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NSAIDS
K. SHIVA TEJA
2ND YEAR PG
CONTENTS
 INTRODUCTION
 HISTORY
 CLASSIFICTION
 PROSTAGLANDINS AND ACTIONS
 MECHANISM OF ACTION OF NSAID’S
 CHOICE OF NSAID’S
 NSAID’S – PERIODONTAL CONSIDERATIONS AND HOST
MODULATORY THERAPY
 NSAID’S – ENZYMES COMBINATION
 CONCLUSION
 REFERENCES
 INTRODUCTION
 PAIN or ALGESIA is an unpleasant subjective sensation. It cannot be easily
defined. Pain is a warning signal and indicates that there is an impairment of
structural and functional integrity of the body.
 TYPES OF PAIN:

 SOMATIC PAIN- caused by inflammation and is well-defined or sharp pain.

 VISCERAL PAIN- may be due to spasm, ischemia or inflammation.

 REFERRED PAIN- cardiac pain referred to the left arm.

 Pain consists of two components- the original ‘sensation’ and the ‘reaction’ to it.
 Pain may be acute or chronic. Acute pain may result from wounds, irritants, burns
or from ischemia. Cause is usually well-defined.
 In chronic pain the origin not well-defined. Eg: pain due to arthritis, cancers and
neuropathic pain.
 ANALGESIC:

 Is a drug which relieves pain without loss of consciousness. Analgesics only

provide symptomatic relief from pain without affecting the cause.
 Analgesics are of two classes:

1. Opioid or morphine type of analgesics.

2. Non-opiod or aspirin type of analgesics.
HISTORY
 OPIOID ANALGESICS
 One of the oldest remedies for relief of pain.
 NSAIDS
 Aspirin-type or nonopioid analgesics.
 Have anti-inflammatory, antipyretic and uricosuric properties.
 The medicinal effects of the bark of the willow have been known since
centuries.
 The active principle ‘salicin’ was isolated from the willow bark (SALIX ALBA).
 In 1875, sodium salicylate was first used in the treatment of rheumatic fever.
 Its great success led to the introduction of acetylsalicylic acid (aspirin) in
1899 (Fredrich Bayer)
CLASSIFICATION
COX ENZYME: PROSTAGLANDINS EFFECTS
FEATURES OF NONSELECTIVE COX INHIBITORS
AND SELECTIVE COX-2 INHIBITORS

Celecoxib
Etoricoxib
parecoxib
PROSTAGLANDINS AND ACTIONS
 INFLAMMATION

• The inflammatory response is complex, involving immune system.

• And various endogenous agents like prostaglandins, bradykinin, histamine,
chemotactic factors & superoxide free radicals formed by the action of lysosomal
enzymes.
• Prostaglandins, prostacyclins and TXA2 have been associated with gingivitis,
periodontitis and alveolar bone resorption. (Goodson et al, 1974,Williams, 1990)
BIOSYNTHESIS OF PROSTANOIDS
• Arachidonic acid is the primary precursor of prostanoids. Prostanoids are also
called ‘EICOSANOIDS’
• Arachidonic acid is a component of the phospholipids of cell membrane.
ROLE OF PGS IN INFLAMMATION
 By 2 roles:
1. Promote inflammation
2. Modulate and regulate inflammatory cell function ( Gordon et al 1976 )
• PG can induce pain , edema , redness and vasodilation when they are induced by
other mediators.
• PG inhibits lysosomal enzyme release during phagocytosis, enhances
chemotaxsis, chemokinesis. ( Estensen et al 1973 )
• Inhibit clonal proliferation of macrophages stem cells migration of macrophages.
• On lymphocytes it suppress cell transformation. ( Mihas 1975)
 Role in Bone Resorption:
• In number of ways it may induce bone resorption by facilitating the release of
osteoclasts activating factor from lymphocytes ( Yoneda & Mundy 1979 ).
• Inhibit bone collagen formation which result in inhibition of the repair of
resorbed bone ( Raisz & Koolemans Beynen 1974 )
 Role in periodontal destruction:
• Production of arachidonic acid metabolites
• After activation of inflammatory cells in the periodontium by bacteria,
phospholipids in the plasma membrane of cells become available for actions by
phospholipase. This leads to free arachidonic acid in the area (AAP 1992)
• Recently, Dybvig (2013) also validated that prostaglandins are an important
mediator of bone loss in periodontitis.
MECHANISM OF ACTION OF NSAIDS
USES
 Acute or chronic conditions where pain and inflammation are present. (Rossi,
2006)
• Rheumatoid arthritis
• Osteoarthritis, Inflammatory arthropathies
• Acute gout, Dysmenorrhea
• Metastatic bone pain , Headache and migraine
• Postoperative pain
• Mild-to-moderate pain due to inflammation and tissue injury
• Pyrexia, Renal colic
• They are also given to just born infants whose ductus arteriosus is not closed with
in 24 hours of birth
INDICATIONS OF NSAIDS IN DENTISTRY
 Irreversible pulpitis
 Apical periodontitis
 Acute alveolar abscess
 Infected cyst
 Sinusitis
 TMJ Arthritis
 MPDS
 After tooth extraction
 Dry socket
 Recurrent apthous ulcers
 Lichen planus
 Agranulocytosis
 Cyclic neutropenia
 CONTRAINDICATIONS
• Gastric ulcers or gastrointestinal inflammatory disease
• NSAID-induced hypersensitivity
• Bleeding concerns, third-trimester pregnancy
• Significant renal disease

