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ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
Helmut Buschmann)

References

Analgesics and Antipyretics


REVISED 2000
ELMAR FRIDERICHS , Grnenthal

GmbH, Center of Research, Aachen, Federal Republic of

Germany
THOMAS CHRISTOPH ,

Grnenthal GmbH, Center of Research, Aachen, Federal Republic of

Germany
HELMUT BUSCHMANN, Grnenthal

GmbH, Center of Research, Aachen, Federal Republic of

Germany

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1. Introduction
Compounds that are used for the treatment of pain, inflammation, and fever are classified into
two main groups according to their mode of action: nonsteroidal anti-inflammatory drugs
(NSAIDs) and so-called centrally acting analgesics.
Nonsteroidal anti-inflammatory drugs are compounds with a predominantly peripheral
mechanism of action. Besides inhibition of pain they exert a more or less pronounced antiinflammatory and fever-reducing effect. In the body key peripheral mediators of pain,
inflammation, and fever are prostaglandins ( Prostaglandins). NSAIDs and related
"peripheral" or "weak analgesics" act via inhibition of cyclooxygenase. Cyclooxygenase is the
key enzyme of prostaglandin synthesis and its inhibition may be the most important, but not the
exclusive mechanism of action of NSAIDs. The supposed additional mechanisms are widely
unknown.
The group of centrally acting analgesics is dominated by the opioid compounds. They act
mainly within the central nervous system, but more recent investigations indicate that an
additional peripheral action component may exist. The endogenous opioid system is the most
important pain control system within the body and opioids are powerful tools for the treatment
of severe pain situations. Central neurotransmitters like noradrenaline and serotonin are
likewise involved in pain inhibition. Directly acting compounds like, e.g., the 2-adrenergic
agonist clonidine as well as indirectly acting inhibitors of noradrenaline and serotonin reuptake
(mainly used as antidepressants) have a definite value as primary analgesics or as co-analgesics

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ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
Helmut Buschmann)

in combination with opioids.


Acute pain is an alarm signal to alert the organism to noxious tissue damage, irritation, or
injury. Ongoing, persistent or chronic pain may lose this function and may become a mere
burden to the patient. Pain does not only indicate physical suffering, but involves a strong
mental and emotional component. According to the definition of the International Association
for the Study of Pain "it is an unpleasant sensory and emotional experience associated with
actual or potential tissue damage, or described in terms of such damage".
The nervous system contains an afferent fiber system that is specialized for registration,
transmission, and processing of nociceptive information. In the periphery small unmyelinated
nerve endings, called nociceptors, are activated by mechanical, thermal, or chemical stimuli.
One type, the mechano-heat nociceptor is specialized for thermal and mechanical stimulation,
whereas the so-called polymodal receptor is less specific and responds to all kinds of
mechanical, thermal, or chemical irritation. Mechano-heat nociceptors have a high stimulation
threshold and respond only to strong stimuli. They are linked to small myelinated and rapidly
conducting A fibers which produce a sharp and well located pain sensation. The sharp pain
stimulus activates withdrawal reflexes and has to protect the body against further damage. The
polymodal receptors respond to weaker stimuli including endogenous compounds like
histamine, bradykinin, and prostaglandins. These receptors are mediators of pain and
inflammation and are released by tissue damage. The impulses of polymodal nociceptors are
transmitted more slowly via thicker, unmyelinated C-fibers and provoke a dull, aching, and less
precisely localized pain sensation. The nerve fibers originating from nociceptors are named
primary afferent fibers. They have their cell body in the dorsal root ganglia and project to the
dorsal root of the spinal cord where they form synapses with fibers of the ascending spinothalamic pathway. Most of the spino-thalamic pain fibers pass the thalamus and project to the
limbic system and the cortex. The limbic system is responsible for the emotional component of
pain whereas in the cortex realization and localization of the origin of pain takes place. The
spino-thalamic fibers form connections with the formatio reticularis of the brain stem, inducing
the various vegetative reactions associated with the pain perception such as sweating,
palpitation, nausea, and blood pressure increase.
Inhibitory control of the pain process can take place in the periphery at the level of the
nociceptors or the primary afferents. These are the regions where local anesthetics and NSAIDs
act. Central pain inhibition can take place at the level of the spinal cord, the thalamus, cortex,
and the limbic system. The pain transmission at the level of the spinal cord is under inhibitory
control of descending fibers, which originate in different parts of brain stem, mid brain, and
cortex. They contain opioid synapses as well as noradrenergic and serotoninergic synapses and
represent the descending spinal pain inhibitory system. Inhibitory opioid synapses are not only
found in the spinal cord but are strategically located along the whole pain pathway. Opioid
receptors are found in the cortex, limbic system, and formatio reticularis and this explains why
opioids not only inhibit pain perception but also reduce the emotional component of pain
suffering and mitigate the vegetative pain symptoms.
According to the clinical situation, pain can be classified as acute and chronic pain. Acute pain
is induced by trauma, tissue damage, or disease and has a well defined localization and time
course. Acute pain normally responds well to NSAIDs and opioid analgesics. Chronic pain is
more complex in nature and often contains an inflammatory component. The association with
trauma and lesion can be lost and then pain no longer fulfills its alarming function. Chronic pain
is often a heavy burden to the patient and induces physical, psychological, and social
deterioration. Chronic pain treatment is an important medical challenge.

