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Systematic review
Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review
  1. Silke Gastine1,
  2. James D Morse2,
  3. Miriam TY Leung3,
  4. Ian Chi Kei Wong4,
  5. Richard F Howard5,
  6. Emily Harrop6,
  7. Christina Liossi7,8,
  8. Joseph F Standing8,9,
  9. Satbir Singh Jassal10,
  10. Richard D Hain11,
  11. Simon Skene12,
  12. Kate Oulton13,
  13. Siew L Law4,
  14. Wan T Quek4 and
  15. Brian J Anderson14
  1. 1Great Ormond St Institute of Child Health, University College London, London, UK
  2. 2Department of Pharmacology & Clinical Pharmacology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand
  3. 3Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Hong Kong
  4. 4Research Department of Practice and Policy, University College London School of Pharmacy, London, UK
  5. 5Department of Anaesthesia and Pain Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  6. 6Helen and Douglas House Hospices, Oxford, UK
  7. 7School of Psychology, University of Southampton, Southampton, UK
  8. 8Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  9. 9Department of Immunity and Inflammation, University College London, London, UK
  10. 10Palliative Care, Rainbows Hospice for Children and Young Adults, Loughborough, UK
  11. 11All-Wales Managed Clinical Network in Paediatric Palliative Medicine, Cardiff and Vale University Health Board, Cardiff, UK
  12. 12Faculty of Arts and Human Sciences, Surrey Clinical Trials Unit, University of Surrey, Guildford, UK
  13. 13Centre for Outcomes and Experience Research in Children's Health, Illness and Disability, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  14. 14Department of Anaesthesiology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand
  1. Correspondence to Professor Brian J Anderson, Department of Anaesthesiology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, Auckland, New Zealand; briana{at}adhb.govt.nz

Abstract

Background Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation.

Aim To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics.

Design A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed.

Review sources PubMed (1960–2020); EMBASE (1980–2020); IPA (1973–2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration.

Results The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4–88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites.

Conclusions We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4–13 years.

  • paediatrics
  • pain
  • chronic conditions
  • clinical decisions
  • pharmacology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

http://dx.doi.org/10.1136/bmjspcare-2021-003461

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

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    • Contributors IW is the Chief Investigator of the DIamorphine Paediatric Palliative Evaluation of feasibility of Randomised controlled trial (DIPPER) study and conceived the project and takes overall responsibility for the conduct of this study review. IW is responsible for the overall content and is the guarantor. SLL and WTQ screened titles and abstracts of articles and retrieved full texts of relevant articles as shown in supplementary tables S1 and table 1. MTYL and JDM created and reviewed PK analysis and graphics. RFH, BJA and JDM contributed to the expert consensus and contributed results and wrote the discussion section. SSJ has been involved with ongoing discussions and critically reviewed the manuscript. All other authors (EH, CL, JFS, SSJ, SS, KO) are involved in DIPPER studies, helped plan this study and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

    • Funding This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0317–20036). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

    • Competing interests Professor Ian Wong is the founder of Therakind Ltd which was funded by Wockhardt Pharmaceutical to conduct the clinical studies for Ayendi® (diamorphine hydrochloride) licensing application.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.