non-acute pain has increased.²

Neonates were believed to be unable to experience pain until late 1980s.³ Several studies have changed our understanding of pain,¹ pain assessment and analgesia in newborn infants.^4-7 As a consequence, the importance of antinociceptive therapy in newborn infants has been increasingly acknowledged, leading to a burst of pain research in newborn neonates. Rational drug therapy in newborns requires the knowledge of drug pharmacokinetics and pharmacodynamics in infants, which are different from the adult parameters. Research has concentrated on the development of pain assessment instruments and clinical trials investigating the effectiveness and safety of a variety of analgesics in infants.⁸

In order to assess the painfulness of a procedure and then the effectiveness of a treatment, there is the obvious need to measure and quantify the pain.⁹ The main goal of pain assessment is to identify an infant's potentially painful condition, quantify the pain level, and to predict the need for an intervention.⁹

Many factors, such as the gestational and postnatal ages, neurobehavioral state, and prior experience in the NICU can affect the newborn's responsiveness to pain.^10-13 In neonates, pain is mainly based on the behavioural response and physiological consequences of nociception, resulting in the concept of "multimodal" pain scales. These pain scales quantify aspects of "behavioural indicators" of pain that include facial action, body movements, tone, cry, state, or consolability, and "physiological indicators" of pain, which include increased heart rate, respiratory rate, blood pressure, decreased heart rate variability, or oxygen desaturation. An example of such a multimodal pain scale is the "Echelle Douleur Inconfort Nouveau-Né" (EDIN) scale.¹⁴

According to the "International Association for the Study of Pain" (IASP), pain is an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage. In situations associated with persistent pain or discomfort, an attempt should be made to assess its intensity and the effectiveness of analgesic treatment using a validated measure for pain such as the EDIN or the "Neonatal Pain Agitation and Sedation" scale (NPAS).

Pharmacokinetics are dependent on the maturation of enzymes and physiological processes responsible for absorption, distribution and elimination of drugs. The expression of drug metabolizing enzymes and the processes of absorption, distribution and elimination of drugs are different in neonates, compared to adults. Therefore, the doses and the interval between doses are different in neonates and adults.

BIBLIOGRAPHIC SEARCH

The bibliographic search was performed using PubMed and EMBASE databases as search engines. The cutoff point was November 2013. The following key words were used: "pharmacological pain management in neonates." Articles were read carefully, and the selected ones were examined. In addition, the books "Neofax: a Manual of Drugs Used in the Neonatal Care" by Young and Mangum¹⁵ and the "Neonatal Formulary"¹⁶ were consulted.

RESULTS

This review reports 127 studies. The kinetic parameters of morphine are summarized in Table 1. Table 2 summarizes the pharmacokinetic parameters of fentanyl, alfentanyl, sufentanil and remifentanil. The kinetic parameters of paracetamol (acetaminophen), midazolam and propofol are summarized in Tables 3, 4 and 5, respectively. Table 6 provides the therapeutic regimens and the monitoring of the various analgesics in neonates.

Table 1
Pharmacokinetic parameters of morphine in neonates. Figures are the mean + SD

Development stage	Number of infants	Dose (µg/kg)	t1/2 (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

• Note A = loading dose of 50 μg/kg of diamorphine followed by an intravenous infusion of 15 μg/kg/h of diamorphine. Note B = loading dose of 50 μg/kg of morphine, followed by a continuous infusion of 15 μg/kg/h of morphine; t_1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.

Table 2
Pharmacokinetic parameters of fentanyl, alfentanyl, sufentanil and remifentanil in neonates. Figures are the mean + SD or median or range

Drug	Development stage	Number of infants	Dose (μg/kg)	t1/2 (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

• Note A = a loading dose of 5 μg/kg fentanyl was followed by a constant infusion ranging from 0.57 to 10.3 µg/kg/h. The rate and duration of fentanyl infusion were determined by the patient's attending physician; Note B = a loading dose of 8µg/kg of alfentanil was followed by a variable-rate continuous infusion from 2.5 to 10 µg/kg/h fentanyl. t_1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.

