Anti-inflammatory drugs

Anti inflammatory drugs Classification

A.      Non selective COX inhibitors (traditional NSAIDs)

1.       Salicylates: Aspirin

2.       Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen

3.       Fenamate: Mephenamic acid

4.       Enolic acid derivative: Piroxicam, Tenoxicam

5.       Acetic acid derivative: Ketorolac, Indomethacin, Nabumetone

6.       Pyrazolone derivative: Phenylbutazone, Oxyphenbutazone

B.      Preferential COX-2 inhibitors

Nimesulide, Diclofenac, Aceclofenac, Meloxicam, Etodolac

C.      Selective COX-2 inhibitors

Celecoxib, Etoricoxib, Parecoxib

D.      Analgesic- antipyretics with poor anti-inflammatory action

1.       Paraaminophenol derivative: Paracetamol (Acetaminophen)

2.       Pyrazolone derivative: Metamizol (Dipyrone), Propiphenazone

3.       Benzoxazocine derivative: Nefopam

All NSAIDs cause prostaglandin (PG) synthesis inhibition. The beneficial effects due to PG synthesis inhibition include:

  • Analgesia: prevention of pain nerve ending sensitization
  • Antipyresis
  • Anti-inflammatory
  • Antithrombotic
  • Closure of ductus arteriosus in newborn

Toxicities due to PG synthesis inhibition include:

  • Gastric mucosal damage
  • Bleeding: inhibition of platelet function
  • Limitation of renal blood flow: Na+ and water retention
  • Delay/ prolongation of labor
  • Asthma and anaphylactoid reactions in susceptible individuals

Adverse effects of NSAIDs

  • Gastrointestinal

Nausea, anorexia, gastric irritation, erosions, peptic ulceration, gastric bleeding/ perforation, esophagitis

  • Renal

Na+ and water retention, chronic renal failure, nephropathy, papillary necrosis

  • CVS

Rise in BP, risk of myocardial infarction (especially with COX-2 inhibitors)

  • Hepatic

Raised transaminases, hepatic failure (rare)

  • CNS

Headache, mental confusion, vertigo, behavioural disturbances, seizure precipitation

  • Hematological

Bleeding, thrombocytopenia, hemolytic anemia, agranulocytosis

  • Others

Asthma exacerbation, rhinitis, nasal polyposis, skin rashes, pruritits, angioedema

Co morbid conditions aggravated by NSAIDs

  • Peptic ulcer
  • Hypertension
  • Congestive heart failure
  • Renal insufficiency
  • Hemostatic disorders 

 Drug interactions with NSAIDs 




↓ diuresis

Oral anticoagulants

Metabolism inhibited; competition of plasma protein binding

β blockers

↓ antihypertensive effect


ACE inhibitors

↓ antihypertensive effect



↑ risk of gi bleed



↑ risk of hypoglycemia


↓ renal excretion of interacting drug


↑ risk of gi bleed



↑ nephrotoxicity



↑ risk of gi bleed


Selective serotonin reuptake inhibitors

↑ risk of gi bleed



Aspirin Pharmacological actions 1. Analgesics, antipyretics, anti-inflammatory actions

  • Aspirin is a weak analgesic
  • It effectively relieves inflammatory, tissue injury related, connective tissue and integumental pain
  • The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG mediated sensitization of nerve ending
  • Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss
  • Anti-inflammatory action is exerted at high doses (3-6 g/day or 100 mg/kg/day)

2. Metabolic effects

  • Cellular metabolism is increased, especially in skeletal muscle – increased heat production
  • There is increased utilization of glucose – blood sugar level decrease
  • Liver glycogen is depleted
  • Plasma free fatty acid and cholesterol levels are reduced

3. Respiration

  • Effect is dose dependent
  • At inflammatory doses, respiration is stimulated by peripheral (increased CO2 production) as well as central (increased sensitivity of respiratory centre to CO2) actions
  • Further rise in salicylate level causes respiratory depression; death is due to respiratory failure

4. Acid base and electrolyte balance

  • Usual doses (0.3-1.0 g) have no effect
  • Anti-inflammatory doses produce respiratory stimulation – respiratory alkalosis which is compensated by increased renal excretion of HCO3- (compensated respiratory alkalosis)
  • Slightly higher doses cause respiratory depression (respiratory acidosis) with depression of renal function (uncompensated metabolic acidosis)

5. CVS

  • No direct effect on heart and blood vessels in therapeutic doses
  • Larger doses increase cardiac output and cause direct vasodilatation
  • Toxic doses depress vasomotor centre: BP may fall
  • CHF may be precipitated in patients with low cardiac reserve

6. GIT

  • Irritate gastric mucosa – cause epigastric distress
  • It also stimulate CTZ: vomiting occur at higher doses

7. Urate excretion

  • Dose related effect is seen
  • < 2 g/day: urate retention and antagonism of all other uricosuric drugs
  • 2-5 g/day: variable effects, often no change
  • > 5 g/day: increased urate excretion

8. Blood

  • Aspirin even in small doses, inhibit TXA2 synthesis by platelets
  • It interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value (this effect last for 2 weeks turnover time of platelet)


  • Aspirin is absorbed from stomach and small intestine
  • It has poor water solubility
  • It is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid
  • It is 80% bound to plasma proteins and has a volume of distribution of 0.17 L/kg
  • Both aspirin and salicylic acid are conjugated in liver with glycine to form salicyluric acid. It also get conjugated with glucuronic acid
  • The metabolites are excreted by glomerular filteration and tubular secretion
  • The plasma t ½ is 15-20 min.
  • The elimination is dose dependent

Adverse effects Side effects

  • Nausea and vomiting
  • Epigastric distress
  • Increased occult blood loss in stool
  • Gastric mucosal damage and peptic ulceration

Hypersensitivity and idiosyncrasy

  • Rashes, fixed drug eruptions
  • Urticaria, angioedema
  • Asthma and anaphylactoid reaction

 Precautions and contraindications

  • Contraindicated in patients sensitive to it and in peptic ulcer, bleeding tendencies, in children suffering from influenza or chicken pox
  • In chronic liver disease
  • Should be avoided in diabetics, in those with low cardiac reserve and frank CHF and in juvenile rheumatoid arthritis  
  • Aspirin should be stopped 1 week before surgery
  • When given chronically during pregnancy, it is responsible for low birth weight babies
  • Lactating mothers
  • G6PD deficiency patients- hemolysis can occur


  • Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin and methotrexate from binding sites of plasma proteins: toxicity may occur
  • Inhibit tubular secretion of uric acid and antagonizes uricosuric action of probenecid
  • Blunts diuretic action of furosemide and thiazide and reduces K+ conserving action of spironolactone
  • Reduce protein bound iodine level


  1. As analgesics
  2. As antipyretics
  3. Acute rheumatic fever
  4. Rheumatoid arthritis
  5. Osteoarthritis
  6. Post myocardial infarction and post stroke patients
  7. Other less established uses are:

• Pregnancy induced hypertension (PIH) and pre eclampsia

• Patent ductus arteriosus

• Familial colonic polyposis

• Prevention of colon cancer

• To prevent flushing attending nicotinic acid ingestion

  • Aspirin has a well established role in preventing adverse events in patients with known cardiovascular disease. (1)
  • The administration of aspirin before surgery and throughout the early postsurgical period has no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increases the risk of major bleeding. (2)
  • Aspirin sensitivity may cause symptoms similar to allergic reactions in susceptible people. Patients with aspirin sensitivity typically also have asthma and nasal polyps, a combination known as the aspirin triad. (3)
  • Aspirin use reduces the risk of colorectal neoplasia through inhibition of prostaglandin-endoperoxidase synthase 2 (PTGS2, cyclooxygenase 2) related pathways. 15-PGDH (hydroxyprostaglandin dehydrogenase 15) expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention. (4)
  • The platelets from IDDM patients are resistant to the effect of aspirin by mechanisms independent of both the cyclooxygenase and PAF pathways of aggregation. (5)
  • Aspirin use is inversely related to prostate cancer incidence and prostate cancer specific mortality. (6)
  • Frequent aspirin use is associated with early aging macula disorder (AMD) and wet late AMD. (7)
  • A daily aspirin regimen reduces the risk of developing pancreatic cancer. (8)
  • When aspirin is used for primary prevention of cardiovascular disease, the absolute harms exceed the benfits. (9)
  • Regular aspirin use is associated with gastrointestinal bleeding. Risk is strongly related to dose than duration of aspirin use. Efforts to minimize adverse effects of aspirin therapy should emphasize using the lowest effective dose among both short and long term users. (10)
  • Acute aspirin intoxication (>300 mg/kg) frequently causes acute renal failure and doses of 500 mg/g may be lethal. Chronic salicylate intoxication has been reported to cause reversible or irreversible acute renal failure in association with a pseudosepsis syndrome. (11)

Propionic acid derivatives

DrugPlasma t ½Dosage
Ibuprofen2-4 hr400-600 mg (5-10 mg/kg) TDS
Naproxen12-16 hr250 mg BD – TDS
Ketoprofen2-3 hr50-100 mg BD-TDS
Flurbiprofen4-6 hr50 mg BD-QID
  • The analgesic, antipyretic and anti-inflammatory efficacy is lower than high dose of aspirin
  • All members inhibit PG synthesis. 
  • Naproxen is most potent
  • Inhibition of platelet aggregation is short lasting with ibuprofen, but longer acting with naproxen

Adverse effects

  • Ibuprofen and all its congeners are better tolerated than aspirin
  • Gastric discomfort, nausea and vomiting
  • Gastric erosion and occult blood loss are rare
  • CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression
  • Rashes, itching and other hypersensitivity phenomenon are infrequent
  • Fluid retention is less marked
  • Not to be given in pregnant women and should be avoided in peptic ulcer patients

