Advertisement

Clinical Pharmacokinetics

, Volume 57, Issue 3, pp 393–417 | Cite as

Correction to: Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review

  • Victoria C. Ziesenitz
  • Janelle D. Vaughns
  • Gilbert Koch
  • Gerd Mikus
  • Johannes N. van den Anker
Correction

Key Points

Fentanyl and its derivatives have been approved for some time, but there is still a lack of knowledge regarding pharmacokinetics in children.

In the future, opportunistic clinical trials should be performed on the pharmacokinetics and pharmacodynamics of fentanyl and its derivatives in much larger cohorts of pediatric patients, and in special subpopulations, such as preterm infants, obese children and children with liver or kidney impairment.

1 Introduction

Fentanyl is commonly used within the field of anesthesia owing to its high lipid solubility and potency. Based on the extensive use of fentanyl, its derivatives were developed and approved in the 1980–90s [1, 2].

Fentanyl and its derivatives exert their pharmacological action through interaction with the µ-opioid receptor, see Table 1 for the relative potencies, physicochemical properties, and pharmacokinetics of these substances in adults. Both fentanyl and sufentanil are drugs with a high extraction ratio while alfentanil has an intermediate extraction ratio [3, 4]. These compounds are metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A to pharmacologically inactive metabolites and show dose-linear pharmacokinetics [5, 6, 7, 8, 9, 10, 11, 12, 13].
Table 1

Overview of pharmacological properties of fentanyl and its derivatives [3, 4, 14, 15, 52, 112, 173, 174, 175, 176, 177, 178, 179, 180]

 

Fentanyl

Sufentanil

Alfentanil

Remifentanil

Potency compared with morphine

100–300

800–1000

40–50

100–200

IV induction dose (µg/kg)

2–6

0.25–2.0

25–100

1–2

IV maintenance dose (µg/kg)

0.5–2

2.5–10

5–10

0.1–1.0

IV infusion rate (µg/kg/h)

0.5–5

0.5–1.5

30–120

0.1–1.0

Other routes of administration than IV

Transdermal, transmucosal (buccal, nasal, sublingual), epidural

Epidural, sublingual

  

Time to onset (min)

1.5

1

0.75

<1

Time to peak effect (min)

4.5–8

2.5–5

1.5

1.5

Duration of peak effect (min)

20–30

30

15

 

Duration of analgesic effect (min)

60–120

100–150

30–60

5–10

Analgesic plasma concentration (ng/mL)

0.6–3.0

0.5–2.5

50–300

0.3–3

Plasma concentration associated with loss of consciousness (ng/mL)

>20.0

>2.5

>400

>4

t 1/2α (min)

1.7 ± 0.1

1.4 ± 0.3

1.31 ± 0.48

1

t 1/2β (min)

13.4 ± 1.6

17.7 ± 2.6

9.4 ± 2.7

6

t 1/2γ (min)

219 ± 10 (120240)

164 ± 22 (120180)

93.7 ± 8.3 (60120)

10–20 (614)

VdC (L/kg)

0.36 ± 0.07

0.16 ± 0.02

0.12 ± 0.04

0.1

\(V_{{{\text{d}}_{\text{ss}} }}\) (L/kg)

4.0 ± 0.4 (3–5)

1.7 ± 0.2 (2.53.0)

1.0 ± 0.3 (0.41.0)

0.35 (0.20.4)

CL (mL/min/kg)

13 ± 2 (1020)

12.7 ± 0.8 (1015)

7.6 ± 2.4 (39)

40 (3060)

Protein binding (%)

80–84

91–92.5

88.7–92.1

70

pKa

8.4

8.0

6.5

7.1

Non-ionized fraction at pH 7.40 (%)

8.5

20

89

67

Metabolism

CYP3A

CYP3A

CYP3A

Plasma and tissue esterases

Lipid solubility (octanol/water distribution coefficient)

813–816

1727–1778

128

18

References

[14, 52, 112, 173, 174, 175, 176, 177, 178, 179]

[3, 14, 112, 173, 174, 175, 177, 178, 179]

[4, 14, 112, 173, 174, 175, 177, 178, 179, 180]

[14, 15, 112, 173, 174, 175, 177, 178, 179]

Italic numbers indicate information from the Summary of Product Characteristics

CL clearance, CYP cytochrome P450, IV intravenous, pKa , t 1/2α distribution half-life, t 1/2β redistribution half-life, t 1/2γ terminal elimination half-life, Vd C volume of distribution of the central compartment, \(V_{{d_{ss} }}\) volume of distribution at steady state

Remifentanil is mainly metabolized through hydrolysis by unspecific plasma and tissue esterases to a metabolite lacking pharmacodynamic activity. Remifentanil shows a dose-independent clearance (CL), and has a much smaller volume of distribution (V d) than fentanyl, resulting in a much shorter half-life [14, 15].

There are also distinct differences in their context-sensitive half-time, which is defined as the time required for the plasma drug concentration in the central compartment to decrease by 50% as a function of the duration of a continuous infusion. However, this does not allow conclusions on the decrease in plasma concentration required for recovery from the drug’s effect [16, 17]. While fentanyl has a markedly prolonged context-sensitive half-time with increased infusion durations compared with alfentanil and sufentanil, remifentanil has a context-sensitive half-time independent of the infusion duration.

Intravenous fentanyl is currently used intraoperatively during general anesthesia [18]. Rapid-onset fentanyl delivery systems such as buccal or sublingual tablets, nasal spray, and lollipop are mainly used off-label in children. Transdermal fentanyl matrix patches are approved for opioid-tolerant children over 2 years of age. Sufentanil is also mainly used during general anesthesia but alfentanil and remifentanil can be used for analgo-sedation. Remifentanil is well suited for short or outpatient surgical procedures [18].

Their adverse effects are related to dose and effect-site concentrations and are mainly mediated by their µ-opioid receptor agonism. Respiratory depression is the most relevant adverse effect. Other side effects include sedation, nausea, vomiting, constipation, pruritus, physical dependence, risk of addiction, bradycardia, and skeletal muscle rigidity, while hemodynamic responses rarely occur upon administration [18].

Despite the extensive use of fentanyl and its derivatives in children, only limited pharmacokinetic (PK) data in pediatric patients are available. This review considers the pharmacology of fentanyl and its derivatives sufentanil, alfentanil, and remifentanil in infants, children, adolescents, and special pediatric sub-populations.

2 Methods

2.1 Search Strategy and Selection Criteria

PubMed was searched systematically for articles published in English until 28 February, 2017, to identify PK studies of fentanyl, sufentanil, alfentanil, and remifentanil in pediatric patients (younger than 18 years of age). In the search string, each of the four compounds using Medical Subject Headings (MeSH), except remifentanil, was linked with AND to the following search terminologies: ‘children’, ‘Pediatrics’ [MeSh], ‘infant, premature’ [MeSh], ‘infant, newborn’ [MeSh], ‘infant’ [MeSh], ‘child, preschool’ [MeSH], ‘child’ [MeSH], ‘adolescent’ [MeSh]. To avoid missing data, an additional search was conducted: ‘compound’ AND pharmacokinetics AND (infant OR infants OR newborn OR newborns OR child OR children OR childhood OR pediatric OR pediatrics OR paediatric OR paediatrics).

2.2 Comprehensive Review

Abstracts of the selected articles were reviewed for eligibility. Studies were included if they contained relevant PK parameters or models, established routes of administration, and patients younger than 18 years of age. Identified studies and case reports were reviewed so that only those presenting original PK data were included. If individual children were considered in adult PK studies and individual pediatric data were given, these data were extracted and included. Studies reporting only drug concentrations in children were assessed in a descriptive manner.

In each publication, the following information was extracted and analyzed: type of study, the number of patients, the pediatric age group (according to the International Conference on Harmonization E11 guidelines [19]), the patient demographics, the used formulation, the route of administration, the number of PK samples taken from each patient, the sampling duration, the assay used for analysis, and relevant PK parameters (such as CL, half-life, and V d). Special populations were defined as patients with chronic kidney or liver disease, obesity, or on cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO).

2.3 Statistical Analysis

To assess the maturation of CL, published individual CL was related to bodyweight and, if relevant with respect to the literature, also to age by linear or non-linear regression models and allometric scaling. For non-linear regression, the Hill equation was applied [20, 21]. This equation describes CL saturation and allows sigmoidal behavior depending on the Hill coefficient h. Such a sigmoidal shape may be necessary for describing maturation processes of CL in infancy and early childhood. Parameter B max stands for maximal CL at saturation, and K 50 corresponds to bodyweight that produces half-maximal CL. Additionally, data were log-transformed to estimate the allometric exponent by the standard power law for CL [22].

Statistical analyses were performed using GraphPad Prism Version 7.00 (GraphPad Software, La Jolla, CA, USA). Pharmacokinetic data were converted into comparable units for presentation in Tables 2, 3, 4 and 5. Data are given as mean ± standard deviation, or range, if not indicated differently.
Table 2

Pharmacokinetic information on fentanyl in children [8, 24, 29, 32, 33, 37, 39, 40, 41, 43, 55, 56, 67, 75, 79, 88, 90, 92, 93, 103, 136, 181, 182, 183, 184, 185, 186, 187]

N

Age

Weight (kg)

Dose (µg/kg)

Route

CL (mL/min/kg)

t 1/2 (min)

V (L/kg)

Comp

No of samples

Lab method

Remarks

References

2

1 ± 0 days

3.2 ± 1.1

30.3 ± 16.0

IV, 2–10 min

16.2 ± 2.59*

294 ± 113

5.94 ± 1.47**

2

13/10 h

RIA

Age 0–1 month

[24]

2

7 ± 0.056 months

6.0 ± 1.2

19.1 ± 14.5

IV, 2–10 min

18.1 ± 1.41*

233 ± 137

4.45 ± 1.64**

2

13/10 h

RIA

Age 1 month–1 year

[24]

6

3.17 ± 0.68 years

17.3 ± 3.4

10.0 ± 3.1

IV, 2–10 min

11.5 ± 4.19*

244 ± 79

3.06 ± 1.02**

2

13/10 h

RIA

Age 1–5 years

[24]

3

12 ± 1.73 years

58.3 ± 13.3

4.3 ± 1.2

IV, 2–10 min

7.05 ± 1.24*

208 ± 71

1.92 ± 1.04**

2

13/10 h

RIA

Age 10–14 years

[24]

19

3.2 ± 4.2 years

 

Max 3.6 ± 3.1/h

IV, 5 min; cont. 70.5 (7–144) h

13.2 ± 9.6

1266

15.2

Non

> 11

RIA

All patients, cont. sedation

[33]

5

0.14 ± 0.08 years

 

Max 4.3 ± 3.7/h

IV, 5 min; cont. 72.6 (48–144) h

8.2 ± 4.6

  

Non

> 11

RIA

Age < 6 monthsa

[33]

9

1.4 ± 1.1 years

 

Max 3.9 ± 3.3/h

IV, 5 min; cont. 70.9 (19-136) h

18.9 ± 11.0

  

Non

> 11

RIA

Age 6 months–6 years

[33]

5

9.5 ± 2.8 years

 

Max 2.5 ± 2.3/h

IV, 5 min; cont. 68.2 (7–136) h

8.0 ± 3.9

  

Non

> 11

RIA

Age > 6 yearsa

[33]

15

1 day–10.9 years c)

 

2/9 ± 7/h

IV, bolus, cont. 91b (37–211) h

19.3 ± 12.4

954 ± 606

17.2 ± 14.7

Non

> 8/> 48 h

RIA

Comparison of fentanyl and alfentanil

[136]

14

3 ± 1 daysd

2.9 ± 0.2d

10–50

IV, 1–3 min

17.94 ± 4.38d

317 ± 70d

5.1 ± 1.0d

2

> 8/18 h

RIA

All patients

[29]

4

0.6 ± 0.13 daysd

3.5 ± 0.2d

10–50

IV, 1–3 min

28.00 ± 11.00d

188 ± 85d

4.66 ± 1.74d

2

> 8/18 h

RIA

Myelomeningocele repair

[29]

4

7.0 ± 2.48 daysd

2.5 ± 0.5d

50

IV, 1–3 min

21.43 ± 9.15d

213 ± 37d

5.87 ± 2.65d

2

> 8/18 h

RIA

Thoracic surgery

[29]

6

1.8 ± 0.5 daysd

2.7 ± 0.3d

25–50

IV, 1–3 min

9.00 ± 1.00d

473 ± 132d

4.88 ± 1.42d

2

> 8/18 h

RIA

Abdominal surgery

[29]

9

 

1.1 ± 0.3

30

IV, 1 min

 

1062 ± 558

  

3/6–9 h

GLC [181]

Preterm and term infants, GA 23–38 weeks

[41]

14

18.3 ± 23.6 days

2.7 ± 0.5

54.1 ± 2.3

IV, 2 min

22.4 ± 8.2

325.8 ± 181.8

8.3 ± 2.4

2/3

23/12 h

RIA [182, 183]

All patients

[32]

3

13.3 ± 20.3 days

2.9 ± 0.4

 

IV, 2 min

21.1 ± 8.5

336.3 ± 193.4

8.1 ± 2.5

2/3

23/12 h

RIA [182, 183]

Preterm infants, GA < 36 weeks

[32]

11

36.7 ± 30.4 days

2.0 ± 0.1

 

IV, 2 min

26.2 ± 7.1

294.3 ± 173.9

9.0 ± 2.7

2/3

23/12 h

RIA [182, 183]

Neonates

[32]

20

 

1.7 ± 0.8

5–12.5/0.68 ± 0.24/h

IV, 10 min, cont. 86 ± 47 h

     

RIA

All patients, GA 32.5 ± 3.6 weeks

[43]

12

  

5–12.5/0.64 ± 0.19/h

IV, 10 min, cont. 93 ± 55 h

12.1 ± 15.4

    

RIA

Preterm infants, GA < 34 weeks

[43]

8

  

5–12.5/0.75 ± 0.30/h

IV, 10 min, cont. 75 ± 24 h

13.0 ± 19.8

    

RIA

Preterm and term infants, GA ≥ 34 weeks

[43]

7

16 ± 9 days

1.9 ± 1.1

1.28 ± 0.58/h

IV, cont. 111 (48–206) h

19.2 ± 8.2

570 ± 156

17 ± 9

1

5

GC-MS [184]

Preterm and term infants GA 27–39 weeks; C max 0.7–2 ng/mL

[39]

38

10 (5; 21) hourse

1.8 (1.2; 2.6)e

10.5/h/1.5/h

IV, cont. 58 (45; 78) he

11.5 ± 4.0 (4.6–18.5)

  

Non

5/60h

RIA [185]

Preterm and term infants, GA 26–42 weeks

[40]

1

15 months

~ 8

50/18/h

IV, bolus, cont. 123 min

7.3

173

1.85

 

14/~ 5 h

GLC [56, 181]

Case report, renal failure, CPB

[55]

1

3 years

10.2

1.64/18/h

IV, bolus, cont. 136 min

0.41

4620

0.142

 

8

~ 5 h

GLC [56, 181]

Case report, Wilm’s tumor

[55]

10

18.9 ± 15.8 months

8.6

50/9–18/h

IV, 1 min; cont. 112 (81–141) min

12.8 ± 7.3

141 ± 98

1.385 ± 0.875

2

 

GLC [181]

CPB

[56]

19

3.54 years (5 months–16 years)

13.2 (3.5–50)

30–50/9–18/h

IV, bolus; cont.