Table 3
Pharmacokinetic parameters of paracetamol (acetaminophen) in neonates. Figures are the mean or the mean + SD

Development stage	Number of infants	Dose (mg/kg)	t1/2 (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%)*	0.9 (20%)*	90
Preterm	48	Note C	na	Note D	1.0 l/kg (30)*	87
Preterm	50	Note E	na	1.2 (30.5)*	1.1 l/kg (29.6)*	91
Adults	-	-	2.0 ± 0.4	5.0 ± 1.4 l/kg	0.9 ± 0.1 l/kg	34

• na = not available; Note A = median postconceptional age was 40 weeks (range was 28 to 64 weeks); Note B = infants were given either single or multiple doses of four different formulations of paracetamol; Note C = paracetamol was given intravenously in either single (n = 30) or multiple (n = 18) doses. A loading dose of 30 mg/kg was followed by a maintenance dose of 20 mg/kg every 6 to 12 hours. Note D = clearance increased from 0.7 ml/min/mg at 27 postconceptional weeks to reach 1.7 ml/kg/min by 42 weeks. Note E = infants received intravenously paracetamol adjusted every 6 hours according to the following dosing regimens for 4 days. The dose was 10 mg/kg for infants aged between 28 to <32 weeks, 12.5 mg/kg for infants aged between 32 to <36 weeks and 15 mg/kg for infants aged ≥ 36 weeks.
• ^*
  The values in brackets indicate the percent variability. t_1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.

Table 4
Pharmacokinetic parameters of midazolam in neonates and children. Figures are the median or the mean + SD

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

• Note A = all neonates received midazolam during artificial ventilation; Note B = midazolam was administered as a continuous infusion to 109 infants, as a bolus dose to 22 infants, and as a combination of both to 56 infants. Note C = neonates undergoing mechanical ventilation had a body weight < 1,500 g; t_1/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.

Table 5
Pharmacokinetic parameters of propofol in neonates and children. The figures are the median or the mean + SD

Development stage	Number of infants	Dose (µg/kg)	t1/2 (hours)	Cl (ml/kg/min)	Vd (l/kg)	Reference
Preterm	9	3	12.8	13.6a	3.7b	110
Preterm	25	3	na	28.0 ml/min (32)*	1.3 l (19)*	109
Preterm	25	3	na	29.0 ml/min	1.3 l	112
1 to 3 years	12	4	1.6 (0.01)*	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

• na = not available;
• ^*
  The values in brackets indicate the percent variability;
• ^a
  the range was 3.7 to 78.2 ml/min/kg;
• ^b
  the range was 1.33 to 7.96 l/kg; t-]/2 = ß-phase elimination; Cl = clearance; Vd = apparent volume of distribution.

Table 6
Analgesic dosing regimens for neonates and monitoring of the various analgesics in infants.

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

• IV = intravenously; IM = intramuscularly; PO = by mouth; PR = rectally.

DRUGS FOR THE MANAGEMENT OF PAIN IN NEONATES

Opioids

Opioids include morphine, methadone, fentanyl, alfentanil, sufentanil, and remifentanil.

Morphine

Morphine is the most commonly used opiate for analgesia, although a wide variability occurs in clinical dosages.¹⁷ This drug has an onset of action of 5 min; the time of peak of effect and the duration of action are 45 to 90 min and 4 to 5 hours, respectively.¹⁸ The analgesic effects of morphine are caused mainly by an activation of µ-receptors, although it can also act on k-opioid receptors subtypes.¹⁸

After major surgery, continuous morphine doses of 10 to 40 µg/kg have been shown to be effective in alleviating pain in infants and children between 0 and 14 years of age.^19-23 No difference in analgesic effect was found between continuous and intermittent dosing.¹⁹

Morphine causes histamine release and may lead to hypotension, bradycardia, and bronchospasm, especially in infants with chronic lung disease.^24-27 Caution should be used when prescribing morphine to infants with asthma or bronchopulmonary dysplasia, because of the risk of histamine-induced bronchospasm.²⁸

Chay et al.²⁹ suggest that the mean morphine concentration required to produce adequate sedation in 50% of infants was found to be 125 ng/ml. Concentrations of morphine above 300 ng/ml may be associated with adverse effects, which include effects on the gastrointestinal tract and possibly on the neurologic system.^9,-29

Lynn and Slattery³⁰ studied the morphine pharmacokinetics in 10 infants ≤ 10 weeks of age. Infants 1 to 4 days of age showed longer elimination half-lives than the older infants (6.8 versus 3.9 hours). Clearance in newborns ranged from 2.1 and 15.5 ml/kg/min, and it was lower than in adults.³⁴ The lower clearance and the longer elimination half-life in newborns (0 to 7 days of life) explain the prolonged duration of the action of morphine in very young infants.

