Safety and Efficacy of Non-Prescription (OTC) Analgesics and NSAIDs: Proceedings of the International Conference held at The South San Francisco Conference Center, San Francisco, CA, USA on Monday 17th March 1997

154 Pages·1998·4.24 MB·English

by  L. F. Prescott (auth.)

SAFETY AND EFFICACY OF
NON-PRESCRIPTION (OTC) ANALGESICS
AND NSAIDs
SAFETY AND EFFICACY OF
NON-PRESCRIPTION (OTC)
ANALGESICS AND NSAIDs
Proceedings of the International Conference
held at The South San Francisco Conference Center,
San Francisco, CA, USA
on Monday 17th March 1997
Editors:
K.D. Rainsford
Division 0/ Biomedical Sciences, School 0/ Science and Mathematics,
Sheffield HaI/am University, Sheffield, UK
M.C. Powanda
MIP Biomedical Consultants, LLC, Mill Valley, CA, USA
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging-in-Publication Data is available.
ISBN 978-94-010-6044-8 ISBN 978-94-011-4878-8 (eBook)
DOI 10.1007/978-94-011-4878-8
Printed on acid-free paper
All Rights Reserved
© 1998 Springer Science+Business Media New York
Originally published by Kluwer Academic Publishers,New York in 1998
Softcover reprint of the hardcover 1s t edition 1998
No part of this publication may be reproduced or utilized in any form or by any means, electronic,
mechanical, including photocopying, recording or by any information storage and retrieval system,
without written permission from the copyright owner.
CONTENTS
List of Contributors, Co-Authors and Participants vii
Preface ix
1. Current status of issues concerning the safety of over-the-counter
analgesics and nonsteroidal anti-inflammatory drugs
LF Prescott
2. Review of published clinical trial data on the adverse reactions from
ibuprofen and paracetamol/acetaminophen at OTC dosages
KD Rainsford 11
3. Adverse drug reactions in the gastrointestinal system attributed to
ibuprofen
DA Henry, A Drew, S Beuzeville 19
4. The epidemiology of non-gastrointestinal adverse reactions from
OTC analgesics
JK Jones, LJ Miwa 47
5. Renal safety of ibuprofen: pharmacokinetic aspects
DC Brater 73
6. Therapeutic considerations from pharmacokinetics and metabolism:
ibuprofen and paracetamol
GG Graham, MK Milligan, RO Day, KM Williams, JB Ziegler 77
7. Acute human toxicity from NSAIDs and analgesics
GN Volans, R Fitzpatrick 93
8. Regulatory considerations concerning safety of OTC NSAIDs and
analgesics
GE Ehrlich 101
9. Evaluation of analgesic mechanisms and NSAIDs for acute pain
using the oral surgery model
RA Dionne 105
10. Multicentre study of the efficacy of ibuprofen compared with
paracetamol in throat pain associated with tonsilitis
F Boureau 119
11. Ibuprofen plus caffeine in the treatment of migraine
WF Stewart, RB Lipton 123
v
vi Contents
DEBATE - Safety and efficacy issues with OTC anaigesics/NSAIDs
Chair: KD Rainsford. Panel: Above contributors and WW
Buchanan, BA Callingham, N Bellamy, DE Furst 125
Index 149
LIST OF CONTRIBUTORS, CO-AUTHORS AND
PARTICIPANTS
Professor N Bellamy Dr BA Callingham
Division of Rheumatology Department of Pharmacology
University of Western Ontario University of Cambridge
London Health Sciences Centre - Victoria Tennis Court Road
Campus Cambridge, CB2 I QJ
Suite 303, Colbourne 3 UK
London, Ontario, N6A 4G5
Canada Professor W Dawson
Bionet
Dr S Beuzeville Cheviot
Department of General Medicine South Town Road
Newcastle Mater Hospital Medstead, Alton
Newcastle, NSW Hants, GU34 5PP
Australia UK
DrFBoureau Professor RO Day
Centre d'Evaluation et de Traitement de la Department of Clinical Pharmacology and
Douleur Toxicology
Hopital Sainte-Antoine St Vincent's Hospital
184 rue du Faubourg Saint Antoine Victoria Street
75571 Paris Cedex 12 Dariinghurst, NSW 2010
France Australia
Professor DC Brater Dr RA Dionne
Department of Medicine Clinical Pharmacology Unit
Indiana University Medical Center National Institute for Dental Health
Emerson Hall, Room 317 NIH, 9000 Rockville Pike
Indianapolis, IN 46202-5124 Bethesda, MD 20892
USA USA
Professor WW Buchanan DrA Drew
Osler Health Institute Department of Clinical Toxicology
565 Sanatorium Road Newcastle Mater Hospital
Hamilton, Ontario, L9C 7N4 Newcastle, NSW
Canada Australia
DrRADionne Professor GE Ehrlicb
Chief - Clinical Pharmacology Unit Department of Medicine
National Institutes for Dental Research University of Pennsylvania