13.3 ± 6.5

102 ± 85

1.203 ± 0.777

2

> 9/> 2 h

GLC [181]

CPB

[67]

12

5.5 ± 11.5 days

3.2 ± 0.6

5–10/3.3 ± 1.6/h

IV, bolus; cont.

   

Non

11

RIA

All patients, CPB, ECMO

[75]

9

6.7 ± 13.3 days

3.2 ± 0.6

5–10/3.2 ± 1.7/h

IV, bolus; cont.

25.3 ± 41.9

  

Non

 

RIA

Survivors, CPB, ECMO

[75]

3

2 ± 1.7 days

3.1 ± 0.8

5–10/3.6 ± 1.3/h

IV, bolus; cont.

8.1 ± 12.8**

  

Non

 

RIA

Non-survivors, CPB, ECMO

[75]

130

5.9e months (1.2–28.4)

6.4e (3.7–11.6)

2.67e (1.46–4.08)/h

IV, bolus/ cont.

14.8e (5.7–24.0)

  

2

6e (4–10)

MS

All patients, Pop-PK, covariate model

[37]

121

5.1e months (1.0–21.8)

6.1e (3.7–9.9)

2.79e (1.67–4.17)/h

IV, bolus/ cont.

5.9

  

2

6e (4–11)

MS

< 40 kg, Pop-PK, allometric theory-based model

[37]

93

8.1e months (3.7–35.0)

7.6e (5.1–12.8)

2.63e (1.63–3.75)/h

IV, bolus

7.4

  

2

5e (4–8)

MS

Bolus only, Pop-PK, allometric theory-based model

[37]

6

16.6 ± 1.5 years

137.4 ± 14.3

1.00 ± 0.36

IV, bolus

11.2 ± 2.6

290 ± 118

4.7 ± 2.1

Non

≥ 10/24 h

LC-MS/MS [8]

Obese adolescents

[79]

13

14b (3–36) months

11b (5–17)

2/1.12/h/0.375/h

EPI, cont. 38.0b (37.3–38.8) h

 

334b (137–1730)

 

Non

6

LC–MS/MS [186, 187]

t 1/2 calculated based on MRT: 954b (215–1892) min

[88]

11

68b (45–131) months

21b (16–52)

2/1.12/h/0.375/h

EPI, cont. 38.0b (35.5––39.0) h

 

358b (206–563)

 

Non

6

LC–MS/MS [186, 187]

t 1/2 calculated based on MRT: 478b (425–796) min

[88]

21

5.5 ± 1.3 years

20.9 ± 5.7

12.2 ± 1.09

OTFC

17.5

 

2.44

2

> 3

≤ 4 h

RIA [182]

OTFC bioavailability 33%

[90]

21

5.5 ± 1.3 years

20.9 ± 5.7

12.2 ± 1.09

OTFC

46.0 ± 16.0f

168 ± 90

9.8 ± 4.1f

Non

> 3

≤ 4 h

RIA [182]

C max 1.60 ± 0.55 ng/mL, t max 59 ± 32 min; AUC 5.03 ± 2.20 h·ng/mL

[90, 93]

17

6.7 ± 4.9 years

21.5 ± 4.9

12.7 ± 1.2

OTFC

15.2 ± 6.3

276

4.9 ± 2.8

2

12 ± 1/3.67 h

RIA [182]

OTFC bioavailability 36%, C max 1.03 ± 0.31 ng/mL, t max 53 ± 40 min; CL, t 1/2 and VdSS data combined with [90], n = 38

[90, 92]

17

6.7 ± 4.9 years

21.5 ± 4.9

12.7 ± 1.2

OTFC

68.5 ± 39.8f

198 ± 222

11.6 ± 6.6f

Non

 

RIA [182]

C max 1.06 ± 0.31 ng/mL, t max 56 ± 41 min, AUC 4.54 ± 3.60 h·ng/mL

[92, 93]

38

6.3 ± 1.6 years

 

12.4 ± 1.04

OTFC

57.7 ± 32.3f

184 ± 168

10.7 ± 5.5f

Non

 

RIA [182]

Combined data, C max 1.32 ± 0.51 ng/mL, t max 58 ± 36 min, AUC 4.78 ± 2.96 h·ng/mL

[90, 92, 93]

10

7.9 ± 1.94 years

28.2 ± 10.2

13.9 ± 1.41

PO

55.5 ± 37.5f

282 ± 168

17.5 ± 7.20f

Non

16 (8–16)/10 h

LC–MS/MS

C max 1.83 ± 1.19 ng/mL, t max 104 ± 98 min, AUC 6.46 ± 3.96 h·ng/mL

[93]

8

42.4 ± 16.4 months

14.6 ± 2.9

1.72/h (patch 25 µg/h)

TD

 

867 ± 373

  

18/144 h

RIA [182]

C max 1.64 ng/mL, t max 1080 min, AUC 91.75 h·ng/mL, C ss 1.32 ng/mL

[103]

Reported statistical significance is indicated as follows: p < 0.05*, p < 0.005**, p < 0.001***

AUC area under the plasma concentration–time curve, CPB cardiopulmonary bypass, CL clearance, CL/F apparent clearance after non-intravenous administration, Cmax maximum plasma concentration, Comp compartmental analysis, cont continuous, Css concentration at steady-state, ECMO extracorporeal membrane oxygenation, EPI epidural, GA gestational age, GLC gas liquid chromatography, IV intravenous, Lab laboratory, LC–MS liquid chromatography– mass spectrometry, Max maximum, MRT mean residence time, OTFC oral transmucosal fentanyl citrate, PO per os, Pop-PK population pharmacokinetics, RIA radioimmunoassay, TD transdermal, Tmax time to maximum plasma concentration, t1/2 half-life, V volume of distribution, V/F apparent volume of distribution after non-intravenous administration

aMean clearance values of the youngest and the oldest children were switched in the results section of the publication and recalculated for this review

bMedian data (range)

cDemographics also include alfentanil group

dMean ± SEM

eMedian data (interquartile range)

fCL/V and V/F

Table 3

Pharmacokinetic information on sufentanil in children [108, 109, 110, 114, 115, 116, 119, 120, 188, 189]

N

Age

Weight (kg)

Dose (µg/kg)

Route

CL (mL/min/kg)

t 1/2 (min)

V (L/kg)

Comp

No of samples/duration

Lab method

Remarks

References

9

11.0 ± 10.8 days

3.24 ± 0.36

10–15

IV, bolus

6.7 ± 6.1*

737 ± 346*

4.15 ± 1.01*

3

24/20 h

RIA [188]

Neonates 1–30 days

[108]

7

13.9 ± 9.1 months

8.7 ± 3.2

10–15

IV, bolus

18.1 ± 2.8*

214 ± 41

3.09 ± 0.95

3

24/20 h

RIA [188]

Infants 1 month–2 years

[108]

7

6.4 ± 3.2 years

21.0 ± 6.7

10–15

IV, bolus

16.9 ± 3.2*

140 ± 30

2.73 ± 0.50

3

24/20 h

RIA [188]

Children 2–11 years

[108]

5

15.4 ± 1.9 years

58.4 ± 9.4

10–15

IV, bolus

13.1 ± 3.6

209 ± 23

2.75 ± 0.53

3

24/20 h

RIA [188]

Adolescents 12–18 years

[108]

20

5.2 ± 1.7 years

19.1 ± 5.2

2.42 ± 0.67

IV, bolus

30.5 ± 8.8

97.0 ± 42.0

2.94 ± 0.63

2/non

17/8 h

RIA [188]

Surgical patients

[110]

1

7 days

3.0

10

IV, bolus

4.3

434

2.6

3

24/20 h

RIA [188]

Case report, congestive heart failure

[109]

1

28 days

 

10

IV, bolus

18.8

160

3.2

3

24/20 h

RIA [188]

Same patient

[109]

1

4 days

3.1

10

IV, bolus

6.7

332

2.9

3

24/20 h

RIA [188]

Case report, congestive heart failure

[109]

1

20 days

 

10

IV, bolus

19.3

242

3.3

3

24/20 h

RIA [188]

Same patient

[109]

1

2 days

3.3

10

IV, bolus

1.7

1140

2.7

3

24/20 h

RIA [188]

Case report, congestive heart failure

[109]

1

27 days

 

10

IV, bolus

12.9

248

3.6

3

24/20h

RIA [188]

Same patient

[109]

1

17 years

76

3

IV, bolus

28.3

39

1.137

2

13/8 h

RIA [188, 189]

Orthopedic surgery patient

[114]

1

10 years

45

2/4.44/h

IV, bolus, cont. (48 h)

15.8

2940

24.2

2

20 + 19/48 h + 24 h

RIA [188]

Head trauma patient

[115]

41

4.05a (0.18–17.4) years

14a (3.2–80)

1.42a (0.47–4.39)/h

Total dose: 2197a (621–47,221) µg

IV, cont. 99a (25–600) h

10.8

504a (102–12,300)

 

2

> 3 + 10/24 h + 36 h

HPLC–MS

 

[116]

6

11.7 ± 3.8 years

44.7 ± 12.9

3–5

IV, 1 min

16.4 ± 6.1b

89.7 ± 15.7b

1.65 ± 0.6b

2/non

11/3 h

RIA

Surgical patients

[119]

6

11.8 ± 1.7 years

28.7 ± 5.7*

3–5

IV, 1 min

12.8 ± 12.0b

76.0 ± 32.8b

1.28 ± 0.62b

2/non

11/3 h

RIA

Chronic renal failure

[119]

7

5.2 ± 2.1 months

5.3 ± 1.1

15

IV, 1 min

27.5 ± 9.3

53 ± 15

1.6 ± 0.46*

2

10/2 h

RIA

Age < 10 months, not surface-cooled, pre-CPB

[120]

6

15.5 ± 5.2 months

8.9 ± 1.6

15

IV, 1 min

18.1 ± 10.7

55 ± 10

3.0 ± 1.35

2

10/2 h

RIA

Age > 10 months, not surface-cooled, pre-CPB

[120]

7

5.1 ± 3.4 months

5.3 ± 2.4

15

IV, 1 min

21.5 ± 5.0

120 ± 36*

3.7 ± 1.1

2

10/2 h

RIA

Age < 10 months, surface-cooled, pre-CPB

[120]

Reported statistical significance is indicated as follows: p < 0.05*, p < 0.005**, p < 0.001***

CL clearance, Cmax maximum plasma concentration, Comp compartmental analysis, cont continuous, CPB cardiopulmonary bypass, HPLC–MS high-performance liquid chromatography–mass spectrometry, IV intravenous, Lab laboratory, RIA radioimmunoassay, t1/2 half-life, V volume of distribution

aMedian data (range)

bResults were switched by mistake in the publication

Table 4

Pharmacokinetic information on alfentanil in children [13, 131, 132, 134, 135, 136, 137, 142, 143, 144, 148, 149, 188, 190, 191]

N

Age

Weight (kg)

Dose (µg/kg)

Route

CL (mL/min/kg)

t 1/2 (min)

V (L/kg)

Comp

No of samples

Lab method

Remarks

References

5

6.2 ± 4.2 months

7.4 ± 2.6

50

IV, 30 s

8.39 ± 0.80a

76.2 ± 8.2a

0.552 ± 0.105a

2

14/6 h

RIA [188]

Age < 1 year; AUC 6.183 ± 0.602a min·mg/L

[13]

8

5.4 ± 4.4 years

20.2 ± 11.3

50

IV, 30 s

7.73 ± 0.61a

84.0 ± 12.8a

0.416 ± 0.050a

2

14/6 h

RIA [188]

Age > 1 year; AUC 6.784 ± 0.583a min·mg/L

[13]

5

6.0 ± 6.4 years

23.9 ± 19.0

120

IV, 30 s

7.76 ± 0.89a

64.0 ± 7.3a

0.603 ± 0.138a

2

14/6 h

RIA [188]

Age > 1 year; AUC 15.982 ± 1.760a min·mg/L

[13]

20

2.8 ± 1.5 years (10 months–6.5 years)

 

23.0 ± 9.2

IV, bolus

11.1 ± 3.9

63 ± 24

1.07 ± 0.71

Non

12/5 h

RIA [188]

Orthopedic surgery patients; free fraction 11.5 ± 0.9%

[132]

18

2.8 ± 1.6 years

 

20

IV, bolus

10.9 ± 4.1

63 ± 25

1.07 ± 0.78

Non

12/5 h

RIA [188]

Low dose (20 µg/kg)

[132]

2

2.3 ± 0.6 years

 

50

IV, bolus

12.6 ± 1.1

60 ± 1

1.08 ± 0.08

Non

12/5 h

RIA [188]

High dose (50 µg/kg)

[132]

8

5.4 ± 1.1 years

21.0 ± 3.2

20

IV, bolus

4.7 ± 1.7

40 ± 9

0.164 ± 0.110

2

16/6 h

RIA [188]

Genitourinary surgery patients; plasma protein binding 94.4 ± 1.5% @ 50 ng/mL, 92.4 ± 2.4% @ 500 ng/mL

[131]

16

1 day–10.9 yearsc

 

20/100 ± 60/h

IV, cont. 109b (29–304) h

2.3 ± 2.8

294 ± 222

1.3 ± 0.9

Non

> 8/> 48 h

RIA

Comparison of fentanyl and alfentanil, MRT 378 ± 294 min

[136]

9

5.0 ± 2.8 years (9 months–10 years)

 

25–100

IV, 30 s

5.6 ± 2.4

60 ± 11

0.48 ± 0.19

2

15/4 h

RIA [188]

Surgical patients

[135]

6

1–3 days

1.328 ± 0.546

25

IV, 30 s

2.2 ± 2.4*

525 ± 305

1.0 ± 0.39

2

8/12 h

RIA [188]

Preterm infants, GA 29.5 ± 3.3 weeks

[135]

13

1.5 ± 1.4 days

3.34 ± 0.97

8/5.63 ± 1.88/h

IV, 10 min, cont. (27 h)

3.24 ± 2.23

248 ± 155

0.54 ± 0.21

Non

4 + 4/24 h + 12 h

RIA [188]