Pharmacokinetics and interactions

  • All are well absorbed orally and highly bound to plasma proteins (90-99%)
  • They inhibit platelet interactions
  • All propionic acid derivatives enter brain, synovial fluid and cross placenta
  • Thay are largely metabolized in liver by hydroxylation and glucuronide conjugation and excreted in urine as well as bile
  • Drug interactions are seen with:

o   Oral anticoagulants

o   Oral hypoglycemic

o   Diuretics

o   Thiazides

o   Furosemide

o   β blockers 


  1. Used as simple analgesic and antipyretic
  2. Used in rheumatoid arthritis, osteoarthritis and other musculo skeletal disorders
  3. Indicated in soft tissue injuries, fractures, vasectomy, tooth extraction, post partum and post operatively; suppress swelling and inflammation


  • Rated as safest NSAID
  • Is found to be equally or more efficacious than combination of aspirin and codeine in relieving dental surgery pain
  • It is weaker anti-inflammatory, not suitable for gout or similar conditions
  • Ibuprofen is suitable for self medication with regards to its relative wide spectrum of indication, good tolerance and safety. Overall, it has been rated as the safest conventional NSAID by the spontaneous adverse drug reaction reporting system in the United Kingdom. (12)
  • Patient may develop centrocaecal field defects and reduced visual acquity while on ibuprofen therapy. Marked improvement in symptoms is seen when the drug is withdrawn. (13)
  • PPARγ plays an essential role in mediating the RhoA inhibiting effect of ibuprofen. Ibuprofen may provide additional therapeutic targets in the disorders characterized by RhoA activation including spinal cord injuries and Alzheimer’s disease. (14)
  • Acetaminophen and ibuprofen have equal tolerability. Acetaminophen produces a greater body temperature reduction at 0.5 hour after intervention compared with ibuprofen. However, ibuprofen provides a longer duration of antipyretic effect than acetaminophen 4 hours after intervention, and the intial temperature decrement lasts longer. (15)
  • Combined acetaminophen and ibuprofen tablet provide superior pain relief after oral surgery to acetaminophen or ibuprofen alone. (16)
  • Ibuprofen/ paracetamol combination analgesia, at non-prescription doses, confers modest short term benefits for knee pain/ osteoarthritis. Paracetamol 3g/day may cause similar degrees of blood loss as ibuprofen 1200 mg/day, and the combination of the two appears to be additive. (17)
  • Ibuprofen could inhibit cardiac Na+ and Ca2+ channels as it slows Vmax in both fast and slow response AP. It shortens the ERP and decreases the excitation propogation within the heart, which might provide a substrate for an arrhythmiogenic re-entry circuit. Thus ibuprofen when used improperly, may impose a potential hazard in inducing cardiac arrhythmias in patients with existing heart diseases. (18)
  • Oral paracetamol may be an alternative to oral ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in preterm infants. (19)
  • Ibuprofen is effective in reducing the incidence of acute mountain sickness. (20)
  • Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. (21)
  • Ibuprofen is a potential neuroprotective agent against Parkinson’s disease. (22)
  • Ibuprofen protects against the hypotension, acidosis and depression of cardiac index of canine endotoxin shock. (23)
  • Oral paracetamol is comparable to ibuprofen in terms of the rate of ductal closure and decreased risk of hyperbilirubinemia or gastrointestinal bleeding. Paracetamol is accepted as a first line drug treatment for PDA in preterm infants. (24)
  • Ibuprofen pharmacokinetics is only minimally influenced by advanced age, the presence of alcoholic liver disease or rheumatoid arthritis. Levels of ibuprofen in breast milk is negligible. Ibuprofen can be combined with acetaminophen without altering the pharmacokinetic profile. (25)


  • Anti-inflammatory activity is stronger
  • Particularly potent in inhibiting leucocyte migration – more valuable in acute gout
  • It is recommended for rheumatoid arthritis and ankylosing spondylitis
  • Naproxen caries low thrombotoc risk. Dose should be reduced in elderly
  • Naproxen sodium appears to be an improved form of naproxen for use as a analgesic agent. Doses up to 1375 mg/day is well tolerated. (26)
  • Both naproxen sodium and piroxicam are efective in the treatment of musculo-skeletal disorders. Naproxen sodium does not give rise to any side effects. (27)
  • In the treatment of osteoarthritis, celecoxib is as effective as naproxen and diclofenac but has significantly fewer serious upper gastrointestinal events. (28)
  • The vascular risks of high dose diclofenac and ibuprofen are comparable to coxibs whereas high dose naproxen is associated with less vascular risk than other NSAIDs. (29)
  • A single dose of oral naproxen sodium, 550 mg (equivalent to naproxen, 500 mg) or 440 mg (equivalent to naproxen, 400 mg) reduces the acute postoperative pain in adults. (30)
  • Naproxen phosphatidylcholine appears to induce less GI injury and bleeding in two rodent model system while maintaining anti-inflammatory and COX-inhibitory activity. (31)
  • Naproxen induces cell cycle arrest and apoptosis in human urinary bladder cancer cell lines and chemically induced cancers by targeting PI3K. (32)
  • The combination of sumatriptan plus naproxen sodium decreases significantly migraine recurrence presented by patients taking sumatriptan alone. (33)
  • Co-administration of naproxen and apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. (34)
  • Sumatriptan 85 mg plus naproxen sodium 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well tolerated adverse effect profile. (35)
  • The use of naproxen + esomeprazole combination has significantly better upper gastrointestinal tolerability compared with those treated with enteric coated naproxen in the treatemnt of rheumatoid disease. (36)
  • Naproxen is more effective than mefenamic acid in patients with heavy menstrual bleeding. (37)
  • Rectal naproxen is effective and safe for reducing perineal pain after vaginal delivery. (38)
  • The administration of naproxen results in a reduction in bleeding and spotting days. (39)
  • Both naproxen sodium and inuprofen are well tolerated an dprovide pain relief after oral surgery. The duration of pain relief is longer with naproxen sodium than with ibuprofen. (40)


  • An additional action to stabilize lysosomes and inhibit LOX
  • Anti-inflammatory efficacy is similar to ibuprofen and side effects are more
  • It is a NSAID which acts by blocking cyclooxygenase (COX 1 and 2), an enzyme involved in the production of prostaglandins, messengers in the development of inflammation. It reduces the signs of inflamation by blocking the enzyme and therefore prostaglandin production. (41)
  • Topical application of ketoprofen improves gait disturbance in rat models of acute inflammation. (42)
  • There is a drug-drug interaction between aspirin and ketoprofen. Concurrent administration of aspirin decreases ketoprofen protein binding and increases its plasma clearance. Salicylate reduce metabolic ketoprofen conversion to conjugates and their renal elimination. It enhances metabolic conversion of ketoprofen to nonconjugate metabolites. (43)
  • Extended release ketoprofen significantly inhibits platelet aggregation and thromboxane B2 production in healthy volunteers. Addition of aspirin has no additional effect. (44)
  • Phonophoresis of ketoprofen allows the attainment of higher local concentrations, whereas systemic exposure is lower. The result indicate that, in contrast to sham phonopheresis, ultrasound can increase the transdermal delivery of ketoprofen. (45)
  • Intraoperative ketoprofen is safe and effective in children during adenoidectomy. (46)
  • Pre-emptive analgesia with intravenous ketoprofen (100 mg) produces better postoperative pain relief in patients undergoing breast surgery. (47)
  • Ketoprofen extended release and diclofenac are therapeutically equivalent for the treatment of osteoarthritis. Clinically significant signs of potential hepatotoxicity is seen in diclofenac treated group. (48)
  • Ketoprofen may be a better alternative to the more commonly used drug diclofenac for postoperative pain relief. (49)
  • Pre-emtove analgesia with intravenous ketoprofen is ineffective in patients undergoing urological surgery. (50)
  • Oral ketoprofen (75 mg or 150 mg) in a dual release formulation is an effective and well tolerated drug in the acute treatment of migraine attacks. (51)
  • Ketoprofen inhibits expression inflammatory mediators in dental pulp cells stimulated with LPS. The inhibitory effect is associated with inhibition of the mitogen activated protein kinase pathway. (52)


  • More effective than ibuprofen
  • Gastric side effects are more
  • It is used as an ocular anti-inflammatory as well
  • Intravenous flurbiprofen axetil provides better analgesia effects and few side effects to patients with refractory cancer pain. It could increase analgesia effects when combined with anesthetic drugs in treatment of moderate or severe pain, especially breakthrough pain and suit to patients who cannot take oral drugs for the reason of constipation and psychosomatic symptoms. (53)
  • Flurbiprofen reduces inflammatory response in the eye in the first few days following cataract extraction and may therefore reduce the risk of severe and potentially disastrous reactions which sometimes occur. (54)
  • The lidocaine/ fluribiprofen axetil combnation, compared with lidocaine 40 mg or flurbiprofen 50 mg, effectively reduces pain during the injection of propofol. (55)
  • Topical flurbiprofen is an effective treatment for episcleritis. (56)
  • Flurbiprofen can be transported to PLA nanoparticles across an in vitro BBB model and the transported flurbiprofen modulated γ-secretase activity by selectively decreasing Aβ42 levels. It can be used for the treatment of Alzhiemer’s disease and other neurological disorders. (57)
  • The topical application is an effective method to deliver flurbiprofen to the human body, particularly to soft tissues near the body surface. (58)
  • Cross sensitivity and cross desensitization between aspirin and flurbiprofen is seen in patient with rhinosinusitis and asthma. (59)
  • Post-thymectomy intravenous administration of flurbiprofen axetil provides safe and effective analgesia for myasthenia gravis patients. (60)

