Braz J Oral Sci. July-September 2005 - Vol. 4 - Number 14Analgesic choice in dentistry. Part I: The mechanism of action Filipe Polese Branco 1* Marcos Luciano Pimenta Pinheiro 2** Abstract Maria Cristina Volpato 3*
Analgesics are frequently used in dentistry for the management of
Eduardo Dias de Andrade3*
dental pain. Dental clinicians should choose the medicine based on its
mechanism of action and toxicity, to promote a successful analgesic
effect as well as comfort to the patient. The purpose of this first
article is to describe the pharmacological mechanisms of action of the
*Science Physiological Department, Piracicaba
three analgesics considered for the management of mild to moderate
Dental School, Campinas State University,Piracicaba-SP, Brazil. **Diamantina Dental School, Diamantina,Key Words:
analgesics, mechanism of action, dentistry
Correspondence to: Eduardo Dias de Andrade Department of Physiological Sciences Piracicaba Dental School Campinas State University Av. Limeira, 901 13414-903 Piracicaba-SP, Brazil E-mail: [email protected] Braz J Oral Sci. 4(14):762-765 Analgesic choice in dentistry. Part I : The mechanism of actionIntroduction
synthesis of several mediators, including the prostaglandins
Analgesics are commonly recommended for mild, moderate
that protect the gastric mucosa and regule renal blood flow,
or acute pain. About 16 million of these drugs are annually
and the thromboxanes, which initiate platelet aggregation5.
prescribed by American dentists. In Brazil, analgesics are
Tissue damage resulting from pulpits, periodontitis, or oral
the most sold out class of medicine; dipyrone is the first in
surgery will induce the production of COX-2, which, in turn,
this list followed by acetaminophen (paracetamol) and
leads to the synthesis of the prostaglandins that sensitize
pain fibers and promote inflammation.
Although these drugs are safe, recent studies alert to
Traditional NSAIDs, such as aspirin, act by blocking both
intoxication risk and severe adverse effects, even at doses
cyclooxygenase enzymes (COX-1 and COX-2). This non-
or concentrations nearly the same as those used to relieve
selective inhibition is responsible for many of the unwanted
pain, increasing the need for either pharmacological
effects of this drug6. Aspirin, like all the other NSAIDs, induce
inhibition of thromboxane synthesis resulting in a decrease
The clinician should employ a variety of effective and safe
in the platelet aggregation. For most NSAIDs this effect is
analgesic regimens based on estimates of anticipated pain
reversible within 24 hours; however, aspirin is unique in
intensity, mechanism of action and toxicity1.
that it irreversibly damages cyclooxygenase for the life of
The purpose of this first article was to describe the
the platelet5. Although an increase in the time of coagulation
pharmacological mechanisms of action of three analgesics
can be accepted in normal patients, aspirin might promote
considered for the management of mild to moderate acute
post-operative hemorrhage, mainly if the clot is not totally
dental pain in dentistry as well as parameters to choose each
formed. There are some reports of hemorrhage after aspirin
ingestion in dentistry7-8. Use of aspirin in children during or immediately after a viral
infection has been associated with the increase in the
Aspirin has been used in dentistry as an anti-inflammatory,
incidence of Reye’s syndrome9. This syndrome is a rare acute
analgesic and antipyretic drug prescribed for use within short
encephalopathy associated with fatty degeneration of the
periods2. The mechanism of action of aspirin, a nonsteroidal
liver and its etiology remains uncertain. It is known to occur
anti-inflammatory drug (NSAID), was established
after viral infections such as chickenpox (varicella) and
approximately 30 years ago3. Clinical trials have shown
repeatedly that aspirin is effective in the management of
Table 1 shows the clinical use of aspirin in dentistry.