Neonates, GA 37.6 ± 2.4 weeks

[134]

5

1–3 days

2.97 ± 1.14

25

IV, 30 s

1.7 ± 0.47

328 ± 48

0.82 ± 0.30

Non

9/24 h

RIA [188]

GA 36.8 ± 0.98 weeks; MRT 473 ± 70 min

[143]

5

1–3 days

1.33 ± 0.59

25

IV, 30 s

1.35 ± 0.69

455 ± 111

0.84 ± 0.48

Non

9/24 h

RIA [188]

Preterm infants, GA 29.3 ± 2.1 weeks; MRT 657 ± 162 min

[143]

22

1–4 days

1.343b (0.69–4.084)

19.8b (17.8–22.1)

IV, 2 min

0.87b (0.4–9.62)

321b (64–1251)

0.50b (0.13–1.04)

1/2

5–8/7 h

RIA [188]

Preterm infants, GA 30b (25–36) weeks; C max 66b (20–606) ng/mL

[142]

7

19b (7–51) h

2.3b (1.46–3.32)

11b (10–15)

IV, 1 min

2.1b (1.7–7.2)

43b (34–237)

0.27b (0.08–0.62)

Non

5/6 h

CGC [191]

No muscle rigidity; mean GA 36 (30–40 weeks) of all patients

[144]

13

22b (6–41) h

2.4b (1.69–3.95)

11b (9–15)

IV, 1 min

2.9b (0.9–25.3)

153b (31–650)

0.66b (0.15–2.94)

Non

5/6 h

CGC [191]

Muscle rigidity; mean GA 36 (30–40 weeks) of all patients

[144]

10

5.0 ± 2.8 years (9 months–10 years)

 

25–100

IV, 30 s

7.25 ± 4.3

41.6 ± 16

0.40 ± 0.21

2

14/2 h

RIA [188]

Surgical patients; AUC120/AUC ratio 0.90 ± 0.05

[137]

9

4.6 ± 4.5 years (9 months–15 years)

 

25–100

IV, 30 s

7.59 ± 3.6

45.8 ± 13.3

0.46 ± 0.16

2

14/2 h

RIA [188]

Cholestatic hepatic disease; AUC120/AUC ratio 0.84 ± 0.08

[137]

3

  

25–100

IV, 30 s

11.2 ± 2.7

41 ± 19

0.47 ± 0.23

2

14/2 h

RIA [188]

Cholestatic hepatic disease, subgroup, before transplant

[137]

3

  

25–100

IV, 30 s

7.0 ± 3.8*

82 ± 38

0.83 ± 0.55

2

15/2 h

RIA [188]

Cholestatic hepatic disease, subgroup, same patients, 8–12 h post-transplant; AUC120/AUC ratio 0.71 ± 0.17

[137]

10

12.6 ± 3.2 years

 

25–100

IV, 30 s

8.2 ± 4.4

41.5 ± 11

0.45 ± 0.10

2

14/2 h

RIA [188]

End-stage renal disease; AUC120/AUC ratio 0.90 ± 0.07

[137]

6

6.7 ± 2.7 months

6.5 ± 1.7

20/60/h (total: 998 ± 257)

IV, bolus, cont. (130 ± 28 min)

8.2 ± 2.2

69 ± 25

0.48 ± 0.12

Non

> 4 + 14

> 0.25 + 6 h

CGC

Age < 1 year, CPB

[149]

5

5.1 ± 1.9 years

18.6 ± 7.6

20/60/h (total: 3396 ± 1144)

IV, bolus, cont. (147 ± 15 min)

6.3 ± 0.8

62 ± 9

0.31 ± 0.08

Non

> 4 + 14

> 0.25 + 6 h

CGC

Age > 1 year, CPB

[149]

5

0.8 ± 0.3 years (4–11 months)

6.5 ± 1.2

200

IV, 10 min

   

2

> 6/> 0.25 h

CGC

Same cohort, before CPB; V1 0.068 ± 0.037 L/kg, AUC 17.9 ± 2.9 min·mg/L

[148]

5

0.8 ± 0.3 years (4–11 months)

6.5 ± 1.2

80

IV, 10 min

11.5 ± 5.0

60 ± 18

0.63 ± 0.23

2

15/6 h

CGC

Same cohort, after CPB; V1 0.235 ± 0.058 L/kg, AUC 11.1 ± 2.9 min·mg/L

[148]

6

4.1 ± 2.9 years (1–9 years)

15.8 ± 6.9

200

IV, 10 min

   

2

> 6/> 0.25 h

CGC

Same cohort, before CPB; V1 0.080 ± 0.032 L/kg, AUC 18.3 ± 5.4 min·mg/L

[148]

6

4.1 ± 2.9 years (1–9 years)

15.8 ± 6.9

80

IV, 10 min

10.2 ± 4.6

48 ± 9

0.49 ± 0.10

2

15/6 h

CGC

Same cohort, after CPB; V1 0.179 ± 0.099 L/kg***, AUC 12.9 ± 3.4 min·mg/L*** compared to before CPB

[148]

14

1.5 ± 2.2 years

8.7 ± 5.6

 

IV, cont. (TCI)

2.5

799

2.462

3

20–40/24 h

RIA [188]

simple model; CL 2.4 mL/min/kg in CPB-adjusted model

[190]

Reported statistical significance is indicated as follows: p < 0.05*, p < 0.005**, p < 0.001***

AUC area under the plasma concentration–time curve, CGC capillary gas chromatography, CL clearance, Comp compartmental analysis, cont continuous, CPB cardiopulmonary bypass, GA gestational age, IV intravenous, Lab laboratory, RIA radioimmunoassay, MRT mean residence time, t1/2 half-life, TCI target-controlled infusion, V volume of distribution

aMean ± SEM

bMedian data (range)

cDemographics also include fentanyl group

Table 5

Pharmacokinetic information on remifentanil in children [150, 152, 153, 171, 172, 192, 193]

N

Age

Weight (kg)

Dose (µg/kg)

Route

C max (ng/mL)

CL (mL/min/kg)

t 1/2 (min)

V (mL/kg)

Comp

No of samples

Lab method

Remarks

References

8

5.1 ± 2.9 weeks

3.7 ± 0.7

5

IV, 1 min

24.2 ± 10.2*

90.5 ± 36.8*

5.4 ± 1.8

452.7 ± 144.8*

Non

10/1 h

GC–MS [192]

Age < 2 months

[150]

6

7.6 ± 4.3 months

8.7 ± 2.6

5

IV, 1 min

25.4 ± 3.7*

92.1 ± 25.8*

3.4 ± 1.2

307.9 ± 89.2

Non

10/1 h

GC–MS [192]

Age 2 months–2 years

[150]

7

4.6 ± 1.8 years

16.5 ± 4.7

5

IV, 1 min

34.8 ± 8.2

76.1 ± 22.4

3.6 ± 1.8

240.1 ± 130.5

Non

13/4 h

GC–MS[192, 193]

Age 2–7 years; metabolite GR90291 (n = 7): C max 5.8 ± 1.1 ng/mL, t 1/2 81.0 ± 44.6 min

[150]

6

9.7 ± 2.3 years

36.3 ± 9.7

5

IV, 1 min

42.5 ± 13.7

59.7 ± 22.5

5.3 ± 1.4

248.9 ± 91.4

Non

13/4 h

GC–MS [192, 193]

Age 7–13 years; metabolite GR90291 (n = 7): C max 6.9 ± 2.1 ng/mL, t 1/2 64.2 ± 25.7 min

[150]

4

14.0 ± 1.2 years

58.6 ± 25.7

5

IV, 1 min

35.0 ± 10.2

57.2 ± 21.1

3.7 ± 1.1

223.2 ± 30.6

Non

13/4 h

GC–MS [192, 193]

Age 13–16 years; metabolite GR90291 (n = 3): C max 6.5 ± 1.0 ng/mL, t 1/2 55.5 ± 26.9 min

[150]

3

16.3 ± 0.6 years

60.6 ± 6.9

5

IV, 1 min

42.7 ± 12.9

46.5 ± 2.1

5.7 ± 0.7

242.5 ± 109.2

Non

13/4 h

GC–MS [192, 193]

Age 16–18 years; metabolite GR90291 (n = 3): C max 10.7 ± 6.6 ng/mL, t 1/2 103.2 ± 75.4 min

[150]

12

6.3 ± 4.6 years

27.0 ± 20

5

IV, 1 min

 

38.7 ± 9.6

8.2 ± 3

234.5 ± 105.5

2

9/0.75 h

HPLC

Pre-CPB

[171]

12

6.3 ± 4.6 years

27.0 ± 20

5

IV, 1 min

 

46.8 ± 14*

6.9 ± 2.6

235.3 ± 110.2

2

9/0.75 h

HPLC

Post-CPB (same cohort)

[171]

26

1.77a (0.08–9.25) years

10.5a (3.1–39.8)

Max 48/h

IV, 194a (19–1236) min

 

68.3

  

2

> 8

HPLC

Pop-PK (post-CPB n = 21)

[152]

9

2.19 (0.5–4.0) years

11.4 (6.4–14.7)

15.8 ± 12.3/h (entire study: 65.0 ± 32.6 µg/kg)

IV, cont. (entire study: 218 ± 77.9 min)

13.8 ± 7.80

21.4

4.02

124

1

3a (1–9)

GC–MS [171]

Pop-PK, pre-CPB

[172]

9

2.19 (0.5–4.0) years

11.4 (6.4–14.7)

20.3 ± 7.2/h

IV, cont.

12.7 ± 6.39

21.4

9.65

298

1

3a (1–5)

GC–MS [171]

Pop-PK, during CPB (same cohort)

[172]

9

2.19 (0.5–4.0) years

11.4 (6.4–14.7)

19.3 ± 10.5/h

IV, cont.

11.7 ± 7.03

21.4

9.65

298

1

7a (3–8)

GC–MS [171]

Pop-PK, post-CPB (same cohort)

[172]

7

0.74 (0.3–1.0) years

7.59 (6.6–9.6)

 

IV, cont.

 

2.22 L/min/70 kg

 

168 L/70 kg

2

Total: 77

GC–MS [192]

Clearance 2.99 L/min/70 kg, volume of distribution 16.23 L/70 kg, remarks Pop-PK, final model parameter estimates

[153]

Reported statistical significance is indicated as follows: p < 0.05*, p < 0.005**, p < 0.001***

Cmax maximum concentration, V volume of distribution, Max. maximum, cont. continuous, t1/2 elimination half-life, Pop-PK population pharmacokinetics, CPB cardiopulmonary bypass, IV intravenous, CL clearance, comp compartmental analysis, GC-MS gas chromatography–mass spectrometry, HPLC high-performance liquid chromatography

aMedian data (range)

3 Results

3.1 Literature Search

The original search retrieved 8976 publications (fentanyl n = 5900, sufentanil n = 590, alfentanil n = 776, remifentanil n = 1710). After removal of duplicate entries and screening of the abstracts, 372 full text articles were downloaded. Five publications were found by scanning through the references of the articles.

Clinical studies were mostly prospective non-randomized open-label trials. Fentanyl and its derivatives were mainly administered intravenously, but data on oral-transmucosal fentanyl citrate (OTFC), transdermal fentanyl, and epidural fentanyl and sufentanil were available. There were 44 publications focusing on pharmacokinetics [fentanyl n = 19 (1 including alfentanil), sufentanil n = 8, alfentanil n = 13 (1 including fentanyl), remifentanil n = 5], whereas drug concentrations were determined in another 30 studies (fentanyl n = 18, sufentanil n = 8, alfentanil n = 3, remifentanil n = 1).

The eligible PK studies presented data of 821 patients younger than 18 years of age, which included more than 46 preterm infants, 64 neonates, 115 infants/toddlers, 188 children, and 28 adolescents. In 380 patients, age was not specified. Congenital heart defects (n = 312), pulmonary/thoracic diseases (n = 91), neurological disorders (n = 42), and abdominal (n = 38) disorders were the most common underlying diagnoses. Nineteen patients with chronic kidney disease were included, nine with liver disease, six were obese, 282 were on CPB, and 25 were undergoing kidney or liver transplants. Studies were mainly conducted during anesthesia or analgo-sedation. Studies that measured plasma concentrations without PK assessments (n = 27) included data of 671 pediatric patients, including 130 preterm neonates, 134 neonates, 64 infants/toddlers, 80 children, and 9 adolescents.

3.2 Statistical Analysis

Maturation of fentanyl CL in preterm and term neonates showed a weak correlation to bodyweight (R 2 = 0.22; Fig. 1). Individual CL data were not available for older children and therefore these results cannot be extrapolated from children to adults in a linear manner for theoretical considerations. Maturation of sufentanil and alfentanil CL was assessed by fitting the Hill function (R 2 = 0.71 for sufentanil; Fig. 2, and R 2 = 0.70 for alfentanil; Fig. 3, both weighted by 1/y 2) to the dataset of all available CL values including neonates for sufentanil and neonates and preterm infants for alfentanil.
Fig. 1

Linear regression of fentanyl clearance (CL) and bodyweight in preterm and term neonates (R 2 = 0.22, solid gray line)

Fig. 2

Nonlinear regression (Hill function) of sufentanil clearance (CL) and bodyweight in children including term neonates (R 2 = 0.71, solid gray line). Allometric function of sufentanil CL and bodyweight in children including term neonates (R 2 = 0.67, dotted black line). B max maximum CL, h Hill coefficient, K 50 bodyweight at which half-maximum CL is reached

Fig. 3

Nonlinear regression (Hill function) of alfentanil clearance (CL) and bodyweight in children including preterm and term neonates (R 2 = 0.70, solid gray line). Allometric function of alfentanil CL and bodyweight in children including preterm and term neonates (R 2 = 0.65, dotted black line). B max maximum CL, h Hill coefficient, K 50 bodyweight at which half-maximum CL is reached

For sufentanil, B max as a parameter for maximum CL was estimated at 876 mL/min, which lies in the documented range of adults (10–15 mL/min/kg, 700–1050 mL/min for 70 kg). The bodyweight at which half-maximum CL is reached (K 50) was estimated at 16.3 kg, which corresponds to the 50th bodyweight percentile of a child aged ~4 to 4.3 years [23]. The allometric exponent for estimating sufentanil CL was determined at 0.99 for children aged older than 1 month (excluding neonates) weighing 3–70 kg (actual age 1 month to 18 years).

For alfentanil, B max was fixed to 420 mL/min, which corresponds to average adult CL values (3–9 mL/min/kg, 210–630 mL/min for 70 kg) and K 50 was estimated at 28.0 kg (corresponding to an age of ~8.8 years [23]). The allometric exponent for estimating alfentanil CL was determined to be 0.75 for children aged older than 1 month (excluding preterm and term neonates) weighing 4.3–51 kg (actual age 3 months to 14 years). Thus, the Hill function reasonably well described maturation of CL for both substances by a sigmoidal shape taking the maturation of CL in early childhood into account.