NIH, 9000 Rockville Pike Philadelphia, PA
Bethesda, MD 20892 USA
USA
vii
viii List of Contributors
Dr R Fitzpatrick Dr MK Milligan
Medical and Toxicology Unit School of Physiology and Pharmacology
Guy's and St Thomas' Hospital Trust University of NSW
Bromley Road Sydney, NSW 2052
London, SE4 5ER Australia
UK
DrIJ Miwa
Professor DE Furst The Degge Group
Virginia Mason Research Center 1616 North Fort Myer Drive
1000 Seneca Street Suite 1430
Seattle, WA 98101 Arlington, VA
USA USA
Professor GG Graham Professor LF Prescott
School of Physiology and Pharmacology Clinical Pharmacology Unit
University of NSW University Department of Medicine
Sydney, NSW 2052 Western General Hospital
Australia Crewe Road
Edinburgh, EH4 2XU
DrDA Henry UK
Faculty of Medicine and Health Sciences
Discipline of Clinical Pharmacology Professor KD Rainsford
University of Newcastle and Mater Division of Biomedical Sciences
Misericordiae Hospital School of Science and Mathematics
Callaghan, NSW 2308 Sheffield Hallam University
Australia Pond Street
Sheffield, S 1 1W B
Dr JB Hickham UK
Department of Medicine
Indiana University Medical Center Professor WF Stewart
Emerson Hall Department of Epidemiology
Indianapolis, IN 46202-5124 Johns Hopkins University
USA 615 North Wolfe Street, Room 6033
Baltimore, MD 21205
DrJK Jones USA
The Degge Group
1616 North Fort Myer Drive Dr G Volans
Suite 1430 National Poisons Information Service
Arlington, VA Medical Toxicology Unit
USA Guy's and St Thomas' Hospital Trust
Bromley Road
Dr RB Lipton London, SE4 5ER
Department of Neurology UK
Albert Einstein Medical College
Bronx, NY Dr KM Williams
USA Department of Clinical Pharmacology and
Toxicology
St Vincent's Hospital
Darlinghurst, NSW 2010
Australia
PREFACE
The availability of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)
sold over-the-counter (OTC) to the public without prescription has become an issue of
major concern in recent years. The problem has been highlighted in the UK, USA and
other countries because of the continuing high rates of cases of poisoning and the
influence of switching from prescription-only status for many NSAIDs to OTC sale
brought about, in a large part, by governments and health maintenance organisations
(especially in the USA) anxious to save on costs of these drugs. Concern in the UK
about poisoning from paracetamol and the appreciable morbidity and mortality from
aspirin was such that a major review was initiated in 1996 by the UK government's
Medicines Control Agency (MCA). Doubtless, many other governments have also
undertaken reviews of the safety issues concerning OTC analgesics and NSAIDs. In
the UK the situation has culminated in the decision announced in August 1997, as this
book was going to press, that the number of tablets/capsules of the solid dosage forms
of paracetamol and aspirin would be limited for sale OTe. This decision was
essentially based on the need to limit the unit quantity of these drugs so as to reduce
the likelihood of poisoning with paracetamol and the development of gastrointestinal
and other more serious side-effects from aspirin. Time.w ill tell whether these new
regulations will influence the occurrence of these adverse events. In the meantime,
wider issues concerning safety and efficacy of OTC analgesics and NSAIDs remain to
be resolved.
This Symposium held at the South San Francisco Conference Center (USA) on
Monday, 17 March, 1997 enabled leading authorities from throughout the world to
come together and discuss the central issues concerning the safety and efficacy of OTC
analgesics and NSAIDs at what was a timely period for the reasons outlined above. The
conference opened with a series of presentations on the central themes - overall safety
evaluation and assessment of the current status, the clinico-epidemiologic evidence of
adverse drug reactions from different drugs, pharmacokinetic and pharmacotoxicologic
mechanisms and the expanding use of the drugs for pain and other states. Particular
interest was addressed to the potential for NSAIDs to be used prophylactically to
prevent certain chronic inflammatory/degenerative diseases (e.g. Alzheimer's and
related dementias, colon cancer). Thus, it was possible to bring together potential ability
('good news') against the background of an evaluation of safety.