dental pain4. Optimal use of this drug is based on the understanding of its
action on the arachidonic acid metabolism pathways. Aspirin
Paracetamol has become increasingly popular as a safe and
blocks the cyclooxygenase enzymes, which exist in at least
mild aspirin substitute, either alone or in associations, without
two known isoforms: cyclooxygenase 1 (COX-1) and
decreasing in the platelet aggregation. It is currently found
cyclooxygenase 2 (COX-2). COX-1 is responsible for the
in more than 200 formulations, most of which are available
Table 1. Clinical use of aspirin, paracetamol and dipyrone in dentistry. Recommended doses Precautions or contraindications
- Coagulation defects- Chickenpox or influenza*
- Glucose-6-phosphate dehydrogenase deficiency
* Aspirin has being associated with Reye’s syndrome in children, although no causal relationship has been demonstrated31. ** In Brazil, paracetamol drops solution includes sodium metabissulfite.Braz J Oral Sci. 4(14):762-765 Analgesic choice in dentistry. Part I : The mechanism of action
over the counter. It is often categorized as a NSAID even
(COX-2b) that is particularly sensitive to paracetamol. Then
though it provides little anti-inflammatory activity in clinical
the presumable site of action of paracetamol might be both
in the locally acting “COX-2b” and COX-3 in the centrally
The exact site and mechanism of action of paracetamol remain
acting, but these points still need to be proved.
unclear. Flower et al.12 reported that paracetamol might
The potential for adverse effects from paracetamol seems to
produce analgesia by increasing pain threshold. Björkman
be singularly confined to the situation in which there is an
et al.13 suggested that the potential mechanism of action
acute overdose, and herein lies its main therapeutic
might involve the inhibition of the nitric oxide pathway and
advantage over aspirin. The most serious manifestation of
is mediated by several neurotransmitters, including the N-
paracetamol overdose is hepatotoxicity. The degree of liver
metil-D-aspartate and the P substance. Actually, this
damage is directly related to the amount of drug ingested,
discussion focuses on the relation between paracetamol and
and people with preexisting liver disease are most
Flower and Vane14 showed that paracetamol inhibited COX
The clinical use of paracetamol in dentistry is shown in Table 1.
activity in dog brain homogenates more than in homogenatesfrom spleen, suggesting the existence of different isoforms
Dipyrone, a drug of the pyrazolone group, exhibits analgesic
The great step forward in our understanding of the NSAIDs
and antipyretic activity and its action may be central as well
came in the early 1990s whem the existence of two isoforms
as peripheral22. In dentistry, dipyrone, like aspirin and
of COX was proved on a molecular basis, COX-1,
paracetamol, is indicated to produce low or moderate
constitutively expressed, and COX-2, inducible by pro-
inflammatory stimuli15. However, not all questions were
An important point to understand the mechanism of
answered by the characterization of two COX enzymes
inflammation and pain is to understand the hyperalgesia,
originating from different genes. One such question is the
which results from excitatory actions of endogenous
effect of paracetamol, which, unlike NSAIDs, produce
mediators released by inflamed or damaged tissues23. The
analgesia and antipyresis but has little effect on inflammation.
biochemical mechanism of up-regulation (hyperalgesia) is
The existence of additional COX enzymes was therefore
through the increase of cAMP and Ca2+. Prostaglandins and
dopamine are the most potent stimulators of neuronal tissue
Investigations of the relative sensitivity of the 2 enzymes to
adenylate cyclase and are the most active up-regulators of
paracetamol found that although the drug was a weak inhibitor
nociceptors. It has been shown that inhibitors of cAMP
of both enzymes, COX-1 was marginally more sensitive than
inactivation potentiate the up-regulation of the nociceptors24.
