TUXI pholcodine clinical consequences

1
TUXI (pholcodine) clinical consequences ?

• Erik Florvaag MD PhD
• Laboratory of Clinical Biochemistry and Section
  for Clinical Allergology, Department of
  Occupational Medicine
• Haukeland University Hospital,
• Institute of Internal medicine,
• University of Bergen
• Norway

2
TUXI (pholcodine) clinical
consequences ?

• Stimulation of IgE and IgE-antibodies
• ? Risk of anaphylaxis during general
  anaesthesia
• Neuro muscular blocking agents (NMBAs)
• ? Diagnosing elevated serum IgE
• Total IgE gt 1000 kU/L

3
Anaphylaxis during general anaesthesia

• Large variations in reported frequencies between
  nations
• 1/5 000 - lt 1/20 000
• NMBAs most frequent culprit drugs
• Most reactions IgE mediated
• 50 without prior exposure to anaesthetics

Vecuronium
Photos Anne Berit Guttormsen. With permission
from the patient
4
Norsk nettverk for anafylaksi under anestesi -
NARA

• Etablerte standardiserte håndteringsstrategier
• Akutte behandlings- og diagnostikk-prosedyrer
• Allergologisk utredning

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Akutte behandlings- og diagnostikk-prosedyrer

• Serologi
• s-Tryptase 3 punktsprofil
• s-IgE
• Detaljer om anestesi og reaksjon
• Raporter til skadeutvalg og legemiddelverk
  (RELIS)
• Pasientinformasjon

Anafylaksipakken
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Standardisert allergologisk utredning

• Sykehistorie
• Hudtester
• Prikktest EAACI
• Intrakutantest AAACI/FN
• In vitro tester
• sIgE
• Histaminfrigjøringstest (HR-T)
• Konklusjoner, pasientinformasjon

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Anaphylaxis during anaesthesia in Norway A six
year single centre follow up studyT. Harboe, AB.
Guttormsen, A. Irgens, T. Dybendal, E. Florvaag.
Anesthesiology 2005 102897-903.

• Main conclusions 83 reactions
• IgE mediated anaphylaxis 71.1
• NMBAs 93.2
• Latex 3.6
• Non IgE mediated 28.9
• In hospital frequency (HUH) 15 200 (CI 13
  125-114 285)
• IgE ab to Suxamethonium 120 risk of
  anaphylaxis to Sux

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Screening IgE to NMBAs

• 2000
• Morphine RIA (Baldo) established
• 30 control sera total IgE gt 1000 kU/L
• ? 30 positive MO-RIAs
• ? All could be inhibited with Morphine
• ie. IgE binding to Morphine was specific !

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IgE antibodies to Morphine Norway

• Why are so many Norwegians IgE sensitized to
  Morphine ?
• Is it of any clinical significance ?
• MO not useful for screening IgEs to NMBA

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Differences in reported frequencies between
countries - Norway vs Sweden

• Anaphylaxis related to rocuronium (Esmeron)
• NMA, 2000
• France 16 500
• Norway 15 000
• Sweden 183 300
• Denmark 0180 000
• USA 1500 000

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The WHO Adverse Drug Reactions database in Uppsala

• Figure 6.
• Cumulative spontaneous reports from Norway (open
  bars) and Sweden (filled bars)
• per May 6th 2004
• allergic, anaphylactic and anaphylactoid
  reactions to NMBAs.

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Differences between countries

• Possible causes
• Reporting bias
• Genetics
• Anaesthetic practices
• Diagnostic facilities
• Differently sensitised populations

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Differently sensitised populationsNorway vs
Sweden

• Different exposures
• QAI containing epitopes (Baldo, 1985)
• ? Daily life/household chemicals
• ? Drugs

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Daily life/household chemicals
Table III. Calculated content of MOR or SUX
reactive material, as measured by IgE-antibody
inhibition, in some house hold
chemicals.
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Exposure to drugs
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Pholcodine exposure - Norway

