Clin Pharmacokinet DOI 10.1007/s40262-014-0135-4
ORIGINAL RESEARCH ARTICLE
Evidence-Based Morphine Dosing for Postoperative Neonates and Infants Elke H. J. Krekels • Dick Tibboel • Saskia N. de Wildt Ilse Ceelie • Albert Dahan • Monique van Dijk • Meindert Danhof • Catherijne A. J. Knibbe
•
Ó Springer International Publishing Switzerland 2014
Abstract Background and Objectives From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 lg/kg1.5/h, with a 50 % dose reduction in neonates with a postnatal age (PNA) \10 days, yield similar morphine and metabolite concentrations across patients younger than 3 years. Compared with traditional dosing, this modelderived dosing regimen yields significantly reduced doses in neonates aged \10 days. Methods Concentration predictions of the population model were prospectively evaluated in postoperative term neonates and infants up to the age of 1 year who received morphine doses according to the model-derived algorithm. The efficacy of this dosing algorithm was evaluated using
E. H. J. Krekels M. Danhof C. A. J. Knibbe Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands E. H. J. Krekels D. Tibboel S. N. de Wildt I. Ceelie M. van Dijk C. A. J. Knibbe Intensive Care and Department of Pediatric Surgery, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands I. Ceelie A. Dahan Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands M. van Dijk Department of Pediatrics, Division of Neonatology, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands C. A. J. Knibbe (&) Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands e-mail: [email protected]
morphine rescue medication and actual average infusion rates. Results Morphine and metabolite concentrations were accurately predicted by the paediatric pharmacokinetic morphine model. With regard to efficacy, 5 out of 18 neonates (27.8 %) with a PNA of \10 days needed rescue medication versus 18 of the 20 older patients (90 %) (p = 0.06). The median (interquartile range [IQR]) total morphine rescue dose was 0 (0–20) lg/kg in younger patients versus 193 (19–362) lg/kg in older patients (p = 0.003). The median (IQR) actual average morphine infusion rate was 4.4 (4.0–4.8) lg/kg/h in younger patients versus 14.4 (11.3–23.4) lg/kg/h in older patients (p \ 0.001). Conclusion Morphine paediatric dosing algorithms corrected for pharmacokinetic differences alone yield effective doses that prevent over-dosing for neonates with a PNA \10 days. The fact that many neonates and infants with a PNA C10 days still required rescue medication warrants pharmacodynamic studies to further optimize the dosing algorithm for these patients.
1 Introduction Postoperative pain in children is regularly treated with morphine, and correct dosing is essential to prevent inadequate pain relief, opioid-related adverse drug reactions and opioid-withdrawal symptoms. However, validated dosing guidelines across the paediatric age range are currently lacking. Population pharmacokinetic and/or pharmacodynamic modelling approaches, also known as non-linear mixedeffects modelling, are useful to develop evidence-based rather than empirical or consensus-based paediatric drug
E. H. J. Krekels et al.
dosing algorithms [1]. They allow derivation of pharmacokinetic and/or pharmacodynamic parameters from sparse, dense and/or unbalanced data obtained during routine clinical practice. Moreover, the sources of variability in the population can be quantified, while in a covariate analysis, patient characteristics, such as bodyweight or age, can be identified that are predictive of this variability [2]. These patient characteristics form the basis of model-derived dosing algorithms [3, 4]. Assessments of model-derived dosing algorithms in prospective clinical trials ascertain that the obtained endpoints are in agreement with the model-based predictions [1]. Recently, a population model for the pharmacokinetics of morphine and its two pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G), was developed for a population of postoperative and ventilated preterm and term neonates, infants and children up to 3 years of age [5]. This model showed that morphine clearance non-linearly increases with bodyweight. Additionally, morphine glucuronidation is reduced by half in neonates with a postnatal age (PNA) \10 days, independent of gestational age. After the predictive value of this model was confirmed by extensive model validation [5, 6], a paediatric dosing algorithm for morphine was derived that would correct for developmental changes in morphine pharmacokinetics, to yield similar morphine and metabolite concentrations in postoperative and ventilated neonates, infants and children under the age of 3 years [5]. According to this evidencebased dosing algorithm, morphine maintenance infusions are dosed on the basis of lg/kg1.5/h with a 50 % dose reduction in neonates \10 days, while loading doses are still dosed on the basis of lg/kg. The current proof-of-principle study prospectively evaluates the model-derived paediatric dosing regimen for morphine in postoperative patients under the age of 1 year. Morphine and metabolite concentrations measured after dosing according to this model-derived regimen were compared with concentration predictions by the paediatric morphine pharmacokinetic model for each individual patient [5]. The studied dosing algorithm yields higher infusion rates in neonates and infants with a PNA C10 days than our traditional dosing scheme (e.g. 14.1 vs 10.0 lg/kg/h for an infant of 8 kg), while it yields substantially reduced morphine infusion rates in neonates with a PNA \10 days (e.g. 4.3 vs 10.0 lg/kg/h for a young neonate of 3 kg). Therefore the analgesic efficacy of this model-derived dosing regimen was evaluated in both age groups separately. This was done by recording the morphine rescue dose that was administered according to a validated age-appropriate pain protocol, and the average actual morphine infusion rate over 48 h after surgery.
2 Patients and Methods 2.1 Study Design In a previous single-centre, double-blind, randomized controlled trial comparing the postoperative analgesic efficacy of paracetamol and morphine over 48 h in term neonates and infants younger than 1 year [7], all patients receiving morphine, either as a primary double-blind analgesic and/or as an open-label rescue medication, were dosed according to the new model-derived dosing algorithm, which was implemented using Table 1. Morphine and metabolite concentrations in plasma that could be obtained from these patients were compared with modelpredicted concentrations of these samples. The analgesic efficacy of the model-derived dosing regimen was assessed in all patients allocated to the morphine arm of this study [7]. 2.2 Patients Term neonates and infants under the age of 1 year, undergoing major abdominal or non-cardiac thoracic surgery between March 2008 and July 2010 at the Erasmus
Table 1 Dosing table used to implement the model-derived morphine dosing algorithm for continuous maintenance infusions in clinical practice Bodyweight (kg)
Model-derived dosing algorithm PNA \ 10 days 2.5 lg/kg1.5/h Infusion rate (lg/kg/h)
10 B PNA \ 365 days 5 lg/kg1.5/h Infusion rate (lg/kg/h)
1.5–2
3.1
6.1
2–2.5 2.5–3
3.5 4.0
7.1 7.9
3–3.5
4.3
8.7
3.5–4
4.7
9.4
4–4.5
5.0
10.0
4.5–5
5.3
10.6
5–5.5
5.6
11.2
5.5–6
–
11.7
6–6.5
–
12.3
6.5–7
–
12.8
7–7.5
–
13.2
7.5–8
–
13.7
8–8.5
–
14.1
8.5–9
–
14.6
9–9.5
–
15.0
9.5–10 10–10.5
– –
15.4 15.8
PNA postnatal age
Optimized Morphine Dosing for Neonates and Infants
MC–Sophia Children’s Hospital in Rotterdam, were eligible for inclusion. The exclusion criteria were (1) postconceptual age younger than 36 weeks; (2) bodyweight less than 1.5 kg; (3) extracorporeal membrane oxygenation treatment; (4) neurological dysfunction; (5) hepatic dysfunction or renal insufficiency; (6) pre- or postnatal administration of opioids or psychotropic drugs for more than 24 h; (7) known allergy or intolerance of paracetamol or morphine; and (8) administration of opioids in the 24 h prior to surgery. The study was approved by the Erasmus MC ethics review board. Written informed consent was obtained from the parents or legal guardians before inclusion of the patients.
postoperative medication with a known interaction with morphine pharmacokinetics was administered. Blood samples were obtained to determine the accuracy of the concentration predictions by the paediatric pharmacokinetic morphine model [5]. A maximum of eight blood samples or a total of 3 % of the blood volume of a patient was obtained from an indwelling arterial line when present. Whenever possible, a blood sample was taken prior to a morphine rescue dose or prior to a scheduled paracetamol or placebo bolus dose. Additional samples were taken when possible at varying times, to obtain information on a wide range of the concentration–time curve. Blood samples were centrifuged at 3,000 rpm and plasma was subsequently stored at -80 °C till further analysis.