Maturation of remifentanil CL was described by linear regression (R 2 = 0.69; Fig. 4). The Hill function was fitted as well but B max could not be determined probably owing to few data in the saturation phase. Moreover, linear maturation of remifentanil CL may be explained by the fact that remifentanil is metabolized by unspecific tissue and plasma esterases. Maturation of their metabolic capacity, however, has not yet been studied.
Fig. 4

Linear regression of remifentanyl clearance (CL) and bodyweight in children including neonates (R 2 = 0.69, solid gray line). Allometric function of remifentanil CL and bodyweight in children neonates (R 2 = 0.72, dotted black line)

The allometric exponent for remifentanil CL was determined at 0.76 for children (including neonates) weighing 2.5–96.8 kg (actual age 5 days to 17 years). Results of linear or non-linear regression (solid line) together with allometric scaling (dotted line) are presented in the figures. Reported parameter values in the figure legends are from the linear analysis or the Hill equation fit.

4 Pharmacokinetics

4.1 Fentanyl

4.1.1 Intravenous Fentanyl

Few studies in neonates, infants, and children have reported age-dependent differences (see Table 2). Clearance and V d in neonates and infants are higher than in adults and children, probably owing to an increased hepatic blood flow (normalized to weight) and/or altered protein binding [24]. In a single neonatal case report, protein binding was 63%, clearly lower than in adults [25].

Fentanyl plasma concentrations after an intravenous bolus (~30 µg/kg) were found to be lower in infants than in children, and in children lower than in adults [26]. These findings may result from a larger V d or age-related differences in protein binding. An increase in CL probably reflects maturation of CYP enzymes suggesting that the Michaelis–Menten constant is age dependent [27, 28].

Neonates undergoing major surgery showed a highly variable disposition after a bolus of 25–50 µg/kg, which was hemodynamically well tolerated [29]. No difference was found between doses and postnatal age. A rebound phenomenon was described in half of the patients owing to tissue redistribution. Furthermore, half-life was prolonged in neonates with markedly increased intraabdominal pressure (1.5–3 times the population mean of 317 min), which may have compromised the blood flow in the splanchnic veins to the portal vein [30] impacting fentanyl metabolism [4, 31]. In neonates and infants during non-cardiac surgery, CL increased with age, with the most rapid increase at a postnatal age of 2 weeks, whereas V d and half-life did not change after a bolus of 54.1 ± 2.3 µg/kg [32].

After a fentanyl continuous infusion, half-life was prolonged and V d at steady state was increased owing to a slow redistribution from peripheral compartments [33]. Clearance was highest in children 6 months to 6 years of age compared with younger or older children (8.2 vs. 18.9 vs. 8.0 mL/min/kg), which was attributed to increased liver metabolism. There was considerable heterogeneity of patients regarding age and underlying disease.

The accuracy of a computerized-assisted continuous infusion using an adult PK dataset was evaluated in children between 2.7 and 11 years of age undergoing non-cardiac surgery [34]. The measured fentanyl concentrations mostly exceeded the predicted concentrations; thus, the finally derived pediatric two-compartment model included age and bodyweight as covariates. However, this model is only applicable to infusion durations of up to 4 h. This study also calculated a shorter context-sensitive half-time for children compared with adults after an infusion duration of up to 200 min, but the true effect-site concentrations in children vs. adults and whether there are any differences among them remain unknown.

An increase of plasma concentrations correlated with elevated CO2 throughout all age groups. Therefore, infants were not more prone to ventilatory depression than children or adults [35, 36]. An opportunistic sampling strategy was applied in children after cardiac surgery, which proved that this technique is applicable to clinical routine because PK parameters were comparable to prior formal studies [37].

In summary, fentanyl was studied in children of all ages, but the majority of the data was generated in the newborn period. Age-related changes in pharmacokinetics were observed but data are scarce considering most studies were conducted when high doses of fentanyl were used.

4.1.1.1 Preterm Neonates

Unfortunately, PK sampling in neonates is usually limited. Therefore, estimation of half-life may become inaccurate if extrapolation of data is not carefully performed [38]. Postnatal and postmenstrual age both affect pharmacokinetics because preterm infants showed slightly higher CL than neonates born at term (26.2 vs. 21.1 mL/kg/min), but the preterm infants were older regarding postnatal age (36.7 vs. 13.3 days) [29, 32]. Other studies reported a significant correlation between postnatal age (R 2 = 0.64) or gestational age (GA) (r = 0.46, R 2 = 0.21) and birth weight (r = 0.48, R 2 = 0.23) with CL [39, 40], but for the last two it was actually as weak as in the pooled analysis of this review (weight R 2 = 0.22; Fig. 1, GA R 2 = 0.23), and for postnatal age was not even significant.

Difficulties in estimation of half-life were seen in preterm infants (GA 31.8 ± 4.7 weeks) in whom fentanyl plasma concentrations after a bolus (30 µg/kg) were almost stable from 0.5 to 2 h, resulting in an elimination half-life of 6–32 h [41]. There were no adverse hemodynamic changes towards fentanyl reported.

Although body fat mass is much lower and total body water is much higher in premature infants than in newborns or older infants [42], V d was increased in comparison to newborns and older children and half-life was prolonged [29, 32, 33]. This may be attributed to lower plasma protein levels (albumin and α-1-acid-glycoprotein) in preterm infants and thus a higher free fraction of the drug [42].

Fentanyl showed dose-linear pharmacokinetics during continuous infusion in preterm neonates. Clearance was slightly lower in preterm infants <34 weeks GA than ≥34 weeks GA, but with high inter-individual and inter-day variability. Circulatory parameters were stable and fentanyl provided effective analgesia. Meconium excretion occurred later and plasma bilirubin was higher in the fentanyl group, most probably owing to a longer gastrointestinal transit time.

Premature neonates showed no signs of cardiorespiratory compromise during continuous infusions [39, 43] but baroreflex control of heart rate was depressed after fentanyl administration. Thus, the ability of neonates to adapt to a decrease in blood pressure by increasing heart rate and thus cardiac output is disturbed [44].

In preterm infants with a GA <33 weeks, a fentanyl bolus was more suitable for treating acute pain episodes in ventilated infants than a continuous infusion, which led to increased side effects such as longer ventilation duration and reduced gastrointestinal motility [45]. Chest wall rigidity and laryngospasm have been observed even after low bolus doses of 3–5 µg/kg in preterm and term infants [46].

Plasma binding of fentanyl in vitro in umbilical cord blood was 77% in preterm infants compared with 70% in neonates [47], but fentanyl concentrations (125 ng/mL) considerably exceeding therapeutic ranges (1–20 ng/mL, factor 6.25–125) were used. Alpha-1-acid-glycoprotein levels were lower in preterm compared with term neonates, while albumin levels were similar. Fentanyl already caused an analgesic effect and respiratory depression at plasma concentrations of 1–3 ng/mL [48]. Samples from the umbilical cord in preterm and term infants undergoing ex utero intrapartum therapy owing to airway and lung pathologies [49] proved analgesic fentanyl concentrations in all patients.

In summary, fentanyl, which currently is the most frequently used opioid analgesic in the neonatal intensive care unit, shows highly variable kinetics in preterm neonates after bolus dosing or continuous infusion (17-fold variation between individual patients with a range of 3.4–58.7 mL/min/kg; Fig. 1) [50]. Withdrawal symptoms may occur after several days of continuous infusion. Fentanyl may cause relevant side effects at low doses; therefore, studies are needed evaluating the PK-pharmacodynamic relationship of fentanyl in this vulnerable group of patients.

4.1.1.2 Kidney Disease

Chronic kidney disease or end-stage renal failure not only impact renal elimination, but also non-renal CL of drugs [51]. Fentanyl does not undergo renal metabolism, but is excreted via the kidneys into the urine, predominantly as inactive metabolites [52, 53, 54]. Therefore, absent kidney function should not significantly alter pharmacokinetics.

Two children with renal disease receiving fentanyl for surgery are described in a case series [55]. While pharmacokinetics did not differ during corrective cardiac surgery from other studies in the first patient, the second patient showed an extreme prolongation of half-life [56]. A study described above included two children with renal failure, but their fentanyl CL was comparable to other patients [33].

4.1.2 Cardiopulmonary Bypass

Extracorporeal circulation (CPB or ECMO) leads to changes in pharmacokinetics, such as hemodilution owing to circuit priming, an increased V d owing to the addition of a large exogenous volume, a prolonged half-life, changes in plasma protein concentrations, and a reduction in renal or hepatic function [57]. Extracorporeal membrane oxygenation may have an even greater impact on pharmacokinetics than CPB owing to a longer treatment duration, such as days to weeks [57].

Hypothermia during CPB impacts drug metabolism, as hepatic CL decreases as a result of reduced liver blood flow and activity of drug-metabolizing enzymes [58]. Renal CL decreases during extracorporeal circulation owing to reduced glomerular filtration caused by impaired renal perfusion [59].

Drug sequestration and adhesion to the surface of circuit components cause alterations in drug disposition. Drug adsorption correlates with the lipophilicity of the drug, but adsorption also depends on the equipment used for ECMO [60]. In a series of studies, initiation of CPB leads to a 60–89% decrease of plasma concentrations, attributed to a rapid sequestration of fentanyl within the bypass circulation owing to binding of fentanyl to components of the CPB system [56, 61]. Therefore, fentanyl was not recommended as the primary analgesic agent in patients on ECMO because the lipophilic drug is highly adsorbed to ECMO circuit components and shows a decreased CL during hypothermia [62].

After the initial decrease, fentanyl plasma concentrations remained stable during the further course of CPB [55, 64], also during hypothermia [65]. Even priming of the pump with 20 ng/mL of fentanyl did not prevent this effect [66]. When more modern equipment was used, only minimal variability in plasma concentrations was observed before, during, and after hypothermic CPB using a low-volume circuit and constant fentanyl infusion [63]. A significant reduction in serum albumin levels was observed as a result of CPB, which was likely caused by hemodilution, probably not affecting the unbound fraction of fentanyl [66]. Additionally, the degree of hemodynamic impairment may be a major determinant of fentanyl distribution [67]. During modified ultrafiltration after CPB, at least stable [68] or increasing fentanyl plasma concentrations were reported [69].

In the studies conducted early after its introduction, higher doses of fentanyl per kilogram of bodyweight (>10 and up to 50 µg/kg) were used because there were only limited other anesthetic agents. Fentanyl suppressed the stress response to surgery and still provided hemodynamic stability as it lacks myocardial depressant effects [70, 71]. No correlation was found between fentanyl concentrations, bispectral index, and hemodynamic, metabolic, or hormonal markers of depth of anesthesia [72].

During ECMO, neonates rapidly developed tolerance towards the sedating effect of fentanyl, resulting in a progressive escalation of fentanyl infusion rates and rising steady-state plasma concentrations, increasing the risk of neonatal abstinence syndrome [38, 73, 74]. Clearance may be impaired in seriously ill patients during ECMO, which may be owing to decreased liver blood flow during compromised circulatory function [75].

4.1.2.1 Obesity

Obesity has become a challenge in pediatric anesthesia because the rates of pediatric overweight and obesity are rising [76, 77]. Pediatric obesity is defined by a body mass index >95th percentile [78].

A pilot study in morbidly obese adolescents (mean body mass index 49.6 kg/m2) showed enhanced CL while V d was comparable to that in lean adults after dosing based on ideal body weight [79]. Although the results suggest that a loading dose of fentanyl may be based on total body weight followed by maintenance doses based on ideal body weight and/or lean body weight [80, 81], obese patients are more at risk for respiratory side effects of opioids [82, 83, 84, 85, 86].

4.1.3 Epidural Fentanyl

Epidural administration of fentanyl resulted in peak plasma concentrations 30 min after the loading dose, but a substantial variability during continuous epidural infusion supplemented by patient-controlled bolus doses in children aged 6–11 years was observed [87]. In children of comparable age, half-life was not only longer in infants than children (median 15.9 vs. 7.96 h) but longer than observed after intravenous administration [88]. In addition, an increase in plasma concentrations was noted after discontinuation of the infusion attributed to redistribution. Consequently, continued clinical monitoring is required during neuraxial analgesia.

4.1.4 Transmucosal Fentanyl

After comparable doses, maximal fentanyl concentrations were lower in children after administration of OTFC, whereas the time to achieve them was longer in adults [89]. Oral transmucosal fentanyl citrate given as a premedication to children aged 2–10 years resulted in a bioavailability of 33% compared with 50% in adults [90, 91]. The efficacy of 10–15 µg/kg of OTFC was comparable to 2 µg/kg of intravenous fentanyl. Bioavailability was also low (36%) in another study in patients of the same age, but pharmacokinetics was similar [92]. Time to maximum plasma concentration (C max) was highly variable (14–121 min), most probably owing to variability in gastrointestinal absorption, resulting in difficulties in the timing of administration. When the intravenous solution was given orally (10–15 µg/kg, maximum 400 µg), pharmacokinetics was comparable to the previous two studies, but the apparent oral V d was significantly larger and the time to C max was much longer (the latter could be owing to methodological difficulties) [93]. Side effects of OTFC for preoperative sedation were nausea and vomiting, pruritus, respiratory depression, and chest-wall rigidity. Oral transmucosal fentanyl citrate should be carefully used in children less than 6 years of age [94, 95, 96, 97]. Intranasal fentanyl (dosed 1–2 µg/kg) has been effectively used in premedication, emergency analgesia, and palliative care [98, 99, 100, 101, 102].

4.1.5 Transdermal Fentanyl

Transdermal application is a convenient non-invasive route of administration. In children who were treated with transdermal fentanyl for postoperative pain control (dose 25 µg/h, 1.72 µg/h/kg), C max was negatively correlated with the patients’ age, but not with bodyweight [103]. Respiratory depression was not observed. In another study, time to reach C max ranged from 18 to 66 h in children after patch application (25 µg/h) [104]. Transdermal pharmacokinetics is similar to those in adults [105, 106, 107].

4.2 Sufentanil

4.2.1 Intravenous Sufentanil

Sufentanil pharmacokinetics (Table 3) showed age-related differences in children undergoing cardiac surgery after a single dose (10–15 µg/kg) [108]. Clearance was lowest in neonates compared with infants, children, and adolescents. Half-life was longest and V d at steady state was largest in newborns compared with the older age groups. Neonates needed additional anesthetic agents at significantly higher plasma concentrations compared with older children to suppress the hemodynamic response to painful stimuli, but younger infants did not receive premedication before surgery [38]. Clearance and V d increased while the half-life decreased slightly in a case series of neonates who were studied twice during the first 4 weeks of life [109].