The pharmacokinetics of morphine have been studied by various authors and the kinetic parameters are summarised in Table 1. Pokela et al.³¹ studied the pharmacokinetics of morphine (100 µg/kg) in 27 infants. The clearance and the half-life varied considerably with postnatal age. The kinetic parameters obtained in 10 neonates younger than 1 week are summarised in Table 1. In 10 infants aged between 1 week to 2 months, the half-life and the clearance were 2.6 + 1.7 hours and 11.9 + 5.1 ml/kg/min, respectively.

Bhat et al.³² studied the pharmacokinetics of morphine in 20 newborn infants aged from 26 to 40 weeks of gestation. Ten infants had a gestational age < 30 weeks and the kinetic parameters are summarised in Table 1. A trend of decreasing distribution volume and elimination half-lives was increasing with gestation age, but a considerable degree of variation was seen. The morphine clearance increased as a function of gestational age at a rate of 0.9 ml/kg/min per week of gestation. During the first week of life, adequate blood levels can be maintained by administering 100 µg/kg morphine at 4 to 6 hour intervals in term infants, and in prematures, the frequency of morphine administration must be less frequent. Morphine binds to plasma protein at a percentage between 18 and 22.³²

Barrett et al.³³ reports that the administration of 50 µg/kg of diamorphine, followed by an intravenous infusion of 15 µg/kg/h to 26 prematures aged from 26 to 38 weeks, produced a steady-state plasma concentration of morphine of 62.5 + 22.8ng/ml. Table 1 summarizes the morphine pharmacokinetic parameters. Gestational age correlated with infant clearance (r² = 0.31; p = 0.003) and half-life (r² = 0.35; p = 0.01) of morphine.³³ The currently used dosing regimen of diamorphine achieves an effective morphine concentration in infants, but the loading dose could be modified to achieve a more rapid onset of analgesia.³³

An intravenous loading dose of morphine (100 µg/kg) followed by an infusion of 10 µg/kg/h was administered to infants with a postmenstrual age of 23 to 26 weeks. An infusion of 20 or 30 µg/kg/h of morphine was administered to infants with postmenstrual age of 27 to 29 or 30 to 32 weeks, respectively.³³ The total number of infants was 449. The clearance was 50% of the mature value at 54.2 weeks of postmenstrual age, and increased from 0.5 ml/kg/min at 24 weeks of postmenstrual age to 1.5 ml/kg/min at 32 weeks of postmenstrual age. The volume of distribution (Table 1) did not change with age.

Morphine metabolism was studied in 12 children and 9 prematures maintained on a continuous infusion of morphine ranging from 10 to 360 µg/kg/h.³⁵ All neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. Five neonates and all children had detectable concentrations of morphine-6-glucuronide (M6G) in plasma and urine. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine, were significantly higher in children than neonates (p < 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period.

Methadone

Methadone is a synthetic µ-agonist with long duration of action because it is eliminated slowly.⁶ Methadone causes a desensitization of delta-opioid receptors involved in pain sensitization. The action on the delta-opioid receptors reverses the tolerance that occurs with morphine and, as a NMDA receptor antagonist, methadone produces additive analgesia and delayed development of tolerance.^9,-28 Its potency is similar to that of morphine but has a more rapid distribution and a slower elimination. Methadone has a slow onset of action of about 20 min after intravenous administration and 30 to 60 min after oral administration;²⁸ it has a bioavailability of 75 to 85% and a prolonged elimination halflife of 41 hours in neonates.³⁷ The volume of distribution of methadone is 7.1 + 2.5 l/kg in children and 6.1 + 2.4 l/kg in adults³⁶. In adult liver microsomes, methadone is N-demethylated by CYP2B6 and CYP3A4,³⁷ and these enzymes undergo a considerable interindividual variability in human adult liver microsomes.³⁷

Few data on the efficacy, safety and pharmacokinetics of methadone are available in neonates. A study on the pharmacokinetics of methadone in neonates is lacking and should be performed. Methadone is widely used for the treatment of opioid withdrawal in neonates and children.^38,39 Intravenous methadone has been shown to be an effective analgesic for postoperative pain relief⁴⁰ and it has been recommended as the first-line opioid for severe and persistent pain in children.⁴¹ Chana and Anand⁴² suggested using oral methadone as the first-line opioid for severe and persistent pain in children.

