CLINICAL PBARMACOLOGY OF LIDOCALNE-PRILOCAINE CREAM Ilrr INFANTS ANNA TADDIO ...

285 Pages·1998·14.52 MB·English

CLINICAL PBARMACOLOGY OF LIDOCALNE-PRILOCAINE CREAM Ilrr INFANTS
ANNA TADDIO
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy,
Graduate Department of Pharmacy,
University of Toronto
8 Copyright by Anna Taddio 1997
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Clinical Pharmacology of Lidocaine-Prilocaine Cream in Infants
Doctor of Philosophy 1997
Anna Taddio
Graduate Department of Pharmacy, University of Toronto
Abstract
Introduction: Despite evidence that infants experience pain, analgesics are not administered
frequently during painfbl procedures. The objective of this research was to determine whether
procedural pain in infants could be diminished with topical lidocaine-prilocaine 5% cream
(EMLA). The following specific hypotheses were tested: EMLA is efficacious for treatment of
pain in infants undergoing vaccination and circumcision; EMLA is safe for treatment of pain in
infants undergoing circumcision and heel lancing; and untreated pain from circumcision has long-
term effects on infant pain behaviour that can be observed during routina vaccination.
Methods: Five studies were performed to test the hypotheses. The first study was a double-blind
randomized controlled trial of the efficacy of EMLA for treatment of pain during routine 4 or 6
month vaccination. Pain was assessed using behaviour, crying and visual analogue scale scores.
The second study was a retrospective analysis of vaccination pain scores of circumcised and
uncircumcised male infants from the first study. The third study was a double-blirid randomized
controlled trial of the efficacy and safety of EMLA for treatment of pain during neonatal
circumcision. Pain was assessed using facial activity, crying, heart rate, and blood pressure.
Safety was assessed by measuring methemoglobin, lidocaine, and prilocaine concentrations. The
fourth study was an observational study investigating vaccination pain responses among
uncircumcised male infants and circumcised male infants who participated in the third study. Pain
mfth
was measured using infant facial activity, crying, and visual analogue scale scores. The study
was an open trial of the safety of EMLA in preterm neonates aged 30 to 37 weeks gestation.
Safety was assessed in a similar way as in the third study.
Results: EMLA was efficacious for pain management during vaccination and circumcision.
Lidocaine and prilocaine were measurable in low concentrations and methernoglobin
concentrations were not elevated after administration of EMLA. Circumcised infants
demonstrated an increase in pain response during routine vaccination compared with
uncircumcised infants. Infants pre-treated with EMLA for pain from circumcision scored between
the uncircumcised infants and the infants circumcised with a placebo.
Conclusions: EMLA decreases procedural pain in infants.
Acknowledgments
I wish to thank my supervisor, Dr. Gideon Koren, for his inspiration and confidence in my
abilities. Appreciation is also expressed to Dr. Thomas R. Einarson, Dr. Joel Katz, Dr. J. Steven
Leeder, and Dr. Bonnie Stevens for their respective contributions to this research effort. Finally, I
wish to thank my husband, Andrew Lane Llersich, my sister, Lucia, and my parents, Nicola and
Nina, for their loving support.
I would like to acknowledge the support provided by the Connaught Scholarship, The
Hospital for Sick Children's Trainee Start-up Research Fund, Astra Pharma Canada, and the
Medical Research Council of Canada-Pharmaceutical Manufacturer's Association of Canada.
Permissions to reproduce published papers in this thesis were obtained from the respective
journals.

