Table Of ContentAnalgesics
From Chemistry and Pharmacology to
Clinical Application
Edited by
Helmut Buschmann, Thomas Christoph,
Elmar Friderichs, Corinna Maul,
Bernd Sundermann
with contributions by
Gregor Bahrenberg, Johannes Bartholomaus, Petra Bloms-Funke,
Helmut Buschmann, Thomas Christoph, Werner Englberger,
Robert Frank, Elmar Friderichs, Clemens Gillen,
Hagen-Heinrich Kennies, Ulrich Jahnel, Corinna Maul,
Michael Przewosny, Claudia Putz, Klaus Schiene, Wolfgang Schroder,
Bernd Sundermann, Thomas Tzschentke
WILEY-VCH
Analgesics. Edited by H. Buschmann, T. Christoph, E. Friderichs, C. Maul, B. Sundermann
Copyright © 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30403-7
Dr. Gregor Bahrenberg
Dr. Klaus Schiene
Dr. Johannes Bartholomaus
Dr. Wolfgang Schroder
Dr. Petra Bloms-Funke
Dr. Bernd Sundermann
Dr. Helmut Buschmann
Dr. Thomas Tzschentke
Dr. Thomas Christoph
Dr. Werner Englberger
Dr. Robert Frank
Dr. Elmar Friderichs
Dr. Clemens Gillen
Dr. Hagen-Heinrich Hennies
Griinenthal GmbH
Dr. Ulrich Jahnel
Center of Research
Dr. Corinna Maul
P.O. Box 50 04 44
Dr. Michael Przewosny
52088 Aachen
Dr. Claudia Plitz
Germany
This book was carefully produced. Nevertheless, authors and publisher do not warrant the
information contained therein to be free of errors. Readers are advised to keep in mind that
statements, data, illustrations, procedural details or other items may inadvertently be
inaccurate.
1., korrigierter Nachdruck 2003
Cover picture after an original illustration by Rene Descartes (17th century)
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Printed in the Federal Republic of Germany.
Preface
Pain has been a human problem since the beginning of time but the last decade has
seen an explosion of information about the transmitters, receptors and channels
involved in the transmission and modulation of noxious messages generated in
peripheral tissues. This has lead to the identification of a number of potential new
targets for analgesic therapy. We now have more experimental drugs available, which
allows us to study the roles of transmitters and receptors in physiological events. There
are now numerous animal models for clinical pain states such as inflammation and
neuropathies, and these models have shown that several transmitter systems which
have minor actions in acute pains can play important roles in more persistent pains.
This ability to test drugs in contexts other than acute pain models has arisen from good
communication between bench scientists, clinicians and Industry. Until recently
investigations into the mechanisms of clinical pain syndromes all relied on animal
studies using acute stimuli. The symptoms of pain arising from nerve injury, neuropathic
pain, such as allodynia, spontaneous pain, hyperalgesia, sensory deficits and in some
cases a sympathetic component are simply not seen in the older acute models. There
are now several animal models which mimic peripheral and central neuropathic states.
The same is true for inflammation.
A number of major discoveries over the last thirty years, such as the opioid receptors
and the endogenous opioids, the spinal, supraspinal and peripheral sites of action of
opioids, the key role of glutamate in signalling in the nervous system, the important
actions of peptides such as substance P, the ability of descending controls, both
noradrenergic and serotoninergic, to influence pain transmission may not yet have
yielded many new drugs but has enormously aided the conceptual basis for
understanding pain and analgesia. The Gate Theory of Pain, published in 1965, was the
first study to make us think about the ways in which transmission of pain could alter yet
the pharmacological details have only recently been eluidated. Plasticity, the capacity of
the pain signalling and modulating systems to alter in different circumstances, has
changed our ways of thinking about pain control. Signalling events are not fixed, not the
same in all pain conditions, but subject to alteration. Types of pain, symptoms of pain,
the intensity and area are all factors that alter the pharmacology.
High throughput screening should expedite the identification of useful agents, which,
combined with improved combinatorial chemistry, should lead to fast and efficient
production of novel agents with good affinity for particular targets. Genomics can be
used to identify targets related to specific disease, and, in the field of pain and
analgesia, to identify targets associated with particular pathological processes within
this area. Here again, the validity of the models will be critical in screening molecules.