2.3 Interventions
2.4 Pharmacokinetic Blood Sample Analysis
All patients received a 100 lg/kg morphine intravenous bolus loading dose 30 min before the anticipated end of the surgical procedure. In the morphine arm of the study, patients aged \10 days received a postoperative continuous morphine intravenous infusion of 2.5 lg/kg1.5/h, while older neonates and infants received 5 lg/kg1.5/h (Table 1). As this was a double-blind trial, the patients allocated to the morphine arm of the study also received four times daily placebo saline infusions of the same volume as the paracetamol bolus dose a patient in the paracetamol arm of the study would receive. During the first 48 h of postoperative recovery in the intensive care unit, trained nurses assessed each patient’s pain levels every 2 h and when a patient appeared to be in discomfort, according to an age-appropriate, standardized pain protocol [8] based on COMFORT-B scores [9] and Numeric Rating Scale (NRS-11) pain scores. Open-label morphine rescue medication was administered to patients in both arms of the study when the NRS-11 score was C4. Patients aged \10 days received a bolus dose of 10 lg/kg and older patients received 15 lg/kg. Patients were reassessed after 10 min and received additional bolus doses if necessary. If analgesia was not adequate after three bolus doses within 1 hour, the patients received an additional loading dose of 100 lg/kg, after which the morphine infusion rate was increased by 1.25 lg/kg1.5/h in neonates aged \10 days and by 2.5 lg/kg1.5/h in older neonates and infants. When after this increase the patient again needed more than three rescue bolus doses within 1 h, another loading dose was administered and infusion rates were increased by the same amount again. The morphine infusion was stopped or reduced in the case of morphinerelated adverse events or after 12 h of adequate analgesia, indicated by an NRS-11 score \4. In the case of discomfort, indicated by COMFORT-B scores of C17 and NRS11 pain scores of \4, midazolam was administered. No
The frozen plasma samples were thawed at room temperature. Seven hundred microlitres of acetonitrile, which contained 2H3-morphine (2H3-M), 2H3-morphine-3-glucuronide (2H3-M3G) and 2H3-morphine-6-glucuronide (2H3M6G) (Cerilliant, Round Rock, TX, USA) as internal standards and 100 ll of 1 mM zinc sulphate, was added to 200 ll of the samples. The samples were mixed for 2 min and centrifuged for 5 min at 13,000 rpm. Two hundred microlitres of the supernatant was dried under a gentle stream of nitrogen at 50 °C. The residues were reconstituted in 100 ll of 0.1 % (v/v) formic acid in water and 20 ll of this sample was injected into a high-pressure liquid chromatography (HPLC) system, which contained an Ultimate 3000 autosampler (Dionex, Amsterdam, The Netherlands), an HPG680 pump (Dionex) and a 3 lm, ˚ , 50 9 2.1 mm YMC-pack ODS-AQ column (YMC 120 A Inacom, Overberg, The Netherlands) with an ODS precolumn (Phenomenex, Utrecht, The Netherlands) at 30 °C. The mobile phase consisted of 0.1 % formic acid in water with 3 % acetonitrile (LiChrosolv; Merck BV, Amsterdam, The Netherlands) as modifier and the flow rate was 0.5 ml/ min. The system was controlled by Chromeleon (Dionex). The eluent of the HPLC system was monitored by a Quattro micro API tandem mass spectrometer (Waters, Etten-Leur, The Netherlands). Peak areas of reaction ions from morphine, M3G, M6G and the internal standards 2H3M, 2H3-M3G and 2H3-M6G were obtained in the multiple reaction mode and integrated by Masslynx 4.1 data software (Waters). The m/z was 165.0 (285.9 [ 165.0) for morphine and 286.0 (461.9 [ 286.0) for M3G and M6G. For the internal standards the m/z was 165.0 (288.9 [ 165.0) for 2H3M and 289.0 (464.9 [ 289.0) for 2H3-M3G and 2H3-M6G. All analytes could be analysed in one run and all samples were analysed on 1 day. The sample concentrations were calculated by the internal standard method with weighing factor 1/(X).
E. H. J. Krekels et al.
Blank pooled human serum was used for control samples, and serum spiked with morphine, M3G and M6G (Cerilliant) in methanol/water was used for the calibration curve and quality controls. Accuracy was within ±15 % in the concentration range tested. The lower limits of quantification were 1.5 lg/l for morphine and M6G and 2.5 lg/l for M3G. Recovery was 80 % or higher for morphine, 74 % or higher for M3G and 76 % or higher for M6G in the concentration range tested. Recovery was 93 % for 2H3-M, 85 % for 2H3-M3G and 82 % for 2H3-M6G. All concentrations were within the range of the calibration curve. 2.5 Pharmacokinetic Model Evaluation The paediatric population pharmacokinetic model for morphine and its metabolites consisted of two compartments for morphine and one compartment for each of the metabolites [5]. The distribution volume of all compartments scaled linearly with bodyweight, while changes in the formation and elimination of both glucuronides were best described by bodyweight-based exponential equations with an exponent of 1.44. Within this relationship, the formation of the metabolites was reduced by almost 50 % in neonates with a PNA \10 days. Non-linear mixed-effects modelling software NONMEM version VI (ICON, Ellicott City, MD, USA) was used to obtain model-based concentration predictions of morphine and metabolites for each plasma sample. In predicted versus observed plots, the available morphine and metabolite concentrations were visually compared with both individual and population concentration predictions from the model [5]. Individual predicted concentrations were based on a model fit of the observed concentrations to the model, using dosing history, bodyweight and PNA of the patient, and observed concentrations as input. Population predicted concentrations were obtained using the population parameter values of a typical individual with specified bodyweight and PNA and the dosing history of the patient. Model-based population predictions were obtained to compare steady state concentrations of morphine and its metabolites obtained with the new dosing algorithm with concentrations obtained with the traditional regimen. For each individual included in the analysis of analgesic efficacy (Table 3), steady state concentrations were obtained based on the initial morphine infusion rate in the study and on the traditional morphine infusion rate.
described in the ‘Interventions’ section, was expressed as the percentage of patients in need of rescue medication, the total morphine rescue dose in all patients and the number of rescue events, with an event defined as an administration of a morphine bolus dose, an additional morphine loading dose or an increase of the morphine infusion rate. COMFORT and NRS scores at the time of rescue medications were also compared. Additionally, the average morphine infusion rate over the actual duration of the postoperative infusion for each patient was calculated. This average infusion rate takes into account both the maintenance infusion rate and rescue morphine administrations. Finally, since there were bodyweight- and age-related differences in the infusion rates of the model-derived morphine dosing algorithm, the average morphine infusion rate in each individual patient was compared with the initially prescribed model-derived infusion rate for that patient. The percentage of patients with an average morphine infusion rate within 25 % of the prescribed infusion rate was determined. 2.7 Statistical Analysis To ascertain that the patients from whom pharmacokinetic samples could be obtained were representative of the patients who were analysed for the analgesic efficacy, the demographics and clinical characteristics of the patients in these groups were statistically compared, using the Fisher exact test for the dichotomous items (sex, location of surgery, need for postoperative ventilation) and the Mann–Whitney test for continuous items (postnatal age, bodyweight, duration of surgery). The same was done for neonates aged\10 days and neonates and infants aged C10 days included in the analgesic efficacy assessment of the new morphine dosing algorithm. To statistically compare the analgesic efficacy of the model-derived morphine dosing algorithm between neonates with a PNA of \10 days and neonates and infants aged C10 days, the Fisher exact test was used for the dichotomous endpoints (need for rescue medication and actual morphine infusion rate within 25 % of the prescribed dose) and the Mann–Whitney test was used for the remaining continuous endpoints (number of rescue events per patient, morphine rescue dose, COMFORT and NRS scores at the time of rescue events, average actual morphine infusion rate).
3 Results 2.6 Analgesic Efficacy 3.1 Patients Data from patients with a PNA \10 days and a PNA C10 days were analysed separately and compared. The need for nurse-controlled open-label morphine rescue medication in the first 48 postoperative hours, as
The original trial included 38 patients receiving morphine as the primary analgesic and 33 patients receiving paracetamol as the primary analgesic [7]. Morphine and
Optimized Morphine Dosing for Neonates and Infants
metabolite concentrations were available from eight patients with an indwelling arterial line in the morphine arm and from seven patients in the paracetamol arm. In the patients in the paracetamol arm of the study, morphine and metabolite concentrations resulted from the standard loading dose of morphine administered at the end of surgery and from potential morphine rescue boluses. All 38 patients in the morphine arm of the trial were included in the evaluation of the analgesic efficacy of the modelderived morphine dosing regimen. Table 2 summarizes the demographics and clinical characteristics of the 15 patients in the group included in the assessment of the pharmacokinetic population model predictions of morphine and metabolite concentrations and of the 38 patients in the group analysed for analgesic efficacy of the model-derived morphine dosing regimen. The demographics and clinical characteristics of these two groups were not statistically significantly different. Table 3 provides similar demographic information on the neonates aged \10 days and neonates and infants aged C10 days included in the analysis of the analgesic efficacy of the new morphine dosing regimen. Age and bodyweight were expected to differ between these two groups. There Table 2 Demographic and clinical characteristics of the patients in the assessment of the pharmacokinetic model predictions of morphine and its metabolite concentrations and the patients in the analysis of the analgesic efficacy of the morphine dosing algorithm
IQR interquartile range, PNA postnatal age
Table 3 Demographic and clinical characteristics of the patients with a postnatal age (PNA) \10 days and C10 days included in the analysis of the analgesic efficacy of the morphine dosing algorithm
IQR interquartile range
were no statistically significant differences between these two groups with regard to the other demographics. 3.2 Pharmacokinetic Model Evaluation A total of 84 blood samples for concentration measurements of morphine and its metabolites could be obtained from 15 patients. Figure 1 shows the plots of individual predicted versus observed concentrations of morphine (a), M3G (b) and M6G (c). The individual predictions were based on a model fit to the observed concentrations. These plots indicated no bias around the line of unity and adequate precision of the individual predicted serum concentrations. The population predicted concentrations in Fig. 1 for morphine (d), M3G (e) and M6G (f) were based on patients’ age, bodyweight and dosing history alone. The limited bias in the plots of the population predicted versus observed concentrations suggested that these predictions were accurate in this patient population. The wider spread of datapoints around the line of unity in these plots illustrates the considerable interindividual variability in morphine pharmacokinetics in this population.