Fenamate (Anthranilic acid derivative): Mephenamic acid

  • An analgesic, antipyretic and weak anti-inflammatory
  • Inhibit synthesis of PGs as well as antagonizes some of its action
  • Exerts central as well as peripheral analgesic actions
  • Adverse effects
  • Diarrhea
  • Epigastric distress
  • Gut bleeding
  • Skin rashes, dizziness
  • Hemolytic anemia is rare but serious complication
  • Pharmacokinetics
  • Oral absorption is slow but almost complete
  • It is highly bound to plasma proteins- displacement interactions can occur
  • Partly metabolized and excreted in urine as well as bile
  • Plasma t ½ is 2-4 hours
  • Uses
  • Analgesic in muscle, joint and soft tissue pain
  • Dysmennorhea
  • Rheumatoid arthritis and osteoarthritis
  • Mostly patients with mefenamic acid overdosage are symptom free. Some may develop muscle twitching which may progress to grand mal convulsions in some patients. (61)
  • The topical mefenamic acid emulgel can be used extensively to impart better patient compliance. It is helpful in enhancing spreadability, adhesion, viscosity and extrusion. (62)
  • Mefenamic acid and vitex agnus are both effective on IUD induced bleeding; mefenamic acid is more effective. (63)
  • Tacrine-meenamic acid hybrids causes inhibition of acetylcholinesterase (AChE). Thus they could be effective in patients with Alzheimer’s disease (AD) by increasing cholinergic function. (64)
  • Naproxen is more effective than mefenamic acid in patients with heavy menstrual bleeding. (65)
  • Mefenamic acid ingestion can cause secondary angle closure glaucoma and myopia in a patient which can be managed by stopping the medication, symptomatic treatment and reassurance. (66)
  • Mefenamic acid is found to be more effective and equally tolerable than paracetamol as an antipyretic in pediatric patients with febrile illness and can be alternative to paracetamol. (67)
  • Mefenamic acid, by its ability to inhibit prostaglandin activity in addition to inhibiting prostaglandin synthesis, may offer advantage in the treatment of patient with primary dysmenorrhea. (68)
  • Toxic interactions is between lithium carbonate and mefenamic acid. (69)
  • Mefanamic suppositories is as effective for antipyretic purposes as equivalent oral doses of mefenamic suspension and the suppositories are well tolerated. (70)
  • Mefenamic acid plus vitamin E is effective in providing pain relief in patients with primary dysmenorrhea who do not achieve appropriate pain relief with mefenamic acid. (71)
  • Oral drotaverine with mefenamic acid is effective in women undergoing hysteroscopy and endometrial biopsy. (72)
  • Both interstitial and mesangial changes are common features of acute renal failure due to mefenamic acid therapy. (73)
  • Multifocal fixed drug eruption can be induced by mefenamic acid. (74)

Enolic acid derivative (Oxicams) Piroxicam

  • Long acting potent NSAID with antiinflammtory potency similar to indomethacin and good analgesic-antipyretic action
  • Non selective, reversible inhibitor of COX
  • It lowers PG concentration in synovial fluid and inhibits platelet aggregation- prolong bleeding time
  • It decreases the production of IgM rheumatoid factor and leucocyte chemotaxis
  • Pharmacokinetics
  • It is rapidly and completely absorbed
  • 99% plasma protein bound
  • Metabolized largely in liver by hydroxylation and glucuronide conjugation
  • Excreted in urine and bile
  • Plasma t ½ is long nearly 2 days
  • Steady state concentration is achieved in a week
  • Single daily administration is sufficient
  • Adverse effects
  • Gi side effects are more common
  • Causes less fecal blood loss
  • Rashes and pruritis are seen in <1% patients
  • Edema and reversible azotemia
  • Uses
  • Rheumatoid arthritis, ankylosing spondylitis
  • Acute gout, musculoskeletal injuries
  • Dental pain
  • Use of 20 mg Piroxicam 2 hours pre-operation reduces pain score and the time that patients required analgesic post-operation compare with the use of piroxicam starting the same time with anesthesia or one hour post-operation. (75)
  • Piroxicam and intracavitary platinum based chemotherapy is effective in controlling malignant effusion in patients with advanced malignant mesothelioma. (76)
  • Both isoxicam and piroxicam reduces pain and nocturnal awakening following surgery in patients surgery in patientw who has sustained skiing accidents. (77)
  • Both naproxe sodium and piroxicam are effective in the treatment of musculo-skeletal disorders. Naproxen sodium does not give rise to any side effects. (78)
  • Oral beta-cyclodextrin-piroxicam has quick onset of action, long lasting effects and good gastric tolerance compared with intramuscular piroxicam in the treatment of postoperative pain after major orthopedic urgery. (79)
  • IM pirxicam appears to perform better than IM diclofenac for renal colic pain relief. With fewer injection site side effects, IM piroxicam should replace IM diclofenac for renal colic. (80)
  • Piroxicam photosensitivity in man is induced by contact sensitization with thimerosal. (81)
  • Flurbiprofen is found to be superior to piroxicam in improving pain on movement and at rest in patients with osteoarthritis. The incidence of side effects are less with flurbiprofen. (82)
  • The administration of a single dose of piroxicam before embryo transfer has no additional effect on pregnancy outcome in patients receiving adequate doses of progesterone for luteal phase supplementation after IVF or ICSI. (83)
  • Aceclofenac has anti-inflammatory and analgesic efefcts similar to those of piroxicam in the management of gonarthritis and seems to be better tolerated because it induces less adverse reactions than piroxicam. (84)
  • Consistent with increased apoptosis, piroxicam reduces tumors in the small intestine. In the cecum, piroxicam increases tumorigenesis but apoptosis is not decreased, suggesting that other mechanisms besides apoptosis are involved in the differential organ specific effect on tumorigenesis of piroxicam in the colon cancer model. (85)
  • Piroxicam/cisplatin has antitumor activity against canine transitional cell carcinoma. a disease that closely mimics human invasive urinary bladder cancer. Induction of tumor apoptosis and reduction in angiogenic factor concentrations are observed. (86)
  • Meloxicam at a dose of 15 mg/day is comparable in efficacy and safety to piroxicam 20 mg in patients with osteoarthritis of the hip. (87)
  • Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous reaction characterized by an acute episode of sterile pustules over erythematous edematous skin, reported with the use of piroxicam. (88)
  • Both naproxen and piroxicam causes significant pain relief and improvement of mobility in the patients with osteoarthritis of foot. (89)
  • Nanoemulgel formulation can be used as a feasible alternative to conventional formulations of piroxicam with advanced permeation characteristics for transdermal application. (90)
  • The nanocream containing the newly synthesized palm oil esters is successful for transdermal delivery of piroxicam. (91)
  • Piroxicam prodices impairment on antipyrine disposition as a consequence of reduction in the activity of hepatic microsomal drug metabolizing enzymes, particularly the cytochrome P-450 system. Thus, there could be a potential danger of long term piroxicam therapy on the oxidative degradation of steroid hormones and other endogenous compounds that are metabolized by the mixed function oxidase system. (92)
  • The plasma concentrations, elimination half life, AUC and volume of distribution are not influenced by age and sex. Thus, elderly patients receiving the recommended dose of piroxicam are not exposed to undue risk related to pharmacokinetic considerations. (93)
  • Oxaprozin and piroxicam are comparable in efficacy and safety in patients with active osteoarthritis. (94)
  • Sublingual piroxicam shows significant analgesic effect with excellent tolerability for the acute management of migraine without aura. (95)
  • Fixed rug eruptions are reported with the use of piroxicam. (96)
  • Piroxicam (NSAIDs) should form an integral part of the treatment of acute ankle sprains. (97)

