Table Of ContentBotulinum Toxin in Painful Diseases
Series Editor
H. Reichmann
Dresden
Pain and Headache
Vol. 14
Volume Editor
W.H. Jost
Wiesbaden
57 figures and 31 tables, 2003
Basel · Freiburg · Paris · London · New York ·
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Botulinum Toxin in
Painful Diseases
Prof. Dr. med. Wolfgang H. Jost
Department of Neurology and
Clinical Neurophysiology
German Clinic of Diagnostics
Wiesbaden (Germany)
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and
Index Medicus.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that durg selection and
dosage set forth in this text are in accord with current recommendations and practice at the time of publication.
However, in view of ongoing research, changes in government regulations, and the constant flow of information
relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for
any change in indications and dosage and for added warnings and precautions. This is particularly important
when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or
utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying,
or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2003 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 0255–3910
ISBN 3–8055–7500–9
Library of Congress Cataloging-in-Publication Data
Botulinum toxin in painful diseases / volume editor, W. H. Jost.
p. ; cm. – (Pain and headache ; v. 14)
Includes bibliographical references and index.
ISBN 3–8055–7500–9 (hard cover : alk. paper)
1. Botulinum toxin–Therapeutic use. 2. Pain–Chemotherapy. 3. Analgesia. I. Jost,
Wolfgang H. II. Series.
[DNLM: 1. Pain–drug therapy. 2. Botulinum Toxin Type A–therapeutic use. 3.
Neuromuscular Agents–therapeutic use. WL 704 B751 2003]
RB127.B688 2003
615�.329364–dc21
2002043380
Art. No. 16594
Contents
VII Preface
1 Pharmacology of Botulinum Neurotoxins
Bigalke, H. (Hannover); Naumann, M. (Würzburg)
14 Botulinum Toxin A in Pain Management: Mechanisms of Action
and Rationale for Optimum Use
Göbel, H. (Kiel)
23 Myofascial Pain Syndrome
Reilich, P.; Pongratz, D. (München)
42 Type A Botulinum Toxin in Myofascial Facial Pain and Dysfunction
von Lindern, J.-J. (Bonn)
54 Pain in Cervical Dystonia
Erbguth, F.J. (Nürnberg)
71 Treatment of Painful Dystonia with Botulinum Toxin
Naumann, M. (Würzburg); Herting, B. (Dresden)
82 Botulinum Toxin in Tension-Type Headache
Jost, W.H. (Wiesbaden); Göbel, H. (Kiel)
102 Botulinum Toxin in the Treatment of Migraine
Göbel, H. (Kiel); Jost, W.H. (Wiesbaden)
126 Treatment of Spasticity-Related Pain Syndromes
Wissel, J. (Beelitz-Heilstätten)
140 Treatment of Piriformis Syndrome with Botulinum Toxin
Reichel, G. (Zwickau)
159 Botulinum Toxin in Low Back Pain
Jost, W.H. (Wiesbaden); Reilich, P.; Pongratz, D. (München)
170 Subject Index
Contents
VI
VII
Preface
Hardly any other drug has a similar history of success and a likely future
as botulinum toxin. It was initially used for therapeutic application in strabis-
mus, blepharospasm and hemifacial spasm, and continued in focal dystonia and
spasticity, followed by the treatment of wrinkles, hyperhidrosis and a great
number of ensuing indications. An analgesic effect was first noticed when treat-
ing symptoms or disorders associated with pain. Meanwhile, pain has become
the target symptom in many diseases. Many studies conducted in recent years
have come up with quite different results. First of all, there are the various
headache syndromes. After having established the efficacy of the agent,
researchers undertook the task of studying why botulinum toxin gives pain
relief. There are a number of models that now explain its mode of action; how-
ever, a conclusive evaluation is still lacking. It is beyond doubt that botulinum
toxin helps in certain pain syndromes. We have still got to find out which the
major ones are, what would be the optimum dose of toxin, and where the pre-
ferred site of injection should be. On the one hand, we hope to relieve pain in
patients whose symptoms could not be treated adequately before, and on
the other, we expect new impulses as to the pathogenesis and therapy of pain
disorders to enhance greater advances for the benefit of our patients.