Characteristic
Patients included in analysis of population pharmacokinetic model predictions (n = 15)
Patients included in analysis of analgesic efficacy of new morphine dosing algorithm (n = 38)
p value
PNA (days, median (IQR))
3 (1–62)
20 (2–88)
0.56
Bodyweight (kg, median (IQR))
3.3 (3.0–4.5)
3.6 (3.1–5.1)
0.42
Sex (n, male/female)
7/8
26/12
0.21
Location of surgery (n, thorax/abdomen)
5/10
11/27
0.75
Duration of surgery (min, median (IQR))
149 (117–224)
139 (100–194)
0.30
Postoperative ventilation (n (%))
7 (47)
14 (37)
0.55
Characteristic
Neonates with PNA \10 days (n = 18)
Neonates and infants with PNA C10 days (n = 20)
p value
PNA (days, median (IQR))
2 (1–3)
72 (37–194)
\0.001
Bodyweight (kg, median (IQR))
3.1 (2.9–3.5)
4.8 (3.7–7.7)
\0.001
Sex (n, male/female)
13/5
13/7
0.73
Location of surgery (n, thorax/abdomen)
4/14
7/13
0.48
Duration of surgery (min, median (IQR))
126 (94–155)
163 (104–240)
0.06
Postoperative ventilation (n (%))
9 (50)
5 (25)
0.18
d
Individual predicted concentration [ng/ml]
1
10
100
1
10
100
10
10
Observed concentration [ng/ml]
1
Morphine
Observed concentration [ng/ml]
1
Morphine
100
100
b
e
1
10
100
1
10
100
1
1
100
Observed concentration [ng/ml]
10
100
Morphine−3−Glucuronide
Observed concentration [ng/ml]
10
Morphine−3−Glucuronide
c
f
1
10
100
1
10
100
10
10
Observed concentration [ng/ml]
1
Morphine−6−Glucuronide
Observed concentration [ng/ml]
1
Morphine−6−Glucuronide
100
100
Fig. 1 Individual predicted concentrations obtained from a model fit to the observed concentrations versus observed concentrations of morphine (a), morphine-3-glucuronide (b) and morphine-6-glucuronide (c); and population predicted concentrations based on patients’ bodyweight, age and dosing history alone versus observed concentrations of morphine (d), morphine-3-glucuronide (e) and morphine-6-glucuronide (f). Triangles and circles indicate datapoints from individuals in the morphine arm and the paracetamol arm of the study, respectively
Population predicted concentration [ng/ml]
Individual predicted concentration [ng/ml] Population predicted concentration [ng/ml]
Individual predicted concentration [ng/ml] Population predicted concentration [ng/ml]
a
E. H. J. Krekels et al.
Optimized Morphine Dosing for Neonates and Infants
a
Morphine
Morphine−3−glucuronide
b
30
Steady state concentration [ng/ml]
Steady state concentration [ng/ml]
50 25
20
15
10
5
30
20
10
0
0 0
100
200
300
c
0
100
200
300
Age [days]
Age [days]
Steady state concentration [ng/ml]
40
Morphine−6−glucuronide
10
8
6
4
2
0 0
100
200
300
Age [days]
Fig. 2 Population predicted steady state concentrations of morphine (a), morphine-3-glucuronide (b) and morphine-6-glucuronide (c) versus age, based on population parameter estimates and the bodyweight and age of the patients in the analysis of analgesic efficacy. Solid
circles indicate concentrations based on the new dosing algorithm and open circles represent concentrations obtained with the traditional dosing scheme
Figure 2 depicts the relationship between PNA and model predicted steady state concentrations for the patients included in the analysis of the analgesic efficacy (Table 3), based on the new dosing algorithm and the traditional dosing scheme. The range in steady state morphine concentrations (a) and M6G concentrations (c) obtained between all patients with the new dosing regimen was considerably reduced compared with the traditional scheme and only small differences between neonates aged \10 days and older neonates and infants remained. With the old dosing schedule. M3G concentrations (b) were rather similar between the two age groups, while the new algorithm yielded lower M3G concentrations in neonates aged \10 days compared with the older neonates and infants.
3.3 Analgesic Efficacy An overview of the need for morphine rescue medication in patients aged \10 days and C10 days who were allocated to morphine treatment is provided in Table 4. Neonates aged \10 days had a lesser need for rescue mediation (p = 0.06), a smaller number of rescue events (p \ 0.001) and a lower total rescue dose (p = 0.003) than older neonates and infants. The COMFORT and NRS scores at the time of rescue were also lower in the younger neonates than in the older neonates and infants (p = 0.008 and p = 0.01, respectively). Average morphine infusion rates were calculated over the actual duration of the postoperative infusion and
E. H. J. Krekels et al. Table 4 Analgesic efficacy of the model-derived morphine dosing algorithm, expressed as need for rescue medication Variable
All patients (n = 38)
Patients in need of rescue medication (n (%))
23 (60.5)
5 (27.8)
18 (90.0)
2 (0–6)
0 (0–2)
5 (1–10)
COMFORT score at time of rescue dose (median (IQR)) NRS at time of rescue dose (median (IQR))
18 (16–21) 5 (5–6)
16.5 (15–18) 5 (4–5)
18 (16–21) 5 (5–7)
0.008 0.01
Total morphine rescue dose during the first 48 h after surgery (lg/kg, median (IQR))
20 (0–235)
193 (19–362)
0.003
Rescue events during the first 48 h after surgery (n, median (IQR))
Patients aged 0–10 days (n = 18)
0 (0–20)
Patients aged 10–365 days (n = 20)
p value between age groups 0.06 \0.001
IQR interquartile range, NRS numeric rating scale
a
b 40
30
Infusion rate [ µg/kg/h]
Infusion rate [ µg/kg/h]
40
20
10
30
20
10
2.0
2.5
3.0
3.5
4.0
2
Bodyweight [kg]
4
6
8
10
Bodyweight [kg]
Fig. 3 Average actual postoperative morphine infusion rates during the postoperative infusion time for each individual patient (symbols) and initial infusion rates according to the model-derived dosing algorithm (solid lines) for patients with a postnatal age (PNA)
\10 days (a) and patients with a PNA C10 days (b). The dashed lines represent the infusion rates according to the traditional dosing regimen in our facilities, which is 10 lg/kg/h
consisted of the initial morphine infusion rate and additional morphine rescue doses or infusions according to the standardized pain protocol. The median (interquartile range [IQR]) average actual morphine infusion rates were 4.4 (4.0–4.8) lg/kg/h in neonates aged \10 days and 14.4 (11.3–23.4) lg/kg/h in older patients (p \ 0.001). Expressed as lg/kg1.5/h, the median (IQR) average actual infusion rates were 2.5 (1.9–2.6) and 6.7 (5.1–11.5), respectively. As dose non-linearities were included in the dosing algorithm, Fig. 3 depicts the average actual morphine infusion rates for each individual patient and the initially prescribed morphine infusion rates. Twelve out of 18 neonates aged\10 days (67 %) versus nine out of 20 older patients (45 %) had actual infusion rates within 25 % of the initial dose (p = 0.59). Three neonates aged \10 days (17 %) required less than 75 % of the initial infusion rate, while this was not the case for any of the older patients (p = 0.23). For unknown reasons, a 1-day-old boy of 3 kg
required on average 5.6 times the initial morphine infusion rate during his 38 h postoperative infusion. In Fig. 3, a reference line representing the traditional intravenous morphine dose in our unit for the patient population in the current study (10 lg/kg/h) was also added. This shows that initial morphine intravenous infusion rates were lower than the traditional dose in neonates aged \10 days and higher than the traditional infusion rate for neonates and infants aged C10 days and a bodyweight exceeding 4 kg.