COX-216. In view of the low sensitivity to paracetamol of both
When the nociceptor is up regulated, drugs that block the
COX-1 and COX-2, the existence of a new, so far unknown
release of prostaglandin or sympathomimetic amines are not
isoform of COX provisionally named COX-3 has been
effective as analgesic agents. Ferreira et al.24 described that
repeated administration of nociceptor up-regulatory stimuli
Chandrasekharan et al.17 discovered the enzyme COX-3, an
induces a state of persistent hyperalgesia, which cannot be
enzyme derived from the same COX-1 gene, observing its
treated with standard COX inhibitors (NSAIDs). Dipyrone
highest levels of message in the cerebral cortex and heart.
can be considered an analgesic that directly down-regulates
Common analgesic/antipyretic drugs and NSAIDs were
the nociceptor, because it reduces the state of persistent
tested for their ability to inhibit of COX-1, -2, and -3 activities.
At a higher concentration of substrate, only COX-3 was
concentrations25. Unlike aspirin and other NSAIDs dipyrone
inhibited by paracetamol. These authors concluded that the
has been suggested as a classic analgesic acting in the
inhibition of COX-3 in the brain might be the long sought-
prevention and elimination of dental pain6.
after mechanism of the action of paracetamol.
Recent research carried out at the Hospital das Clínicas de
But pain is a difficult process to unravel. Prostanoids
São Paulo showed that more than 50% of the patients
produced at sites of inflammation can sensitize nerve endings
reported dipyrone as the preferable analgesic26. In dentistry,
and therefore promote the localized feelings of pain
dipyrone is the most effective analgesic used in elective
associated with inflammatory events and tissue injury18.
surgery and demonstrates the same potency as do
These prostanoids can be produced by COX-2 induced by
the local inflammatory processes. It remains unclear how
Dipyrone use has been discussed because of its absolute
paracetamol causes its analgesic effects, once it is not a
risk of mortality caused by agranulocytosis, aplastic anemia,
peripheral anti-inflammatory drug. Therefore, paracetamol
anaphylaxis and upper gastrointestinal complications.
might act in an additional enzyme19. Simmons et al.20 have
Andrade28 reported that this risk appears to be similar to that
previously proposed the existence of an isoform of COX-2
caused by paracetamol and substantially lower than the risk
Braz J Oral Sci. 4(14):762-765 Analgesic choice in dentistry. Part I : The mechanism of action
associated with aspirin and diclofenac, drugs commonly used
Gordon SM, Brahim JS, Rowan J, Kent A, Dionne RA.
for short-term pain relief. These considerations are well
Peripheral prostanoid levels and nonsteroidal anti-inflammatory drug analgesia: replicate clinical trials in a tissue
explained in the Boston Study29 and in the Painel
injury model. Clin Pharmacol Ther 2002; 72: 175-83. internacional de avaliação da segurança da dipirona30,
Warner TD, Mitchell JA Cyclooxygenase-3 (COX-3): filling
showing the safety of this drug, as will be discussed in the
in the gaps toward a COX continuum? Proc Natl Acad Sci
Simmons DL, Botting RM, Robertson PM, Madsen ML, Vane
The clinical use of dipyrone in dentistry is presented in Table 1.
JR. Induction of an acetaminophen-sensitive cyclooxygenasewith reduced sensitivity to nonsteroid antiinflamatory drugs.
In conclusion, only dipyrone is a classic analgesic, acting
Proc Natl Acad Sci USA 1999; 96: 3275-80.
effectively even after the hyperalgesia process sets out. It is
Cooper AS, Desjardins PJ. Peripheral acting (nonopioid)analgesics. In: Neidle EA, Yagiela JÁ. Pharmacology and
commonly prescribed in Brazil and seems to have the same
therapeutics for dentistry. 3rded. Saint Louis: Mosby; 1989.
analgesic efficacy, as do paracetamol and aspirin.
Gladtke E. Use of antipyretic analgesics in the pediatric patient. References
Phero JC, Becker D. Rational use of analgesic combinations.
Lynn B. Effect of neonatal treatment with capsaicin on the
numbers and properties of cutaneous afferent units from the
Ardekian L, Gaspar R, Peled M, Brener B, Laufer D. Does
hairy skin of the rat. Brain Res 1984; 322: 255-60.
low-dose aspirin therapy complicate oral surgical procedures?