Realistically many discoveries are still serendipitous, but with a better understanding of
the neurobiology of pain their effects can be better verified. Molecular and genetic
approaches have recently allowed the identification of channels or receptors that has
lead to a far better understanding of the peripheral processes that lead to pain from
thermal, chemical and other stimuli. At the level of the peripheral nerve, the roles of
particular sodium channels In the generation of activity after tissue damage may provide
local-anaesthetic-like drugs that target only pain-related activity. Agents acting on
calcium channels that control both neuronal activity and transmitter release also have
potential.
VI
Within the last 10, years several new compounds were launched in the field of
non-steroidal antiinflammatory drugs (NSAIDs) with a clear focus on cyclooxygenase
type 2 selective compounds. In the field of opioids on the other hand no new drugs have
passed phase III clinical trials. In this field Innovation has been achieved through new
pharmaceutical formulations of known drugs such as transdermal systems, e.g.
buprenorphine patch, transmucosal systems, e.g. fentanyl lollipop, or rectal delivery
systems containing e.g. morphine. These were developed in order to reduce opioid side
effects, but also to overcome pharmacokinetical limitations, in particular to prolong
compliance and duration of action.
This book deals with established analgesics as well as with new chemical entities for
established and new targets. Compounds are classified with respect to their
physiological target. In every case the structural formula is given as well as further
information e.g. on the pharmacological profile, synthetic routes or major metabolites if
important. In addition, structure-activity relationships are discussed if available.
Consequently following this scheme, a huge number of compounds is evaluated and a
clear picture especially of pain research in the Industrial setting Is constructed.
Based on the snapshot-like collection of information in this book the cyclooxygenase
and the opioid systems are still the most attractive targets and ligands acting on this
system are still not surpassed by ligands of other targets. It Is also clear, however, that
we are at the beginning of an era of promising new approaches to pain therapy. The
future will show which targets will survive the race for the best therapy.
The book presented here will be highly valuable for advanced students in
pharmaceutical and medicinal chemistry as well as for scientists in the field of
chemistry, biochemistry and pharmacology in industrial and academic research.
August 2002
Anthony Dickenson, London
Ulnke Holzgrabe, Wurzburg
A View from Grunenthal
Pain research is a traditional and well established field within the pharmaceutical
industry. Beginning with the isolation of morphine In a small pharmacy by Adam
Sertiirner (1806), the next major breakthrough in pain treatment was achieved by the
synthesis of acetylsalicylic acid by Felix Hoffmann In the Bayer Laboratories in
Wuppertal (1897). Further outstanding contributions by the pharmaceutical industry
were the first fully synthetic opioids pethidine (1939) and methadone (1946).
Continued efforts up to now have resulted in many potent and clinically accepted
analgesics with reasonable side effects and covering nearly all facets of pain
treatment. However, pain treatment is far from being satisfactory in respect to more
complex pain states, e.g. neuropathy, visceral pain or migraine.
Grunenthal's Interest in pain research started in 1962, when Kurt Flick designed a
simple molecule containing the essential structural elements of morphine to be a
potent analgesic. This prediction was clinically confirmed and today this compound -
tramadol - is one of the leading centrally acting analgesics.
Forty years after the discovery of tramadol, research at Grunenthal is still focused on
the search for even better analgesics. Due to the intense accumulation of knowledge
about pain the Idea was born to collect this In a comprehensive overview with the
intention to stimulate further scientific efforts In this area. It is our hope that this book
will be a useful reference meeting the challenge to improve pain therapy.
Klaus-Dieter Langner and Eric-Paul Paques
Aachen, August 2002
Contents
Preface
V
A View from Grunenthal
VII
I
Introduction
1
What is pain?