Acetic acid derivative- Ketorolac

  • Potent analgesic but moderate anti-inflammatory activity
  • It inhibits PG synthesis and relieves pain primarily by peripheral mechanism
  • Rapidly absorbed after oral and im administration
  • It is highly plasma protein bound and 60% excreted unchanged in urine
  • Major metabolic pathway is glucuronide conjugation
  • Plasma t ½ is 5-7 hours
  • Due to higher cost of ketorolac, the pain and difficulty associated with its administration, the risk of extravasation, and the exposure to needle stick inuries, there is no use for IM or IV ketorolac over oral ibuprofen in the emergency department for routine analgesia. In specific acute pain syndromes associated with nausea and vomiting, like renal colic, may its use be warranted. (98)
  • Single dose IV ketorolac is as effective as titrated iv meperidine for the relief of acute renal colic and causes less functional impairment. (99)
  • Intravenous ketorolac, when administered preoperatively for single stage adjustable strasbismus surgery under topical anaesthesia, is effective in reducing pain during and after surgery. (100)
  • Paracetamol 1 g IV posseses a similar analgesic efficacy to ketorolac 30 mg IV after thyroidectomy. Paracetamol may represent alternative to ketorolac for pain prevention after mildly to moderately painful surgery in situations where the use of NSAIDs is unsuitable. (101)
  • Ketorolac is effective analgesic in the management of acute pain. (102)
  • Ketorolac is effective in reducing mast cell degranulation, as indicated by significantly decreased tryptase tear levels, as well as the clinical and cytological allergic reaction. (103)
  • The patients receiving ketorolac intraoperatively have significantly lower pain scores at later recovery time points and significantly lower occurences of nausea after ambulatory parathyroidectomy. (104)
  • The significant effect of ketorolac on renal function is reduced excretion of potassium. Bleeding time is also increased. (105)
  • Tramadol is a suitable and safe analgesic for the relief of post extraction pain and is more effective than ketorolac with prolonged analgesa and minimal side effects for third molar tooth extraction. (106)
  • IM Ketorolac and oral ibuprofen provide comparable analgesia in ED patients with acute musculoskeletal pain. (107)
  • Ketorolac tromethamine controls postoperativ epain better than hydrocodone and acetaminophen in the immediate postsurgery period after anterior cruciate ligament reconstruction. (108)
  • Ketorolac may be used in pain relief in patients with acute coronary syndrome. (109)
  • First line therapy with IV ketorolac and IV fluids resulted in adequate resolution of pain in 53% of episodes with acute vaso-occlusive pain treatment of children with sickle cell disease. (110)
  • The analgesic efficacy of ketorolac is comparable to that of ibuprofen and the drug is well tolerated in the doses without extra medication being required. (111)
  • IV Ketorolac can be used for primary purpose of fever reduction in which enteric antipyretic administration failed. (112)
  • Intranasal ketorolac challange and desensitization followed by rapid oral aspirin challanges is effective, safe and less time consuming for desensitization of aspirin-exacerbated respiratory disease. (113)
  • Ketorolac 30 mg and ketorolac 15 mg plus complex B vitamins can provide acceptable analgesia in many patients with severe pain after cesarean delivery. (114)
  • Ketorolac is safe and effective analgesic for relief of postoperative pain. (115)
  • Topical ketorolac 0.5% solution is effective in controlling symptoms of vernal keratoconjunctivitis. (116)
  • Adverse effects
  • Nausea, abdominal pain
  • Dyspepsia
  • Ulceration
  • Loose stools
  • Drowsiness, headache, dizziness
  • Pruritis
  • Pain at injection site
  • Rise in serum transaminase
  • Fluid retention
  • Uses:
  • Postoperative, dental and acute musculoskeletal pain
  • Used in renal colic, migraine and pain due to bony metastasis
  • Orally used for short term management of moderate pain
  • It is not used as pre anesthetic medication or in obstetric analgesia
  • Topical ketorolac is used in noninfective ocular conditions


  • Potent anti-inflammatory drug with prompt antipyretic action
  • Highly potent inhibitor of PG synthesis and suppresses neutrophil motility
  • In toxic doses, it uncouples oxidative phosphorylation
  • There is a lowering effect of indomethacin on plasma renin activity due to interference with renal renin release. This may be due to blockade of prostaglandin synthesis. (117)
  • Indomethacin is effective in the management of hydramnios and preventing its complications. (118)
  • Indomethacin has no effect on slowing the Alzheimer’s disease progression. (119)
  • There is extensive O-demethylation and N-deacylation in man. Demethylation followed by deacylation constitutes the major pathway for catabolism in man and direct deacylation is a minor one. (120)
  • Indomethacin is a valuable drug in the treatment of arthritis. Suppositories can be used when capsule are contraindicated due to peptic ulcer. It is absorbed satisfactorally from the rectum. (121)
  • High dosage is associated with more severe, polysymptomatic reactions, headache being the dominant complaint. On low dosage, reaction frequently consisted of single, relatively mild symptoms, most usual complaint being giddiness. Side effects are common in with a history of previous pyrazole intolerance, in particular dyspepsia, and more common in females than males. Side effects are less common in osteoarthrosis than in rheumatoid arthritis, ankylosing spondylitis and gout. (122)
  • Indomethacin and ibuprofen lysine are approved in United States for the treatment of patent ductus arteriosus (PDA). Indomethacin has a protective effect on the incidence of intraventricular hemorrhage (IVH) but reduces the blood flow to the kidneys and the brain. Ibuprofen is less toxic but has no effect on IVH. Both the drugs are equally effective. (123)
  • The forearm vasoconstrictor responses to brachial arterial infusions of angiotensin II, norepinephrine and to neurogenic reflex stimulation elicited by lower body suction are greatly depressed in patients with Bartter’s syndrome than in normal subjects. During indomethacin treatment, these responses are restored to normal. (124)
  • Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent broncho pulmonary dysplasia (BPD) even though it reduces patent ductus arteriosus (PDA). (125)
  • Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduces the incidence of the condition. (126)
  • The 1 week therapy with indomethacin is beneficial in the treatment for polyhydramnios. (127)
  • Anti inflammatory agents may alter the regulation of intestinal epithelium cytotoxicity without improvement in barrier function. These indicate the possible role of indomethacin, hydrocortisone in altering cell survival mechanisms leading to cellular necrosis vs apoptosis under hypoxic, pro-inflammatory environments. (128)
  • Indomethacin freely crosses placenta and interferes with fetal prostaglandin production and alter normal physiology of fetal cardiovascular system. It should be avoided in pregnant women > 32 weeks gestation, as the risk of pulmonary hypertension in neonate is significant. (129)
  • Indomethacin has a direct and toxic effect on the pancreas and may cause acute pancreatitis in some patients. (130)
  • At 12 mg/kg/day, indomethacin induces severe gastrointestinal toxicity (hemorrhage, ulcers and necrosis with peritonitis) while at the dosages of 6 and 2 mg/kg/day, causes moderate to slight dose related functional and morphological renal alterations (increase of serum urea, reduction of serum albumin, increase of serum potassium and/ or chloride and subacute inflammation). (131)
  • Indomethacin is not effective in preventing ectopic bone formation for acetabular fractures. (132)
  • Indomethacin can induce headache in patients with hemicrania continua or paroxysmal hemicrania (such as reversible cerebral vasoconstriction syndrome or aseptic meningitis). (133)
  • Indomethacin treatment prevents high fat diet induced obesity and insulin resistance. (134)
  • Indomethacin causes inhibition of Escherichia coli heat stable enterotoxin before its activation of guanylate cyclase. (135)
  • 0.2 mg/kg indomethacin followed by a continuous infusion of 0.1 mg/kg/h can be used in patients with acute or sustained intracranial pressure ICP- hypertension associated with a high venous oxygen saturation (> 60%) and/ or relatively high CBF (> 40 ml/100 g/ min). Indomethacin is contraindicated in cardiac ischemia, renal insufficiency and bleeding gastric ulcer. (136)
  • There is a chemopreventative and chemotherapeutic efficacy of indomethacin against colorectal cancer. (137)
  • Indomethacin has a more prominent initial effect while ibuprofen decreases renal function during the second and third courses similarly to indomethacin in treatment of patent ductus arteriosus. (138)
  • IV morphine produces more rapid analgesia than rectally administered indomethacin in the treatment of ureteric colic. (139)
  • Ininfants with very low birth weight (VLBW), oral ibuprofen is as effective as intravenous indomethacin for closure of PDA and is associated with significantly fewer cases of necrotizing enterocolitis among infants with birth weights < 1250 g and significantly lower rates of elevated creatinine levels among neonates with birth body weights ranging from 1000 to 1500 g. (140)
  • In the treatment of acute goutlike arthritis, oral prednisolone/ acetaminophen combination is as effective as oral indomethacin/ acetaminophen combination in relieving pain but is associated with fewer adverse effects. (141)
  • With administration of indomethacin (75 mg/day for 6 days) in patient with liver cirrhosis with marked hypoxemia, PaO2 is elevated up to 50 mmHg from 44 mmHg. Thus hepatogenic pulmonary angiodysplasia is a functional vasodilation that is modulated by vasoactive substances like prostaglandins and/or other eicosanoids. (142)
  • Indomethacin may be used in the treatment of acute pancreatitis. (143)
  • Pharmacokinetics:
  • Well absorbed orally
  • Rectal absorption is slow but dependable
  • 90% bound to plasma proteins
  • Partly metabolized in liver to inactive products and excreted by kidney
  • Plasma t ½ is 2-5 hours
  • Adverse effects
  • High incidence of CNS and gastrointestinal side effects
  • Gastric irritation, nausea, anorexia
  • Gastric bleeding and diarrhea
  • Frontal headache
  • Dizziness, ataxia, mental confusion, hallucination
  • Depression, psychosis
  • Leucopenia, rashes and other hypersensitivity reactions
  • Increased risk of bleeding due to decreased platelet aggregability
  • Contraindicated in:
  • Machinery operators
  • Drivers
  • Psychiatric patients
  • Epileptics
  • Kidney disease
  • Pregnant women and children
  • Uses:    
  • Reserve drug in ankylosing spondylitis, acute exacerbation of destructive arthropathies, psoriatric arthritis and gout
  • Malignancy associated fever
  • Medical closure of patent ductus arteriosus
  • Bartter’s syndrome


  • Possess analgesic, antipyretic and anti-inflammatory activity
  • Effective in treatment of rheumatoid arthritis and osteoarthritis, soft tissue injury
  • Plasma t ½ is 24 hours
  • COX dependent platelet aggregation in RA patients seems to be more inhibited by naproxen than by nabumetone. This may be relevant for patients requiring non-steroidal anti-inflammatory drug treatment but who have an increased risk of bleeding as well. (144)
  • Nabumetone is as effective as diclofenac in osteoarthritis of the knee. Both drugs are well tolerated, have a very good response to treatment. (145)
  • Nabumetone does dose dependently inhibit the cyclooxygenase activity of platelet PGHS-1 of healthy subjects both in vivo and ex vivo. Thus it is unlikely that its safety profile in patients may be related to selective inhibition of the inducible PGHS-2. (146)
  • There is a high percentage of tolerability to the maximum therapeutic dosage of nabumetone and meloxicam in patients with NSAID intolerance, both in those with cutaneous/ mucous manifestations and in those with respiratory disease. (147)
  • Nabumetone is similar in efficacy to diclofenac SR and piroxicam in relieving the symptoms of osteoarthritis. Nabumetone’s GI safety profile is generally superior to that of both comparator NSAIDs. (148)
  • Nabumetone does not inhibit gastroprotective prostanoid synthesis; whereas its active metabolite 6MNA is an effective inhibitor of prostanoid synthesis in target tissues. (149)
  • A single full dose of nabumetone can be tried as a safe alternative in most patients with a hypersensitivity reaction to ns-NSAIDs. (150)
  • Adverse effects:
  • Abdominal cramps and diarrhea
  • Lower incidence of gastric erosions, ulcers and bleeding

