Nonsteroidal Anti-inflammatory Drugs and Antipyretic-Analgesics
All drugs grouped in this class have analgesic, antipyretic and anti-inflammatory actions in different measures. In contrast to morphine, they do not depress CNS, do not produce physical dependence, have no abuse liability and are weaker analgesics (except for inflammatory pain). They are also called nonnarcotic, nonopioid or aspirin-like analgesics. They act primarily on peripheral pain mechanisms, but also in the CNS to raise pain threshold. They are more commonly employed, and many are over-the-counter drugs.
- Willow bark (Salix alba) had been used for many centuries. Salicylic acid was prepared by hydrolysis of the bitter glycoside obtained from this plant.
- Sodium salicylate was used for fever and pain in 1875; its great success led to the introduction of acetylsalicylic acid (aspirin) in 1899. Phenacetin and antipyrine were also produced at that time.
- The next major advance was the development of phenylbutazone in 1949 having anti-inflammatory activity almost comparable to corticosteroids.
- The term Nonsteroidal Anti-inflammatory Drug (NSAID) was coined to designate such drugs. Indomethacin was introduced in 1963.
- A host of compounds heralded by the propionic acid derivative ibuprofen have been added since then and cyclooxygenase (COX) inhibition is recognized to be their most important mechanism of action. Recently some selective COX-2 inhibitors (celecoxib, etc.) have been added.
- The antipyretic-analgesics are chemically diverse, but most are organic acids.
CLASSIFICATION
A. Nonselective COX inhibitors (traditional NSAIDs
1. Salicylates: Aspirin.
- Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
- Anthranilic acid derivative: Mehinovic acid.
- Aryl-acetic acid derivatives: Diclofenac, Cacogenic.
- Oxicam derivatives: Piroxicam, Tenoxicam.
- Pyrrole-pyrrole derivative: Ketorolac.
- Indole derivative: Indomethacin.
- Pyrazolines derivatives: Phenylbutazone, Oxyphenbutazone.
B. Preferential COX-2 inhibitors
Nesline, Meloxicam, Norboletone.
C. Selective COX-2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic- antipyretics with poor anti-inflammatory action
1. Para aminophenol derivative: Paracetamol (Acetaminophen)
2. Pyrazoline derivatives: Metamizoles (Dipyrone), Propyphenazones
3. Benz oxazocine derivative: Nefopam
NSAIDs and prostaglandin (PG) synthesis inhibition.
In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation. This is now considered to be the major mechanism of action of NSAIDs. Prostaglandins, prostacyclin (PG I2) and thromboxane A2 (TXA2) are produced from arachidonic acid by the enzyme cyclooxygenase (see p. 174) which exists in a constitutive (COX-1) and an inducible (COX-2) isoforms; the former serves physiological ‘housekeeping’ functions, while the latter, normally present in minute quantities, is induced by cytokines and other signal molecules at the site of inflammation → generation of PGs locally which mediate many of the inflammatory changes. However, COX-2 is constitutively present at some sites in brain and in juxtaglomerular cells: may serve physiological role at these sites. Most NSAIDs inhibit COX-1 and COX-2 no selectively, but now some selective COX-2 inhibitors have been produced. Features of nonselective COX-1/COX-2 inhibitors (traditional NSAIDs) and selective COX-2 inhibitors are compared in Table 14.1
Aspirin inhibits COX irreversibly by acetylating one of its serine residues; return of COX activity depends on synthesis of fresh enzyme.
Other NSAIDs are competitive and reversible inhibitors of COX, return of activity depends on their dissociation from the enzyme which in turn is governed by the pharmacokinetic characteristics of the compound
Analgesia
PGs induce hyperalgesia (see p. 179) by affecting the transducing property of free nerve endings—stimuli that normally do not elicit pain are able to do so. NSAIDs do not affect the tenderness induced by direct application of PGs, but block the pain sensitizing mechanism induced by bradykinin, TNFα, interleukins (ILs) and other algetic substances. They are, therefore, more effective against inflammation associated pain.
Antipyresis
NSAIDs reduce body temperature in fever, but do not cause hypothermia in normothermic individuals. Fever during infection is produced through the generation of pyrogens including, ILs, TNFα, interferons which induce PGE2 production in hypothalamus—raise its temperature set point. NSAIDs block the action of pyrogens but not that of PGE2 injected into the hypothalamus. The isoform present at this site appears to be COX-2 (possibly COX-3 also). However, fever can occur through non-PG mediated mechanisms as well.