In children aged 2–8 years undergoing surgery, CL was twice as rapid as in adults after a bolus dose (1–3 µg/kg) [110]. Volume of distribution was larger than in adults when normalized to bodyweight, but similar to that in adults when normalized to body surface area. Sufentanil plasma binding was lowest in newborns (80.5%) compared with infants (88.5%), children (91.9%), and adults (92.2%), while sufentanil is usually highly protein bound (92.5%) in adults [111, 112]. Sufentanil was 79.3% plasma-protein bound in neonates compared with 90.7% in their mothers, while α1-acid-glycoprotein levels in the neonates were 50% of the adult values [113].

Two studies investigating pharmacokinetics included one pediatric patient [114, 115]. Long half-lives were reported in patients receiving a continuous infusion [115, 116]. Allometric scaling for dose adaptation in pediatric patients was suggested [116]. Dose linearity of 250–1500 µg of sufentanil was shown in adolescents and adults aged 14–68 years. Sufentanil metabolic CL was almost identical to hepatic blood flow [12].

In summary, sufentanil pharmacokinetics show weight-related increases in CL and V d while most maturation processes occur around 4 years of age (Fig. 2) and during the first weeks of life [109]. Normalized to bodyweight, CL and V d in infants and children older than 1 month of age reached twice the adult values [3, 12, 110]. The allometric exponent of 0.99 best describing the maturation of CL differs from previous practice, suggesting an allometric exponent of 0.75 in pediatric patients [117]. A linear model, however, would overestimate the CL of sufentanil in children exceeding 35–40 kg of bodyweight (Fig. 1).

4.2.1.1 Preterm neonates

Sufentanil has been used in preterm neonates but no pharmacokinetics was assessed [118].

4.2.1.2 Kidney Disease

Renal failure had no significant effect on the pharmacokinetics in children and adolescents undergoing general anesthesia before kidney transplantation [119]. Children with chronic renal failure, however, showed a higher individual variability in CL and half-life.

4.2.1.3 Cardiopulmonary Bypass

Sufentanil V d was significantly smaller in infants under 10 months of age, while half-life and CL were similar after a single intravenous dose (15 µg/kg) in infants and children undergoing CPB [120]. Surface cooling led to an increase in the V d and almost twice the half-life value, while CL was similar to the uncooled groups. Hemodynamic responses could be observed upon sufentanil administration. Sufentanil plasma concentrations were clearly overestimated by a computerized-assisted continuous infusion, probably because of a rapid decline of plasma concentrations after initiation of CPB [121].

4.2.2 Epidural Sufentanil

Plasma concentrations after epidural administration reach a C max 20 min after the loading dose [87]. Considerable redistribution was observed and a slow elimination after continuous infusion with a median half-life of 19.6 h in children aged 3–36 months comparable to an earlier study [122, 123].

4.2.3 Transmucosal Sufentanil

Intranasal application was described as a safe and effective method for premedication in children [124, 125]. Higher doses, however, led to a higher incidence of postoperative nausea and vomiting. Compared with midazolam, the latter showed advantages regarding respiratory depression, postoperative nausea and vomiting, and time to discharge [126, 127, 128]. Plasma concentrations after intranasal application (single dose 2 µg/kg) showed a C max 15–30 min after administration [129]. In another study, C max occurred 13.8 min after application and bioavailability was 24.6% [130].

4.3 Alfentanil

4.3.1 Intravenous Alfentanil

Alfentanil (Table 4) CL in children aged 5.4 ± 1.1 years was similar to adults, but half-life was significantly less and V d significantly smaller (0.16 ± 0.11 vs. 0.46 ± 0.16 L/kg) in children [131]. Protein binding was comparable (91.8–94.4%) in both groups. Similar protein binding (free fraction 11.5 ± 0.9%) was reported in children aged 10 months to 6.5 years [132]. Half-life was shorter and CL was higher compared with adults (11.1 ± 3.9 vs. 5.9 ± 1.6 mL/min/kg). In contrast, plasma protein binding in neonates was clearly lower than in their mothers (67.2 vs. 88.2%) [113].

An increase in dose from 50 to 120 µg/kg resulted in a proportional increase in exposure in children between 3 months and 14 years of age undergoing surgery [13], suggesting dose-independent PK. Half-life, CL, and V d were similar in infants compared with older children.

In contrast, a non-linear increase in plasma concentrations was observed when comparing different doses (85-µg/kg bolus with a 65-µg/kg/h infusion, and 65-µg/kg bolus with a 50-µg/kg/h infusion) in children aged 3–12 years [133]. Approximately doubled plasma concentrations were observed after the higher dose (279 ± 78 vs. 135 ± 30 ng/mL), suggesting dose-dependent pharmacokinetics [133]. Dose linearity was assessed in neonates but the results were inconclusive because a limited number of plasma samples was drawn [134].

Overall, pharmacokinetics seems to be dose independent because there was no evidence for saturation of metabolism and drug accumulation when PK parameters after dosing of 20–200 µg/kg were compared [13, 135]. Fentanyl (2 µg/kg/h) had a much longer half-life (15.9 vs. 4.9 h) and a much larger Vd at steady state (17.2 vs. 1.3 L/kg) given as continuous infusion when compared with alfentanil (20 µg/kg/h) [136]. Children who were controls in other studies had similar PK profiles than discussed above [135, 137].

Alfentanil pharmacokinetics was used to predict CYP3A-mediated drug CL by physiologically based PK modeling. Allometric scaling failed to predict alfentanil CL in neonates in one study [138], but another study reported no age-dependent bias in a model for term neonates up to the age of 18 years. However, in premature neonates, V d and half-life were underestimated [139]. A new physiologically based PK model [140] showed improved predictions regarding the ontogeny function for CYP3A when compared with previously reported models [141]. In the pooled analysis of this review, the allometric exponent describing maturation of CL was 0.75 for children between 3 months and 14 years of age.

In summary, alfentanil CL in infants and children normalized to bodyweight was comparable to adult values and occasionally exceeded them. Clearance in neonates and preterm neonates was significantly less, while half-life is prolonged. Most maturation processes of CL occur around the age of 8.8 years, but there were limited PK data in children with a bodyweight over 25 kg (Fig. 3).

4.3.1.1 Preterm Neonates

Plasma protein binding in vitro in umbilical cord blood samples was 65% compared with 79% in term neonates, which correlated with gestational age (GA) and level of α-1-acid-glycoprotein, lower than in older children (92.4–94.4%) [47, 131]. In premature neonates with a GA of 29.5 ± 3.3 weeks, CL was lower (2.2 ± 2.4 vs. 5.6 ± 2.4 mL/kg/min), V d was larger (1.0 ± 0.39 vs. 0.48 ± 0.19 L/kg), and half-life was much longer after a bolus (25 µg/kg) compared with older infants and children (age 5.0 ± 2.8 years) [135]. The differences in body composition in preterm infants, such as a higher body water content and less fat and muscle mass as well as reduced protein binding might explain these differences.

A high variability of pharmacokinetics was observed after a bolus dose (20 µg/kg) in another preterm cohort (GA 25–36 weeks), but CL was lower and half-life was longer, whereas the V d was similar in older children [142]. No association was observed between weight, GA, age, or sex. Alfentanil did not seem to accumulate in preterm infants even if given as 5-µg/kg/h infusion. Although the total infusion duration was not reported, it seemed to be longer than 48 h.

Term and preterm neonates with a GA of 26–35 weeks who received a bolus dose (25 µg/kg) during their first 3 days of life showed no alterations in hemodynamics. Pharmacokinetics showed a considerable variability and did not differ between preterm and term neonates, but CL was lower and half-life was longer when compared with older children [143].

When low-dose alfentanil (mean 11.7 µg/kg) was administered to newborn and preterm infants during their first 3 days of life, 65% of patients showed symptoms of skeletal muscle rigidity which disappeared spontaneously after 10 min. Pharmacokinetics was not different between both groups [144].

In summary, half-life was longer and CL lower in newborns and preterm neonates compared with children, while there were conflicting results for V d [135, 143]. Reported chest wall rigidity remains a safety concern in this age group [144]. Therefore, more studies are needed to investigate the relationship of pharmacokinetics and pharmacodynamics [38].

4.3.1.2 Liver Disease

Liver disease may have a variable effect on pharmacokinetics owing to altered intrinsic enzyme activity, hepatic blood flow, hepatocellular function, and protein binding. Existing data do not allow correlations between distinct hepatic diseases and specific PK alterations [145]. Hepatic diseases with preserved hepatic blood flow may not affect the pharmacokinetics of high-extraction ratio drugs. In contrast, the hepatic CL of low extraction-ratio drugs depends mainly on enzymatic activity [146].

Pharmacokinetics seemed to be unaffected by cholestatic liver disease in children aged 0.75–15 years [137]. Liver transplant patients were studied before the anhepatic phase and 8–12 h after reperfusion. A significant decrease in CL was found after liver transplant (7.0 ± 3.8 vs. 11.2 ± 2.7 mL/kg/min), while the increases in apparent V d and half-life were not significant. Dose reduction of alfentanil is recommended during liver transplantation [147].

4.3.1.3 Kidney Disease

No difference in pharmacokinetics compared with healthy children could be found in children with end-stage renal disease dependent undergoing peritoneal or hemodialysis who received alfentanil during anesthesia for kidney transplantation [11].

4.3.1.4 Cardiopulmonary Bypass

The initial V d was smaller and the dose-normalized area under the plasma concentration–time curve was significantly greater before (bolus 200 µg/kg) than after (bolus 80 µg/kg) CPB in infants and children [148]. Alfentanil administration led to a significant hemodynamic response in both patient and dose groups comparable to previous data [36, 149]. A higher recovery of alfentanil (80%) compared with fentanyl (29%) after 60 min circulation time through CPB was observed in vitro [61].

4.4 Remifentanil

4.4.1 Intravenous Remifentanil

The pharmacokinetics (Table 5) was studied in children of different age groups during surgery [150]. The half-life was similarly short across all age groups and comparable to adult values, while V d was highest and CL was fastest in infants under 2 months of age compared with older infants, children, and adolescents, when normalized to bodyweight [150, 151]. About 17% of patients developed arterial hypotension after a bolus dose of 5 µg/kg. Another study described remifentanil pharmacokinetics during postoperative sedation by a two-compartment allometric model [152]. Regarding the hypotensive effect in infants, it was estimated that a plasma concentration of 14 ng/mL would cause a 30% decrease in mean arterial blood pressure [153]. When compared with halothane, remifentanil did not cause new-onset postoperative respiratory depression [154]. However, because of the short recovery time from anesthesia, supplemental analgesia has to be administered for postoperative pain management.

Although remifentanil is not recommended during the first year of life, it was shown to have a favorable safety and efficacy profile in neonates [155, 156]. Remifentanil is currently used for the sedation of neonates during mechanical ventilation [157, 158]. Despite higher dose requirements in newborns and young infants, they were more tolerant towards the respiratory depressant effect [159]. Recovery times were short even in neonates [160].

In summary, remifentanil has predictable pharmacokinetics in children aged 5 days to 17 years and CL showed bodyweight-linear maturation. When assessed by an allometric function, however, the allometric exponent was 0.76 (Fig. 4), and both models described maturation of remifentanil CL equally well (R 2 = 0.69 vs. R 2 = 0.72). However, in daily anesthetic practice, the linear regression might be a more practical approach. Neonates and infants younger than 2 months of age had an enhanced CL compared with older children normalized to bodyweight, thus they may require higher infusion rates.

Remifentanil is well suited for analgo-sedation during short painful procedures, but a less favorable option for postoperative pain control in non-ventilated or sedated children owing to its short duration of action [161], and has gained wide acceptance [162, 163, 164]. Studies elucidating the PK-pharmacodynamic relationship are particularly needed in children of all age groups because of its popularity [165].

4.4.1.1 Preterm Neonates

Remifentanil degradation was assessed in the cord blood of preterm and term infants in vitro [166]. The in-vitro half-life and degradation rate did not differ between groups without any correlation to GA, indicating a high non-specific esterase activity already in very preterm infants. There are no PK data reported in preterm neonates, although remifentanil is increasingly used in this age group [167, 168].

4.4.1.2 Liver Disease

No reported dose adjustment is necessary owing to renal and hepatic impairment, but patients with severe hepatic disease may be more prone to respiratory depression [169, 170].

4.4.1.3 Kidney Disease

A case report of a newborn with congenital malformations and impaired renal function who received remifentanil for surgery proved a short duration of drug action [169].

4.4.1.4 Cardiopulmonary Bypass

While there was no difference in V d and half-life before/after CPB, CL increased 20% after CPB [171]. Because of low variability, plasma concentrations were well predicted even in the post-CPB phase. A study in patients who received remifentanil by computer-controlled infusion pump during open heart surgery described changes in the V d before, during, and after CPB [172].

5 Limitations of the Review

Between all studies was large heterogeneity regarding study design, setting, drug administration, and PK and pharmacodynamic parameters. Although most studies were prospective non-randomized clinical trials, a few randomized controlled and even double-blinded studies were included. Dosing schemes were variable in relation to bolus dose, short infusion, or continuous infusion, which may affect PK parameters, e.g. half-life.

Different laboratory methods for the quantification of the parent drug and its metabolites, for example radioimmunoassay or liquid chromatography–mass spectrometry, may account for the variability in pharmacokinetics. Reported results were calculated or estimated using compartmental and non-compartmental PK analysis. Effects of the previously described limitations are carried forward to linear and nonlinear regression analyses using individual patients’ PK data because information on different doses, different dosing schemes, and data established by different PK parameter estimation methods were combined.

6 Conclusions

This review provides a comprehensive overview of the pharmacology of fentanyl and its derivatives sufentanil, alfentanil, and remifentanil in the pediatric population. Despite the frequent use of these drugs in this population, there have been surprisingly few studies in children. There are some pediatric PK data available for all four drugs, but 800 patients are a relatively small number when compared with the extensive use of synthetic opioids in children. Most of the PK data pertains to fentanyl, which was the first synthetic opioid in its class.

Preterm and term infants showed lower CL and protein binding for fentanyl, sufentanil, and alfentanil with a large variation in drug disposition in these age groups for critical illness and/or maturation processes. In contrast, remifentanil CL was enhanced particularly in younger children.

Clearance of fentanyl, sufentanil, and alfentanil increases rapidly during the first years of life. Infants and young children even had higher CL normalized to bodyweight, which might be caused by a higher metabolic capacity in these age groups or, for high-extraction ratio drugs, by increased liver blood flow. The pharmacokinetics of fentanyl and its derivatives seemed not to be altered by chronic renal or hepatic disease, but sample sizes have been small and data need to be validated in larger cohorts of patients. To increase safety, studies in those age groups in which the drugs are used off-label are especially needed, such as remifentanil in neonates and infants younger than 1 year of age.