Pyrazolones- Metamizol (Dipyrone)

  • Prompt acting analgesic and antipyretic but poor anti-inflammatory and not uricosuric
  • It can be given orally, im as well as iv
  • IV injection causes precipitous fall in BP
  • Banned in USA as it causes agranulocytosis
  • Gastric irritation and pain at injection site occurs
  • The safety of metamizol and paracetamol is comparable and several times higher than that of non-steroidal anti-inflammatory drugs used for postoperative pain management. The drugs should be administered at the lowest efefctive doses, over the shortest possible time; the absolute contraindications should be considered. Metamizol should not be used for more than 7 7 postoperative days and the recommended doses should not be exceeded. It also has a spasmolytic action which is useful in contraction pains. (151)
  • Mtamizole is prohibited ub the United States because of the risk of agranulocytosis but is widely used in Mexico and other counteries. It’s use is common and may be underrecognized in immigrant Latino patients. (152)
  • The inhibitory effect of diclofenac and metamizol on platelet aggregation is not related to a reduced surface expression of P-selectin and GPIIb/IIIa on platelets. (153)
  • The overdose of metamizol may induce reversible acute renal failure and abortion in early pregnancy suggesting that it has toxic effects per se. (154)
  • Propacetamol and metamizol does not produce a clinically significant decrease in temperature in febrile ICU patients whereas external cooling decreases both temperature and energy expenditure. (155)
  • Both metamizol and pethidine suppresses post anesthetic shivering but pethidine induces a quicker and more reliable response. (156)
  • Lysine cloxinate (LC) is significantly superior to metamizol in treating severe migraine attacks. LC promotes significantly more burning at the site if injection. (157)
  • Metamizol is commonly associated with hypersensitivity reactions which are IgE mediated and some of them are potentially severe. The cellular allergen stimulation test (CAST) has low sensitivity to metamizol hypersensitivity reaction. (158)
  • Metamizol can be used as a reducing agent for determining inorganic phosphorus colorimetrically in a protein free filtrate of serum or plasma or in a diluted urine specimen. (159)
  • Single intravenous dose of metamizol 2 g, ketorolac 30 mg and propacetamol 1 g is effective in the treatment of post operative pain after heart surgery. The analgesic effects of metamizol, ketorolac and propacetamol is not associated with clinically significant impairment in hemodynamic function when administered to hemodynamically stable patients. (160)
  • Cizolirtine citrate an dmetamizol sodium both are effective in the treatment of adult acute renal colic. (161)
  • There is a dose response effect of 40 mg/kg over 15 mg/kg of intravenous dipyrone (metamizol) based on better movement induced pain control, lower morphine consumption and fewer opioid related side effects in postoperative pain after herniorrhaphy. (162)
  • Delayed skin reactions occurs due to metamizol including anaphylaxis, urticaria/ angioedema, Steven Johnson syndrome, Toxic epidermal necrolysis, Fixed drug eruptions, contact dermatitis, agranulocytosis, thrombocytopenia and vasculitis. (163)
  • There is a earlier onset of a more profound pain relief of 0.5 and 1 g metamizol over 1 g acetylsalicylic acid in patients with moderate episodic tension-type headache. (164)
  • Intraoperative metamizol can cause acute anaphylactic collapse in patients. (165)
  • Metamizol is associated with acute renal failure and severe thrombocytopenia. (166)
  • There is an excellent efficacy of paracetamol and metamizole combined with opioids in treatment of postoperative pain after total hip arthroplasty. Metamizole is proved to be a better analgesic than paracetamol. (167)
  • Neither iv paracetamol nor iv metamizol provides a significant reduction in total postoperative morphine consumption compared with placebo in the management of postoperative pain after elective breast surgery. (168)
  • Controlled release oxycodone administered twice in the first 24 h postoperatively is superior to intravenous tramadol/ metamizol for postoperative analgesia after retinal surgery, with fewer adverse events and greater patient satisfaction. (169)
  • Cardiogenic shock can occur secondary to metamizole induced Type II Kounis syndrome. (170)


  • Properties similar to metamizol
  • Better tolerated
  • Agranulocytosis has not been reported
  • When propyphenazone 220 mg is administered orally to volunteers, maximum plasma concentrations between 1.5 g/ml and 3.5 g/ml is found 30 min later. The major metabolic route is demethylation. The main urinary metabolite is the enolglucoronide of N-(2)-demethylprophyphenazone. (171)
  • Propyphenazone is a sensitizing agent in susceptible individuals and can elicit IgE mediated anaphylaxis. (172)
  • Prenatal coadministration of propyphenazone with caffeine or paracetamol causes intrauterine growth retardation but does not increase external or internal congenital anomalies. There is a risk of midline defects like umbilical hernia and gastroschisis. (173)
  • Propyphenazone is associated with Kounis syndrome which is characterised by acute inferior myocardial infearction with low atrial rhythm. (174)
  • Patient receiving caffeine/dihydroergotamine mesilate/ propyphenazone (Tonopan) mey develop allergy to pyrazolones, with facial angioedema, difficulty breathing and pruritis. (175)
  • Saridon (Propyphenazone/ Paracetamol/ Caffeine combination) is an effective analgesic that combines advantage of fast onset and effective analgesia as compared with paracetamol alone, ibuprofen and aspirin. (176)
  • Asthma can be induced by propyphenazone without aspirin and acetaminophen sensitivity. (177)
  • Paracetamol, propyphenazone and dipyrone does not increase the risk of upper gastrointestinal bleeding. (178)

Preferential COX-2 inhibitors- Nimesulide

  • Relatively weak inhibitor of PG synthesis and moderately COX-2 selective
  • Anti inflammatory action is exerted due to following mechanisms:
  • Reduced generation of superoxide by neutrophills
  • Inhibition of PAF synthesis
  • TNFa release
  • Free radical scavenging
  • Inhibition of metalloproteinase activity in the cartilage
  • Almost completely absorbed orally, 99% plasma protein bound
  • Extensively metabolized and excreted mainly in urine with a t ½ of 2-5 hours
  • Adverse effects
  • Gastrointestinal (epigastralgia, heart burn, nausea, loose motions)
  • Dermatological (rash, pruritis)
  • Central (somnolence, dizziness)
  • Fulminant hepatic failure (banned in many counteries)
  • Nimesulide given for 2 weeks is far efficacious and is at least comparable to other NSAIDs in treating osteoarthritis. (179)
  • There is life threatening hepatotoxic effects of nimesulide. United Stated and many European counteries have banned the drug. (180)
  • The serious heaptic adverse reactions following nimesulide use is very rare. Its administration is contraindicated in children less than 12 years. (181)
  • Nimesulide should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period. (182)
  • N-acylated and N-sulfonylated of N-(4-amino-2-phenoxy phenyl) methanesulfonamide obtained from nimesulide can be conveniently prepared. (183)
  • Nimesulide and paracetamol combination offers no advantage over nimesulide alone or paracetamol alone, either in terms of degree of analgesia or onset of action. (184)
  • Nimesulide inhibits cytokine induced COX-2 expression and protein at sub and therapeutic concentrations. AT least part of this activity may be the result of nimesulide inhibition of calcium and/or free radical generation induced by cytokines. (185)
  • Nimesulide-betadex has a more rapid onset of analgesic action than nimesulide with an equivalent analgesic effect and may offer a useful alternative in postoperative cases in which rapid relief of pain is required. (186)
  • The analgesic effect of nimesulide has a faster onset (< 15 minutes) and is stronger than that of ibuprofen in opinion of patients with moderate and severe pain after extraction of impacted thord molars. (187)
  • The neuroprotective effects of nimesulide against kainate induced oxidative stress in vivo are not mediated through its direct free radical scavenging ability because the concentrations at which nimesulide is able to reduce in vitro kainate excitotoxicity are excessively higher than those attained in plasma after therapeutic doses. (188)
  • Nimesulide protects against permanent focal cerebral ischemia, even with a 2h post treatment delay. It has a therapeutic potential in the treatment of stroke. (189)
  • Nimesulide can induce acute renal failure. (190)
  • Celecoxib and nimesulide inhibits proliferation of ectopic endometrial stromal cells by inducing apoptosis and blocking the cell cycle at the G0/G1 phase. (191)
  • Nimesulide is used in the treatment of painful osteoarthritis. (192)
  • Nimesulide 1% spray is effective with a good safety profile and can be considered is a good alternative to oral analgesic therapy in minor soft tissue injuries. (193)
  • Nimesulide prevents H pylori associated gastric carcinogenesis and suggest that COX-2 may be target for chemoprevention of gastric cancer. (194)
  • Nimesulide can be used in the treatment of Alzhiemer’s disease. (195)
  • The suppression of Survivin expression play an important role in nimesulide induced growth inhibition. It could act as an effective therapeutic agent for hypopharyngeal carcinoma therapy. (196)
  • Natural Terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide hepatotoxicity. (197)