Maternal methadone is transferred across the placenta and can induce significant withdrawal symptomatology in newborns.⁴³ The relationship between a maternal dose of methadone and the incidence and severity of neonatal signs of withdrawal were studied in 30 mothers and their infants. The ratio of neonatal to maternal plasma concentrations of methadone was 2.2:1. At methadone plasma levels greater than or equal to 0.06 µg/ml, symptomatic patients appeared to be protected from withdrawal. The apparent excretory half-life of methadone in the neonate was 32.5 hours.⁴⁴

Fentanyl

Fentanyl is a synthetic opioid that acts as a "morphinelike" agonist. Fentanyl crosses the blood-barrier more rapidly than morphine.¹⁶ Its potency is 50 to 100-fold that of morphine on a weight basis.¹⁵ Fentanyl has an onset of action of 3 min and a duration of effect of 0.5 hours.¹⁸ It maintains hemodynamic stability, blocks endocrine stress responses, and prevents pain-induced responses and increases pulmonary vascular resistance.^5-45 This drug causes less histamine release than morphine and decreases the heart rate and mildly decreases blood pressure.¹⁶ It is commonly used for patients undergoing cardiovascular surgery or for patients with poor cardiac function.¹⁶ It has been used in neonates under artificial ventilation, with bronchopulmonary dysplasia, pulmonary hypertension and/or diaphragmatic hernia.⁴⁶ In neonates, the continuous fentanyl infusion should be reduced by 25% to 50% when compared with older infants.⁴⁷

Fentanyl is widely distributed in tissues. Hepatic clearance is linked to the ontogeny of the unbound fraction to α₁-acid glycoprotein. It binds to 77% and 70% to the plasma proteins of preterm and term neonates, respectively.⁴⁸ The clearance of fentanyl is immature at birth but it increases dramatically after birth and reaches the adult values within 2 weeks of life.^7,49 Fentanyl is metabolized into the inactive norfentanyl by CYP3A4^15,50 and this enzyme appears during the first week of life.^51,52,53

The clearance of fentanyl, after a loading dose of 10.5 µg/kg followed by a continuous infusion of 1.5 µg/kg/h, was studied by Saarenmaa et al.⁵⁴ in the first days of life. The infants (n = 38) had a gestational age from 26 to 42 weeks. The clearance of fentanyl was 11.5 ± 4.0ml/kg/min, correlated with the gestational age (r = 0.46; p < 0.01) and body weight (r = 0.48; p < 0.01).

Collins et al.⁵⁵ administered a bolus dose of 30 µg/kg to 9 preterm infants with a gestational age of 31.8 ± 4.7 weeks for induction of anaesthesia for ligation of the patent ductus arteriosus. Fentanyl plasma concentrations ranged between 7.7 and 13.6 ng/ml in the 30 min after administration. Elimination half-life was 14.7 ± 9.3 hours. Systolic blood pressure remained stable throughout surgery. There was a gradual increase in heart rate from 159 ± 12 beats/min at the time of skin incision to 173 ± 15 beats/min at the time of skin closure (p < 0.05). Fentanyl plasma concentrations remained similar between 30 (10.6 ± 1.9 ng/ml) and 120 min (9.6 ± 1.6 ng/ml) after administration.

The pharmacokinetics of fentanyl were studied in neonates by different authors and the pharmacokinetic parameters are summarized in Table 2. The clearance of fentanyl exhibits a highly interindividual variability in neonates.⁵⁸ A significant correlation was observed between postnatal age and total body clearance (r = 0.80; p = 0.03) in 7 newborns undergoing mechanical ventilation.⁵⁹ The kinetic parameters are reported in Table 2.

Fentanyl is frequently used as a continuous infusion in neonates with pulmonary hypertension or in those requiring extracorporeal membrane oxygenation (ECMO). Muscle rigidity appears after high doses of fentanyl used in anaesthetic induction.^60-62 Chest wall rigidity and respiratory depression can be treated with naloxone (10 µg/kg)¹⁵.