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ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
Helmut Buschmann)

Physiologically, pain can be differentiated into nociceptive and neuropathic pain. Nociceptive
pain results from activation of nociceptors by acute or chronic stimulation and is not associated
with damage of nerves. Neuropathic or neurogenic pain in contrast is the result of damage or
dysfunction of the peripheral nerves or of the central parts of the pain processing system.
Examples of neuropathic pain of peripheral origin are deafferentiation pain (stump pain),
diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, and sympathetically
maintained pain like the complex regional pain syndrome. Central neuropathic pain may result
from lesions of the spinal cord or brain lesions following stroke. In chronic cancer pain,
nociceptive pain is often associated with a neuropathic component induced by neoplastic nerve
infiltration or compression of the nerve by tumor growth.
Cancer pain is one of the most important forms of chronic severe pain and guidelines for the
treatment of cancer pain were published by the WHO in 1986 (Fig. (1)).
Meanwhile these guidelines have become the standard not only for treatment of chronic
malignant pain but also for benign chronic and acute pain. The WHO proposal is often
described as "treatment by mouth, by the clock, and by the ladder". That means that for repeated
application of analgesics the oral route should be used. The application interval should be
regular and selection of compounds should follow the increase of potency and efficacy as
indicated in the three-step analgesic ladder. The first step starts with the single use of a nonopioid analgesic. If pain control is insufficient, a weak opioid may be added. If this is not
effective enough, the weak opioid should be replaced by a strong opioid and the non-opioid
may be omitted. Each stage of the treatment may be supplemented by the use of co-analgesics
and other pharmacological and non-pharmacological treatments to improve pain control and to
reduce side effects.
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2.2. para-Aminophenol Derivatives


Paracetamol [103-90-2], acetaminophen, N-(4-hydroxyphenyl)acetamide, C8H9NO2, Mr
151.16, mp 168 169 C.
Synthesis:
a) classical route [125], [134]:

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ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
Helmut Buschmann)

b) Hoechst-Celanese process:

Clinical use [117]: Paracetamol has analgesic and antipyretic properties, but no relevant antiinflammatory action. It is used for the treatment of various mild to moderate pain conditions and
to reduce fever. Paracetamol is one of the most popular analgesics as single drug or in multiingredient preparations, often in combination with NSAIDs or weak opioids. It is used orally or
rectally as suppositories, the oral dose range is 500 1000 mg every 4 5 h up to 4 g daily.
Side effects are rare and may include hematological reactions, leucopenia, agranulocytosis and
other hypersensitivity reactions. Paracetamol has a narrow therapeutic dose range and
overdosage induces severe liver and renal damage [118] via accumulation of a toxic metabolite,
N-acetylbenzoquinoneimine (NABQI). Acetylcysteine or methionine, which increase
glutathione conjugation of the metabolite, are used as antidote.
Paracetamol is not soluble in aqueous solutions and cannot be given parenterally.
Trade names: Benuron (Germany), Tylenol (USA).
Propacetamol [66532-85-2], 4-(acetylamino)phenyl N,N-diethylglycinate, C14H2ON2O3, Mr
264.33) is a soluble glycine prodrug derivative of paracetamol. It is used as hydrochloride
([66532-86-3], C14H2ON2O3 HCl, Mr 300.79), for intramuscular or intravenous application and
is rapidly metabolized to free paracetamol.

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ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
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Trade name: Pro-Dafalgan (Belgium, France).


Phenidine [62-44-2], phenacetin, N-(4-ethoxyphenyl)acetamide, C10H13NO2, Mr 179.22, mp
134 135 C.
Synthesis [125]:

Clinical use: Phenidine is a weak analgesic, antipyretic compound without anti-inflammatory


action. It has been used in combination with other compounds like aspirin, caffeine, or codeine,
but due to hematological and nephrotoxic side effects [119] has been withdrawn from many
markets.
Trade names: Gripponyl (France), Cratodin (Spain).
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4. References
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Therapeutics, 9th ed., McGraw Hill, New York 1995, pp. 521 555, 557 600, 617

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1688.
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1107.
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[246] Farbw. Hoechst, DBP 865 314, 1941.
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[259] Janssen, US 2 898 340, 1959; Searle, US 4 086 234, 1978.