Diclofenac sodium

  • Analgesic, antipyretic and anti-inflammatory drug with efficacy similar to naproxen
  • It inhibits PG synthesis and COX-2 selective
  • Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced
  • It is well absorbed orally, 99% plasma protein bound, metabolized and excreted in urine and bile
  • The plasma t ½ is 2 hours
  • Good tissue permeability and concentration in the synovial fluid is maintained 3 times longer than plasma, exerting extended therapeutic action in the joints
  • Adverse effects
  • Epigastric pain
  • Nausea
  • Headache, dizziness
  • Rashes
  • Increased risk of heart attack and stroke
  • Reversible elevation of serum amino transferases
  • Kidney damage is rare
  • Uses
  • Rheumatoid and osteoarthritis
  • Bursitis
  • Ankylosing spondylitis
  • Toothache
  • Dysmenorrheal
  • Renal colic
  • Post traumatic and post inflammatory conditions
  • Diclofenac induces hepatotoxicity in patients. (198)
  • Diclofenac should not be prescribed to patients with serious underlying heart conditions because of a small increased risk of heart attack and stroke. (199)
  • There is increased vascular and gastrointestinal risk of prescribing high dose diclofenac to patients. (200)
  • Topical diclofenac is as effective as oral diclofenac with significantly reduced side effects in treatment of osteoarthritis of knee. (201)
  • Diclofenac sodium acts by potent cyclo-oxygenase inhibition, reduction of arachidonic acid release and enhancement of arachidonic acid uptake. It results in a dual inhibitory effect on both the cyclo-oxygenase and lipoxygenase pathways. (202)
  • Diclofenac shows pronounced antitumoral properties in pancreatic cancer. It has the ability to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells. (203)
  • Diclofenac potassium attenuated dysmenorrhea and restores exercise performance in women with primary dysmenorrheal. (204)
  • 0.1% diclofenac sodium applied topically 4 times a day for 3-4 weeks is effective in the treatment of filamentary keratitis. There are no recurrences of filaments and no adverse reactions to the drug during 8 months follow-up. (205)
  • Diclofenac sodium reduces both tissue and serum levels of amoxicillin in rats. (206)
  • Patients have been reported to have hypersensitivity to diclofenac. These patients are advised to avoid administration of diclofenac and other drugs derived from phenylacetic acid such as aceclofenac and fenoclofenac. (207)
  • Severe photosensitivity reaction can be induced by topical diclofenac. (208)
  • Diclofenac is used in the pain management. Side effects include urticaria, asthmatic attack, vasospastic angina, ischemic stroke and Kounis syndrome. Anaphylactic shock is rare but has been reported with intramuscular injection of diclofenac. (209)
  • In patients with cholelithiasis who present with biliary colic, a single 75 mg intramuscular dose of diclofenac can provide satisfactory pain relief and decrease substantially the rate of progression to acute cholecystitis. (210)
  • Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib is similar to those in patients on diclofenac with long term use of these drugs. (211)
  • Diclofenac sodium when used as an anti-inflammatory agent post operative does not interfere with surgical wound healing. (212)
  • Darrier disease (DD) is an uncommon autosomal dominant disorder with complete penetrance and variable expressivity. Improvement in the symptoms of Darrier disease patients is seen with diclofenac sodium 3% gel. (213)
  • The  possibility of colonic ulcerations should be considered in patients with gastrointestinal bleeding receiving diclofenac. (214)
  • Diclofenac induces acute renal failure in decompensated elderly patient. (215)
  • Pre-treatment with pregabalin, gabapentin and diclofenac has equal efficacy in reducing the incidence and severity of succinylcholine induced myalgia. (216)
  • The lower dose diclofenac submicron particle capsules demonstrate effective pain relief in patients with osteoarthritis. (217)
  • The new 0.074% diclofenac mouthwash is an effective and tolerable medicinal product for post surgical symptomatic relief. (218)
  • Periprostatic nerve block provides superior analgesia for TRUS guided biopsy. Diclofenac patch is useful as an adjunct. (219)
  • Diclofenac is effective and safe option for the treatment of osteoarthritis. (220)
  • Diclofenac sodium given by hydrodissection in phacoemulsification decreased, but did not significantly prevent the development of posterior capsule opacification. (221)


  • Newer cogener of piroxicam with COX-2/COX-1 selectivity ratio of about 10
  • Preferential COX 2 inhibitor as measurable inhibition of platelet TXA2 production occurs at therapeutic doses of meloxicam
  • Plasma t ½ is 15-20 hours
  • Adverse effects
  • Mild gastric side effects
  • Ulcer complication (bleeding, perforation)
  • Meloxicam 15 mg once daily is effective and can be compared favourably with standard NSIADs regarding tolerance when administered to patients with rheumatoid arthritis over an 18 month period. (222)
  • 15 mg meloxicam is an effective and well tolerated therapy for osteoarthritis and compares favourably with diclofenac 100 mg, a well established treatment for this indication. (223)
  • The preemptive combination of tramadol and meloxicam produces a potent analgesic effect post nerve ligation in rats. (224)
  • Meloxicam may represent a potentially safe and effective tocolytic agent. (225)
  • The efficacy, tolerance and formulation of meloxicam oral suspension make it well suited for the treatment of chronic osteoarthritis in the dog. (226)
  • Meloxicam can be successfully used as the initial treatment for patients with extra-abdominal desmoids tumours. (227)
  • Meloxicam has favorable GI tolerability and is effective in the treatment of patients with rheumatic disease. (228)
  • Meloxicam has a beneficial effect on ovarian hyperstimulation syndrome (OHSS) by reducing the increases in ovarian weight and VEGF expression associated with OHSS. These effects may be mediated by the COX-2 inhibitory capacity of meloxicam. (229)
  • The administration of meloxicam can cause ischemic colitis. (230)
  • COX-2 inhibitor meloxicam can interfere with ovulation and may be effective as an emergency contraceptive. (231)
  • Meloxicam is effective in the treatment of Cockatiels (Nymphicus hollandicus) infected with avian Bornavirus. (232)
  • The CTNNB1 mutation status has a significant prognostic value for meloxicam treatment in patients with sporadic desmoids tumors. (233)
  • Low dose aspirin reduces early atherosclerosis, while inhibition of COX-2 by meloxicam is not associated with an increase in atherosclerotic plaque size in the mouse model. (234)
  • There is a neuroprotective effect of meloxicam and selegiline in scopolamine induced cognitive impairment and oxidative stress. (235)
  • Meloxicam and rofecoxib has central effects and improves the psychomotor performance. (236)
  • Leflunomide and meloxicam though reduces rheumatoid arthritis (RA) progression when given alone but in combination therapy produce severe adverse effects. Depression is prominent with RA and therapy with leflunomide and meloxicam exaggerate the condition. (237)


  • Moderately COX -2 selective with properties similar to diclofenac
  • It is metabolized by hydroxylation and glucuronidation conjugation, and excreted in urine with a t ½ of 7 hours
  • Side effects
  • Abdominal pain
  • Rashes
  • Dizziness
  • Etodolac 200 mg results in a duration of action which is approximately twice as long as aspirin’s and produces a peak pain relief which is significantly greater than the lower doses of etodolac and aspirin. (238)
  • Racemic (LR) etodolac has less ulcerogenic properties in the gastrointestinal mucosa. (239)
  • Etodolac 400 mg twice daily is as effective and safe as naproxen 500 mg twice daily in the management of osteoarthritis of the knee. (240)
  • Etodolac SR has good efficacy and tolerability in the treatment of rheumatoid arthritis. (241)
  • Etodolac is a safe and effective alternative in acute migraine treatment and shows comparable efficacy to paracetamol 1000 mg. Etodolac may be considered as an alternate option for acute treatment of migraine. (242)
  • Etodolac attenuates paclitaxel induced peripheral neuropathy by a COX independent pathway. It might b euseful for the treatment of paclitaxel induced peripheral neuropathy. (243)
  • Etodolac enhances clearance of leukemic lymphocytes thus lowers the lymphocyte count in patients with B cell chronic lymphocytic leukemia. (244)
  • Etodolac 400 mg twice daily is as effective and safe as naproxen 500 mg twice daily in the management of osteoarthritis of the knee. (245)
  • The combination of etodolac and eperisone is as effective as etodolac alone in patients of osteorthritis knee. Thus the additional use of muscle relxant has no adjunctive value in patients with OA knee and is not recommended. (246)
  • Etodolac is more effective than naproxen in the management of patients with acute gout. (247)
  • Coadministering of the combination of propanolol and etodolac in patients with advanced cancer who may be receiving anticancer therapy is safe and effective for treating cancer cachexia. (248)
  • Etodolac does not suppress gastric mucosal prostaglandin production, wheras naproxen leads to a significant reduction. Thus Gasrtic injury is less seen with etodolac in comparison to naproxen. (249)
  • Etodolac should be cautiously used in patients with renal, cardiac or hepatic impairment, especially those taking diuretics. (250)
  • Both sulindac and etodolac reduces the occurence of aberrant crypt foci (ACF) and induces an increase in adenomatous polyposis coli (APC) mRNA in rat colon mucosa. (251)
  • Acute generalized exanthematous pustulosis may develop due to etodolac in a patients with an iliopsoas muscle abscess. (252)
  • Short term use of selective and non-selective NSAIDs is not associated with a significant genotoxic effect that could be detected using the SCE method in peripheral lymphocytes. (253)
  • Etodolac has little effect on 7-ethoxyresorufin O-deethylation (CYP1A2), coumarin hydroxylation (CYP2A6), 7-benzyloxyre-sorufin O-debenzylation (CYP2B6), S-mephenytoin hydroxylation (CYP2C19), bufuralol hydroxylation (CYP2D6), chlorzoxazone hydroxylation (CYP2E1) and nifedipine oxidation (CYP3A4) at concentration ranging from 10 to 50 µmol/l. Etodolac inhibits tolbutamide hydroxylation (CYP2C9) with the Ki value of 64 µmol/l, suggesting that it is a weak inhibitor of CYP2C9. (254)