The pathology and/or the surgical lesion lengthen t_1/2 of fentanyl in neonates. In infants undergoing surgical operation, the half-life of fentanyl was 463 and 750 min, whereas the population mean of fentanyl half-life in healthy neonates is 317 min.⁴⁹

When administered intranasally (1 to 2 µg/kg), the bioavailability of Fentanyl is 89%, with a lag of approximately 5 min and a half-life of about 6.5 min. Intranasal versus intravenous administration of fentanyl leads to a delay in the mean fentanyl time to a maximum concentration (13 versus 6 min) and lower maximum concentration (1.2 versus 2.0ng/ml).⁶³

Alfentanyl

Alfentanyl is a short synthetic opioid that is a chemical derivative of fentanyl. The kinetic parameters of alfentanyl are summarised in Table 2. This drug causes less histamine release than fentanyl.⁶⁴ Ten to 20 µg/kg alfentanyl are sufficient for analgesia during endotracheal intubation and suctioning in preterm neonates.^65-67 A target plasma concentration of 400 ng/ml is used in anaesthesia. Alfentanyl binds to plasma protein at percentages of 67.2% and 88.2% in neonates and in their mothers, respectively.⁶⁸ A significant negative correlation was found between alfentanyl plasma concentration and total-body clearance (r = -0.75; p = 0.02⁶⁹. Alfentanyl undergoes extensive metabolism by CYP3A4, CYP3A5 and CYP3A7.⁷¹

Sufentanil

Sufentanil is one of the most potent synthetic opioids available. Its use is primarily for deep anaesthesia in patients undergoing cardiac surgery. The clearance, expressed as per kg of body weight, is increased in children compared to adults⁷². Sulfentanil binds to α1-acid glycoprotein. The fraction of sulfentanil bound to plasma protein is 0.79 in neonates and 0.91 in their mothers.⁷² The free fraction of sufentanil is negatively correlated with α₁-acid glycoprotein plasma concentration (r = -0.73; p < 0.001), whereas there was a weak correlation with plasma albumin concentration (r = - 0.34; p < 0.05).⁷³

The pharmacokinetic parameters of sufentanil are summarised in Table 2. The half-life (hours) of sulfentanil was 13.0 ± 5.8 in neonates, 3.6 ± 0.7 in children (p < 0.01) and 2.3 ± 0.5 in adolescents (p < 0.01).⁷⁴ The clearance (ml/kg/min) was 6.7 ± 6.1 (neonates), 18.1 ± 2.7 (infants), 16.9 ± 3.2 (children), and 16.9 ± 3.2 (adolescents) and 13.1 ± 3.6 (adults; p < 0.01).⁷⁴ The volume of distribution (l/kg) was 4.1 ± 1.0 in neonates, 2.7 ± 0.5 in infants, and 2.5 ± 0.5 in children (p < 0.05).⁷⁴

Remifentanil

Remifentanil is a µ-opioid receptor agonist characterized by a fast onset and by a short time of action. It is rapidly degraded in blood and other tissues by esterases.⁷⁷ The overall median degradation half-life of remifentanil was 143 min (2.4 hours) and ranged from 76 and 221 min.⁷⁸ Remifentanil is rapidly metabolised by preterm infants and does not accumulate in infants.⁸⁰ The pharmacokinetic parameters of remifentanil⁷⁹ are summarized in Table 2. Remifentanil is a good option to attenuate the hemodynamic/endocrine markers of stress related to surgery.⁸¹ Hypotension may become significant when the remifentanil is associated to other drugs like sevoflurane.

Non-opioid analgesics

Non-opioid analgesics can be used to treat mild to moderate pain, either alone or in combination with opioid analgesics to increase their efficacy and decrease the risk of adverse effects in neonates with severe pain. The non-opioid analgesics are paracetamol (acetaminophen), a non-steroidal anti-inflammatory drug, the benzodiazepine midazolam, and the anaesthetics ketamine and propofol. Among the non-opioid analgesics, paracetamol (acetaminophen) is the drug most often used. It also has good antipyretic activity. Midazolam is a commonly used hypnosedative but it is not recommended in neonates. Ketamine is commonly used for analgosedation in children, with only very rare complications. Besides parenteral administration (intravenous or intramuscular) oral administration of ketamine can be used, despite a low bioavailability of 15 to 20%.⁸² Propofol has a low clearance capacity at birth with consequent postnatal related increase.⁸³

Paracetamol (Acetaminophen)

Paracetamol is safe and effective in preterm and term neonates with mild to moderate pain, but it is ineffective for acute pain^10,84. Paracetamol is the only agent recommended for use as an antipyretic in newborns and recently has been proposed as a supplement therapy to opioids for postoperative analgesia.⁸⁵

There is a significant inverse correlation between paracetamol Cmax and gestational age (r = - 0.50; p = 0.007⁴. The recommended doses for oral or rectal paracetamol administration are 25 to 30 mg/kg/day in preterm neonates of 30 weeks' gestation, 45mg/kg/day in preterm neonates of 34 weeks' gestation, and 60 mg/kg/day in term neonates.⁸⁶ Allegaert et al.⁸⁶ suggest an intravenous loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours to achieve a concentration of 11 µg/ml in neonates.

