1. Monday, March 21, 20161 NPPG 2015 Is there life after Codeine? Dr Helen Sammons Associate Professor of Child Health University of Nottingham Derbyshire Children’s Hospital

2. Monday, March 21, 2016 NPPG 2014 2 Introduction I will take you on a journey. Concerns Pharmacology Alerts Reactions Alternatives Where are we now and future questions?

3. Monday, March 21, 2016 Why?

4. 4 Codeine- my journey Conference ESDP 2006

5. Monday, March 21, 20165 Pharmacology Codeine is a prodrug of morphine Polymorphisms causing differences in the activity of cytochrome P-450 isoenzyme 2D6 (CYP2D6) Classified as slow, intermediate, fast or ultra fast metabolisers 7–10% of Caucasians are poor metabolisers Ultra fast metabolisers - 0.7% of the general population but up to 30% of children of Middle Eastern and African/Ethiopian descent

7. Variation in ethnic populations of Ultra fast metabolisers PopulationUM Genotypes/Phenotypes ( ↑ Activity) Prevalence % African/Ethiopian 4 UM (active duplicate genes)29% African American 5, 6 UM (three active duplicate genes) 6.5% Asian 7, 8, 9 UM (active duplicate genes)1.2% Caucasian 5, 6 UM (three active duplicate genes) 3.6% - 6.5% Greek 10 CYP2D6*2xN/UM6.0% Hungarian 11 UM (active duplicate genes)1.9% Northern European 10, 12 UM (active duplicate genes)1-2% Table collated by FDA

8. Safety of codeine 2006 First report of neonatal death following codeine in breast feeding mother 15 th August 2012 Further 3 reports codeine deaths post surgery in literature and 1 near death. FDA organise a safety review 20 th Feb 2013 FDA update post review 2007 FDA advice for codeine in breastfeeding Sept 2012 MRHA requested EMA review 14th June 2013 EMA safety advice Then MHRA safety alert issued

9. FDA- Safety review of codeine A search of FDA’s Adverse Event Reporting System (AERS) database 1969 to May 1, 2012 Identified 13 cases of paediatric death (n=10) or overdose (n=3) associated with codeine. Age from 21 months to 9 years. 8/13 post tonsillectomy, 3/13 resp tract infections 7/13 had genetics performed –3 ultrametabolisers, 3 extensive metabolisers and 1 likely Ultrametaboliser

10. 21/03/201610

11. Where from here? Where are we using it? What are the alternatives and issues? Local and National Level Formulations Protocols TTO packs 21/03/201611

12. Monday, March 21, 201612 What we did: Nationally- 1.Wrote and met with MHRA 2.Liaison of NPPG, RCPCH and APA 3.Paediatric Pain Travelling Club / NPPG 4.Interim statement 5.Final Statement Locally- -Audits, education, new policies and safe change over

13. 3/21/2016Event Name and Venue13

14. 3/21/2016Event Name and Venue14

15. Where are we now? 3/21/201615 NPPG 2014

16. Monday, March 21, 201616 Tonsillectomy Tonsillectomy (including adenotonsillectomy) is a common surgical procedure in children Approximately 18,000 carried out per year in the UK Usually prescribed a combination of Paracetamol and NSAID Significant risk of breakthrough pain for 5–8 days following tonsillectomy 13-40% of children present with pain to GP in the post-operative period

17. Arch Dis Child 2014;99:A172 doi:10.1136/archdischild-2014-306237.390 17 National audit of analgesia post tonsillectomy Ten UK centres 6/10 units reported changing practice post MHRA All except one centre used paracetamol and ibuprofen (one diclofenac) Breakthrough pain relief- codeine in 2 units, morphine in 2 units, tramadol in 2 units and dihydrocodeine in 1 unit 3 centres did not use any additional TTO analgesia Represent approximately 25% of the tonsillectomies in children per year.

18. What is your hospital currently using as TTO analgesia for tonsillectomy? 3/21/201618 NPPG 2014

19. 3/21/2016 NPPG 2014 19

20. Tramadol 3/21/2016 NPPG 2014 20

21. Dihydrocodeine 21/03/2016 NPPG 2014 21

22. Codeine 21/03/2016 NPPG 2014 22

23. Monday, March 21, 201623 What are our alternatives?

24. Monday, March 21, 201624 Oral Morphine Unlicensed below 1 yr of age Not a controlled drug in 10mg/ml strength (but in many hospitals still treated as) BNFc dose – 200-300mcg/kg but experience in hospital ? TTO dose 100 or 200mcg/kg Give a limit number of doses? In hospital observation of doses What about the very young patients?

25. Monday, March 21, 201625 Dihydrocodeine Unlicensed below 4 years Parent compound does have some analgesic effect so less genetic variation than codeine BNFc dose –available to 1 year Oral solution 10mg/5ml. What about the very young patients? Oral solution contains some alcohol.

26. Monday, March 21, 201626 Tramadol Used in Europe Now a schedule 3 controlled drug Lack of available and appropriate formulations in the UK at present- capsules, soluble tablets and drops (100mg/ml (imported) BNFc dose –none for under 12 years & unlicensed One of the same metabolic pathways as codeine but has a reduced effect on resp drive compared to other opiates Nausea and vomiting

27. Monday, March 21, 201627 Oxycodone Not regularly used in UK, no license Formulations- oral solution, Oxynorm®, Longtec®, and Oxycontin® not licensed for use in children. Capsules licensed over 12 years Potency twice that of morphine Time required to have knowledge of analgesia

28. Monday, March 21, 201628 What questions do we still have ? Which is the best analgesic for breakthrough pain? Do other opiates provide a greater margin of safety in those with obstructive sleep apnoea? Which is the most palatable formulation? What is the best way to give parental education and guidance?

29. Parent leaflets

31. Monday, March 21, 2016 NPPG 2014 31 Thank you Any Questions?