Selectice COX-2 inhibitors 

  • They cause less gastric mucosal damage, occurrence of peptic ulcer and ulcer bleeds clearly less
  • They do not depress TXA2 production by platelets, do not inhibit platelet aggregation or prolong bleeding time
  • They exert prothrombotic influence and enhance CV risk


  • COX-2 selectively is modest and similar to diclofenac
  • Exerts antiinflammtory, analgesic and anti pyretic action with low ulcerogenic potential
  • Platelet aggregation in response to collagen exposure remain intact in celecoxib recipient and serum TXB2 levels are reduced
  • Slowly absorbed, 97% plasma protein bound and metabolized by CYP2C9 with a t ½ of 10 hours
  • Used in rheumatoid and osteoarthritis in a dose of 100-200 mg BD
  • Adverse effects
  • Abdominal pain
  • Dyspepsia
  • Mild diarrhea
  • Rashes
  • Edema
  • Small rise in BP
  • Celecoxib is a well tolerated and efficacious analgesic in 50- and 100-mg doses. (255)
  • Celecoxib is used in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) as well as the treatemnt of familial adenomatous polyposis. GI safety of celecoxib is superior to traditional NSAIDs. It is safe, effective and tolerable in elderly population as well as patients with renal and cardiovascular impairment. (256)
  • Upregulation of endoplasmic reticulum (ER) chaperones by celecoxib protects cancer cells from celecoxib induced apoptosis, thus may decrease the potential antitumor activity of celecoxib. (257)
  • Celecoxib use is associated with a dose related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke or heart failure. (258)
  • Celecoxib’s chondroprotective effects- prevention of synovial hyperplasia and inhibition of bone destruction in vitro and in vivo specefically in animal models suggest that it could potentially slow OA disease progression in humans and can be used as a disease modifying agent. The side effects include myocardial infarction and worsening of high blood pressure. (259)
  • There is an increased risk of myocardial infarction with celecoxib therapy, consistent with a class effect for COX-2 specific inhibitors. (260)
  • There is a relative cardiovascular safety of celecoxib when used at the doses recommended for the treatment of arthritis than any of the other selective COX-2 inhibitors or NSAIDs. (261)
  • There is a lowering incidence of cardiorenal toxicity of celecoxib in comparison with ibuprofen in patients with arthritis. (262)
  • The COX-2 inhibitors celecoxib and etodolac induce protein expression of COX-2 in several human tumor cell lines, whereas induction by ibuprofen is only seen in A375 tumor cells. (263)
  • COX-2 inhibition with celecoxib is an effective approach for the treatment of osteoarthritis, as seen by clinical improvement in signs and symptoms comparable to treatment with naproxen. (264)
  • Celecoxib shows sustained anti-inflammatory and analgesic activity similar to diclofenac with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events and better tolerability in long term management of rheumatoid arthritis. (265)
  • In the treatment of osteoarthritis, celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac but has significantly fewer serious upper gastrointestinal events. (266)
  • Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS dependent VEGF/VEGFR2 autocrine signalling. The additive combination of tamoxifen and celecoxib is a potential drug candidate for treatment of breast tumors expressing high levels of VEGF and VEGFR2. This combination might be better tailored clinical regimen than tamoxifen alone for breast cancer treatment. (267)
  • Zileuton is an effective inhibitor of 5-LO activity resuting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton is associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4. (268)
  • Celecoxib can be considered as an effective add-on treatment for unipolar depressive patients. (269)
  • Celecoxib at 400 mg twice daily together with concurrent cisplatin and 5-FU and pelvic radiotherapy has a high incidence of acute toxicities, most frequently hematologic, in patients with locally advanced cervical cancer. (270)
  • The greater efficacy of high dose celecoxib, compared with the low dose, in preventing colorectal adenoma appears confined to individuals with slow metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib. (271)
  • Celecoxib modulates the formation of vasoconstrictor eicosanoids and activates PPARγ. influence of albumin. This may be relevant to prevent renal dysfuntion in conditions of unbalanced effective blood volume. (272)
  • Short term COX-2 inhibition by celecoxib induces transcriptional programs supporting anti-tumor activity in primary breast cancer tissue. The impact on proliferation-associated genes is reflected by a reduction of Ki-67 positive cells. Therefore, COX-2 inhibition should be considered as a treatment strategy for further clinical testing in primary breast cancer. (273)


  • Has highest COX-2 selectivity suitable for one day treatment of osteo/ rheumatoid/ acute gouty arthritis, ankylosing spondylitis, dysmenorrhea and acute dental surgery
  • The t ½ is 24 hour
  • Side effects
  • Dyspepsia
  • Abdominal pain
  • Pedal edema
  • Rise in BP
  • Dry mouth, aphthous ulcers
  • Taste disturbance
  • Paresthesia
  • Etoricoxib is an efficacious alternative in the management of arthritis and pain, with the potential advantages of convenient once-daily administration and superior gastrointestinal tolerability compared with traditional NSAIDs. (274)
  • The incidence of endoscopically detected ulcers is significantly lower with etoricoxib 120 mg than with ibuprofen 2400 mg. Treatment with etoricoxib reduces the incidence of investigator reported and confirmed adverse upper GI events by approximately 50% compared with treatment with nonselective NSAIDs. (275)
  • Etoricoxib is effective and well tolerated analgesic for acute and chronic pain in osteoarthritis. It is also effective in the treatment of acute gout and the relief of short term pain including that associated with menstruation and minor dental procedures. (276)
  • Single dose oral etoricoxib produces hogh levels of good quality pain relief after surgery. The 120 mg dose is as effective as or better than other commonly used analgesics. (277)
  • Postoperative us eof etoricoxib 90 and 120 mg in patients undergoing total knee replacement is non inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption. (278)
  • Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long term use of these drugs. (279)
  • For patients with osteoarthritis, treatment with etoricoxib, 30 mg/d is well tolerated and provides sustained clinical effectiveness that is comparable to ibuprofen 2400 mg/d. (280)
  • COX-2 inhibitors has similar but partial reductions in PGI2 synthesis (significantly less than that caused by naproxen). COX-2 inhibitors has no meaningful effect on systemic thromboxane (naproxane causes a substantial reduction consistent with its effects on ex vivo serum TXB2 production and platelet aggregation). (281)
  • Etoricoxib 120 mg is determined to be the minimum dose that has maximal efficacy in patients with moderate to severe acute pain associated with dental surgery. Both etoricoxib and ibuprofen are generally well tolerated. (282)
  • The risks for renal adverse events (ie hypertension, lower extremity edema, elevated serum creatinine concentration changes and congestive heart failure) with etoricoxib 60,90 and 120 mg/d are low with a shallow dose response and are generally similar to those found with the comparator NSAIDs naproxen 1000 mg/d and ibuprofen 2400 mg/d. (283)
  • The use of pre-emptive single dose of etoricoxib or dexamethasone may be considered an effective protocol for postoperative pain prevention and control after mucogingival surgery. (284)
  • Paracetamol, etoricoxib and ketorolac does not have a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket. (285)
  • Etoricoxib given once daily provides significant relief of symptoms, and disability associated with chronic low back pain observed 1 week after initiating therapy, was maximal at 4 weeks and was maintained over 3 months. (286)
  • Etoricoxib is the most cost effective NSAID for initiating treatment of ankylosing spondylitis. (287)
  • Etoricoxib and ketorolac tromethamine are effective analgesic for retinal laser photocoagulation in diabetic patients. (288)
  • Etoricoxib is effective in the management of headache associated with religious fasting like First of Ramadan headache and Yom Kippur headache. (289)
  • Etoricoxib is an effective preemptive an dpostoperative analgesia (EPPA) in patients with laparotomy or thoracotomy. (290)
  • Etoricoxib 90 mg demonstrates a significantly lower risk for discontinuing treatment due to GI adverse events compared to diclofenac 150 mg in patients with rheumatoid arthritis. Discontinuation from renovascular adverse events were significantly higher with etoricoxib. (291)
  • There is a similar incidence of cardiovascular thrombotic events and renal dysfunction, a higher incidence of edema and hypertension, and a lower incidence of gastrointestinal and hepatic adverse events in etoricoxib versus diclofenac. Etoricoxib is an appropriate choice for the treatment of osteoarthritis and rheumatoid arthritis and for the relief of gouty pain in patients with low cardiovascular risk but an increased risk of gastrointestinal complications. (292)
  • Fixed drug eruption may develop due to etoricoxib in a patient with tolerance to celecoxib. (293)
  • Etoricoxib can induce acute generalized exanthematous pustulosis. (294)
  • In healthy individuals, etoricxib is well absorbed, is metabolized extensively via oxidation (6′- methyl oxidation >1′ -N-oxidation), and the metabolites are excreted largely in the urine. (295)
  • Etoricoxib is used in the management of idiopathic stabbing headache. (296)
  • There is a good long term tolerability of etoricoxib in patients with a history of hypersensitivity to other NSAIDs without differences between single and multiple reactors. (297)
  • Etoricoxib is effective, safe and well tolerated for the treatment of hemophillic arthropathy. (298)