Prenatal and infant paracetamol exposure has been associated with an increased risk of childhood asthma phenotypes.⁸⁸ Risk of asthma was higher when maternal glutathione S-transferase T1 genotype was present (p = 0.006). The risk of wheezing was increased when maternal glutathione S-transferase M1 was present (p = 0.04). The increased risk of asthma and wheezing associated with late gestation paracetamol exposure in the presence of maternal glutathione S-transferase M1 was further enhanced when this enzyme was also present in the child.

The rates of sulphated and glucuronidated paracetamol clearance were assessed in vivo by measuring the excretion of these compounds in the urine.⁸⁹ The rate constant for paracetamol glucuronide formation in neonates was considerably smaller than in adults but the average rate constant for sulphated paracetamol formation was somewhat larger than in adults. The glucuronide to sulphated ratios of paracetamol in the urine was 0.12 ± 0.09 in infants 28 to 32 week old and 0.28 ± 0.35 in infants 32 to 36 weeks old.⁴

The pharmacokinetics of paracetamol were studied by different authors and the pharmacokinetic parameters of the more significant studies are summarised in Table 3. The clearance (ml/kg/min) of paracetamol increased from 0.18, at 28 postconceptional weeks, to 2.6 by 60 weeks.⁹⁰

The doses and the kinetic parameters of this drug are summarised in Table 3. The presence of non-conjugated hyperbilirubinemia was associated with reduced clearance of paracetamol. Paracetamol plasma concentrations between 10 and 23 µg/ml are predicted to reach steady-state after 15 mg/kg paracetamol every 6 hours for a neonate of 40 weeks of postmenstrual age.⁹¹

Midazolam

Midazolam is a short-acting benzodiazepine with rapid onset of action and is the most frequently used hypnosedative to suppress behavioural responses to pain.⁹² It has anxiolytic, muscle relaxant and anticonvulsant activity, now mostly used to generate anterograde amnesia and to stop prolonged seizure in children.¹⁶ Hypnosedatives (midazolam and propofol) can be used as an adjunct to analgesia, but opioids are preferred when sedation is required in ventilated neonates.⁹³ The sedative and anticonvulsant properties of midazolam are related to GABA accumulation and occupation of benzodiazepine receptors.¹⁵ GABA receptors are responsible for most inhibitory neurotransmission. A recent review on the clinical pharmacology of midazolam in neonates and children has been published.⁹⁴

Ng et al.⁹⁵ reviewed the literature on the intravenous midazolam infusion for sedation of infants in the "neonatal intensive care unit." These authors conclude that there are insufficient data to promote the use of midazolam infusion as a sedative for neonates undergoing intensive care.⁸

For sedation, the dose of midazolam in neonates ranges from 50 to 150 µg/kg either by intravenous or intramuscular route.¹⁵ For continuous intravenous infusion, the recommended dose is 10 to 60 µg/kg/h.¹⁵ The dosage needs to be increased after several days of continuous therapy because of development of tolerance and/or increased clearance. When minimal sedation is required, midazolam may be administered intranasally (200 to 300 µg/kg¹⁵. The bioavailability of intranasal midazolam ranges from 50 to 83%^96-98.

Midazolam manages the neonatal seizures refractory to conventional treatment^99,100. The recommended dose for anticonvulsant activity is a loading dose of 150 µg/kg administered intravenously and a maintenance infusion of 60 to 400 µg/kg/h.¹⁵

In adults, the recovery of unchanged midazolam in urine is 1%.³⁴ Midazolam is hydroxylated to form 1-hydroxymidazolam by hepatic CYP3A4^15,131-134 and by CYP3A5^101,102-105. The glucuronidation of 1-hydroxymidazolam is immature in preterm infants.¹⁰⁶ The pharmacokinetic parameters of midazolam in neonates, children and adults are reported in Table 4. Midazolam is not free from adverse effects when administered to neonates. The first intravenous loading dose of midazolam administered to preterms not infrequently causes respiratory depression, hypotension, a fall in cerebral blood flow, and paradoxical agitation.¹⁶