4 Discussion The current study prospectively evaluated concentration predictions of a previously developed population pharmacokinetic model for morphine in young paediatric patients, as well as the analgesic efficacy of a new paediatric dosing
Optimized Morphine Dosing for Neonates and Infants
algorithm derived from this pharmacokinetic model. The model-derived dosing algorithm corrects for age-related differences in morphine pharmacokinetics in these patients, yielding initial morphine maintenance infusion rates of 2.5 lg/kg1.5/h for neonates with a PNA of \10 days and 5 lg/kg1.5/h for older patients (Table 1). In neonates aged \10 days, this unique approach resulted in a 50–75 % reduction of the traditional 10 lg/kg/h morphine dose in our unit. Neonates and infants aged C10 days with a bodyweight exceeding 4 kg received up to 50 % more than our traditional morphine dose (Fig. 3). This study confirms that paediatric morphine dose corrections based on differences in pharmacokinetics improve exposure and efficacy, although further improvements are possible. The development of evidence-based dosing regimens in the paediatric population is complicated by practical, ethical and legal constraints. However, population modelling now makes it possible to obtain drug dosing algorithms for the paediatric population with a similar level of scientific evidence as has been the standard requirement for the adult population for a long time [2]. The pharmacokinetic model from which our paediatric morphine dosing algorithm was derived was developed using data from 248 patients ranging from premature neonates to 3-year-old children, with only 1–4 samples per patient at dosing regimens that varied according to clinical needs. This methodology thereby limits the burden to patients, while still yielding proper, evidence-based dosing algorithms. It is envisioned that this methodology can be extended to other drugs and other vulnerable patient populations, such as critically ill patients, pregnant women, malnourished patients or the elderly. Morphine concentrations in 15 patients in the current study confirmed that concentration predictions by the population pharmacokinetic morphine model are accurate. As the predictive performance of the morphine model had been established previously for paediatric patients in different centres receiving various morphine doses [5, 6], it would have been unethical to obtain more blood samples from other patients who did not have an indwelling line. Combined with the previously published results, the sample size of patients in the pharmacokinetic model assessment in the current study can therefore be considered sufficient to establish the predictive value of the modelbased concentration predictions. In the population pharmacokinetic model for morphine, bodyweight and PNA \10 days were identified as key characteristics predictive of the interindividual variability in the clearance and distribution of morphine and its main metabolites in patients aged \3 years, including term and preterm neonates [5]. The model-derived dosing algorithm evaluated in the current study corrects for the developmental changes in morphine pharmacokinetics in this
young population. Model simulations have shown that loading doses on the basis of lg/kg and continuous morphine intravenous infusion rates on the basis of lg/kg1.5/h, with a 50 % reduction in neonates with a PNA \10 days, will yield similar steady state concentrations of morphine and its metabolites across preterm and term neonates, infants and children up to 3 years of age [5]. The pharmacokinetic data obtained in the current study further support the accuracy of these model-based simulations for term neonates and infants up to 1 year of age. Target plasma concentrations of morphine, which are needed to determine the infusion rate, have not been firmly established in the paediatric population, although concentrations around 20 ng/ml have been suggested in the literature for postoperative neonates and infants [10, 11]. Previous research by our group suggested that an infusion rate of 10 lg/kg/h, which is in the lower range of literaturereported postoperative morphine intravenous infusion rates of 10–40 lg/kg/h [12], is relatively high for neonates but often insufficient for older infants and children [13]. The dosing amounts in the proposed dosing algorithm (2.5 lg/ kg1.5/h for neonates aged \10 days and 5 lg/kg1.5/h for older patients) were therefore selected such that they would lead to a reduced dose in neonates and an increased dose in older and heavier infants and children. With these doses, the model predicts average steady state concentrations of approximately 10 ng/ml throughout the entire study population (Fig. 2). The limited need for rescue medication in the very young suggests that higher doses could be regarded as over-exposure (Fig. 3). Moreover, the required dosing in the older patients was more variable and the model-derived starting dose, although being higher than the traditional dose, did still not appear to yield adequate analgesia in most of these patients (Fig. 3). The number of patients in the current study was too small to determine the influence of the reduced morphine dose in young neonates on the occurrence of acute morphine-related side effects, dependence or withdrawal [14], but this is expected to be beneficial. Similarly, we could not establish whether the increased morphine dose in older neonates and infants yielded significant increases in the occurrence of acute side effects, dependence or withdrawal; however, under-exposure of these patients is just as unethical as over-exposure. The two morphine metabolites, M3G and M6G, are both pharmacologically active. The model-based predictions for the concentrations of these metabolites have also been extensively evaluated previously [5, 6] and in the current study. Given the current dosing algorithm, steady state concentrations of M3G and M6G are 18 and 4 ng/ml, respectively, for neonates aged \10 days and 38 and 5 ng/ ml, respectively, for older neonates and infants. M6G is known to be more potent than morphine [15, 16], while
E. H. J. Krekels et al.
M3G has been suggested to antagonize morphine analgesia [17]. Compared with the young neonates, both metabolite concentrations were increased in neonates and infants C10 days (Fig. 2). There was a twofold difference in M3G concentrations between the two patient groups, which could explain part of the difference in efficacy observed between the two groups. However, when pharmacokinetic models are used as the sole basis for paediatric dosing corrections, it is implicitly assumed that the pharmacodynamics of that drug remain constant within this population. This assumption is acceptable when (1) pathophysiological processes are similar throughout the population; (2) the exposure–effect relationship can be assumed independent of age based on the mechanism of action; and (3) the same clinical endpoints for treatment are used throughout the populations [18]. It is unlikely that morphine meets the first two criteria in our population. The observed difference in rescue medication and morphine consumption between younger and older patients in the current study therefore suggests age-related differences in either pain perception or the analgesic efficacy of morphine. The latter can, for instance, be caused by differences in effect-site distribution and/or differences in sensitivity to morphine and its pharmacologically active metabolites. Although the model-derived corrections for age-related differences in morphine pharmacokinetics already considerably contribute to improving paediatric morphine dosing, defining age-specific target concentrations in this population could further refine the morphine dosing algorithm.
5 Conclusion Clinicians should always strive to expose patients to the lowest drug doses that are still effective. To our knowledge, no prospectively validated paediatric morphine dosing algorithms have been published based on a thorough investigation and understanding of the developmental changes in the pharmacology of morphine in this population. Our paediatric dosing algorithm corrects for developmental changes in its pharmacokinetics, yielding a 50–75 % reduction in initial infusion rates in neonates with a PNA \10 days. As most of these patients did not require rescue medication, this new regimen reduces the risk of over-exposure while still adequately treating these patients. For neonates and infants aged with a PNA C10 days, our model-derived dosing algorithm prescribes an increased initial infusion rate compared with the traditional dose; however, for this patient group further improvements remain necessary as the majority of patients in this study still required rescue dosing.
Acknowledgments We would like to thank Rene´ Mooren for analysing the plasma samples for morphine, M3G and M6G concentrations, and Ko Hagoort for critically reading the manuscript. This study was performed within the framework of the Dutch Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organisation for Scientific Research (NWO). None of the authors has any conflicts of interest that are directly relevant to the content of this article.
References 1. Ince I, De Wildt SN, Tibboel D, et al. Tailor-made drug treatment for children: creation of an infrastructure for data-sharing and population PK-PD modeling. Drug Discov Today. 2009;14: 316–20. 2. De Cock RF, Piana C, Krekels EH, et al. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol. 2011;67:5–16. 3. Knibbe CA, Danhof M. Individualized dosing regimens in children based on population PKPD modelling: are we ready for it? Int J Pharm. 2011;415(1–2):9–14. 4. Knibbe CA, Krekels EH, Danhof M. Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011;7(1): 1–8. 5. Knibbe CA, Krekels EH, van den Anker JN, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet. 2009;48(6):371–85. 6. Krekels EH, DeJongh J, van Lingen RA, et al. Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children. Clin Pharmacokinet. 2011;50(1):51–63. 7. Ceelie I, de Wildt SN, van Dijk M, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial. JAMA. 2013;309(2):149–54. 8. Ceelie I, Van Dijk M, Bax NM, et al. Does minimal access major surgery in the newborn hurt less? An evaluation of cumulative opioid doses. Eur J Pain. 2011;15:615–20. 9. Van Dijk M, De Boer JB, Koot HM, et al. The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain. 2000;84:367–77. 10. Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain. 2000;88:89–95. 11. Olkkola KT, Maunuksela EL, Korpela R, Rosenberg PH. Kinetics and dynamics of postoperative intravenous morphine in children. Clin Pharmacol Ther. 1988;44:128–36. 12. Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: part 2—clinical use. Paediatr Anaesth. 1997;7:93–101. 13. Bouwmeester NJ, Van den Anker JN, Hop WC, et al. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth. 2003;90:642–52. 14. Anand KJ. Pain panacea for opiophobia in infants? JAMA. 2013;309(2):183–4. 15. Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol. 1992;34(2):130–8. 16. Murthy BR, Pollack GM, Brouwer KL. Contribution of morphine-6-glucuronide to antinociception following intravenous
Optimized Morphine Dosing for Neonates and Infants administration of morphine to healthy volunteers. J Clin Pharmacol. 2002;42(5):569–76. 17. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide—a potent antagonist of morphine analgesia. Life Sci. 1990;47(6): 579–85.