 Concurrent use of the following drugs:

• Antihypertensive such as angiotensin-converting enzyme inhibitors, diuretics or
beta-blockers: NSAIDS may be coprescribed if required for 4 days or less
• Anticoagulants (warfarin)
• Antineoplastic doses of methotrexate
• Alcohol
ADVERSE EFFECTS
 Analgesics doses are usually well tolerated but anti- inflammatory doses are
usually associated with adverse effects when used for a long period.
A. G.I tract - Epigastric distress, nausea, vomiting, erosive gastritis, peptic ulcer,
increase occult blood loss in stools are common
B. Allergic reactions are not common and may be manifested as rashes, photo
sensitivity
C. Hemolysis
D. Nephrotoxicity
E. Reye’s syndrome RATIONAL USE OF ANALGESICS IN DENTAL PRACTICE
¹SYEDA AMINA HANIF

F. Salicylism ²AMMARA AZMAT

³SALEHA SADEEQA

G. Paracetamol toxicity
GENERAL GUIDELINES FOR THE USE OF
ANALGESICS
• Eliminate the source of pain, if at all possible
• Individualize regimens based on pain severity and medical history
• Maximize the nonopioid before adding an opioid
• Optimize dose and frequency before switching
• For NSAIDs, consider:
- preoperative dose
- loading dose
• Avoid chronic use of any analgesic whenever possible
• Reduce the dose and duration of any NSAID or opioid in the elderly
CHOICE OF NSAIDS
1. Mild to moderate pain with little inflammation- paracetamol or low dose
ibuprofen.
2. Acute musculoskeletal, osteoarthritic, injury associated inflammation- propionic
acid derivative, diclofenac or rofecoxib.
3. Postextraction or other acute short lasting pain- ketorolac, diclofenac,
nimesulide, propionic acid derivative
4. Gastric intolerance to conventional NSAIDs- etoricoxib, paracetamol
5. H/o asthma, anaphylactic reaction to aspirin or other NSAIDs- nimesulide,COX2
inhibitor
6. Pregnancy- paracetamol best preferred, second best low dose aspirin
7. Pediatric- paracetamol ,aspirin, ibuprofen, naproxen
CHOOSING AN NSAID FOR USE IN THE PERI- OPERATIVE PERIOD

