Article Text
Abstract
Background: Current best practice for treating acute severe pain in children is to administer intravenous or intranasal opioid. Intranasal diamorphine offers less traumatic analgesia than the potentially difficult and distressing intravenous route. However, there has been no direct comparison of intranasal and intravenous diamorphine nor are there pharmacokinetic data for intranasal diamorphine in children.
Objective: To compare plasma morphine concentration–time profiles following intranasal and intravenous diamorphine administration.
Design: Observational.
Setting: A&E department in a city-centre paediatric teaching hospital.
Patients: Children, aged 3–13 years, with isolated limb fracture.
Interventions: An intravenous catheter was sited and baseline blood taken. The first 12 children received intravenous diamorphine (0.1 mg/kg), and the subsequent 12 intranasal diamorphine (0.1 mg/kg) in 0.2 ml sterile water drops. Subsequent samples were taken at 2, 5, 10, 20, 30 and 60 min.
Measurements: Plasma morphine radioimmunoassay.
Results: Peak plasma morphine concentrations were higher (median 109 vs 36 nmol/l), and occurred earlier (median 2 vs 10 min), with greater area under the curve (3761 vs 1794 nmol/l/h) following intravenous compared to intranasal diamorphine (all p<0.001, Mann–Whitney U test). Higher plasma concentrations at 60 min (47 vs 32 nmol/l) were also observed following intravenous diamorphine (p = 0.01, Mann–Whitney U test).
Conclusions: Our evidence supports the wider use of diamorphine administration by nasal drops in children, as it shows that adequate plasma levels of morphine are usually achieved. However, we demonstrated significantly attenuated and delayed peak plasma morphine levels with lower levels at 1 h with intranasal compared with intravenous diamorphine.
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Higher standards of evidence for the prescription and administration of children’s medicines are of national and international importance.1 Analgesia and sedation in children are rarely based on evidence, but on inferred knowledge, adult studies and subjective collective and individual experience. Childhood fractures are common (20/1000/year in the UK) and often cause severe pain.2 The current recommended treatment of such acute severe pain is “intranasal diamorphine followed by/OR intravenous morphine”.3 In 2001, Kendall et al published a study that established that intranasal diamorphine is a largely safe practice and preferable to intramuscular morphine in children.4 However, there are no pharmacokinetic data on intranasal diamorphine in children, and there has been no comparison of intranasal with intravenous opioid, the current “gold standard” for analgesia.
What is already known on this topic
Intravenous opioid is the “gold standard” for the rapid, reliable delivery of analgesia for acute severe pain in children.
Intranasal diamorphine offers a safe, alternative, less traumatic means of delivering analgesia in such children.
Use of the intranasal route is variable and inconsistent across hospitals and departments.
What this study adds
These are the first pharmacokinetic data for intranasal diamorphine, and this is the first direct comparison of intranasal with intravenous diamorphine in children.
Adequate plasma levels of the active metabolite, morphine, are usually achieved using the intranasal route.
Maximum plasma concentrations of morphine following intranasal administration are achieved at 10 min.
The dose of intranasal diamorphine is the same as the intravenous dose. This is based on relatively limited pharmacokinetic data on intranasal diamorphine in studies of small numbers of adults, often habitual users of opiates, or snorted or smoked diamorphine.5 6 7 8 9 In our own unit, we have found that children given intranasal diamorphine tend to need earlier and more frequent subsequent analgesia than those given intravenous diamorphine. In some units, the dose of intranasal diamorphine is titrated against response. In others, the intravenous route is still preferred because clinicians do not feel that there is enough evidence that intranasal diamorphine is comparable to intravenous diamorphine. There has been no scientific evaluation of any of these findings or practices.
Diamorphine is a semi-synthetic derivative of morphine, and is often considered a “pro-drug”, exerting most of its effects via its metabolites. The half-life of diamorphine in vivo is 3 min7 10 as it is quickly hydrolysed by sequential deacetylation of two ester bonds. This produces 6-monoacetylmorphine, followed by morphine11 12 (fig 1). Morphine is then subject to n-demethylation to normorphine that is subsequently conjugated before excretion.13 Morphine contributes significantly to diamorphine’s pharmacological actions.5 7 14 The aim of this study is to compare plasma morphine concentration–time profiles following intranasal and intravenous diamorphine administration.