18. Knibbe CA, Krekels EH, Danhof M. Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011;7:1–8.
ORIGINAL RESEARCH ARTICLE
Evidence-Based Morphine Dosing for Postoperative Neonates and Infants Elke H. J. Krekels • Dick Tibboel • Saskia N. de Wildt Ilse Ceelie • Albert Dahan • Monique van Dijk • Meindert Danhof • Catherijne A. J. Knibbe
•
Ó Springer International Publishing Switzerland 2014
Abstract Background and Objectives From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 lg/kg1.5/h, with a 50 % dose reduction in neonates with a postnatal age (PNA) \10 days, yield similar morphine and metabolite concentrations across patients younger than 3 years. Compared with traditional dosing, this modelderived dosing regimen yields significantly reduced doses in neonates aged \10 days. Methods Concentration predictions of the population model were prospectively evaluated in postoperative term neonates and infants up to the age of 1 year who received morphine doses according to the model-derived algorithm. The efficacy of this dosing algorithm was evaluated using
E. H. J. Krekels M. Danhof C. A. J. Knibbe Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands E. H. J. Krekels D. Tibboel S. N. de Wildt I. Ceelie M. van Dijk C. A. J. Knibbe Intensive Care and Department of Pediatric Surgery, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands I. Ceelie A. Dahan Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands M. van Dijk Department of Pediatrics, Division of Neonatology, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands C. A. J. Knibbe (&) Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands e-mail: [email protected]
morphine rescue medication and actual average infusion rates. Results Morphine and metabolite concentrations were accurately predicted by the paediatric pharmacokinetic morphine model. With regard to efficacy, 5 out of 18 neonates (27.8 %) with a PNA of \10 days needed rescue medication versus 18 of the 20 older patients (90 %) (p = 0.06). The median (interquartile range [IQR]) total morphine rescue dose was 0 (0–20) lg/kg in younger patients versus 193 (19–362) lg/kg in older patients (p = 0.003). The median (IQR) actual average morphine infusion rate was 4.4 (4.0–4.8) lg/kg/h in younger patients versus 14.4 (11.3–23.4) lg/kg/h in older patients (p \ 0.001). Conclusion Morphine paediatric dosing algorithms corrected for pharmacokinetic differences alone yield effective doses that prevent over-dosing for neonates with a PNA \10 days. The fact that many neonates and infants with a PNA C10 days still required rescue medication warrants pharmacodynamic studies to further optimize the dosing algorithm for these patients.
1 Introduction Postoperative pain in children is regularly treated with morphine, and correct dosing is essential to prevent inadequate pain relief, opioid-related adverse drug reactions and opioid-withdrawal symptoms. However, validated dosing guidelines across the paediatric age range are currently lacking. Population pharmacokinetic and/or pharmacodynamic modelling approaches, also known as non-linear mixedeffects modelling, are useful to develop evidence-based rather than empirical or consensus-based paediatric drug
E. H. J. Krekels et al.
dosing algorithms [1]. They allow derivation of pharmacokinetic and/or pharmacodynamic parameters from sparse, dense and/or unbalanced data obtained during routine clinical practice. Moreover, the sources of variability in the population can be quantified, while in a covariate analysis, patient characteristics, such as bodyweight or age, can be identified that are predictive of this variability [2]. These patient characteristics form the basis of model-derived dosing algorithms [3, 4]. Assessments of model-derived dosing algorithms in prospective clinical trials ascertain that the obtained endpoints are in agreement with the model-based predictions [1]. Recently, a population model for the pharmacokinetics of morphine and its two pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G), was developed for a population of postoperative and ventilated preterm and term neonates, infants and children up to 3 years of age [5]. This model showed that morphine clearance non-linearly increases with bodyweight. Additionally, morphine glucuronidation is reduced by half in neonates with a postnatal age (PNA) \10 days, independent of gestational age. After the predictive value of this model was confirmed by extensive model validation [5, 6], a paediatric dosing algorithm for morphine was derived that would correct for developmental changes in morphine pharmacokinetics, to yield similar morphine and metabolite concentrations in postoperative and ventilated neonates, infants and children under the age of 3 years [5]. According to this evidencebased dosing algorithm, morphine maintenance infusions are dosed on the basis of lg/kg1.5/h with a 50 % dose reduction in neonates \10 days, while loading doses are still dosed on the basis of lg/kg. The current proof-of-principle study prospectively evaluates the model-derived paediatric dosing regimen for morphine in postoperative patients under the age of 1 year. Morphine and metabolite concentrations measured after dosing according to this model-derived regimen were compared with concentration predictions by the paediatric morphine pharmacokinetic model for each individual patient [5]. The studied dosing algorithm yields higher infusion rates in neonates and infants with a PNA C10 days than our traditional dosing scheme (e.g. 14.1 vs 10.0 lg/kg/h for an infant of 8 kg), while it yields substantially reduced morphine infusion rates in neonates with a PNA \10 days (e.g. 4.3 vs 10.0 lg/kg/h for a young neonate of 3 kg). Therefore the analgesic efficacy of this model-derived dosing regimen was evaluated in both age groups separately. This was done by recording the morphine rescue dose that was administered according to a validated age-appropriate pain protocol, and the average actual morphine infusion rate over 48 h after surgery.
2 Patients and Methods 2.1 Study Design In a previous single-centre, double-blind, randomized controlled trial comparing the postoperative analgesic efficacy of paracetamol and morphine over 48 h in term neonates and infants younger than 1 year [7], all patients receiving morphine, either as a primary double-blind analgesic and/or as an open-label rescue medication, were dosed according to the new model-derived dosing algorithm, which was implemented using Table 1. Morphine and metabolite concentrations in plasma that could be obtained from these patients were compared with modelpredicted concentrations of these samples. The analgesic efficacy of the model-derived dosing regimen was assessed in all patients allocated to the morphine arm of this study [7]. 2.2 Patients Term neonates and infants under the age of 1 year, undergoing major abdominal or non-cardiac thoracic surgery between March 2008 and July 2010 at the Erasmus
Table 1 Dosing table used to implement the model-derived morphine dosing algorithm for continuous maintenance infusions in clinical practice Bodyweight (kg)
Model-derived dosing algorithm PNA \ 10 days 2.5 lg/kg1.5/h Infusion rate (lg/kg/h)
10 B PNA \ 365 days 5 lg/kg1.5/h Infusion rate (lg/kg/h)
1.5–2
3.1
6.1
2–2.5 2.5–3
3.5 4.0
7.1 7.9
3–3.5
4.3
8.7
3.5–4
4.7
9.4
4–4.5
5.0
10.0
4.5–5
5.3
10.6
5–5.5
5.6
11.2
5.5–6
–
11.7
6–6.5
–
12.3
6.5–7
–
12.8
7–7.5
–
13.2
7.5–8
–
13.7
8–8.5
–
14.1
8.5–9
–
14.6
9–9.5
–
15.0
9.5–10 10–10.5
– –
15.4 15.8
PNA postnatal age
Optimized Morphine Dosing for Neonates and Infants
MC–Sophia Children’s Hospital in Rotterdam, were eligible for inclusion. The exclusion criteria were (1) postconceptual age younger than 36 weeks; (2) bodyweight less than 1.5 kg; (3) extracorporeal membrane oxygenation treatment; (4) neurological dysfunction; (5) hepatic dysfunction or renal insufficiency; (6) pre- or postnatal administration of opioids or psychotropic drugs for more than 24 h; (7) known allergy or intolerance of paracetamol or morphine; and (8) administration of opioids in the 24 h prior to surgery. The study was approved by the Erasmus MC ethics review board. Written informed consent was obtained from the parents or legal guardians before inclusion of the patients.
postoperative medication with a known interaction with morphine pharmacokinetics was administered. Blood samples were obtained to determine the accuracy of the concentration predictions by the paediatric pharmacokinetic morphine model [5]. A maximum of eight blood samples or a total of 3 % of the blood volume of a patient was obtained from an indwelling arterial line when present. Whenever possible, a blood sample was taken prior to a morphine rescue dose or prior to a scheduled paracetamol or placebo bolus dose. Additional samples were taken when possible at varying times, to obtain information on a wide range of the concentration–time curve. Blood samples were centrifuged at 3,000 rpm and plasma was subsequently stored at -80 °C till further analysis.