1
H. Buschmann
II
Pain Therapy Today
2
Cyclooxygenase Inhibition: From NSAIDS to Selective COX-2 Inhibitors
13
T. Christoph and H. Buschmann
3
Opioids
3.1
Introduction
127
E. Friderichs
3.2
Opioid Peptldes
151
B. Sundermann and C. Maul
3.3
Synthetic Opioids
159
C. Maul, H. Buschmann and B. Sundermann
3.4
Opioids with Clinical Relevance
171
E. Friderichs and H. Buschmann
3.5
Drug Delivery Systems for Opioids
247
J. Bartholomaus
4
NA and 5-HT Reuptake Inhibitors and 0,2 Agonists
265
T. Tzschentke
III
New Approaches in Pain Therapy
5
Gabapentin and Gabapentinoids
287
C. Maul, H. Buschmann and B. Sundermann
6
Voltage-gated Ion Channels
6.1
Sodium Channels
297
P. Bloms-Funke
6.2
Potassium Channels
333
W. Schroder
6.3
Calcium Channels
353
H.-H. Hennies and B. Sundermann
IX
7
Glutamate Receptors
7.1
Metabotropic Glutamate Receptors
379
K. Schiene and C. Maul
7.2
NMDA Receptors
389
W. Englberger, M. Przewosny and C. Maul
7.3
AMPA and Kainate Receptors
429
C. Maul and B. Sundermann
8
Acetylcholine Receptors
8.1
Nicotlnic Acetylcholine Receptors
435
8. Sundermann and C. Maul
8.2
Muscarinic Acetylcholine Receptors
445
C. Maul and B. Sundermann
9
Further Opioid Receptors
9.1
The 5-Opiod Receptor
455
C. Putz
9.2
Opioid-receptor-like 1 (ORL1)
467
B. Sundermann and C. Maul
10
Adenosine
477
C. Maul, H. Buschmann and B. Sundermann
11
P2 Receptors
487
H.-H. Hennies, C. Maul, and B. Sundermann
12
Natural and Synthetic Cannabinoids
497
C. Maul and B. Sundermann
13
Vanilloids and the VR1 Receptor
507
R. Frank
14
Substance P/NKi Receptors
519
G, Bahrenberg and C. Maul
15
CGRPrReceptor Antagonists
543
C. Gillen
16
Nitric Oxide
555
C. Maul, H.-H. Hennies and B. Sundermann
IV
Outlook
17
Outlook - The Future of Pain Management
569
U. Jahnel and C. Gillen
18
Glossary
577
Parti
Introduction
What is Pain?
Helmut Buschmann
Introduction
Pain is the most common symptomatic reason for seeking
a medical consultation.
Everyone is affected by pain at some point in their lives,
whether it is from headaches, cuts and bruises or more
severe pain resulting from surgery, which would be
pre-controlled in anticipation of the event.
Although chronic types of pain may generally appear to
have no purpose, acute pain acts as an important warning
mechanism to the person by instructing the brain to
remove the individual from that particular pain stimulus. If
for example a person lifts a hot object, pain signals to the
brain to put the object down to avoid severe burns.
The treatment of pain, a major problem in medicine, is
complicated by many factors. Pain is not a uniform
sensation, as illustrated by its many common descriptions,
e.g. sharp, dull, aching, burning, shooting, cramping,
stabbing and throbbing. There are several ways to classify
pain, but the first distinction usually made is that between
acute and chronic pain. Pain is a subjective sensation
which cannot be measured objectively, and its intensity is
not always a direct reflection of the nociceptive inputs
provoking it. Nociceptive inputs which are easily ignored
by an individual in one situation may be unbearable in
another.
Pain - a common
phenomenon
Acute pain as a warning
mechanism
The treatment of pain, a
major problem in medicine
Definition of Pain
Various definitions of pain have been proposed but the
most widely accepted is that of the International
Association for the Study of Pain (IASP):
Analgesics. Edited by H. Buschmann, T. Christoph, E. Friderichs, C. Maul, B. Sundermann
Copyright © 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30403-7
Buschmann
A definition of pain (IASP)
...pain remains grossly
undertreated and is
frequently mistreated...