The extensive debate which followed in formal presentations was exciting for
enabling the core issues to be examined and assessed by experts who have been at the
cutting edge of regulatory, medical and scientific evaluations of OTC analgesics/
NSAIDs. Most important issues were thoroughly discussed and diverse areas critically
evaluated and presented to enable others to gain the benefit of seeing the issues clearly
for themselves. The full debate is recorded here and, with some minor editing, faithfully
records these issues from which we hope the reader will get a good sense of enthusiasm
ix
Rainsford KD, Powanda MC (eds.), Safety and Efficacy ofN on· Prescription (OTC) Analgesics and NSAIDs, ix-x.
© 1998 Kluwer Academic Publishers.
x Preface
anti interest that attended the debate.
This symposium would not have been possible without the generous financial help of
a number of organisations and willing advice and help of many participants. We
acknowledge with thanks the financial support of Boots Healthcare International
(Nottingham, UK) and the assistance of Dr Harvey Homan, Mrs Sharon Buckle, Mr
John Morrissey and their colleagues. Our thanks for financial support to Whitehall
Robins (Madison, NJ, USA) and that from a number of other companies and
organisations (listed in Inflammopharmacology 1997;5: 159--60) whose support enabled
conference participants to attend this meeting and give insight and contribute to
discussions on the many important items that were considered. The conference would
not have been so successful without those who participated in the meeting giving up
much time to attend and giving so much valuable insight from their experience.
We would also like to acknowledge the invaluable help of Dr Sherwood Reichard
and Ms Nancy Bailey (MAPS, August, GA, USA) for excellent conference organisa
tion; the staff of the South San Francisco Conference Center for their willing help and
cooperation that enabled the conference to run smoothly and for the use of their
extensive facilities; the secretarial and administrative help of Mrs Veronica Rainsford
Koechli and Mrs Marguerite Lyons; and the help of Mr Phil Johnstone and colleagues
at Kluwer Academic Publishers who worked hard to get this publication out with
expedition so as to be timely for all to read.
The Organisers of this Conference have been solely responsible for control of
content and selection of presenters, debates and moderators at this conference. The
have made every effort to ensure the data has been objectively selected and presented,
with favourable and unfavourable information and balanced and critical discussion
and evaluation on all products and/or alternative therapies. All the papers in these
proceedings have been peer-reviewed.
K.D. Rainsford (Sheffield, UK)
M.e. Powanda (Mill Valley, CA, USA)
Organisers and Editors
August 1997
1.
CURRENT STATUS OF ISSUES CONCERNING THE SAFETY
OF OVER-THE-COUNTER ANALGESICS AND
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
L.F. PRESCOTI
Clinical Pharmacology Unit and Clinical Research Centre, Western General Hospital,
Edinburgh, EH4 2XU, UK
INTRODUCTION
The safety of over-the-counter (OTC) analgesics has long been an issue and toxicity has
led to the abandonment of a number of these drugs over the years. Acetanilide enjoyed
great popularity for decades but it caused methaemoglobinaemia and haemolysis and
has long since disappeared. Phenacetin lasted longer but it was mistakenly believed to
be the primary cause of analgesic nephropathy and it too has virtually gone from the
stage. There are important international and regional differences in the fashions of
OTC analgesic use but these differences are not based On considerations of risk or
benefit. Commercial interests also influence the availability and use of OTC analgesics
and the overall result is a slowly changing scene in which the choice of agents and the
rank order of their popularity varies in different regions over the years. The picture is
further complicated by the use of analgesic combinations and the inclusion of these
drugs in a wide range of remedies for common self-limiting conditions. Currently
available OTC analgesics include aspirin and nonsteroidal anti-inflammatory drugs, p
aminophenol derivatives and the pyrazoles (Table I). There are specific toxicological
problems with all of these drugs and special problems arise from their uncontrolled use
by virtually the whole population. The safety assessment of OTC analgesics must
include the consequences of abuse and overdosage, their use by potentially vulnerable
subjects such as the young, old, pregnant, and ill, the potential for adverse drug
interactions and their pharrnacokinetic properties (Table 2).
Nonprescription ibuprofen has been marketed in the USA and UK for some 10
years and naproxen has become available more recently in the USA. The introduction
of these nonsteroidal anti-inflammatory drugs to the OTC marked caused some initial
concern as they both have considerable potential for toxicity, particularly with respect
to the gastrointestinal tract and the kidney. The liberalisation of these drugs should not
be interpreted as an indication of their inherent safety [1]. The focus of attention is
inevitably directed towards ibuprofen as it is now well established as an OTC analgesic
and there has been considerable experience of its use in this situation.
Rainsford KD. Powanda Me (eds.), Safety and Efficacy of Non-Prescription (aTe) Analgesics and NSAIDs. 1-9.
© 1998 Kluwer Academic Publishers.