2.3 Interventions
2.4 Pharmacokinetic Blood Sample Analysis
All patients received a 100 lg/kg morphine intravenous bolus loading dose 30 min before the anticipated end of the surgical procedure. In the morphine arm of the study, patients aged \10 days received a postoperative continuous morphine intravenous infusion of 2.5 lg/kg1.5/h, while older neonates and infants received 5 lg/kg1.5/h (Table 1). As this was a double-blind trial, the patients allocated to the morphine arm of the study also received four times daily placebo saline infusions of the same volume as the paracetamol bolus dose a patient in the paracetamol arm of the study would receive. During the first 48 h of postoperative recovery in the intensive care unit, trained nurses assessed each patient’s pain levels every 2 h and when a patient appeared to be in discomfort, according to an age-appropriate, standardized pain protocol [8] based on COMFORT-B scores [9] and Numeric Rating Scale (NRS-11) pain scores. Open-label morphine rescue medication was administered to patients in both arms of the study when the NRS-11 score was C4. Patients aged \10 days received a bolus dose of 10 lg/kg and older patients received 15 lg/kg. Patients were reassessed after 10 min and received additional bolus doses if necessary. If analgesia was not adequate after three bolus doses within 1 hour, the patients received an additional loading dose of 100 lg/kg, after which the morphine infusion rate was increased by 1.25 lg/kg1.5/h in neonates aged \10 days and by 2.5 lg/kg1.5/h in older neonates and infants. When after this increase the patient again needed more than three rescue bolus doses within 1 h, another loading dose was administered and infusion rates were increased by the same amount again. The morphine infusion was stopped or reduced in the case of morphinerelated adverse events or after 12 h of adequate analgesia, indicated by an NRS-11 score \4. In the case of discomfort, indicated by COMFORT-B scores of C17 and NRS11 pain scores of \4, midazolam was administered. No
The frozen plasma samples were thawed at room temperature. Seven hundred microlitres of acetonitrile, which contained 2H3-morphine (2H3-M), 2H3-morphine-3-glucuronide (2H3-M3G) and 2H3-morphine-6-glucuronide (2H3M6G) (Cerilliant, Round Rock, TX, USA) as internal standards and 100 ll of 1 mM zinc sulphate, was added to 200 ll of the samples. The samples were mixed for 2 min and centrifuged for 5 min at 13,000 rpm. Two hundred microlitres of the supernatant was dried under a gentle stream of nitrogen at 50 °C. The residues were reconstituted in 100 ll of 0.1 % (v/v) formic acid in water and 20 ll of this sample was injected into a high-pressure liquid chromatography (HPLC) system, which contained an Ultimate 3000 autosampler (Dionex, Amsterdam, The Netherlands), an HPG680 pump (Dionex) and a 3 lm, ˚ , 50 9 2.1 mm YMC-pack ODS-AQ column (YMC 120 A Inacom, Overberg, The Netherlands) with an ODS precolumn (Phenomenex, Utrecht, The Netherlands) at 30 °C. The mobile phase consisted of 0.1 % formic acid in water with 3 % acetonitrile (LiChrosolv; Merck BV, Amsterdam, The Netherlands) as modifier and the flow rate was 0.5 ml/ min. The system was controlled by Chromeleon (Dionex). The eluent of the HPLC system was monitored by a Quattro micro API tandem mass spectrometer (Waters, Etten-Leur, The Netherlands). Peak areas of reaction ions from morphine, M3G, M6G and the internal standards 2H3M, 2H3-M3G and 2H3-M6G were obtained in the multiple reaction mode and integrated by Masslynx 4.1 data software (Waters). The m/z was 165.0 (285.9 [ 165.0) for morphine and 286.0 (461.9 [ 286.0) for M3G and M6G. For the internal standards the m/z was 165.0 (288.9 [ 165.0) for 2H3M and 289.0 (464.9 [ 289.0) for 2H3-M3G and 2H3-M6G. All analytes could be analysed in one run and all samples were analysed on 1 day. The sample concentrations were calculated by the internal standard method with weighing factor 1/(X).
E. H. J. Krekels et al.
Blank pooled human serum was used for control samples, and serum spiked with morphine, M3G and M6G (Cerilliant) in methanol/water was used for the calibration curve and quality controls. Accuracy was within ±15 % in the concentration range tested. The lower limits of quantification were 1.5 lg/l for morphine and M6G and 2.5 lg/l for M3G. Recovery was 80 % or higher for morphine, 74 % or higher for M3G and 76 % or higher for M6G in the concentration range tested. Recovery was 93 % for 2H3-M, 85 % for 2H3-M3G and 82 % for 2H3-M6G. All concentrations were within the range of the calibration curve. 2.5 Pharmacokinetic Model Evaluation The paediatric population pharmacokinetic model for morphine and its metabolites consisted of two compartments for morphine and one compartment for each of the metabolites [5]. The distribution volume of all compartments scaled linearly with bodyweight, while changes in the formation and elimination of both glucuronides were best described by bodyweight-based exponential equations with an exponent of 1.44. Within this relationship, the formation of the metabolites was reduced by almost 50 % in neonates with a PNA \10 days. Non-linear mixed-effects modelling software NONMEM version VI (ICON, Ellicott City, MD, USA) was used to obtain model-based concentration predictions of morphine and metabolites for each plasma sample. In predicted versus observed plots, the available morphine and metabolite concentrations were visually compared with both individual and population concentration predictions from the model [5]. Individual predicted concentrations were based on a model fit of the observed concentrations to the model, using dosing history, bodyweight and PNA of the patient, and observed concentrations as input. Population predicted concentrations were obtained using the population parameter values of a typical individual with specified bodyweight and PNA and the dosing history of the patient. Model-based population predictions were obtained to compare steady state concentrations of morphine and its metabolites obtained with the new dosing algorithm with concentrations obtained with the traditional regimen. For each individual included in the analysis of analgesic efficacy (Table 3), steady state concentrations were obtained based on the initial morphine infusion rate in the study and on the traditional morphine infusion rate.
described in the ‘Interventions’ section, was expressed as the percentage of patients in need of rescue medication, the total morphine rescue dose in all patients and the number of rescue events, with an event defined as an administration of a morphine bolus dose, an additional morphine loading dose or an increase of the morphine infusion rate. COMFORT and NRS scores at the time of rescue medications were also compared. Additionally, the average morphine infusion rate over the actual duration of the postoperative infusion for each patient was calculated. This average infusion rate takes into account both the maintenance infusion rate and rescue morphine administrations. Finally, since there were bodyweight- and age-related differences in the infusion rates of the model-derived morphine dosing algorithm, the average morphine infusion rate in each individual patient was compared with the initially prescribed model-derived infusion rate for that patient. The percentage of patients with an average morphine infusion rate within 25 % of the prescribed infusion rate was determined. 2.7 Statistical Analysis To ascertain that the patients from whom pharmacokinetic samples could be obtained were representative of the patients who were analysed for the analgesic efficacy, the demographics and clinical characteristics of the patients in these groups were statistically compared, using the Fisher exact test for the dichotomous items (sex, location of surgery, need for postoperative ventilation) and the Mann–Whitney test for continuous items (postnatal age, bodyweight, duration of surgery). The same was done for neonates aged\10 days and neonates and infants aged C10 days included in the analgesic efficacy assessment of the new morphine dosing algorithm. To statistically compare the analgesic efficacy of the model-derived morphine dosing algorithm between neonates with a PNA of \10 days and neonates and infants aged C10 days, the Fisher exact test was used for the dichotomous endpoints (need for rescue medication and actual morphine infusion rate within 25 % of the prescribed dose) and the Mann–Whitney test was used for the remaining continuous endpoints (number of rescue events per patient, morphine rescue dose, COMFORT and NRS scores at the time of rescue events, average actual morphine infusion rate).