 For prescribing the drugs for long term use outlined by Orme and by Ingham and
Portenoy can be adapted.
Drug Selection
• Choose from a limited selection of NSAIDs spanning the different chemical
groups.
• Prefer established drugs with long clinical experience and good safety profile (e.g.
ibuprofen).
• Record concurrent drug therapy and be aware of possible pharmacokinetic and
pharmacodynamics interactions.
• Avoid NSAIDs in patients with known contraindications to their use.
• • Use only one NSAID at a time, and ensure adequate
• dosage.
Route of Administration
• Be aware of available preparations. Many of the newer NSAIDs have the potential
advantage of being available in a range of formulations including oral, rectal,
parenteral and topical.
• Use the least invasive route possible.
Dosage
• Adapt dosages to suit patients requirements, particularly with respect to duration
of action.
• Increase dose until adequate analgesia occurs or maximum recommended dose is
reached.
• Review therapy frequently and change to an alternative NSAID, possibly from
another class, if there is poor response to treatment.
Toxicity
• Observe for potential toxicity (gastrointestinal, renal, hematological, etc.).
• Increase frequency of monitoring for at-risk patients(the elderly and those with
concurrent disease).
• Consider prophylaxis against adverse gastrointestinal events in these patients.
SYNERGISTIC EFFECT

Combiflam : ibuprofen+ paracetamol (400 + 325mg)

Dolokind plus : aceclofenac + paracetamol (100 +500 mg)
Diclozee plus : diclofenac Na + acetoaminophen (50 + 500 mg)
Diclomol : diclofenac Na + acetoaminophen (50 + 500 mg)
Serazee plus : diclofenac K + seratiopeptidase (50 +10 mg)
Ibugesic plus : ibuprofen+ paracetamol (400 + 325mg)
Asonac-SR plus : aceclofenac + paracetamol + seratiopeptidase (100 + 500 + 15mg )
NSAIDS COMMONLY USED IN DENTAL PRACTICE
NSAID DOSING REGIMENS FOR DENTAL PAIN
HALF-LIFES OF NSAIDS IN HEALTHY PATIENTS
During pregnancy Paracetmol it readily crosses the placenta in its unconjugated
form, in therapeutic doses it does not appear to increase the risk of birth defects or
other adverse pregnancy outcomes.

A Californian study also showed an 80% increase in the risk of miscarriage

associated with first trimester use of both aspirin and NSAIDs. This association was
not seen with paracetamol.

Paracetamol is considered to be safe for use during lactation. The estimated dose
received via breast milk is 6% of the maternal dose.

NSAIDs, such as ibuprofen and diclofenac, are considered to be compatible with

breastfeeding. The infant doses relative to the maternal doses are 0.65% and 1%
respectively.
Analgesics and pain relief in pregnancy and breastfeeding
Debra Kennedy
DICLOFENAC

• Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) taken or applied to

reduce inflammation and as an analgesic reducing pain.
• The name "diclofenac" derives from its chemical name: 2-(2,6-dichloranilino)
phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf
Pfister and introduced as Voltaren in 1973.
• Commercially available as: Voveran, Diclonac, Movonac : 50 mg tab. Diclomax :
25, 50 mg tab. Volini Spray contains Diclofenac, Linseed Oil, Menthol, and Methyl
Salicylate as active ingredients.
 MECHANISM OF ACTION
• Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates
it inhibits the lipoxygenase pathways, thus reducing formation of the
leukotriene's (also pro-inflammatory autacoids).
• It also may inhibit phospholipase A2 as part of its mechanism of action. These
additional actions may explain its high potency - it is the most potent NSAID on a
broad basis.
• The action of one single dose is much longer (6 to 8 hr) than the very short half-
life of the drug indicates. This could be partly because it persists for over 11 hours
in synovial fluids.
The diclofenac mouthwash presented a very well effect and safety in treating
inflammation associated with oral or periodontal operation.

The Effect of Diclofenac Mouthwash on Periodontal Postoperative Pain

Jaber Yaghini, Ahmad Moghareh Abed, and Najmeh Roshanzamir
 KETOROLAC

 A novel NSAID with potent analgesic and modest anti-inflammatory activity. In

postoperative pain it has equaled the efficacy of morphine, but does not interact
with opioid receptors and is free of opioid side effects.

 In short-lasting pain, it has compared favorably with aspirin. Ketorolac is rapidly

absorbed after oral and i.m. administration. It is highly plasma protein bound and
60% excreted unchanged in urine. Major metabolic pathway is glucuronidation;
plasma t½ is 5–7 hours.
 Uses: Ketorolac is frequently used in postoperative, dental and acute
musculoskeletal pain: 15–30 mg i.m. or i.v. is comparable to 10–12 mg
morphine, and can be repeated every 4–6 hours(max. 90 mg/day). It can also
be used for renal colic, migraine and pain due to bony metastasis.