Clinical Pharmacology ................................................................................................... 47
Pharmacokinetics ........................................................................................................... 51
Adverse Effects ............................................................................................................. 58
Summary and Research Strategy ......................................................................................... -69
CHAPTER 1 . EMLA IN INFANT VACCINATION. ............................................................... -70
Hypothesis 1 ....................................................................................................................... -71
Abstract .............................................................................................................................. -72
Introduction ..... ...................... . ................................................................................... 7 3
Methods .............................................................................................................................. 73
Results .............. ............. , ............................................................................................... 78
Discussion .......................................................................................................................... -82
. .
Statement of Slgruficance. ................................................................................................... -86
CHAPTER 2 . ASSOCIATION BETWEEN INFANT VACCINATION PAIN AND
NEONATAL CIRCUMCISION .......................................................................................... 87
Hypothesis 2 ........................................................................................................................ 88
Abstract .............................................................................................................................. -89
Introduction ........................................................................................................................ 89
Methods .............................................................................................................................. 90
Results ..................................... .. ............................................................ 91
Discussion ........................................................................................................................... 92
. .
Statement of S~gndicanc.e.. .................................................................................................. 93
CHAPTER 3 . EMLA IN NEONATAL CIRCUMCISION ........................................................ 94
Hypotheses 3 and 4 ............................................................................................................ -96
Abstract. .......................................................... .... ................................................................ 97
Introduction .................... .............................................................................................. 98
..,
Methods ............................................................................................................................. -99
............................................R......e...s...u....l..t...s... .. 103
Discussion ......................................................................................................................... 107
. .
Statement of Slgntficance ................................................................................................... 111
CHAPTER 4 . CONFIRMATION OF LONG-TERM SEQLJELAEO F PAIN .......................... 112
Hypotheses 5 and 6 ......................................................................................................... 112
vi

List of Tables
Table 1 . Chemical Formulation of EMLA.... .................................................................. 41
Table 2 . Procedures Involving Needle Pain ................................................................... 48
Table 3 . Superficial Surgical Procedures ....................................................................... 48
Table 4 . Plasma Concentrations of Lidocaine and Prilocaine After Application of
EMLA in Infants ................................................................................................ 52
Table 5 . Pharmacokinetics of Lidocaine and Prilocaine in Adult Subjects ...................... 54
Table 6 . Modified Behavioral Pain Scale (MBPS) ......................................................... 77
Table 7. MBPS and VAS Pain Scores for EMLA and Placebo ...................................... 79
Table 8 . Cry Characteristics for Subjects receiving EMLA and Placebo ......................... 81
Table 9 . Demographic Characteristics of the Neonates in the Lidocaine-Prilocaine
and Placebo Groups and Their Mothers ............................................................ 104
Table 10. Response to Circumcision in the Lidocaine-Prilocaine and Placebo
Groups ............................................................................................................. 105
Table 1 I . Plasma Lidocaine and Prilocaine Concentrations in the Lidocaine-
Prilocaine Group .............................................................................................. 107
Table 12. Flow of Participating Infants Through Trial ................................................. 121
Table 13 . Demographic Characteristics of Wants at Time of Vaccination .................... 123
Table 14. Revised Infant Temperament Questionnaire Scores ..................................... 123
Table 15. Birth Characteristics .................................................................................... 124
Table 16 . Relation Between Infant Characteristics and Pain Response ......................... 126
Table 17. Subject Characteristics ................................................................................ 137
Table 18 . Methemoglobin Levels (%) after Application of Lidocaine-Prilocaine
Cream (EMLA) to Pretem Neonates 30 to 3 7 Weeks of Gestational Age ........ 138
Table i 9 . Efficacy Studies of EMLA for Procedural Pain in Neonates ......................... 158
Table 20 . Meta-Analysis Results for Heart Rate Changes During Circumcision ........... 160
Table 2 1. Safety Studies with EMLA in Neonates ....................................................... 166
List of Figures
Figure I . Lidocaine ....................................................................................................... 41
Figure 2 . Prilocaine ...... .............. ............................................................................ 4 2
Figure 3 . Reduction of Methemoglobin ........................................................................ -62
Figure 4 . Pain Response During HIB Injection in Circumcised and Uncircumcised
Boys .................................................................................................................. 93
Figure 5 . Mean Facial Activity Scores during Circumcision in the Lidocaine-
Pdocaine and Placebo Groups .................................................................... 110
Figure 6 . Infant Pain Response to Vaccination for Infants in All Groups ...................... 127
List of Appendices
Appendix 1. EMLA in Subcutaneous Injection ........................................................... -218
Appendix 2 . EMLA in Intramuscular Injection ............................................................ 227
Appendix 3 . Pain Assessment Too1 for Vaccination ..................................................... 237
Appendix 4 . Additional Notes to Chapter 1 ................................................................. 252
Appendix 5 . Safety of EMLA in Piglets ....................................................................... 255
Appendix 6 . Additional Notes to Chapter 3 ................................................................. 269
Appendix 7 . Additional Notes to Chapter 4 ................................................................. 273
Appendix 8. Additional Notes to Chapter 5 ................................................................. 274