3 Results 2.6 Analgesic Efficacy 3.1 Patients Data from patients with a PNA \10 days and a PNA C10 days were analysed separately and compared. The need for nurse-controlled open-label morphine rescue medication in the first 48 postoperative hours, as
The original trial included 38 patients receiving morphine as the primary analgesic and 33 patients receiving paracetamol as the primary analgesic [7]. Morphine and
Optimized Morphine Dosing for Neonates and Infants
metabolite concentrations were available from eight patients with an indwelling arterial line in the morphine arm and from seven patients in the paracetamol arm. In the patients in the paracetamol arm of the study, morphine and metabolite concentrations resulted from the standard loading dose of morphine administered at the end of surgery and from potential morphine rescue boluses. All 38 patients in the morphine arm of the trial were included in the evaluation of the analgesic efficacy of the modelderived morphine dosing regimen. Table 2 summarizes the demographics and clinical characteristics of the 15 patients in the group included in the assessment of the pharmacokinetic population model predictions of morphine and metabolite concentrations and of the 38 patients in the group analysed for analgesic efficacy of the model-derived morphine dosing regimen. The demographics and clinical characteristics of these two groups were not statistically significantly different. Table 3 provides similar demographic information on the neonates aged \10 days and neonates and infants aged C10 days included in the analysis of the analgesic efficacy of the new morphine dosing regimen. Age and bodyweight were expected to differ between these two groups. There Table 2 Demographic and clinical characteristics of the patients in the assessment of the pharmacokinetic model predictions of morphine and its metabolite concentrations and the patients in the analysis of the analgesic efficacy of the morphine dosing algorithm
IQR interquartile range, PNA postnatal age
Table 3 Demographic and clinical characteristics of the patients with a postnatal age (PNA) \10 days and C10 days included in the analysis of the analgesic efficacy of the morphine dosing algorithm
IQR interquartile range
were no statistically significant differences between these two groups with regard to the other demographics. 3.2 Pharmacokinetic Model Evaluation A total of 84 blood samples for concentration measurements of morphine and its metabolites could be obtained from 15 patients. Figure 1 shows the plots of individual predicted versus observed concentrations of morphine (a), M3G (b) and M6G (c). The individual predictions were based on a model fit to the observed concentrations. These plots indicated no bias around the line of unity and adequate precision of the individual predicted serum concentrations. The population predicted concentrations in Fig. 1 for morphine (d), M3G (e) and M6G (f) were based on patients’ age, bodyweight and dosing history alone. The limited bias in the plots of the population predicted versus observed concentrations suggested that these predictions were accurate in this patient population. The wider spread of datapoints around the line of unity in these plots illustrates the considerable interindividual variability in morphine pharmacokinetics in this population.
Characteristic
Patients included in analysis of population pharmacokinetic model predictions (n = 15)
Patients included in analysis of analgesic efficacy of new morphine dosing algorithm (n = 38)
p value
PNA (days, median (IQR))
3 (1–62)
20 (2–88)
0.56
Bodyweight (kg, median (IQR))
3.3 (3.0–4.5)
3.6 (3.1–5.1)
0.42
Sex (n, male/female)
7/8
26/12
0.21
Location of surgery (n, thorax/abdomen)
5/10
11/27
0.75
Duration of surgery (min, median (IQR))
149 (117–224)
139 (100–194)
0.30
Postoperative ventilation (n (%))
7 (47)
14 (37)
0.55
Characteristic
Neonates with PNA \10 days (n = 18)
Neonates and infants with PNA C10 days (n = 20)
p value
PNA (days, median (IQR))
2 (1–3)
72 (37–194)
\0.001
Bodyweight (kg, median (IQR))
3.1 (2.9–3.5)
4.8 (3.7–7.7)
\0.001
Sex (n, male/female)
13/5
13/7
0.73
Location of surgery (n, thorax/abdomen)
4/14
7/13
0.48
Duration of surgery (min, median (IQR))
126 (94–155)
163 (104–240)
0.06
Postoperative ventilation (n (%))
9 (50)
5 (25)
0.18
d
Individual predicted concentration [ng/ml]
1
10
100
1
10
100
10
10
Observed concentration [ng/ml]
1
Morphine
Observed concentration [ng/ml]
1
Morphine
100
100
b
e
1
10
100
1
10
100
1
1
100
Observed concentration [ng/ml]
10
100
Morphine−3−Glucuronide
Observed concentration [ng/ml]
10
Morphine−3−Glucuronide
c
f
1
10
100
1
10
100
10
10
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1
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Fig. 1 Individual predicted concentrations obtained from a model fit to the observed concentrations versus observed concentrations of morphine (a), morphine-3-glucuronide (b) and morphine-6-glucuronide (c); and population predicted concentrations based on patients’ bodyweight, age and dosing history alone versus observed concentrations of morphine (d), morphine-3-glucuronide (e) and morphine-6-glucuronide (f). Triangles and circles indicate datapoints from individuals in the morphine arm and the paracetamol arm of the study, respectively
Population predicted concentration [ng/ml]
Individual predicted concentration [ng/ml] Population predicted concentration [ng/ml]
Individual predicted concentration [ng/ml] Population predicted concentration [ng/ml]
a
E. H. J. Krekels et al.
Optimized Morphine Dosing for Neonates and Infants
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Fig. 2 Population predicted steady state concentrations of morphine (a), morphine-3-glucuronide (b) and morphine-6-glucuronide (c) versus age, based on population parameter estimates and the bodyweight and age of the patients in the analysis of analgesic efficacy. Solid
circles indicate concentrations based on the new dosing algorithm and open circles represent concentrations obtained with the traditional dosing scheme
Figure 2 depicts the relationship between PNA and model predicted steady state concentrations for the patients included in the analysis of the analgesic efficacy (Table 3), based on the new dosing algorithm and the traditional dosing scheme. The range in steady state morphine concentrations (a) and M6G concentrations (c) obtained between all patients with the new dosing regimen was considerably reduced compared with the traditional scheme and only small differences between neonates aged \10 days and older neonates and infants remained. With the old dosing schedule. M3G concentrations (b) were rather similar between the two age groups, while the new algorithm yielded lower M3G concentrations in neonates aged \10 days compared with the older neonates and infants.
3.3 Analgesic Efficacy An overview of the need for morphine rescue medication in patients aged \10 days and C10 days who were allocated to morphine treatment is provided in Table 4. Neonates aged \10 days had a lesser need for rescue mediation (p = 0.06), a smaller number of rescue events (p \ 0.001) and a lower total rescue dose (p = 0.003) than older neonates and infants. The COMFORT and NRS scores at the time of rescue were also lower in the younger neonates than in the older neonates and infants (p = 0.008 and p = 0.01, respectively). Average morphine infusion rates were calculated over the actual duration of the postoperative infusion and
E. H. J. Krekels et al. Table 4 Analgesic efficacy of the model-derived morphine dosing algorithm, expressed as need for rescue medication Variable
All patients (n = 38)
Patients in need of rescue medication (n (%))
23 (60.5)
5 (27.8)
18 (90.0)
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18 (16–21) 5 (5–6)
16.5 (15–18) 5 (4–5)
18 (16–21) 5 (5–7)
0.008 0.01
Total morphine rescue dose during the first 48 h after surgery (lg/kg, median (IQR))
20 (0–235)
193 (19–362)
0.003
Rescue events during the first 48 h after surgery (n, median (IQR))
Patients aged 0–10 days (n = 18)
0 (0–20)
Patients aged 10–365 days (n = 20)
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IQR interquartile range, NRS numeric rating scale
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Fig. 3 Average actual postoperative morphine infusion rates during the postoperative infusion time for each individual patient (symbols) and initial infusion rates according to the model-derived dosing algorithm (solid lines) for patients with a postnatal age (PNA)
\10 days (a) and patients with a PNA C10 days (b). The dashed lines represent the infusion rates according to the traditional dosing regimen in our facilities, which is 10 lg/kg/h
consisted of the initial morphine infusion rate and additional morphine rescue doses or infusions according to the standardized pain protocol. The median (interquartile range [IQR]) average actual morphine infusion rates were 4.4 (4.0–4.8) lg/kg/h in neonates aged \10 days and 14.4 (11.3–23.4) lg/kg/h in older patients (p \ 0.001). Expressed as lg/kg1.5/h, the median (IQR) average actual infusion rates were 2.5 (1.9–2.6) and 6.7 (5.1–11.5), respectively. As dose non-linearities were included in the dosing algorithm, Fig. 3 depicts the average actual morphine infusion rates for each individual patient and the initially prescribed morphine infusion rates. Twelve out of 18 neonates aged\10 days (67 %) versus nine out of 20 older patients (45 %) had actual infusion rates within 25 % of the initial dose (p = 0.59). Three neonates aged \10 days (17 %) required less than 75 % of the initial infusion rate, while this was not the case for any of the older patients (p = 0.23). For unknown reasons, a 1-day-old boy of 3 kg
required on average 5.6 times the initial morphine infusion rate during his 38 h postoperative infusion. In Fig. 3, a reference line representing the traditional intravenous morphine dose in our unit for the patient population in the current study (10 lg/kg/h) was also added. This shows that initial morphine intravenous infusion rates were lower than the traditional dose in neonates aged \10 days and higher than the traditional infusion rate for neonates and infants aged C10 days and a bodyweight exceeding 4 kg.