 Orally it is used in a dose of 10–20 mg 6 hourly for short-term management of

moderate pain. In postoperative dental pain ketorolac has been rated superior
to aspirin 650 mg, paracetamol 600 mg and equivalent to ibuprofen 400 mg.

 Commercially available as – Ketorol, Zorovon, Ketanov, Torolac : 10mg tab.

 Hungund et al. that 10-mg ketorolac administered immediately before
periodontal surgery was effective for alleviating the operative painful sequelae.
Patients receiving the preoperative dose of ketorolac had a significant increase in
the amount of time between the presurgical drug administration and the need
for postoperative analgesics.

 10-mg KETOROLAC TROMETHAMINE administered immediately before

periodontal surgery was effective for better response by the patient during the
procedure in terms of pain reduction.
IBUPROFEN
• Is a 2-proprionic acid derivative discovered by the research arm of the British
Boots Group in the 1960s, is a peripherally acting analgesic with a potent anti-
inflammatory action that works through a reversible and balanced COX-1/COX-2
inhibition

• Effective for treating acute pain and inflammation related to endodontic,

surgical, restorative or periodontal procedures.

• One recent modification is the use of gel caps that provide faster absorption and
therefore a quicker onset for meaningful analgesia that occurs about 25-30
minutes after ingestion.
• Another recent advance in formulation includes a mucoadhesive patch that
permits intra-oral delivery of ibuprofen.

• Other modifications to ibuprofen include the addition of other drugs such as

hydrocodone or oxycodone and paracetamol (1000mg) to ibuprofen (600mg).

• This latter combination has been shown to significantly improve pain relief after
endodontic treatment when compared with ibuprofen (600mg) alone.

• Commercially available as - Brufen, Emflam, Ibusynth : 200, 400, 600mg tab.

Ibugesic : 100mg, 400 mg tab. several clinical pain models.
45
• Selecting the most appropriate NSAIDs for each patient should be tailored to
each individual patient based on the patient’s medical background.
• In general, ibuprofen is the preferred NSAIDs based on its favorable GI and
nephrotoxicity profiles.
• Naproxen might be considered in patients who have greater cardiac risk.
• Celecoxib, at the dose of less than or equal to 200 mg day-1, might be an option
in the patients who are at high risk for GI bleeding.

What Is The “Safest” Non-Steroidal Anti-Inflammatory Drugs?

Patompong Ungprasert, Wonngarm Kittanamongkolchai, Chrystal Price, Supawat Ratanapo,
• The preoperative treatment with ibuprofen significantly reduced initial pain
intensity of operative and post operative pain as compared with placebo.
• No adverse reactions related to preoperative medication were observed.
• Conclusions: The results of this study showed that 400 mg ibuprofen
administered immediately before periodontal surgery was effective for alleviating
the operative and post operative painful sequelae.

Preoperative ibuprofen administration for the treatment of post operative

periodontal surgical pain: A double-blind placebo-controlled study
Preetinder Singh1,Yash Paul Dev2,Shivani Rathore3,*,Nitin Khuller1,Sumit Kaushal4
TOPICAL NSAIDS
 Topical formulations are available for application over painful joints and muscles.
• Osteoarthritis
• Sprains
• Sports injuries
• Backache
 Preparations
• Diclofenac 1% gel : voveron emulgel, diclonac gel.
• Ibuprofen 10% gel : ribufen gel.
• Ketoprofen 2.5% gel : rhofenid gel.
• Nimesulide 1% gel : nimulid trans gel.
• Piroxicam 0.5% gel : dolonex gel, minicam gel.
NSAID’S – PERIODONTAL CONSIDERATIONS AND HOST
MODULATORY THERAPY
• Concept of host modulation was 1st introduced by Williams (1990) and Golub
et al (1992)
• In the late twentieth century the concept of host modulation was introduced as
a medical approach to periodontal treatment by Nyman, Schroeder, and Lindhe
showed how it was possible to block periodontal bone loss in animals with the
aspirin–like drug indomethacin. Evidence was then presented that some
NSAIDs, such as flurbiprofen and ibuprofen, can slow down the development of
experimental gingivitis, as well as the loss of alveolar bone in periodontitis.
• Treatment concept that aims to reduce tissue destruction and stabilize or even
regenerate the periodontium by modifying or down regulating destructive
aspects of host response and up regulating protective or regenerative
responses.(CARRANZA)
Since NSAIDs are lipophilic and are well absorbed into gingival tissues, its topical
application is possible.