Side-effects of analgesics
Side-effects of NSAIDs
Side-effects of central acting
analgesics
Pain is an unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage. Pain is always
subjective. Each individual learns the application of the
word through experiences related to injury in early life. It is
unquestionably a sensation in part of the body, but it is
also unpleasant and therefore also an emotional
experience. Many people report pain in the absence of
tissue damage or any likely pathophysiological state;
usually this happens for psychological reasons. There is
no way to distinguish their experience from that due to
tissue damage, if we take this subjective report. If they
regard their experience as pain and if they report it in the
same way as pain caused by tissue damage, it should be
accepted as pain (Merksey, 1979).
Before the 1960s, pain was considered an inevitable
sensory response to tissue damage, but since that time
the definition has broadened to encompass the affective
dimension of pain with greater consideration of the effects
of genetic differences, past experience, anxiety and
expectation.
Research in understanding the underlying mechanisms
behind people's pain has progressed rapidly, but despite
these critical advances pain remains grossly undertreated
and is frequently mistreated. In the words of Jean-Marie
Besson, President of the IASP at the 9th IASP Congress
in Vienna, Austria, in August 1999: 'Some pain states can
now be controlled, yet there are still others which are far
from being treatable.'
Pain, as a whole, is currently a very active area for
pharmaceutical
R&D,
largely
because
of
its
undertreatment and frequent mistreatment, but also
because the older and still widely-used compounds can
cause unacceptable side-effects.
This is especially true for the traditional non-steroidal
anti-inflammatory drugs (NSAIDs) which are associated
with serious gastrointestinal complications such as
bleeding, lesions and ulcers.
Conversely, the perceived dangerous side-effects and
fears of addiction and tolerance associated with potent
opioid analgesics (e.g. morphine) has led to restrictions
and controversy regarding their use. Clinical studies,
however, have demonstrated that these risks are low and
potent opioid analgesics today are more widely accepted
for treating severe cancer pain, but experts are still calling
for broader use of opioids in non-malignant chronic pain.
1 What is Pain?
Class
Anti-ulcer
Cholesterol &
triglyceride reducers
Antidepressants
Calcium antagonists
(plain)
NSAIDs
ACE inhibitors
Cephalosporins &
combinations
Antipsychotics
Non-narcotic
analgesics
Oral antidiabetics
2000 sales
($ billion)
17.4
15.9
13.4
9.8
9.5
7.3
6.9
6.0
6.0
5.9
% of global
sales
5.5
5.0
4.2
3.1
3.0
2.3
2.2
1.9
1.9
1.9
% growth
(vs. 1999)
+ 13
+ 21
+ 18
+ 2
+ 26
+ 3
-5
+ 22
+ 3
+ 26
Table 1: Global pharma
sales - the leading
therapeutic classes.
Source: IMS Health Word
Reviews 2001, SCRIP No.
2630, March 30th 2001,
p. 18.
Physiology and Pathophysiology of Pain
The physiological aspects of lasting pain become apparent
when a mechanical, thermal, chemical or electrical
stimulus strong enough to damage tissue or affect cellular
metabolism stimulates the nociceptive free nerve endings
of C-fibers, which are found all over the surface of the
body and its organs. Several subtypes of A-fibers also
carry afferent nociceptive impulses. The damaged tissue
sends out nerve impulses through nerve tracts in the
spinal cord to the brain (cerebral cortex) where the
stimulus translates to a conscious pain sensation.
In addition to nervous pain impulses, injured tissues
produce
inflammatory
pain-producing
substances,
including bradykinin and other kinins, serotonin, histamine,
acetylcholine, excesses of potassium ions, proteolytic
enzymes and prostaglandins, which can act in synergy to
increase pain levels. Many of these substances, especially
the proteolytic enzymes, can cause direct damage to the
pain nerve endings, but others, such as bradykinin and
prostaglandins, can cause extreme direct stimulation of
pain nerve fibers without actually damaging them. Local
changes accompanying the injury, such as muscular
spasm, ischeamia and inflammation, can also contribute to
the intensity and character of the pain.
Severe and sustained pain can cause long-lasting reflexes
in the spinal cord and sympathetic nervous system that
can lead to changes in the secretion of hormones and
other substances and to a chronic state of increased pain
Pain transmission
Contribution of endogenous
inflammatory and/or pain-
producing substances