Methods
Ethics approval was obtained from the Lothian regional ethics committee. Written informed consent was obtained from the parent of the child, and verbal consent from the child. The study was carried out in the accident and emergency (A&E) department of a city centre tertiary referral paediatric teaching hospital. Samples were collected between April and December 2003.
Children who presented to A&E with a deformed fractured long bone, aged 3–13 years inclusive, were considered for the study. If they were then judged to require intravenous opioid analgesia by the triage nurse and doctor according to current practice, and a member of the study team was available, they and their families were approached for consent.
If there was a need for immediate intravenous access for other clinical reasons or the subject was clinically unstable or multiply injured, they were not included. Other reasons for exclusion from the study were head injury, upper respiratory tract infection or congestion, no accompanying parent or guardian, a medical condition or medication that is a relative or absolute contraindication to opioid administration, and opioid administration within the preceding week.
Twenty four consecutive eligible subjects who presented to the A&E department when an investigating clinician (SB or SK) was on duty, were recruited. The first 12 subjects received intravenous diamorphine, and the subsequent 12 intranasal diamorphine.
Each child had a cannula sited, and blood was immediately drawn back through the cannula for the “T0” sample prior to diamorphine administration. Each subsequent sample (1 ml) was taken from the same cannula. Blood samples were taken at 2, 5, 10, 20, 30 and 60 min following diamorphine administration. A 4 ml sample of “dead-space” blood was first taken and held aside. Next, the sample for analysis was taken and transferred immediately to a blood tube containing lithium heparin, sodium metabisulphate and traysolol, and held on ice. The “dead-space” blood was then returned to the child through the cannula, and the cannula finally flushed with 5 ml 0.9% NaCl. The blood tube was then spun by microfuge at 4000 rpm for 2 min. Plasma was then pipetted into plain ependorph tubes that were immediately transferred to a −70°C freezer.
The total dose of diamorphine administered to each subject was 0.1 mg/kg, via both intranasal and intravenous routes. The intranasal diamorphine dose was administered in 0.2 ml of sterile water dropped into both nostrils over a period of 1 min. At the mid point of the dose, that is, after 30 s, the timing was commenced for the subsequent samples. The intravenous diamorphine was also administered over 1 min, and sampling time commenced 30 s into the dose.
Laboratory methods
A commercially available radioimmunoassay (RIA) kit for morphine was used (Diagnostic Products, Los Angeles, CA) as RIA for plasma morphine has been found to be a reliable and rigorous method.15 The “Coat-A-Count” procedure was a solid-phase, quantitative RIA. The limit of detection was 2.8 nmol/l. The intra-assay coefficient of variation was 13% at 29.4 nmol/l and 5% at 739.5 nmol/l. The inter-assay coefficient of variation was 11% at 63.1 nmol/l and 6.6% at 750 nmol/l. The morphine antibody was highly specific. Detectable cross-reactivities were: 10–20% with nalorphine, 0.35% with morphine-3-glucuronide, and <5% with normorphine and hydromorphone. A solid phase extraction was carried out prior to RIA, using a C18 cartridge (Strata XC, Phenomenex, Torrance, CA). Recovery rates were 94%+ (based on I125 labelled morphine). Laboratory staff were blinded to patient groups. Sample handling techniques similar to those employed by Goldberger et al were used, including rapid freezing, addition of enzyme inhibitor, and solid phase extraction without extreme pH.13
Data analysis
Maximum plasma concentration (Cmax), time of maximum plasma concentration (tmax), and concentration at the last measured time point of 60 min (C60 mins) were determined for morphine by visual inspection of the individual plasma concentration–time profiles.
The area under the plasma concentration–time curve (AUC) was calculated using Excel and a linear trapezoid rule.