NSAIDs that have been evaluated for topical administration include ketorolac
tromethamine rinse and S-ketoprofen dentifrice, piroxicam and meclofenamic acid
in inhibiting gingivitis and progression of periodontitis.

Host modulation therapy: An indispensable part of perioceutics

Minkle Gulati, Vishal Anand, Vivek Govila, Nikil Jain
2
• According to Grenier et al.(2002), nonsteroidal antiinflammatorydrugs (NSAIDs)
inhibit the formation of prostaglandins, including PGE2, which is produced by
neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to
the presence of lipopolysaccharide (LPS).
• PGE2 has been observed to be increased in periodontal disease compared with
the level in healthy patients.
• Grossi et al.(1997) reported that PGE2 also inhibits fibroblast function and has
inhibitory effects on the immune response.
• NSAIDs inhibit prostaglandins and thus reduce tissue inflammation.

Host modulation by therapeutic agents

Sugumari Elavarasu, Santhosh Sekar, Thamaraiselvan Murugan
• They are used to treat pain, acute inflammation, and a variety of chronic
inflammatory conditions. NSAIDs include the following:
• Salicylates (e.g. aspirin)
• Indomethacin
• Propionic acid derivatives (e.g. ibuprofen, flurbiprofen, naproxen)
• Administration of NSAIDs for 3 years has shown significant reduction in alveolar
bone destruction

Host modulation by therapeutic agents

Sugumari Elavarasu, Santhosh Sekar, Thamaraiselvan Murugan
 Indomethacin is the most potent of the clinically available NSAIDs at
decreasing osteoblast viability, DNA content, and increasing caspase activity
in vitro.

 Indomethacin does not inhibit wound healing and may in fact promote
wound healing in vivo.

 Therefore, locally delivered indomethacin may be effective and safe at

decreasing osteoblast function in vivo thus offering a translatable possibly for
HO prophylaxis.
ACTIONS
• Inhibits prostaglandins
• Reduce inflammation
- Used to treat pain, acute inflammation, and chronic inflammatory conditions.
- Inhibits osteoclastic activity in periodontitis (Howell TH in oral biomed 1993)
• NSAIDs such as indomethacin (williams RC 1987) flurbiprofen (jeffcoat MK JP
1989) and naproxen (Howell TH 1993) administered daily for up to 3 years,
significantly slowed the rate of alveolar bone loss compared with placebo.
The results of this study suggest that low dose aspirin may reduce the risk of
periodontal attachment loss.
Association between long-term aspirin use and periodontal
attachment level in humans: a cross-sectional investigation
M Faizuddin, F Tarannum, N Korla,S Swamy
, India.
The first and second author share the first authorship.

They concluded that the inhibition of alveolar bone loss was due to the long-
term ingestion of the NSAIDs aspirin and indomethacin.

Drugs, medications and periodontal disease

P. A. Heasman and F. J. Hughes
• NSAIDs demonstrated less over all bone loss than individuals not taking the
drug.

• In some cases , the clinical parameters measured by plaque index, gingival

index, probing depth, and attachment loss were also improved NSAIDs.

