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ANALGESICS AND ANTIPYRETICS - Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (Elmar Friderichs, Thomas Christoph,
Helmut Buschmann)
References
Germany
THOMAS CHRISTOPH ,
Germany
HELMUT BUSCHMANN, Grnenthal
Germany
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References
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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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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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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4. References
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Group
Compound
First generation
COX-2 selectivity
Reference
(< 100-fold)
etodolac
10
[73]
meloxicam
10
[73], [74]
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5 100
[73], [74]
(100 1000-fold)
celecoxib
375
[78]
rofecoxib
800
[10]
Precursor
Endogenous peptide
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
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.
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