Propofol

Propofol is a rapid-acting intravenous anaesthetic.¹⁶ An intravenous dose of 2.5 mg/kg is used during neonatal intubation. Propofol is a high-extraction drug, its clearance mainly depends upon the hepatic blood flow. In adults, propofol is conjugated in the liver with glucuronic acid and with sulphate. However, multiple cytochrome P450 forms (CYP2B6, CYP2C9 and CYP2A6) contribute to the metabolism of propofol in adults¹⁴³. The urinary excretion of unchanged propofol is < 1% in adults.¹¹⁰

In neonates, the contribution of propofol glucuronidation is 34% versus 77% in adults.¹¹¹ There is a large interindividual variability in the clearance of propofol; in 9 neonates with a postmenstrual age ranging from 27 to 43 weeks, the clearance of propofol ranged from 3.7 to 78.2 ml/kg/min. The volume of distribution ranged from 1.33 to 7.96 l/kg. The kinetic parameters of propofol are summarized in Table 5. In neonates, the clearance is reduced compared with older children.

This drug should never be given to any young child at a rate exceeding 4 mg/kg/h.¹⁶ Prolonged sedation is now widely used to provide sustained sedation for patients requiring intensive care, but should not be used in this way, especially in children less than 3 years old because there is small, but currently unpredictable, risk of sudden "propofol infusion syndrome" collapse.¹⁶

Ketamine

The plasma levels of oral ketamine (10 mg/kg) peak 30 min after the administration, and the bioavailability of ketamine is about 16%.¹⁶

The half-life, the clearance and the volume of distribution of ketamine (1 mg/kg/hour) are 2.8 ± 0.6 hours, 16.0 ± 3.7 ml/kg/ml and 3.2 ± 1.8 l/kg, respectively, in children 1 week to 30 months old.¹¹³ Two mg/kg of ketamine administered intravenously or 4 mg/kg administered intramuscularly provide about 10 to 15 min of surgical anaesthesia.¹⁶ For sustained intravenous administration, a loading dose of 1 mg/kg followed by 500 µg/kg/h¹⁶ is given. Ketamine relieved pain caused by tracheal suction in 16 infants who received 0.5 or 1.0 or 2.0 mg/kg ketamine intravenously.¹¹⁴ A ketamine infusion regimen is usually supplemented with intravenous midazolam (0.2 mg/kg). Midazolam reduces ketamine's cardiovascular stimulation and emergence phenomena, and does not activate metabolites.

DISCUSSION

The analgesic reviewed have a longer half-life in neonates than in adults. They also have a clearance smaller in neonates than in adults. There is an exception with fentanyl, which has a clearance higher in neonates⁵⁹ than in adults.³⁴ The kinetics of fentanyl obtained by Santeiro et al.⁵⁹ were obtained in infants maintained on a continuous infusion of fentanyl (rate 0.53 to 1.9 µg/kg/h), and a postnatal age of 16 + 9 days. There was a significant correlation (r = 0.80; p = 0.03) between postnatal age and clearance. The data obtained by Santeiro et al.⁵⁹ were obtained under different conditions than those obtained with the other neonates and cannot be compared with the data obtained in adults.³⁴ In the cases reported in,⁵⁸ in⁷⁹ and in,¹¹⁵ the clearance was obtained in infants with a postnatal age up to two months. Thus, the comparison of the kinetic parameters between neonates and adults is difficult in these cases. Remifentanil is rapidly degraded in blood and other tissues by esterases⁷⁷ and the degradation rate is similar in the preterm and term serum.⁷⁸

In preterms, paracetamol has a clearance of 1.2 ml/kg/min, with a variability of 30.5%.⁹¹ In a study of population pharmacokinetics, conducted with 283 infants, whose age ranged from 28 and 64 weeks (median 40 weeks),⁹⁰ the clearance of paracetamol was 3.0 ml/kg/min (variability was 44%). In adults, the clearance of paracetamol is 5.0 ml/kg/min.³⁴

The clearance of midazolam is 1.8 ml/min/mg in healthy prematures and 6.6 ml/min/mg in adults. The clearance of propofol is 13.6 ml/kg/min in neonates¹¹⁰ and 27.0 ml/kg/min in adults.³⁴ In children 1 to 3 years old and in adults, the clearance of propofol is 53.0 + 13.0 and 27.0 + 5.0 ml/kg/min,¹²⁰ respectively, suggesting that the clearance of this drug is higher in infancy than in adults. In two other articles^109,-112 the clearance of propofol was 28.0 and 29.0 ml/min, respectively. These values are difficult to compare with the clearance in adults, because they are not corrected for body weight. However, assuming a body weight between 2 and 3 kg, the clearance reported in^109,-112 should be lower than the adult value.