Non steroidal Anti-inflammatory Drugs as

Inhibitors of Periodontal Disease Progression
T. Howard Howell, DDS and Ray C. Williams, DMD
DISADVANTAGES
• Administration for extended periods is necessary for periodontal benefits to
become apparent, and are associated with significant side effects:
- gastrointestinal problems,
- hemorrhage (from decreased platelet aggregation)
- and renal and hepatic impairment.
• Research shows that the periodontal benefits of taking long-term NSAIDs are lost
when patients stop taking the drugs, with a return to or even an acceleration of
the rate of bone loss seen before NSAID therapy, often referred to as a “rebound
effect.” (William RC j dent res 1991)
• Inhibition of COX-1 by nonselective NSAIDs causes side effects
- Gastrointestinal ulceration
- Impaired hemostasis.
• Use of selective COX-2 inhibitors reduce periodontal inflammation without the
side effects typically observed after long-term (nonselective) NSAID
• Selective COX-2 inhibitors slowed alveolar bone loss in animal models (Bezerra
MM J Periodontol 1993) and modified prostaglandin production in human
periodontal tissues (Vardar S J Periodontol 2003)
THE ACTION OF NSAIDS IN THE PERIODONTAL TISSUES IN ANIMAL STUDIES. PORTO ALEGRE, 2011.
NSAID’S – ENZYMES COMBINATION

• Enzyme combination of NSAIDs helps in reduction of unwanted drug effects while

maintaining the anti-inflammatory/ analgesic efficacy.
• Protease enzymes belonging to family metalloprotease, have been successfully
tested for their anti-inflammatory properties, which include trypsin,
chymotrypsin and serratiopeptidse (Miyata et al., 1971; McQuade and Crewther,
1969)
CONCLUSION
 REFERENCES
• Essentials of pharmacology for dentistry K D Tripathi – 2nd edition.
• Pharmacology and therapeutics for dentistry John A Yagiela,Enid A Neidle,Frank J Dowd-4th edition.
• A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology,
comparative efficacy, and toxicity – review article Rheumatol Int (2012) 32:1491–1502 DOI
10.1007/s00296-011-2263-6.
• Association between long-term aspirin use and periodontal attachment level in humans: a cross-
sectional investigation, Australian Dental Journal 2012; 57: 45–50
• Preoperative ibuprofen administration for the treatment of post operative periodontal
surgical pain: A double-blind placebo-controlled study Preetinder Singh ,Yash Paul Dev ,Shivani
1 2

Rathore3,*,Nitin Khuller1,Sumit Kaushal4

• Host modulation by therapeutic agents Sugumari Elavarasu, Santhosh Sekar, Thamaraiselvan
Murugan
• Lippincott’s illustrated reviews-Pharmacology Williams and Wilkins- 2nd edition.
• An Overview of Clinical Pharmacology of Ibuprofen- Rabia Bushra,Nousheen Aslam (Ziauddin
College of Pharmacy, Ziauddin University).
• Prostaglandins and bone : potential risks and benefits related to use of NSAIDs in clinical
dentistry,journal of oral science,vol 50,no3,247-252,2008.
• Effects of NSAIDs on beagle crevicular cyclooxygenase metabolites and periodontal bone loss,
Journal of Periodontal Research:vol 27,issue3,pages 207– 213, May 1992.
• The Effects of Non-Steroidal Anti-Inflammatory Drugs (Selective and Non-Selective) on the
Treatment of Periodontal Diseases, Current Pharmaceutical Design, Volume 11, Number 14, May
2005, pp. 1757-1769(13).
• Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis – an
expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks carmelo
scarpignato1*, angel lanas2, corrado blandizzi3, willem F lems4, matthias hermann5 and richard
H hunt6, for the international NSAID consensus group
• An Update on Analgesics for the Management of Acute Postoperative Dental Pain Daniel A. Haas,
BSc, DDS, BScD, PhD, FRCD(C).
• The effect of inflammatory response modulator agents on gingivitis and periodontitis – Juliano
• Non steroidal Anti-inflammatory Drugs as Inhibitors of Periodontal Disease Progression T. Howard
Howell, DDS and Ray C. Williams, DMD
• Pharmacological agents for periodontal regeneration: A review T. K. Nandini, S. Mahantesha, R.
Mani, K. Kranti
• Pain management for dentists: the role of ibuprofen Alessandro Pozzi, DDS, PhD Luca Gallelli, MD,
PhD
• Definition of Inflammation, Causes of Inflammation and Possible Anti-inflammatory Strategies:
Srdan V. Stankov
• Use of non steroidal anti-inflammatory drugs in dental practice. A review Rafael Poveda Roda
José Vicente Bagán, Yolanda Jiménez Soriano , Lola Gallud Romero
THA
N K
YOU
!