  • Prodrug of valdecoxib
  • Used in post operative and short term pain
  • Efficacy similar to ketorolac
  • Intravenous parecoxib sodium can be used as an analgesic alternative to morphine in acute trauma pain in the emergency department. (299)
  • Fentanyl has a strong inhibitory effect on the nociceptive stimulus cortical activity while parecoxib has no significant effect. (300)
  • Precoxib sodium provides opioid sparing analgesic effects in postoperative patients who underwent total knee arthroplasty under spinal anesthesia. (301)
  • Administration of parecoxib sodium 40 mg IV 30 min before induction of general anesthesia significantly reduces the incidence and severity of remifentanil induced shivering in patients underwent elective lumber discectomy under general anesthesia. (302)
  • Parecoxib IV and IM provides effective analgesia. The 40 mg dose is comparable to ketorolac 60 mg on most measures of analgesia but has a longer duration of action. (303)
  • Parecoxib may be a useful addition to opioid treatment by improving postoperative analgesic management, reducing opioid related adverse events and lowering per patient treatment costs. (304)
  • Both oral valdecoxib and injected parecoxib are effective treatments for acute postoperative pain. (305)
  • Parecoxib sodium is as effective and longer acting at 50- and 100-mg intravenous doses than a standard dose of ketorolac 30 mg intravenously. Parecoxib sodium appears to be safe and well tolerated. (306)
  • The use of parecoxib and valdecoxib after CABG is associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances. (307)
  • Multiple dose administration of parecoxib sodium is safe and well tolerated in healthy elderly subjects, with a decreased risk of gastroduodenal mucosal injury compared with ketorolac. (308)
  • Parecoxib compares favourably with ketorolac and parecoxib can be recommended as a useful component of postoperative pain control in hernia surgery. (309)
  • Preincisional parecoxib administration reduces postoperative pain and morphine consumption compared with postincisional administration and attenuated IL-6 and IL-8 production 24 h after hip replacement surgery. (310)
  • Parecoxib is as effective as ketoprofen in the treatment of pain due to acute renal colic, is well tolerated and has a comparable safety profile. (311)
  • Intraperitoneally parecoxib administration during transient middle cerebral artery occlusion is neuroprotective, as evidenced by a large reduction in mean infarct volume and a lower cortical ADC increment. Increased pro-inflammatory cytokine mRNA levels and hippocampal granule cell BrdU incorporation remain unaffected. (312)
  • Parecoxib with PCA morphine can be used for post cesarean delivery analgesia with same efficacy as ketorolac for an opioid sparing effect. (313)
  • Parecoxib improves pulmonary function in post burn/ smoke inhalational injury model. (314)
  • Parecoxib is more effective in the post surgical analgesia than diclofenac and pethidine in the fractures of the hip joints. It is easier to administer (iv) and seems to be safe. It should be the drug of choice in the post surgical analgesia of the fractures of the hip joints. (315)
  • Parecoxib markedly improves the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of COC-2 and stimulation of nicotinic acetylcholine receptors. (316)
  • Parecoxin may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn. It reduces systemic inflammation and acute lung injury with delayed fluid resuscitation. (317)
  • Intraarticular injection of parecoxib inhibits the ACLT (anterior cruciate ligament transected)-induced OA progression. It is accompanied by a reduction of glutamate and aspartate concentration in the ACLT joint dialysates. Intra-articular parecoxib injection, in addition to the anti-inflammatory effect, inhibiting the EAAs’ (excitatory amino acids) release, may also play a role in inhibiting the traumatic knee injury induced OA progression. (318) 
  • The use of parecoxib with patients controlled analgesic morphine in postoperative analgesia results in comprehensive enhancement of the analgesic efficacy, reducing the opioid requirement and increaing patient satisfaction after gynecological tumor surgery. (319)
  • Parecoxib 40 mg iv and lornoxicam 8 mg iv are equianalgesic and both are equally efficacious in the management of pain after laparoscopic cholecystectomy. (320)
  • The good postoperative analgesia and minimal interference with platelet function may make parecoxib an alternative to the nonselective NSAID diclofenac in providing preemtive analgesia in patienst undergoing general surgery. (321)
  • Preprocedure administration of parecoxib for therapeutic ERCP patients is clinically effective. The analgesic efficacy of standard dose of parecoxib is clearly demonstrated during first 12 hours postprocedure and patient satisfaction is higher. (322)
  • Perioperative administration of parecoxib (40 mg, Bid) is effective for postoperative pain at rest relief in adults undergoing tonsillectomy. (323)
  • Short term infusion of remifentanil can induce significant hyperalgesia in clinical practice, while pretreatment with parecoxib at 40 mg is effective in relieving such remifentanil induced hyperalgesia. It also significantly improves patients’ satisfaction of pain management. (324)
  • Parecoxib is an effective and relatively safe option for acute postoperative pain. (325)
  • Parecoxib sodium is not as effective as fentanyl citrate in alleviating pain during shock wave lithotripsy (SWL). Its use may lower the dose of opioid based analgesia in patients. (326)
  • gastroduodenal ulcers, gastric ulcers and duodenal ulcers or erosions are less common with parecoxib. It does not affect platelet aggregation, interfere with the antiplatelet affect of aspirin, affect prothrombin and partial thromboplastin time or platelets counts when administered with heparin. (327)

Para-amino phenol derivative- Paracetamol

  • It raises pain threshold and has a weak peripheral anti inflammatory component
  • It is a good and promptly acting antipyretic
  • Has negligible anti-inflammatory action
  • Paracetamol does not stimulate respiration or affect acid base balance
  • It has no effect on CVS
  • Gastric irritation is insignificant – mucosal erosion and bleeding occur rarely
  • Regular or as needed dosing with paracetamol does not affect recovery time in low back pain. (328)
  • Although febrile reactions is significantly decreased, prophylactic administration of paracetamol at the time of vaccination should not be routinely recommended since the antibody responses to several vaccine antigens are reduced. (329)
  • Paracetamol is a commonly used moderately effective analgesic and antipyretic. In overdose it causes significant morbidity and mortality. The present approaches to reduce toxicity include public education on the effects of overdose, further research on drug antidote combination tablets and changing legal status of adult doses from the general sales. (330)
  • Children exposed to long term use of paracetamol during pregnancy has substantially adverse developmental outcomes at 3 years of age. (331)
  • Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. (332)
  • In recommended doses (1-2 g/day), paracetamol does not irritate stomach lining, kidney cells and liver cells. High dosage (>2 g/day) resulted in gastrointestinal complications, abnormal kidney function, liver damage. It may cause life threatening effects like liver damage which in turn leads to liver failure and death. (333)
  • In paracetamol poisoning, patients who are malnourished, have been fasting, take enzyme inducing drugs, or regularly drink alcohol to excess are at higher risk of liver damage. Treatment of paracetamol poisoning should be started within 8 hours of ingestion. If the time of ingestion is known, treatment can be based on blood tests taken after four hours. (334)
  • Paracetamol may be a medical alternative in the management of patent ductus arteriosus (PDA). (335)
  • Intravenous paracetamol is an excellent post operative analgesic and antipyretic in children. The therapeutic doses of IV acetaminophen are effective and tolerable in children with least chances of hepatotoxicty. (336)
  • Paracetamol and metamizol are recognized pain management agents for pre-emptive as well as postoperative analgesia. In some patients with the risk of gastrointestinal hemorrhage or contraindications for NSAIDs, both agents are a safe and effective alternative. (337)
  • Postoperative intravenous paracetamol is a safe and effective component of multimodal analgesic regimen, and it reduces postoperative opioid consumption after orthopedic surgery. (338)
  • Although paracetamol (1 gr) has caused a better pain relief quality but it is not suitable analgesic for moderate pain control in acute phase after surgery alone. (339)
  • Tramadol/ paracetamol fixed dose combination can be used in the treatment of moderate to severe pain. (340)
  • Esculetin prevents liver damage induced by paracetamol and CCL4. (341)
  • Acetaminophen use after measles-mumps-rubella vaccination is associated with autistic disorder. (342)
  • Oral paracetamol can be used in treatment of closure of patent ductus arteriosus in preterm neonates. (343)
  • Induction of apoptosis may underlie the nephrotoxic potential of paracetamol and Bcl-xL act as a player in toxic tubular cell injury. (344)
  • Paracetamol is an effective drug to use for postoperative pain following oral surgery. (345)
  • Pharmacokinetics
  • Well absorbed orally
  • Only about 1/4th is protein bound in plasma and it is uniformly distributed in the body
  • Metabolism is mainly by conjugation with glucuronic acid and sulfate
  • Conjugates are rapidly excreted in urine
  • Plasma t ½ is 2-3 hours
  • Effects after oral dose last for 3-5 hours
  • Side effects
  • Is safe and well tolerated
  • Nausea and rashes
  • Leucopenia is rare
  • Uses
  • Over the counter analgesic for headache, mild migraine, dysmenorrheal etc
  • Ineffective in rheumatoid arthritis
  • One of the best drug to be used as antipyretic , especially in children (no risk of Reye’s syndrome)
  • No metabolic effects or acid base disturbances
  • Can be used in all age groups (infants to elderly), pregnant/ lactating women, in presence of other disease states 

Guideline for NSAIDs

Mild to moderate pain with little inflammationParacetamol or low dose ibuprofen
Post operative or similar acute but short lasting painA propionic acid derivative, diclofenac or nimesulide
Acute musculoskeletal, osteoarthritic, injury associated painParacetamol, a propionic acid derivative or diclofenac
Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever Naproxen, piroxicam, indomethacin, high dose aspirin
Gastric intolerance to traditional NSAIDs or predisposed patientsA selective COX-2 inhibitor or paracetamol
Patiet with history of asthma or anaphylactoid reaction to aspirin/ other NSAIDsNimesulide, COX-2 inhibitors
Patient with hypertension or other risk factors for heart attack/ strokeAvoid selective COX-2 inhibitor; a propionic acid derivative or aspirin may be used at the lowest dose for the shortest period
Pediatric patientsParacetamol, ibuprofen and naproxen
Elderly patientsLow dose of chosen NSAID


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