Ferreira SH, Lorenzetti BB, De Campos DI. Induction,
blockade and restoration of a persistent hypersensitive state.
Moncada S, Ferreira SH, Vane JR. The blockade of the local
generation of prostaglandins explains the analgesic action of
Lorenzetti BB, Ferreira SH. Mode of analgesic action of
aspirin. Pol J Pharmacol Pharm 1974; 26: 77-8.
dipyrone: direct antagonism of inflammatory hyperalgesia.
Hersh EV, Moore PA, Ross GL. Over-the-counter analgesics
and antipyretics: a critical assessment. Clin Ther 2000; 22:
Jardim C, Lotufo PA, Maluf EP, Benseñor IM. Painkiller
usage for headache in Brazil. Cephalalgia 2001; 21: 469.
Haas, DA. An update on analgesics for the management of
Maia LC, Valença MGV. Estudo comparativo do efeito da
acute postoperative dental pain. J Can Dent Assoc 2002; 68:
dipirona, paracetamol e ácido acetilsalicílico sobre o sistema
cardiovascular, alívio da dor e sangramento em cirurgias
Andrade ED. Terapêutica medicamentosa em odontologia.
odontológicas eletivas. Um estudo “in vivo”. Âmbito Odontol
Foulke CN. Gingival hemorrhage related to aspirin ingestion.
Andrade SE. Comparative safety evaluation of non-narcotic
A case report. J Periodontol 1976; 47: 355-7.
analgesics. J Clin Epidemiol. 1998; 51:1357-65.
Pawlak DF, Itkin AB, Lapeyrolerie FM, Zweig B. Clinical
International Agranulocytosis and Aplastic Anemia Study (The
effects of aspirin and acetaminophen on hemostasis after
Boston Study) - Risks of agranulocytosis and aplastic anemia.
exodontics. J Oral Surg 1978; 36: 944-7.
A first report of their relation to drug use with reference to
Sullivan-Bolyai JZ, Corey L. Epidemiology of Rey’s Syndrome.
analgesics. J Am Med Assoc 1986; 256: 1749-57.
Agência Nacional de Vigilância Sanitária. Painel internacional
Hurwitz ES. Rey’s Syndrome. Epidemiol Rev 1989; 11: 249-
de avaliação da segurança da dipirona; 2001 Jul 3-4. Brasília:
Botting RM. Mechanism of action of Acetaminphen: Is there
Holmes A, Davidson LE. Reye’s syndrome and analgesic
a cyclooxygenase 3? Clin Infect Dis 2000; 31 Suppl 5: S202-10.
choice in dentistry. Br Dent J 1989; 167: 345-6.
Flower RJ, Moncada S, Vane JR. Analgesic-antipyretics andanti-inflammatory agents; drugs employed in the treatmentof gout. In: Gilman AG, Goodman LS, Gilman A. ThePharmacologic Basis of Therapeutics. 7thed. Elmsford:Pergamon Press; 1985. p.692-5.
Björkman R, Hallman KM, Hedner J, Hedner T, Henning M. Acetaminophen blocks spinal hyperalgesia induced by NMDAand substance P. Pain 1994; 57: 259-64.
Flower RJ, Vane JR. Inhibition of prostaglandin synthetase inbrain explains the anti-pyretic activity of paracetamol (4-acetamidophenol). Nature 1974; 15: 410-1.
Vane JR. The fight against rheumatism: from willow bark toCOX-1 sparing drugs.J Physiol Pharmacol 2000; 51: 573-86.
Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ,Vane JR. Selectivity of nonsteroidal anti-inflammatory drugsas inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci 1993; 90: 1693-7.
Chandrasekharan NV, Dai H, Roos LT, Evanson NK, TomsikJ, Elton TS et al.COX-3, a cyclooxygenase-1 variant inhibitedby acethaminophen and other analgesic/antipyretic drugs:cloning, structure and expression. Proc Natl Acad Sci USA2002; 99: 13926-31.
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