The variation of volume of distribution between neonates and adults varies with the drugs. Morphine has a volume of distribution which is similar in adults and neonates. According to [authors], the volume of distribution of fentanyl is larger in adults than in neonates^56,57. An exception was reported by Santeiro et al.⁵⁹ who found a volume of distribution higher in infants than in adults.

In the cases described by Dewhurst et al ⁵⁸, Penido et al⁷⁹ and by de Wildt et al¹¹⁵ the volume of distribution is higher in infants than in adults, but the postnatal age is up to 2 months. These findings suggest that the volume of distribution of fentanyl,⁵⁹ sufentanil¹¹⁵ and remifentanil¹¹⁶ increases with postnatal development.

In infants, the volume of distribution of paracetamol (acetaminophen) ranges in a narrow interval and the mean values are 0.9 l/kg⁹⁰ and 1.1 l/kg.⁹¹ In adults, the volume of distribution is 0.9 + 0.1 l/kg.³⁴ For midazolam, propofol, and ketamine, little variation of the volume of distribution is observed between neonates and adults.

Effective pain management remains an important indicator of the quality of care provided to neonates, but observations on neuro-apoptosis and integration of newer techniques and compounds prompt caregivers to reconsider the clinical and research aspects of effective pain management.

Pharmacologic pain management for painful events and some medical conditions have improved considerably for infants in the last years. The use of continuous infusion of opioids, epidural analgesia, and peripheral nerve blockage has enhanced the ability of neonatologists to treat postoperative and medical pain safely and effectively. Local anaesthetics and non-opioids analgesics have been instituted for the treatment of pain from some procedures.

The metabolism of newborns must be taken into account when considering pharmacologic treatment for pain. An understanding of newborn pharmacokinetics and pharmacodynamics provides the basis for safe and effective dosing of anaesthesia and analgesia. Pharmacokinetics are affected by the quality of absorption, distribution and elimination of drugs by infants. Consideration also must be given to the differences in preterm and fullterm metabolic functions. Preterm neonates require lower doses or longer dose intervals than fullterm neonates to maintain similar therapeutic concentrations. A reasonable starting dose of opioids for preterm infants who are not mechanically ventilated is between one fourth and one third the recommended starting dose for term neonates.

CONCLUSIONS

All neonates should be closely monitored, and they may develop opioid tolerance rapidly, so large doses of opioids may be required to achieve adequate pain control for infants with continued severe pain. Better evaluation of pain, especially chronic pain and pain in the smallest infants, remains a challenge. The risk/benefit balance should be carefully addressed when considering analgesic and sedative treatment in a neonate, using currently available data and keeping in mind the major knowledge gaps remaining in this field. Analgesia in newborns differs in many ways from that of adults. Both pharmacokinetics and pharmacodynamics vary with the postnatal development. This makes pediatric analgesia more complicated than analgesia in adults. We feel further research is required to ensure that the doses recommended for treatment of analgesia in neonates are evidence-based. Such research may result in an improvement in the efficacy of analgesics in the neonatal period.

• Pacifici GM. Clinical pharmacology of analgesics in infants and the pharmacologic management of pain in neonates. MEDICALEXPRESS. 2014 June;1(3):105-115.

ACKNOWLEDGEMENTS

This work has been supported by the Ministry of the University and Scientific and Technologic Research (Rome, Italy). The author thanks Dr. Rosa Baviello and Dr. Ida Bertolini, of the Medical Library of the University of Pisa, for the prompt retrieving of the literature. A particular thanks to Dr. Vanna Pistotti, of the Library of the Institute for Pharmacological Research Mario Negri (Milan, Italy), who performed the bibliographic search with EMBASE.

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Publication Dates

• Publication in this collection
  June 2014

History

• Received
  03 Mar 2014
• Reviewed
  09 Mar 2014
• Accepted
  30 Mar 2014