Fentanyl and its derivatives have proven efficacy and hemodynamic safety in children with cardiac disease who were exposed to high drug doses during cardiac surgery. Nevertheless, chest wall rigidity may occur especially in preterm and term neonates. Respiratory depression may also occur after prolonged infusion of the synthetic opioids.

Routes of administration have shown to be safe and effective in children, such as transmucosal fentanyl or sufentanil delivery for premedication before surgery. Based on the widely established use of these drugs, opportunistic clinical trials should be conducted to elucidate the pharmacokinetics and pharmacodynamics of fentanyl and its derivatives in much larger cohorts of the pediatric population.

Notes

Compliance with Ethical Standards

Funding

The research leading to this manuscript has received funding from the European Union’s Seventh Framework Programme for research; technological development, and demonstration under Grant Agreement No. 261060 (Global Research in Paediatrics—network of excellence). Janelle D. Vaughns (5T32HD087969) and Johannes N. van den Anker (5T32HD087969 and 5U54HD090254) were supported by National Institutes of Health Grants to conduct this review.

Conflict of interest

Victoria C. Ziesenitz, Janelle D. Vaughns, Gilbert Koch, Gerd Mikus, and Johannes N. van den Anker have no conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Stanley TH. The history and development of the fentanyl series. J Pain Symptom Manag. 1992;7(3 Suppl.):S3–7.CrossRefGoogle Scholar
  2. 2.
    James MK, Feldman PL, Schuster SV, Bilotta JM, Brackeen MF, Leighton HJ. Opioid receptor activity of GI 87084B, a novel ultra-short acting analgesic, in isolated tissues. J Pharmacol Exp Ther. 1991;259(2):712–8.PubMedGoogle Scholar
  3. 3.
    Bovill JG, Sebel PS, Blackburn CL, Oei-Lim V, Heykants JJ. The pharmacokinetics of sufentanil in surgical patients. Anesthesiology. 1984;61(5):502–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Bower S, Hull CJ. Comparative pharmacokinetics of fentanyl and alfentanil. Br J Anaesth. 1982;54(8):871–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes: role of CYP3A4. Drug Metab Dispos. 1996;24(9):932–9.PubMedGoogle Scholar
  6. 6.
    Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M. Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg. 1996;82(1):167–72.PubMedGoogle Scholar
  7. 7.
    Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997;25(9):1072–80.PubMedGoogle Scholar
  8. 8.
    Mahlke NS, Ziesenitz V, Mikus G, Skopp G. Quantitative low-volume assay for simultaneous determination of fentanyl, norfentanyl, and minor metabolites in human plasma and urine by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Int J Legal Med. 2014;128(5):771–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Chauvin M, Bonnet F, Montembault C, Levron JC, Viars P. The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient. Anesth Analg. 1986;65(10):999–1003.PubMedCrossRefGoogle Scholar
  10. 10.
    Meuldermans W, Van Peer A, Hendrickx J, Woestenborghs R, Lauwers W, Heykants J, et al. Alfentanil pharmacokinetics and metabolism in humans. Anesthesiology. 1988;69(4):527–34.PubMedCrossRefGoogle Scholar
  11. 11.
    Murphy MR, Hug CC Jr, McClain DA. Dose-independent pharmacokinetics of fentanyl. Anesthesiology. 1983;59(6):537–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Gepts E, Shafer SL, Camu F, Stanski DR, Woestenborghs R, Van Peer A, et al. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology. 1995;83(6):1194–204.PubMedCrossRefGoogle Scholar
  13. 13.
    Goresky GV, Koren G, Sabourin MA, Sale JP, Strunin L. The pharmacokinetics of alfentanil in children. Anesthesiology. 1987;67(5):654–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Westmoreland CL, Hoke JF, Sebel PS, Hug CC Jr, Muir KT. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology. 1993;79(5):893–903.PubMedCrossRefGoogle Scholar
  15. 15.
    Egan TD, Lemmens HJ, Fiset P, Hermann DJ, Muir KT, Stanski DR, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology. 1993;79(5):881–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992;76(3):334–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Anderson BJ. Pharmacokinetics and pharmacodynamics in the pediatric patient. In: Absalom AR, Mason KP, editors. Total intravenous anesthesia and target controlled infusions. Cham: Springer; 2017. p. 441–516.CrossRefGoogle Scholar
  18. 18.
    Opioide Schäfer M. In: Tonner PH, Hein L, editors. Pharmakotherapie in der Anästhesie und Intensivmedizin. Heidelberg: Springer; 2011. p. 110–8.Google Scholar
  19. 19.
    EMA. ICH topic E11 clinical investigation of medicinal products in the paediatric population. 2001. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002926.pdf. Accessed 18 Aug 2016.
  20. 20.
    Goutelle S, Maurin M, Rougier F, Barbaut X, Bourguignon L, Ducher M, et al. The Hill equation: a review of its capabilities in pharmacological modelling. Fundam Clin Pharmacol. 2008;22(6):633–48.PubMedCrossRefGoogle Scholar
  21. 21.
    Koch G, Schropp J, Jusko WJ. Assessment of non-linear combination effect terms for drug–drug interactions. J Pharmacokinet Pharmacodyn. 2016;43(5):461–79.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Longo G, Montévil M. Scaling and scale symmetries in biological systems: perspectives on organisms lecture notes in morphogenesis. Berlin: Springer; 2014.CrossRefGoogle Scholar
  23. 23.
    Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. CDC growth charts for the United States: methods and development. Vital Health Stat (data from the national health survey). 2000;11(246):1–190.Google Scholar
  24. 24.
    Johnson KL, Erickson JP, Holley FO, Scott JC. Fentanyl pharmacokinetics in the pediatric population. Anesthesiology. 1984;61(3A):1.Google Scholar
  25. 25.
    Rosaeg OP, Kitts JB, Koren G, Byford LJ. Maternal and fetal effects of intravenous patient-controlled fentanyl analgesia during labour in a thrombocytopenic parturient. Can J Anaesth. 1992;39(3):277–81.PubMedCrossRefGoogle Scholar
  26. 26.
    Singleton MA, Rosen JI, Fisher DM. Plasma concentrations of fentanyl in infants, children and adults. Can J Anaesth. 1987;34(2):152–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Anderson BJ, Holford NH. Tips and traps analyzing pediatric PK data. Paediatr Anaesth. 2011;21(3):222–37.PubMedCrossRefGoogle Scholar
  28. 28.
    Grasela TH, Sheiner LB, Rambeck B, Boenigk HE, Dunlop A, Mullen PW, et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokinet. 1983;8(4):355–64.PubMedCrossRefGoogle Scholar
  29. 29.
    Koehntop DE, Rodman JH, Brundage DM, Hegland MG, Buckley JJ. Pharmacokinetics of fentanyl in neonates. Anesth Analg. 1986;65(3):227–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Masey SA, Koehler RC, Ruck JR, Pepple JM, Rogers MC, Traystman RJ. Effect of abdominal distension on central and regional hemodynamics in neonatal lambs. Pediatr Res. 1985;19(12):1244–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Bjorkman S, Redke F. Clearance of fentanyl, alfentanil, methohexitone, thiopentone and ketamine in relation to estimated hepatic blood flow in several animal species: application to prediction of clearance in man. J Pharm Pharmacol. 2000;52(9):1065–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Gauntlett IS, Fisher DM, Hertzka RE, Kuhls E, Spellman MJ, Rudolph C. Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age. Anesthesiology. 1988;69(5):683–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Katz R, Kelly HW. Pharmacokinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med. 1993;21(7):995–1000.PubMedCrossRefGoogle Scholar
  34. 34.
    Ginsberg B, Howell S, Glass PS, Margolis JO, Ross AK, Dear GL, et al. Pharmacokinetic model-driven infusion of fentanyl in children. Anesthesiology. 1996;85(6):1268–75.PubMedCrossRefGoogle Scholar
  35. 35.
    Hertzka RE, Gauntlett IS, Fisher DM, Spellman MJ. Fentanyl-induced ventilatory depression: effects of age. Anesthesiology. 1989;70(2):213–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet. 1995;28(5):385–404.PubMedCrossRefGoogle Scholar
  37. 37.
    Van Driest SL, Marshall MD, Hachey B, Beck C, Crum K, Owen J, et al. Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery. Br J Clin Pharmacol. 2016;81(6):1165–74.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics of sedatives in neonates. Clin Pharmacokinet. 1996;31(6):423–43.PubMedCrossRefGoogle Scholar
  39. 39.
    Santeiro ML, Christie J, Stromquist C, Torres BA, Markowsky SJ. Pharmacokinetics of continuous infusion fentanyl in newborns. J Perinatol. 1997;17(2):135–9.PubMedGoogle Scholar
  40. 40.
    Saarenmaa E, Neuvonen PJ, Fellman V. Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr. 2000;136(6):767–70.PubMedCrossRefGoogle Scholar
  41. 41.
    Collins C, Koren G, Crean P, Klein J, Roy WL, MacLeod SM. Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus. Anesth Analg. 1985;64(11):1078–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.PubMedCrossRefGoogle Scholar
  43. 43.
    Roth B, Schlunder C, Houben F, Gunther M, Theisohn M. Analgesia and sedation in neonatal intensive care using fentanyl by continuous infusion. Dev Pharmacol Ther. 1991;17(3–4):121–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Murat I, Levron JC, Berg A, Saint-Maurice C. Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology. 1988;68(5):717–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Ancora G, Lago P, Garetti E, Pirelli A, Merazzi D, Mastrocola M, et al. Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation. J Pediatrics. 2013;163(3):645–651 e1.CrossRefGoogle Scholar
  46. 46.
    Fahnenstich H, Steffan J, Kau N, Bartmann P. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med. 2000;28(3):836–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Wilson AS, Stiller RL, Davis PJ, Fedel G, Chakravorti S, Israel BA, et al. Fentanyl and alfentanil plasma protein binding in preterm and term neonates. Anesth Analg. 1997;84(2):315–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Cartwright P, Prys-Roberts C, Gill K, Dye A, Stafford M, Gray A. Ventilatory depression related to plasma fentanyl concentrations during and after anesthesia in humans. Anesth Analg. 1983;62(11):966–74.PubMedCrossRefGoogle Scholar
  49. 49.
    Tran KM, Maxwell LG, Cohen DE, Adamson PC, Moll V, Kurth CD, et al. Quantification of serum fentanyl concentrations from umbilical cord blood during ex utero intrapartum therapy. Anesth Analg. 2012;114(6):1265–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Pacifici GM. Clinical pharmacology of fentanyl in preterm infants: a review. Pediatr Neonatol. 2015;56(3):143–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Rodieux F, Wilbaux M, van den Anker JN, Pfister M. Effect of kidney function on drug kinetics and dosing in neonates, infants, and children. Clin Pharmacokinet. 2015;54(12):1183–204.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    McClain DA, Hug CC Jr. Intravenous fentanyl kinetics. Clin Pharmacol Ther. 1980;28(1):106–14.PubMedCrossRefGoogle Scholar
  53. 53.
    Schleimer R, Benjamini E, Eisele J, Henderson G. Pharmacokinetics of fentanyl as determined by radioimmunoassay. Clin Pharmacol Ther. 1978;23(2):188–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Silverstein JH, Rieders MF, McMullin M, Schulman S, Zahl K. An analysis of the duration of fentanyl and its metabolites in urine and saliva. Anesth Analg. 1993;76(3):618–21.PubMedCrossRefGoogle Scholar
  55. 55.
    Koren G, Crean P, Goresky GV, Klein J, MacLeod SM. Pharmacokinetics of fentanyl in children with renal disease. Res Commun Chem Pathol Pharmacol. 1984;46(3):371–9.PubMedGoogle Scholar
  56. 56.
    Koren G, Goresky G, Crean P, Klein J, MacLeod SM. Pediatric fentanyl dosing based on pharmacokinetics during cardiac surgery. Anesth Analg. 1984;63(6):577–82.PubMedCrossRefGoogle Scholar
  57. 57.
    Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. 2003;42(5):403–17.PubMedCrossRefGoogle Scholar
  58. 58.
    Hall R. The pharmacokinetic behaviour of opioids administered during cardiac surgery. Can J Anaesth. 1991;38(6):747–56.PubMedCrossRefGoogle Scholar
  59. 59.
    van den Broek MP, Groenendaal F, Egberts AC, Rademaker CM. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet. 2010;49(5):277–94.PubMedCrossRefGoogle Scholar
  60. 60.
    Wildschut ED, Ahsman MJ, Allegaert K, Mathot RA, Tibboel D. Determinants of drug absorption in different ECMO circuits. Intensive Care Med. 2010;36(12):2109–16.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Hynynen M. Binding of fentanyl and alfentanil to the extracorporeal circuit. Acta Anaesth Scand. 1987;31(8):706–10.PubMedCrossRefGoogle Scholar
  62. 62.
    Wildschut ED, de Wildt SN, Mathot RA, Reiss IK, Tibboel D, Van den Anker J. Effect of hypothermia and extracorporeal life support on drug disposition in neonates. Semin Fetal Neonat Med. 2013;18(1):23–7.CrossRefGoogle Scholar
  63. 63.
    Kussman BD, Zurakowski D, Sullivan L, McGowan FX, Davis PJ, Laussen PC. Evaluation of plasma fentanyl concentrations in infants during cardiopulmonary bypass with low-volume circuits. J Cardiothorac Vasc Anesth. 2005;19(3):316–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Newland MC, Leuschen P, Sarafian LB, Hurlbert BJ, Fleming WF, Chapin JW, et al. Fentanyl intermittent bolus technique for anesthesia in infants and children undergoing cardiac surgery. J Cardiothorac Anesth. 1989;3(4):407–10.PubMedCrossRefGoogle Scholar