All other calculations were carried out using SPSS v 9.0. The Mann–Whitney U test was used to compare morphine pharmacokinetics in the intranasal and intravenous diamorphine groups. A p value of 0.01 was used for significance in view of multiple comparisons of the same data sets. Mann–Whitney U and χ2 tests were used to compare subject characteristics where appropriate.
Results
The two groups were comparable for weight, age, gender and dose of diamorphine (table 1). There were six girls in the intravenous group and eight in the intranasal group (χ2 p = 1.0).
Figures 2 and 3 show the individual plasma morphine time concentration profiles for each subject in the intravenous and intranasal groups, respectively. Note the different y axis scales. The profiles are summarised and shown together in fig 4.
The maximum plasma concentrations of morphine and the plasma concentration at 60 min were significantly lower following intranasal administration of diamorphine. Hence, the AUC was also significantly lower (table 2). Additionally, the maximum peak concentration was achieved more slowly following intranasal diamorphine than intravenous.
No adverse clinical events were detected following the administration of diamorphine during the study.
Discussion
The main strength of this study is that it has produced the first and only pharmacokinetic data on intranasal diamorphine in children. Its second strength is that it is the only comparison of intranasal with intravenous diamorphine, apart from one adult study with only four subjects.8 Also, samples were taken as early as 2 min, and so described the early peak associated with intravenous diamorphine administration. Previous studies have taken first samples at 5 min, thus missing this part of the pharmacokinetic profile.5
We have shown that diamorphine delivered by the intranasal route using drops produces a significantly attenuated and delayed peak of plasma morphine than produced by the same dose administered intravenously.
One of the limitations of this study is the number of subjects and samples, and this reflects the ethical constraints of working with invasive testing in children, the acute clinical setting, and opiate drugs. Despite these factors, we have produced pharmacokinetic profiles on more subjects than in previous studies of intranasal diamorphine in adults.5 6 7 8 10 16 17
Other limitations of this study were the fact that we were unable to analyse the plasma samples for all potentially active metabolites of morphine, and that the number of subjects was insufficient for the analysis of parallel pain scores. The plasma concentration of morphine that is required to provide effective analgesia is unclear. We have, however, provided comparative data from other studies that have reported plasma concentrations of morphine following diamorphine administration (table 3).
The implications of this study relate to individual clinical cases, guideline formation and subsequent research planning. Firstly, the study shows that adequate plasma levels of the active metabolite, morphine, are usually achieved following administration of diamorphine by the intranasal route. This may lead to greater uptake of the technique by clinicians who do not feel that there is enough evidence that intranasal diamorphine has an effect comparable to intravenous diamorphine. The current College of Emergency Medicine guideline contains the word “OR” between “intranasal” and “intravenous” opiate. Now, however, the nature and degree of difference in pharmacokinetic profiles between the two techniques can be a meaningful factor in the decision-making process.
In conclusion, we have carried out a productive and relevant pharmacokinetic study in the acute paediatric clinical setting. Our evidence supports the wider use of intranasal diamorphine, by showing that adequate plasma levels of morphine are usually achieved. However, intranasal diamorphine by nasal drops produces significantly attenuated and delayed peak plasma levels of morphine with lower levels at 1 h compared to intravenous diamorphine. Intranasal diamorphine may under-treat children’s pain in some circumstances when administered as drops at a dose of 0.1 mg/kg.
Acknowledgments
We are indebted to the children and parents who agreed to take part in this study, the staff of the A&E department who supported us, the staff of the department of Child Life and Health laboratories and Catherine Graham of the Wellcome statistics unit in Edinburgh for her input with the AUC calculations. Thanks to Henry McQuay, Nuffield Professor of Anaesthetics, University of Oxford for permission to use the diagram of diamorphine and its metabolites.
REFERENCES
Footnotes
Funding This project was funded by a grant from the British Association of Emergency Medicine, and the Research & Development Department, Lothian Universities Hospital Trust. Diagnostic Products Corporation donated one of the RIA kits. The funding bodies played no part in study design; in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication.
Competing interests None.
Ethics approval Ethics approval was obtained from the Lothian regional ethics committee.
Patient consent Parental consent obtained.
Provenance and peer review Not commissioned; not externally peer reviewed.