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[260] Janssen, US 3 714 159, 1973; ED-OS 2 126 559, 1971.


[261] R. A. Stokbroekx et al., J. Med. Chem. 16 (1973) 782 786.
[262] Janssen, DE 1 238 472, 1961.
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[294] Boehringer Ingelheim, DE 1 303 141, 1961; US 3 236 857, 1966.

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[295] VEB Arzneimittelwerke Dresden, DE-AS 1 770 874, 1968.


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first occurrence in article


Analgesics and Antipyretics - Table 1
COX-2 specific inhibitors

Group

Compound

First generation

COX-2 selectivity

Reference

(< 100-fold)
etodolac

10

[73]

meloxicam

10

[73], [74]

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nimesulide
Second generation

5 100

[73], [74]

(100 1000-fold)
celecoxib

375

[78]

rofecoxib

800

[10]

first occurrence in article


Analgesics and Antipyretics - Table 2
Mammalian endogenous opioid peptides

Precursor

Endogenous peptide

Amino acid sequence

Pro-opiomelanocortin

-endorphin

YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE

Pro-enkephalin

[MET]enkephalin

YGGFM

[LEU]enkephalin

YGGFL

dynorphin A

YGGFLRRIRPKLKWDNQ

dynorphin B

YGGFLRRQFKVVT

-neoendorphin

YGGFLRKYPK

-neoendorphin

YGGFLRKYP

Nociceptin

FGGFTGARKSARKLANQ

Pro-dynorphin

Pro-nociceptin/OFQ
a

OFQ = orphanin FQ.

first occurrence in article


Analgesics and Antipyretics - Table 3
Opiod receptor specifity

Receptor type

Selective ligands

Nonselective ligands

Agonist

Antagonist

Agonist

Antagonist

MOR

morphine

CTOP

levorphanol

naloxone

fentanyl

etorphine

naltrexone

levorphanol

naloxone

methadone
DAMGO

KOR

enadoline

nor-BNI

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-

U50,488

etorphine

naltrexone

levorphanol

naloxone

etorphine

naltrexone

dynorphin

DOR

DPDPE

SNC-80

naltrindol

MOR = mu-opioid receptor. KOR = kappa -opioid receptor. DOR = delta-opioid receptor. DAMGO = [D-Ala2, MePhe 4,
Gly(ol) 5]enkephalin. Enadoline = (5R)-(5,7,8-(-)-N-methyl -N-(7-[1-pyrrolidinyl] -1-oxaspiro[4,5] dec-8-yl)-4benzofuranacetamide, previously CI977. U50,488 = trans-3,4-dichloro -N-methyl -N-[2-(1-pyrrolidinyl) -cyclohexyl] benzeneacetamide methanesulfonate. DPDPE = [D-Pen 2, D-Pen 5]enkephalin. SNC-80 = (+)-4-[(R)--((2S,5R)-4-allyl -2,5dimethyl -1-piperazinyl) -3-methoxybenzyl] -N,N-diethylbenzamide. CTOP = D -Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2. norBNI = nor-binaltorphimine.

first occurrence in article


Analgesics and Antipyretics - Figure 1

WHO-Guidelines for Cancer pain treatment ("WHO-Ladder")

first occurrence in article


Analgesics and Antipyretics - Figure 2

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Simple scheme of the biosynthesis of postraglandins (PG), thromboxanes (TX), and


leukotrienes from arachidonic acid consequent to cell injury (modified after [6])

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[6]
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[10]
C. J. Hawkey: "Cox-2 Inhibitors", Lancet 353 (1999) 307 314.
[73]
J. R. Vane et al., Annu. Rev. Pharmacol. Toxicol. 38 (1998) 97 120.
[74]
J. Berg et al., J. Pharmacol. Toxicol. Meth. 37 (1997) 179 186.
[78]
A. Graul et al., Drugs Future 22 (1997) 711 714.
[117]
B. Ameer et al., Ann. Int. Med. 87 (1977) 202 209.
[118]
R. K. Lewis, F. P. Paloucek, Clin. Pharm. 10 (1991) 765 774.
[119]
U. C. Dubach et al., N. Engl. J. Med. 308 (1983) 357 362.
[125]
A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances, Synthesis, Patents,
Applications, Thieme, Stuttgart New York, 1999 (available in print and CD-ROM).
[134]
Warner-Lambert, US 2 998 450, 1961, (G. Wilbert , J. De Angelis ).

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