This book presents an overview on the current state of pain management
with botulinum toxin. We do not claim to make a final and comprehensive
judgement, but merely want to indicate positions and to awake an interest in this
extraordinary therapeutical approach to pain.
W.H. Jost
Jost WH (ed): Botulinum Toxin in Painful Diseases.
Pain Headache. Basel, Karger, 2003, vol 14, pp 1–13
Pharmacology of Botulinum
Neurotoxins
Hans Bigalkea, Markus Naumannb
a Medical School of Hannover, Institute of Toxicology, Hannover
b Maximilian University, Clinic of Neurology, Würzburg, Germany
Seven serotypes of botulinum toxin (BTX1) are known, but only types A
and B are used therapeutically. They consist of two separate parts with different
functions. One part is the pharmacokinetic unit which navigates the other part,
the pharmacodynamic unit, through the plasma membrane into the compartment
where the latter performs its crucial action. The pharmacodynamic unit is an
enzyme interacting with high specificity with only one or a few chemically
related substrates. The pharmacokinetic unit, termed the heavy chain
(H-chain), is the larger part of the molecule (Mr 100,000), while the enzymatic
portion (Mr 50,000) is referred to as the light chain (L-chain). The organisms
produce the proteins as inactive single chains which, to become active, must be
cleaved by limited proteolysis at a distinct ‘nicking site’. Physiologically, nick-
ing is performed by co-released clostridial proteases which can, however, be
replaced by trypsin or various other proteases [Weller et al., 1988; Habermann
et al., 1991]. The resulting two proteins are connected by an interchain disulfide
bond and ionic interactions and represent the actual neurotoxins (Mr 150,000).
Once the chains are dissociated, toxicity vanishes because the H-chain has no
enzymatic activity and the L-chain is not capable of penetrating membranes.
Figure 1 provides an overview of the structure of the clostridial neurotoxins.
The botulinum neurotoxins are embedded in a complex formed from hemag-
glutinins and a non-toxic, non-hemagglutinating protein. The complexes of
serotypes A and B vary in molecular sizes (Mr 900,000 and 600,000, respec-
tively). They enhance oral toxicity by stabilizing the neurotoxins and, most likely,
facilitate their absorption from the intestine, as recently shown for type A and C1
1In contrast to the common nomenclature of neurotoxins, in this book the abbreviation
BTX stands for botulinum toxin and not for bungarotoxin.
Bigalke/Naumann
2
Pharmacokinetic unit
870
871
1286
HOOC
a
b
H2N
Reduction
(Thioredoxin reductase)
499
460
H
N
C
O
S
2
440
‘Nicking’
223
227
HELIH
Zn
2�
448
Enzyme
S
Limited proteolysis
(clostridial proteases)
HC
HN
L
Zn
2�
x
x
NH2
HOOC
1286
870
449
1
Fig. 1. a Schematic structure of single chain BTX-A. The numbers identify represent-
ative amino acid positions, e.g. nicking site. The resulting di-chain molecule consists of the
L-chain (enzyme) in which the Zn2�-binding moiety is located and the H-chain (pharmaco-
kinetic unit). The C-terminal (HC) of the H-chain is responsible for binding. The N-terminal
portion (HN) of the H-chain is the translocation unit (see fig. 2). b Three-dimensional struc-
ture of BTX-A. The designations refer to the major components of the toxin as described in
figure 1a. The Zn2�-containing active site is buried within the catalytic domain. The nicking
site between the L- and H-chains is indicated by ‘X’. The translocation domain belt wraps
around the catalytic domain and is indicated by arrows. For a stereo view, see Lacy et al.
[1998]. (Courtesy of R. Stevens, University of California, Berkeley, Calif., USA.)