4 Discussion The current study prospectively evaluated concentration predictions of a previously developed population pharmacokinetic model for morphine in young paediatric patients, as well as the analgesic efficacy of a new paediatric dosing
Optimized Morphine Dosing for Neonates and Infants
algorithm derived from this pharmacokinetic model. The model-derived dosing algorithm corrects for age-related differences in morphine pharmacokinetics in these patients, yielding initial morphine maintenance infusion rates of 2.5 lg/kg1.5/h for neonates with a PNA of \10 days and 5 lg/kg1.5/h for older patients (Table 1). In neonates aged \10 days, this unique approach resulted in a 50–75 % reduction of the traditional 10 lg/kg/h morphine dose in our unit. Neonates and infants aged C10 days with a bodyweight exceeding 4 kg received up to 50 % more than our traditional morphine dose (Fig. 3). This study confirms that paediatric morphine dose corrections based on differences in pharmacokinetics improve exposure and efficacy, although further improvements are possible. The development of evidence-based dosing regimens in the paediatric population is complicated by practical, ethical and legal constraints. However, population modelling now makes it possible to obtain drug dosing algorithms for the paediatric population with a similar level of scientific evidence as has been the standard requirement for the adult population for a long time [2]. The pharmacokinetic model from which our paediatric morphine dosing algorithm was derived was developed using data from 248 patients ranging from premature neonates to 3-year-old children, with only 1–4 samples per patient at dosing regimens that varied according to clinical needs. This methodology thereby limits the burden to patients, while still yielding proper, evidence-based dosing algorithms. It is envisioned that this methodology can be extended to other drugs and other vulnerable patient populations, such as critically ill patients, pregnant women, malnourished patients or the elderly. Morphine concentrations in 15 patients in the current study confirmed that concentration predictions by the population pharmacokinetic morphine model are accurate. As the predictive performance of the morphine model had been established previously for paediatric patients in different centres receiving various morphine doses [5, 6], it would have been unethical to obtain more blood samples from other patients who did not have an indwelling line. Combined with the previously published results, the sample size of patients in the pharmacokinetic model assessment in the current study can therefore be considered sufficient to establish the predictive value of the modelbased concentration predictions. In the population pharmacokinetic model for morphine, bodyweight and PNA \10 days were identified as key characteristics predictive of the interindividual variability in the clearance and distribution of morphine and its main metabolites in patients aged \3 years, including term and preterm neonates [5]. The model-derived dosing algorithm evaluated in the current study corrects for the developmental changes in morphine pharmacokinetics in this
young population. Model simulations have shown that loading doses on the basis of lg/kg and continuous morphine intravenous infusion rates on the basis of lg/kg1.5/h, with a 50 % reduction in neonates with a PNA \10 days, will yield similar steady state concentrations of morphine and its metabolites across preterm and term neonates, infants and children up to 3 years of age [5]. The pharmacokinetic data obtained in the current study further support the accuracy of these model-based simulations for term neonates and infants up to 1 year of age. Target plasma concentrations of morphine, which are needed to determine the infusion rate, have not been firmly established in the paediatric population, although concentrations around 20 ng/ml have been suggested in the literature for postoperative neonates and infants [10, 11]. Previous research by our group suggested that an infusion rate of 10 lg/kg/h, which is in the lower range of literaturereported postoperative morphine intravenous infusion rates of 10–40 lg/kg/h [12], is relatively high for neonates but often insufficient for older infants and children [13]. The dosing amounts in the proposed dosing algorithm (2.5 lg/ kg1.5/h for neonates aged \10 days and 5 lg/kg1.5/h for older patients) were therefore selected such that they would lead to a reduced dose in neonates and an increased dose in older and heavier infants and children. With these doses, the model predicts average steady state concentrations of approximately 10 ng/ml throughout the entire study population (Fig. 2). The limited need for rescue medication in the very young suggests that higher doses could be regarded as over-exposure (Fig. 3). Moreover, the required dosing in the older patients was more variable and the model-derived starting dose, although being higher than the traditional dose, did still not appear to yield adequate analgesia in most of these patients (Fig. 3). The number of patients in the current study was too small to determine the influence of the reduced morphine dose in young neonates on the occurrence of acute morphine-related side effects, dependence or withdrawal [14], but this is expected to be beneficial. Similarly, we could not establish whether the increased morphine dose in older neonates and infants yielded significant increases in the occurrence of acute side effects, dependence or withdrawal; however, under-exposure of these patients is just as unethical as over-exposure. The two morphine metabolites, M3G and M6G, are both pharmacologically active. The model-based predictions for the concentrations of these metabolites have also been extensively evaluated previously [5, 6] and in the current study. Given the current dosing algorithm, steady state concentrations of M3G and M6G are 18 and 4 ng/ml, respectively, for neonates aged \10 days and 38 and 5 ng/ ml, respectively, for older neonates and infants. M6G is known to be more potent than morphine [15, 16], while
E. H. J. Krekels et al.
M3G has been suggested to antagonize morphine analgesia [17]. Compared with the young neonates, both metabolite concentrations were increased in neonates and infants C10 days (Fig. 2). There was a twofold difference in M3G concentrations between the two patient groups, which could explain part of the difference in efficacy observed between the two groups. However, when pharmacokinetic models are used as the sole basis for paediatric dosing corrections, it is implicitly assumed that the pharmacodynamics of that drug remain constant within this population. This assumption is acceptable when (1) pathophysiological processes are similar throughout the population; (2) the exposure–effect relationship can be assumed independent of age based on the mechanism of action; and (3) the same clinical endpoints for treatment are used throughout the populations [18]. It is unlikely that morphine meets the first two criteria in our population. The observed difference in rescue medication and morphine consumption between younger and older patients in the current study therefore suggests age-related differences in either pain perception or the analgesic efficacy of morphine. The latter can, for instance, be caused by differences in effect-site distribution and/or differences in sensitivity to morphine and its pharmacologically active metabolites. Although the model-derived corrections for age-related differences in morphine pharmacokinetics already considerably contribute to improving paediatric morphine dosing, defining age-specific target concentrations in this population could further refine the morphine dosing algorithm.
5 Conclusion Clinicians should always strive to expose patients to the lowest drug doses that are still effective. To our knowledge, no prospectively validated paediatric morphine dosing algorithms have been published based on a thorough investigation and understanding of the developmental changes in the pharmacology of morphine in this population. Our paediatric dosing algorithm corrects for developmental changes in its pharmacokinetics, yielding a 50–75 % reduction in initial infusion rates in neonates with a PNA \10 days. As most of these patients did not require rescue medication, this new regimen reduces the risk of over-exposure while still adequately treating these patients. For neonates and infants aged with a PNA C10 days, our model-derived dosing algorithm prescribes an increased initial infusion rate compared with the traditional dose; however, for this patient group further improvements remain necessary as the majority of patients in this study still required rescue dosing.
Acknowledgments We would like to thank Rene´ Mooren for analysing the plasma samples for morphine, M3G and M6G concentrations, and Ko Hagoort for critically reading the manuscript. This study was performed within the framework of the Dutch Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organisation for Scientific Research (NWO). None of the authors has any conflicts of interest that are directly relevant to the content of this article.
References 1. Ince I, De Wildt SN, Tibboel D, et al. Tailor-made drug treatment for children: creation of an infrastructure for data-sharing and population PK-PD modeling. Drug Discov Today. 2009;14: 316–20. 2. De Cock RF, Piana C, Krekels EH, et al. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol. 2011;67:5–16. 3. Knibbe CA, Danhof M. Individualized dosing regimens in children based on population PKPD modelling: are we ready for it? Int J Pharm. 2011;415(1–2):9–14. 4. Knibbe CA, Krekels EH, Danhof M. Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011;7(1): 1–8. 5. Knibbe CA, Krekels EH, van den Anker JN, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet. 2009;48(6):371–85. 6. Krekels EH, DeJongh J, van Lingen RA, et al. Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children. Clin Pharmacokinet. 2011;50(1):51–63. 7. Ceelie I, de Wildt SN, van Dijk M, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial. JAMA. 2013;309(2):149–54. 8. Ceelie I, Van Dijk M, Bax NM, et al. Does minimal access major surgery in the newborn hurt less? An evaluation of cumulative opioid doses. Eur J Pain. 2011;15:615–20. 9. Van Dijk M, De Boer JB, Koot HM, et al. The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain. 2000;84:367–77. 10. Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain. 2000;88:89–95. 11. Olkkola KT, Maunuksela EL, Korpela R, Rosenberg PH. Kinetics and dynamics of postoperative intravenous morphine in children. Clin Pharmacol Ther. 1988;44:128–36. 12. Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review: part 2—clinical use. Paediatr Anaesth. 1997;7:93–101. 13. Bouwmeester NJ, Van den Anker JN, Hop WC, et al. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth. 2003;90:642–52. 14. Anand KJ. Pain panacea for opiophobia in infants? JAMA. 2013;309(2):183–4. 15. Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol. 1992;34(2):130–8. 16. Murthy BR, Pollack GM, Brouwer KL. Contribution of morphine-6-glucuronide to antinociception following intravenous
Optimized Morphine Dosing for Neonates and Infants administration of morphine to healthy volunteers. J Clin Pharmacol. 2002;42(5):569–76. 17. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide—a potent antagonist of morphine analgesia. Life Sci. 1990;47(6): 579–85.
18. Knibbe CA, Krekels EH, Danhof M. Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011;7:1–8.