  65. 65.
    Koren G, Barker C, Goresky G, Bohn D, Kent G, Klein J, et al. The influence of hypothermia on the disposition of fentanyl: human and animal studies. Eur J Clin Pharmacol. 1987;32(4):373–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Koren G, Crean P, Klein J, Goresky G, Villamater J, MacLeod SM. Sequestration of fentanyl by the cardiopulmonary bypass (CPBP). Eur J Clin Pharmacol. 1984;27(1):51–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Koren G, Goresky G, Crean P, Klein J, MacLeod SM. Unexpected alterations in fentanyl pharmacokinetics in children undergoing cardiac surgery: age related or disease related? Dev Pharmacol Ther. 1986;9(3):183–91.PubMedCrossRefGoogle Scholar
  68. 68.
    Hodges UM, Berg S, Naik SK, Bower S, Lloyd-Thomas A, Elliot M. Filtration of fentanyl is not the cause of the elevation of arterial blood pressure associated with post-bypass ultrafiltration in children. J Cardiothoracic Vasc Anesth. 1994;8(6):653–7.CrossRefGoogle Scholar
  69. 69.
    Taenzer AH, Groom R, Quinn RD. Fentanyl plasma levels after modified ultrafiltration in infant heart surgery. J Extracorpor Technol. 2005;37(4):369–72.Google Scholar
  70. 70.
    Crean P, Koren G, Goresky G, Klein J, Macleod S. Fentanyl-oxygen versus fentanyl-N2O/oxygen anaesthesia in children undergoing cardiac surgery. Can Anaesth Soc J. 1986;33(1):36–40.PubMedCrossRefGoogle Scholar
  71. 71.
    Gruber EM, Laussen PC, Casta A, Zimmerman AA, Zurakowski D, Reid R, et al. Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg. 2001;92(4):882–90.PubMedCrossRefGoogle Scholar
  72. 72.
    Kussman BD, Gruber EM, Zurakowski D, Hansen DD, Sullivan LJ, Laussen PC. Bispectral index monitoring during infant cardiac surgery: relationship of BIS to the stress response and plasma fentanyl levels. Paediatr Anaesth. 2001;11(6):663–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr. 1991;119(4):639–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990;73(6):1136–40.PubMedCrossRefGoogle Scholar
  75. 75.
    Leuschen MP, Willett LD, Hoie EB, Bolam DL, Bussey ME, Goodrich PD, et al. Plasma fentanyl levels in infants undergoing extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg. 1993;105(5):885–91.PubMedGoogle Scholar
  76. 76.
    Vaughns JD, Ziesenitz VC, van den Anker JN. Clinical pharmacology of frequently used intravenous drugs during bariatric surgery in adolescents. Curr Pharm Des. 2015;21(39):5650–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Smith HL, Meldrum DJ, Brennan LJ. Childhood obesity: a challenge for the anaesthetist? Paediatr Anaesth. 2002;12(9):750–61.PubMedCrossRefGoogle Scholar
  78. 78.
    Barlow SE, Expert C. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(Suppl. 4):S164–92.PubMedCrossRefGoogle Scholar
  79. 79.
    Vaughns JD, Ziesenitz VC, Williams EF, Mushtaq A, Bachmann R, Skopp G, et al. Use of fentanyl in adolescents with clinically severe obesity undergoing bariatric surgery: a pilot study. Pediatr Drugs 2017;19(3):251–7.CrossRefGoogle Scholar
  80. 80.
    Adams JP, Murphy PG. Obesity in anaesthesia and intensive care. Br J Anaesth. 2000;85(1):91–108.PubMedCrossRefGoogle Scholar
  81. 81.
    Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Pract Ed. 2010;95(4):112–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Schumann R. Anaesthesia for bariatric surgery. Best Pract Res Clin Anaesthesiol. 2011;25(1):83–93.PubMedCrossRefGoogle Scholar
  83. 83.
    Shibutani K, Inchiosa MA Jr, Sawada K, Bairamian M. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (“pharmacokinetic mass”). Anesthesiology. 2004;101(3):603–13.PubMedCrossRefGoogle Scholar
  84. 84.
    Shibutani K, Inchiosa MA Jr, Sawada K, Bairamian M. Pharmacokinetic mass of fentanyl for postoperative analgesia in lean and obese patients. Br J Anaesth. 2005;95(3):377–83.PubMedCrossRefGoogle Scholar
  85. 85.
    Ingrande J, Lemmens HJ. Dose adjustment of anaesthetics in the morbidly obese. Br J Anaesth. 2010;105(Suppl. 1):i16–23.PubMedCrossRefGoogle Scholar
  86. 86.
    Leykin Y, Miotto L, Pellis T. Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol. 2011;25(1):27–36.PubMedCrossRefGoogle Scholar
  87. 87.
    Lejus C, Schwoerer D, Furic I, Le Moing JP, Levron JC, Pinaud M. Fentanyl versus sufentanil: plasma concentrations during continuous epidural postoperative infusion in children. Br J Anaesth. 2000;85(4):615–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Karas-Trzeciak M, Grabowski T, Woloszczuk-Gebicka B, Borucka B. Fentanyl with ropivacaine infusion for postoperative pain relief in infants and children: kinetics of epidural fentanyl. Paediatr Anaesth. 2015;25(8):818–23.PubMedCrossRefGoogle Scholar
  89. 89.
    Preston RA, Csontos ER, East KA, Kessler KF, Fisk SP, Streisand JB. Plasma fentanyl concentrations after oral transmucosal fentanyl citrate: children versus adults. Anesthesiology. 1993;79:1.Google Scholar
  90. 90.
    Dsida RM, Wheeler M, Birmingham PK, Henthorn TK, Avram MJ, Enders-Klein C, et al. Premedication of pediatric tonsillectomy patients with oral transmucosal fentanyl citrate. Anesth Analg. 1998;86(1):66–70.PubMedGoogle Scholar
  91. 91.
    Lotsch J, Walter C, Parnham MJ, Oertel BG, Geisslinger G. Pharmacokinetics of non-intravenous formulations of fentanyl. Clin Pharmacokinet. 2013;52(1):23–36.PubMedCrossRefGoogle Scholar
  92. 92.
    Wheeler M, Birmingham PK, Dsida RM, Wang Z, Cote CJ, Avram MJ. Uptake pharmacokinetics of the fentanyl oralet in children scheduled for central venous access removal: implications for the timing of initiating painful procedures. Paediatr Anaesth. 2002;12(7):594–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Wheeler M, Birmingham PK, Lugo RA, Heffner CL, Cote CJ. The pharmacokinetics of the intravenous formulation of fentanyl citrate administered orally in children undergoing general anesthesia. Anesth Analg. 2004;99(5):1347–51.PubMedCrossRefGoogle Scholar
  94. 94.
    Epstein RH, Mendel HG, Witkowski TA, Waters R, Guarniari KM, Marr AT, et al. The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children. Anesth Analg. 1996;83(6):1200–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Streisand JB, Stanley TH, Hague B, van Vreeswijk H, Ho GH, Pace NL. Oral transmucosal fentanyl citrate premedication in children. Anesth Analg. 1989;69(1):28–34.PubMedCrossRefGoogle Scholar
  96. 96.
    Friesen RH, Carpenter E, Madigan CK, Lockhart CH. Oral transmucosal fentanyl citrate for preanaesthetic medication of paediatric cardiac surgery patients. Paediatr Anaesth. 1995;5(1):29–33.PubMedCrossRefGoogle Scholar
  97. 97.
    Schechter NL, Weisman SJ, Rosenblum M, Bernstein B, Conard PL. The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics. 1995;95(3):335–9.PubMedGoogle Scholar
  98. 98.
    Borland ML, Bergesio R, Pascoe EM, Turner S, Woodger S. Intranasal fentanyl is an equivalent analgesic to oral morphine in paediatric burns patients for dressing changes: a randomised double blind crossover study. Burns. 2005;31(7):831–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Borland M, Jacobs I, King B, O’Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007;49(3):335–40.PubMedCrossRefGoogle Scholar
  100. 100.
    Finn M, Harris D. Intranasal fentanyl for analgesia in the paediatric emergency department. EMJ. 2010;27(4):300–1.PubMedCrossRefGoogle Scholar
  101. 101.
    Harlos MS, Stenekes S, Lambert D, Hohl C, Chochinov HM. Intranasal fentanyl in the palliative care of newborns and infants. J Pain Symptom Manag. 2013;46(2):265–74.CrossRefGoogle Scholar
  102. 102.
    Mudd S. Intranasal fentanyl for pain management in children: a systematic review of the literature. J Pediatr Health Care. 2011;25(5):316–22.PubMedCrossRefGoogle Scholar
  103. 103.
    Paut O, Camboulives J, Viard L, Lemoing JP, Levron JC. Pharmacokinetics of transdermal fentanyl in the peri-operative period in young children. Anaesthesia. 2000;55(12):1202–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Collins JJ, Dunkel IJ, Gupta SK, Inturrisi CE, Lapin J, Palmer LN, et al. Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates. J Pediatr. 1999;134(3):319–23.PubMedCrossRefGoogle Scholar
  105. 105.
    Lehmann KA, Zech D. Transdermal fentanyl: clinical pharmacology. J Pain Symptom Manag. 1992;7(3 Suppl.):S8–16.CrossRefGoogle Scholar
  106. 106.
    Delgado-Charro MB, Guy RH. Effective use of transdermal drug delivery in children. Adv Drug Deliv Rev. 2014;73:63–82.PubMedCrossRefGoogle Scholar
  107. 107.
    Zernikow B, Michel E, Anderson B. Transdermal fentanyl in childhood and adolescence: a comprehensive literature review. J Pain. 2007;8(3):187–207.PubMedCrossRefGoogle Scholar
  108. 108.
    Greeley WJ, de Bruijn NP, Davis DP. Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth Analg. 1987;66(11):1067–72.PubMedCrossRefGoogle Scholar
  109. 109.
    Greeley WJ, de Bruijn NP. Changes in sufentanil pharmacokinetics within the neonatal period. Anesth Analg. 1988;67(1):86–90.PubMedCrossRefGoogle Scholar
  110. 110.
    Guay J, Gaudreault P, Tang A, Goulet B, Varin F. Pharmacokinetics of sufentanil in normal children. Can J Anaesth. 1992;39(1):14–20.PubMedCrossRefGoogle Scholar
  111. 111.
    Meistelman C, Benhamou D, Barre J, Levron JC, Mahe V, Mazoit X, et al. Effects of age on plasma protein binding of sufentanil. Anesthesiology. 1990;72(3):470–3.PubMedCrossRefGoogle Scholar
  112. 112.
    Meuldermans WE, Hurkmans RM, Heykants JJ. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Arch Int Pharmacodyn Ther. 1982;257(1):4–19.PubMedGoogle Scholar
  113. 113.
    Meuldermans W, Woestenborghs R, Noorduin H, Camu F, van Steenberge A, Heykants J. Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma. Eur J Clin Pharmacol. 1986;30(2):217–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Helmers JH, van Leeuwen L, Zuurmond WW. Sufentanil pharmacokinetics in young adult and elderly surgical patients. Eur J Anaesthesiol. 1994;11(3):181–5.PubMedGoogle Scholar
  115. 115.
    Scholz J, Bause H, Schulz M, Klotz U, Krishna DR, Pohl S, et al. Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients. Br J Clin Pharmacol. 1994;38(4):369–72.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Bartkowska-Sniatkowska A, Bienert A, Wiczling P, Rosada-Kurasinska J, Zielinska M, Warzybok J, et al. Pharmacokinetics of sufentanil during long-term infusion in critically ill pediatric patients. J Clin Pharmacol. 2016;56(1):109–15.PubMedCrossRefGoogle Scholar
  117. 117.
    Calvier EA, Krekels EH, Valitalo PA, Rostami-Hodjegan A, Tibboel D, Danhof M, et al. Allometric scaling of clearance in paediatric patients: when does the magic of 0.75 fade? Clin Pharmacokinet. 2017;56(3):273–85.PubMedCrossRefGoogle Scholar
  118. 118.
    Nguyen The Tich s, Vecchierini MF, Debillon T, Pereon Y. Effects of sufentanil on electroencephalogram in very and extremely preterm neonates. Pediatrics. 2003;111(1):123–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Davis PJ, Stiller RL, Cook DR, Brandom BW, Davin-Robinson KA. Pharmacokinetics of sufentanil in adolescent patients with chronic renal failure. Anesth Analg. 1988;67(3):268–71.PubMedCrossRefGoogle Scholar
  120. 120.
    Davis PJ, Cook DR, Stiller RL, Davin-Robinson KA. Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery. Anesth Analg. 1987;66(3):203–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Kern FH, Ungerleider RM, Jacobs JR, Boyd JL 3rd, Reves JG, Goodman D, et al. Computerized continuous infusion of intravenous anesthetic drugs during pediatric cardiac surgery. Anesth Analg. 1991;72(4):487–92.PubMedCrossRefGoogle Scholar
  122. 122.
    Woloszczuk-Gebicka B, Grabowski T, Borucka B, Karas-Trzeciak M. Pharmacokinetics of sufentanil administered with 0.2% ropivacaine as a continuous epidural infusion for postoperative pain relief in infants. Paediatr Anaesth. 2014;24(9):962–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Benlabed M, Ecoffey C, Levron JC, Flaisler B, Gross JB. Analgesia and ventilatory response to CO2 following epidural sufentanil in children. Anesthesiology. 1987;67(6):948–51.PubMedCrossRefGoogle Scholar
  124. 124.
    Henderson JM, Brodsky DA, Fisher DM, Brett CM, Hertzka RE. Pre-induction of anesthesia in pediatric patients with nasally administered sufentanil. Anesthesiology. 1988;68(5):671–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Lundeberg S, Roelofse JA. Aspects of pharmacokinetics and pharmacodynamics of sufentanil in pediatric practice. Paediatr Anaesth. 2011;21(3):274–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Karl HW, Keifer AT, Rosenberger JL, Larach MG, Ruffle JM. Comparison of the safety and efficacy of intranasal midazolam or sufentanil for preinduction of anesthesia in pediatric patients. Anesthesiology. 1992;76(2):209–15.PubMedCrossRefGoogle Scholar
  127. 127.
    Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog. 1993;40(3):63–6.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Zedie N, Amory DW, Wagner BK, O’Hara DA. Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther. 1996;59(3):341–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Haynes G, Brahen NH, Hill HF. Plasma sufentanil concentration after intranasal administration to paediatric outpatients. Can J Anaesth. 1993;40(3):286.PubMedCrossRefGoogle Scholar
  130. 130.
    Nielsen BN, Friis SM, Romsing J, Schmiegelow K, Anderson BJ, Ferreiros N, et al. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014;24(2):170–80.PubMedCrossRefGoogle Scholar