• Tuxi Weifa
• Pholcodine 2 mg/mL
• OTC (100 mL)
• 5-9 years 2.5 mL q/t.i.d
• 9-12 years 5 ml t.i.d
• gt 12 years 10 mL t.i.d
• Side effects
• Less infrequently Itching, allergic skin lesions
• Very infrequently Erythema multiforme,
  Stevens-Johnsons syndrome, toxic epidermal
  necrolysis, anaphylaxis

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Schematic illustration of the structures of MOR,
PHO and SUX.
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Morphine is monovalent for two, non-cross
reacting allergenic epitopes

• QAI Morphine Mo

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Prevalence of IgE antibodies to morphine.
Relation to the high and low incidences of NMBA
anaphylaxis in Norway and Sweden, respectively.
E. Florvaag, S.G.O. Johansson, H. Öman, L.
Venemalm, F.Degerbeck, T. Dybendal and M.
Lundberg Acta Anaesthesiol Scand
200549437-444
Bergen
Stockholm
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Pholcodine stimulates a dramatic increase of IgE
in IgE-sensitized individuals. A pilot study.E.
Florvaag, S.G.O. Johansson, H. Öman,T. Harboe, A.
Nopp Allergy 2006 6149-55.
? IgE pholcodine
O IgE suxame-thonium
Total IgE response after pholcodine exposure
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Pholcodine exposure study
22
Pholcodine exposure study
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Exit TUXI

• The Norwegian producer Weifa AS
• - marketing lisence not renewed by 26.03.2007
• The Norwegian Medicines Agency (NMA)
• - strongly supportive of this decision

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Risk of IgE sensitization to Suxamethonium

• If IgE sensitized to PHO
• 7-40 risk of IgE sensitization to SUX
• Dependent on levels of
• total IgE
• IgEab to PHO

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Estimated risks of anaphylaxis (NMBA) during
general anaesthesia Norway

• If IgE sensitized to SUX (HUH)
• Risk of anaphylaxis to Suxa 1/20
• General risk of anaphylaxis 1/5200

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Diagnosing S-IgE gt 1000 kU/L Norway 2006

• S-IgE 1000-5 000 kU/L
• 33 related to PHO sensitization
• S-IgE gt 5 000 kU/L
• 74 related to PHO sensitization

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Diagnosing S-IgE gt 1000 kU/L Norway 2006

• Diagnostic consequences
• History Used TUXI last 5 years ?
• Analysis IgEab to PHO, (MOR), SUX
• Therapeutic consequences
• Stop PHO exposure !
• Medical certificate if IgE to SUX
• stating level of IgE to SUX
• Probable increased risk of anaphylaxis to
  SUX/NMBAs
• Monitor normalization of IgE and IgEab
• IgE SUX lt 0.35 kUA/L

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A typical Pholcodine case
Male FH 1972 Not allergic. Last few weeks general
itching and discrete urticarial rash. Had last
taken TUXI two years ago

• 20.09.06 Laboratory of Clinical Biochemistry
• S-IgE 9 600 kU/L lt120
• S-F4-Hvete 0.41 kUA/L lt0.35
• S-T2-Gråor 0.41 kUA/L lt0.35
• S-T4-Hassel 0.69 kUA/L lt0.35
• S-ECP 33.1 ug/L lt 22.0
• S-Folkodin 17.0 kUA/L lt0.35
• S-Morfin 15.0 kUA/L lt0.35
• S-C202-Suxameth. 4.70 kUA/L lt0.35

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Anaphylaxis during anaesthesia
perspectives from Bergen and Stockholm -

• Bergen Group
• Anne Berit Guttormsen
• Torkel Harboe
• Turid Dybendal
• Erik Florvaag

• Stockholm/Uppsala Group
• S.G.O. Johansson
• H. Öman
• L. Venemalm
• F. Degerbäck
• M. Lundberg

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International sales of PholcodineWHO 1994-98
doses pr million inhabitants

• France
• Norway
• United Kingdom
• New Zealand
• Australia
• Sweden
• Denmark

• 2 936
• 2 773
• 1 552
• 1 458
• 1 240
• 0
• 2