  131. 131.
    Meistelman C, Saint-Maurice C, Lepaul M, Levron JC, Loose JP, Mac Gee K. A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology. 1987;66(1):13–6.PubMedCrossRefGoogle Scholar
  132. 132.
    Roure P, Jean N, Leclerc AC, Cabanel N, Levron JC, Duvaldestin P. Pharmacokinetics of alfentanil in children undergoing surgery. Br J Anaesth. 1987;59(11):1437–40.PubMedCrossRefGoogle Scholar
  133. 133.
    Browne BL, Prys-Roberts C, Wolf AR. Propofol and alfentanil in children: infusion technique and dose requirement for total i.v. anaesthesia. Br J Anaesth. 1992;69(6):570–6.PubMedCrossRefGoogle Scholar
  134. 134.
    Wiest DB, Ohning BL, Garner SS. The disposition of alfentanil in neonates with respiratory distress. Pharmacotherapy. 1991;11(4):308–11.PubMedGoogle Scholar
  135. 135.
    Davis PJ, Killian A, Stiller RL, Cook DR, Guthrie RD, Scierka AM. Pharmacokinetics of alfentanil in newborn premature infants and older children. Dev Pharmacol Ther. 1989;13(1):21–7.PubMedCrossRefGoogle Scholar
  136. 136.
    Freid EB, Miles MV, Nocera MA, Zaritsky AL. Prolonged continuous infusions of fentanyl or alfentanil in critically ill children: pharmacokinetics and pharmacodynamics. Anesthesiology. 1994;81(3A):A257-A.Google Scholar
  137. 137.
    Davis PJ, Stiller RL, Cook DR, Brandom BW, Davis JE, Scierka AM. Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children. Anesth Analg. 1989;68(5):579–83.PubMedCrossRefGoogle Scholar
  138. 138.
    Bjorkman S. Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children : how accurate are available scaling methods? Clin Pharmacokinet. 2006;45(1):1–11.PubMedCrossRefGoogle Scholar
  139. 139.
    Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet. 2006;45(10):1013–34.PubMedCrossRefGoogle Scholar
  140. 140.
    Salem F, Johnson TN, Abduljalil K, Tucker GT, Rostami-Hodjegan A. A re-evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data. Clin Pharmacokinet. 2014;53(7):625–36.PubMedCrossRefGoogle Scholar
  141. 141.
    Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931–56.PubMedCrossRefGoogle Scholar
  142. 142.
    Marlow N, Weindling AM, Van Peer A, Heykants J. Alfentanil pharmacokinetics in preterm infants. Arch Dis Child. 1990;65(4 Spec No):349–51.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Killian A, Davis PJ, Stiller RL, Cicco R, Cook DR, Guthrie RD. Influence of gestational age on pharmacokinetics of alfentanil in neonates. Dev Pharmacol Ther. 1990;15(2):82–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Pokela ML, Ryhanen PT, Koivisto ME, Olkkola KT, Saukkonen AL. Alfentanil-induced rigidity in newborn infants. Anesth Analg. 1992;75(2):252–7.PubMedCrossRefGoogle Scholar
  145. 145.
    Rodighiero V. Effects of liver disease on pharmacokinetics: an update. Clin Pharmacokinet. 1999;37(5):399–431.PubMedCrossRefGoogle Scholar
  146. 146.
    Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet. 1999;37(1):17–40.PubMedCrossRefGoogle Scholar
  147. 147.
    Ferrier C, Marty J, Bouffard Y, Haberer JP, Levron JC, Duvaldestin P. Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology. 1985;62(4):480–4.PubMedCrossRefGoogle Scholar
  148. 148.
    den Hollander JM, Hennis PJ, Burm AG, Vletter AA, Bovill JG. Pharmacokinetics of alfentanil before and after cardiopulmonary bypass in pediatric patients undergoing cardiac surgery: Part I. J Cardiothorac Vasc Anesth. 1992;6(3):308–12.CrossRefGoogle Scholar
  149. 149.
    den Hollander JM, Hennis PJ, Burm AG, Bovill JG. Alfentanil in infants and children with congenital heart defects. J Cardiothorac Anesth. 1988;2(1):12–7.CrossRefGoogle Scholar
  150. 150.
    Ross AK, Davis PJ, Dear Gd GL, Ginsberg B, McGowan FX, Stiller RD, et al. Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg. 2001;93(6):1393–401.PubMedCrossRefGoogle Scholar
  151. 151.
    Staschen CM, Mahmood I. A population pharmacokinetic model of remifentanil in pediatric patients using body-weight-dependent allometric exponents. Drug Metabol Drug Interact. 2013;28(4):231–7.PubMedCrossRefGoogle Scholar
  152. 152.
    Rigby-Jones AE, Priston MJ, Sneyd JR, McCabe AP, Davis GI, Tooley MA, et al. Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery. Br J Anaesth. 2007;99(2):252–61.PubMedCrossRefGoogle Scholar
  153. 153.
    Standing JF, Hammer GB, Sam WJ, Drover DR. Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty. Paediatr Anaesth. 2010;20(1):7–18.PubMedCrossRefGoogle Scholar
  154. 154.
    Galinkin JL, Davis PJ, McGowan FX, Lynn AM, Rabb MF, Yaster M, et al. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. II. Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg. 2001;93(6):1387–92.PubMedCrossRefGoogle Scholar
  155. 155.
    Welzing L, Roth B. Experience with remifentanil in neonates and infants. Drugs. 2006;66(10):1339–50.PubMedCrossRefGoogle Scholar
  156. 156.
    Allegaert K. The clinical pharmacology of short acting analgo-sedatives in neonates. Curr Clin Pharmacol. 2011;6(4):222–6.PubMedCrossRefGoogle Scholar
  157. 157.
    Stoppa F, Perrotta D, Tomasello C, Cecchetti C, Marano M, Pasotti E, et al. Low dose remifentanyl infusion for analgesia and sedation in ventilated newborns. Miner Anestesiol. 2004;70(11):753–61.Google Scholar
  158. 158.
    Kamata M, Tobias JD. Remifentanil: applications in neonates. J Anesth. 2016;30(3):449–60.PubMedCrossRefGoogle Scholar
  159. 159.
    Barker N, Lim J, Amari E, Malherbe S, Ansermino JM. Relationship between age and spontaneous ventilation during intravenous anesthesia in children. Paediatr Anaesth. 2007;17(10):948–55.PubMedCrossRefGoogle Scholar
  160. 160.
    Davis PJ, Galinkin J, McGowan FX, Lynn AM, Yaster M, Rabb MF, et al. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles. Anesth Analg. 2001;93(6):1380–6.PubMedCrossRefGoogle Scholar
  161. 161.
    Allegaert K, Thewissen L, van den Anker JN. Remifentanil in neonates: a promising compound in search of its indications? Pediatr Neonatol. 2012;53(6):387–8.PubMedCrossRefGoogle Scholar
  162. 162.
    Davis PJ, Cladis FP. The use of ultra-short-acting opioids in paediatric anaesthesia: the role of remifentanil. Clin Pharmacokinet. 2005;44(8):787–96.PubMedCrossRefGoogle Scholar
  163. 163.
    Marsh DF, Hodkinson B. Remifentanil in paediatric anaesthetic practice. Anaesthesia. 2009;64(3):301–8.PubMedCrossRefGoogle Scholar
  164. 164.
    Sammartino M, Garra R, Sbaraglia F, De Riso M, Continolo N. Remifentanil in children. Paediatr Anaesth. 2010;20(3):246–55.PubMedCrossRefGoogle Scholar
  165. 165.
    Rothstein P. Remifentanil for neonates and infants: piano, piano con calma. Anesth Analg. 2001;93(6):1370–2.PubMedCrossRefGoogle Scholar
  166. 166.
    Welzing L, Ebenfeld S, Dlugay V, Wiesen MH, Roth B, Mueller C. Remifentanil degradation in umbilical cord blood of preterm infants. Anesthesiology. 2011;114(3):570–7.PubMedCrossRefGoogle Scholar
  167. 167.
    Norman E, Wikstrom S, Hellstrom-Westas L, Turpeinen U, Hamalainen E, Fellman V. Rapid sequence induction is superior to morphine for intubation of preterm infants: a randomized controlled trial. J Pediatrics. 2011;159(6):893–899 e1.CrossRefGoogle Scholar
  168. 168.
    Sammartino M, Garra R, Sbaraglia F, De Riso M, Continolo N, Papacci P. Experience of remifentanil in extremely low-birth-weight babies undergoing laparotomy. Pediatr Neonatol. 2011;52(3):176–9.PubMedCrossRefGoogle Scholar
  169. 169.
    Eck JB, Lynn AM. Use of remifentanil in infants. Paediatr Anaesth. 1998;8(5):437–9.PubMedCrossRefGoogle Scholar
  170. 170.
    Dershwitz M, Hoke JF, Rosow CE, Michalowski P, Connors PM, Muir KT, et al. Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology. 1996;84(4):812–20.PubMedCrossRefGoogle Scholar
  171. 171.
    Davis PJ, Wilson AS, Siewers RD, Pigula FA, Landsman IS. The effects of cardiopulmonary bypass on remifentanil kinetics in children undergoing atrial septal defect repair. Anesth Analg. 1999;89(4):904–8.PubMedGoogle Scholar
  172. 172.
    Sam WJ, Hammer GB, Drover DR. Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery. BMC Anesthesiol. 2009;9:5.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Freye E. Pharmakokinetik der Opioide: Bedeutung für den praktischen Einsatz. In: Freye E, editor. Opioide in der Medizin. 6th ed. Berlin: Springer; 2004. p. 229–35.CrossRefGoogle Scholar
  174. 174.
    Freye E. Opioide im Rahmen der Allgemeinanästhesie. In: Freye E, editor. Opioide in der Medizin. 6th ed. Berlin: Springer; 2004. p. 193–228.CrossRefGoogle Scholar
  175. 175.
    Kretz F-J, Schäffer J, Gleiter CH, Krebsbach W, Hindley U, Remppis S. Pharmakologie: Grundlagen und klinisch-praktische Details. In: Kretz F-J, Schäffer J, Gleiter CH, Krebsbach W, Hindley U, Remppis S, editors. Anästhesie Intensivmedizin Notfallmedizin Schmerztherapie. 5th ed. Heidelberg: Springer; 2008. p. 18.Google Scholar
  176. 176.
    Peng PW, Sandler AN. A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology. 1999;90(2):576–99.PubMedCrossRefGoogle Scholar
  177. 177.
    Opioide Schäfer M. In: Tonner PH, Hein L, editors. Pharmakotherapie in der Anästhesie und Intensivmedizin. 1st ed. Heidelberg: Springer; 2011. p. 109–30.Google Scholar
  178. 178.
    Schäfer M, Zöllner C. Opioide. In: Rossaint R, Werner C, Zwissler B, editors. Die Anästhesiologie: Allgemeine und spezielle Anästhesiologie, Schmerztherapie und Intensivmedizin. 3rd ed. Berlin: Springer; 2012. p. 240.Google Scholar
  179. 179.
    Scholz J, Steinfath M, Schulz M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil: an update. Clin Pharmacokinet. 1996;31(4):275–92.PubMedCrossRefGoogle Scholar
  180. 180.
    Bovill JG, Sebel PS, Blackburn CL, Heykants J. The pharmacokinetics of alfentanil (R39209): a new opioid analgesic. Anesthesiology. 1982;57(6):439–43.PubMedCrossRefGoogle Scholar
  181. 181.
    Gillespie TJ, Gandolfi AJ, Maiorino RM, Vaughan RW. Gas chromatographic determination of fentanyl and its analogues in human plasma. J Anal Toxicol. 1981;5(3):133–7.PubMedCrossRefGoogle Scholar
  182. 182.
    Michiels M, Hendriks R, Heykants J. A sensitive radioimmunoassay for fentanyl: plasma level in dogs and man. Eur J Clin Pharmacol. 1977;12(2):153–8.PubMedCrossRefGoogle Scholar
  183. 183.
    Schuttler J, White PF. Optimization of the radioimmunoassays for measuring fentanyl and alfentanil in human serum. Anesthesiology. 1984;61(3):315–20.PubMedCrossRefGoogle Scholar
  184. 184.
    Watts V, Caplan Y. Determination of fentanyl in whole blood at subnanogram concentrations by dual capillary column gas chromatography with nitrogen sensitive detectors and gas chromatography/mass spectrometry. J Anal Toxicol. 1988;12(5):246–54.PubMedCrossRefGoogle Scholar
  185. 185.
    Woestenborghs RJ, Stanski DR, Scott JC, Heykants JJ. Assay methods for fentanyl in serum: gas–liquid chromatography versus radioimmunoassay. Anesthesiology. 1987;67(1):85–90.PubMedCrossRefGoogle Scholar
  186. 186.
    Koch DE, Isaza R, Carpenter JW, Hunter RP. Simultaneous extraction and quantitation of fentanyl and norfentanyl from primate plasma with LC/MS detection. J Pharm Biomed Anal. 2004;34(3):577–84.PubMedCrossRefGoogle Scholar
  187. 187.
    Liu J, Pan H, Gold MS, Derendorf H, Bruijnzeel AW. Effects of fentanyl dose and exposure duration on the affective and somatic signs of fentanyl withdrawal in rats. Neuropharmacology. 2008;55(5):812–8.PubMedCrossRefGoogle Scholar
  188. 188.
    Michiels M, Hendriks R, Heykants J. Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil: preliminary pharmacokinetic profile in man. J Pharm Pharmacol. 1983;35(2):86–93.PubMedCrossRefGoogle Scholar
  189. 189.
    Heykants J, Woestenborghs R, Timmerman P. Reliability of sufentanil plasma level assays in patients. Anesthesiology. 1986;65(1):112–3.PubMedCrossRefGoogle Scholar
  190. 190.
    Fiset P, Mathers L, Engstrom R, Fitzgerald D, Brand SC, Hsu F, et al. Pharmacokinetics of computer-controlled alfentanil administration in children undergoing cardiac surgery. Anesthesiology. 1995;83(5):944–55.PubMedCrossRefGoogle Scholar
  191. 191.
    Hynynen M, Takkunen O, Salmenpera M, Haataja H, Heinonen J. Continuous infusion of fentanyl or alfentanil for coronary artery surgery: plasma opiate concentrations, haemodynamics and postoperative course. Br J Anaesth. 1986;58(11):1252–9.PubMedCrossRefGoogle Scholar
  192. 192.
    Grosse CM, Davis IM, Arrendale RF, Jersey J, Amin J. Determination of remifentanil in human blood by liquid-liquid extraction and capillary GC-HRMS-SIM using a deuterated internal standard. J Pharm Biomed Anal. 1994;12(2):195–203.PubMedCrossRefGoogle Scholar
  193. 193.
    Lessard D, Comeau B, Charlebois A, Letarte L, Davis IM. Quantification of GR90291 in human blood by high resolution gas chromatography-mass selective detection (HRGC-MSD). J Pharm Biomed Anal. 1994;12(5):659–65.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Pediatric Pharmacology and PharmacometricsUniversity of Basel Children’s HospitalBaselSwitzerland
  2. 2.Department of Pediatric CardiologyUniversity Children’s HospitalHeidelbergGermany
  3. 3.Department of Anesthesia and Pain MedicineChildren’s National Health SystemWashingtonUSA
  4. 4.Division of Clinical PharmacologyChildren’s National Health SystemWashingtonUSA
  5. 5.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity HospitalHeidelbergGermany
  6. 6.Intensive Care, Department of Pediatric SurgeryErasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands

Personalised recommendations