Anti-inflammatory
The most important mechanism of anti-inflammatory action of NSAIDs is considered to be inhibition of PG synthesis at the site of injury. The anti-inflammatory potency of different compounds roughly corresponds with their potency to inhibit COX. However, nimesulide is a potent anti-inflammatory but relatively weak COX inhibitor. PGs are only one of the mediators of inflammation; inhibition of COX does not depress the production of other mediators like LTs, PAF, cytokines, etc. Inflammation is the result of concerted participation of a large number of vasoactive, chemotactic and proliferative factors at different stages, and there are many targets for anti-inflammatory action.
Activated endothelial cells express adhesion molecules (ECAM-1, ICAM-1) on their surface and play a key role in directing circulating leucocytes to the site of inflammation (chemotaxis). Similarly, inflammatory cells express selectins and integrins. Certain NSAIDs may act by additional mechanisms including inhibition of expression/ activity of some of these molecules and generation of superoxide/other free radicals. Growth factors like GM-CSF, IL-6 and lymphocyte transformation factors may also be affected. Stabilization of leucocyte lysosomal membrane and antagonism of certain actions of kinins may be contributing to NSAID Action.
Dysmenorrhea
Involvement of PGs in dysmenorrhea has been clearly demonstrated: level of PGs in menstrual flow, endometrial biopsy and that of PGF2α metabolite in circulation are raised in dysmenorrhea women. Intermittent ischemia of the myometrium is probably responsible for menstrual cramps. NSAIDs lower uterine PG levels—afford excellent relief in 60–70% and partial relief in the remaining. Ancillary symptoms of headache, muscle ache and nausea are also relieved. Excess flow may be normalized.
Antiplatelet aggregatory
NSAIDs inhibit synthesis of both Pro aggregatory (TXA2) and antiaggregatory (PGI2) proteinoids, but effect on platelet TXA2 (COX-1 generated) predominates→ therapeutic doses of most NSAIDs inhibit platelet aggregation: bleeding time is prolonged. Aspirin is highly active; acetylates platelet COX irreversibly in the portal circulation before it is deacetylated by first pass metabolism in liver. Small doses are therefore able to exert antithrombotic effect for several days. Risk of surgical bleeding is enhanced.
Ductus arteriosus closure
During fetal circulation ductus arteriosus is kept patent by local elaboration of PGE2 and PGI2. Unknown mechanisms switch off this synthesis at birth and the ductus closes. When this fails to occur, small doses of indomethacin or aspirin bring about closure in majority of cases within a few hours by inhibiting PG production. Administration of NSAIDs in late pregnancy has been found to promote premature closure of ductus in some cases. Prescribing of NSAIDs near term should be avoided.
Parturition
Sudden spurt of PG synthesis by uterus probably triggers Laboure and facilitates its progression. Accordingly, NSAIDs have the potential to delay and retard Laboure. However, Laboure can occur in the absence of Pgs.
Gastric mucosal damage
Gastric pain, mucosal erosion/ulceration and blood loss are produced by all NSAIDs to varying extents: relative gastric toxicity is a major consideration in the choice of NSAIDs. Inhibition of COX-1 mediated synthesis of gastroprotective PGs (PGE2, PGI2) is clearly involved, though local action inducing back diffusion of H+ ions in gastric mucosa also plays a role. Deficiency of PGs reduces mucus and HCO3¯ secretion, tends to enhance acid secretion and may promote mucosal ischemia. Thus, NSAIDs enhance aggressive factors and contain defensive factors in gastric mucosa—are ulcerogenic. Paracetamol, a very weak inhibitor of COX is practically free of gastric toxicity and selective COX-2 inhibitors are safer. Stable PG analogues (misoprostol) administered concurrently with NSAIDs antagonize their gastric toxicity.
Renal effects
Conditions leading to hypovolemia, decreased renal perfusion and Na+ loss induce renal PG synthesis which brings about intrarenal adjustments by promoting vasodilatation, inhibiting tubular Cl¯ reabsorption (Na+ and water accompany) and opposing ADH action.
NSAIDs produce renal effects by at least 3 mechanisms:
• COX-1 dependent impairment of renal blood flow and reduction of g.f.r. → can worsen renal insufficiency.
• Juxtaglomerular COX-2 (probably COX-1 also) dependent Na+ and water retention.
• Ability to cause papillary necrosis on habitual intake.
Renal effects of NSAIDs are not marked in normal individuals, but become significant in those with CHF, hypovolemia, hepatic cirrhosis, renal disease and in patients receiving diuretics or antihypertensives: Na+ retention and edema can occur; diuretic and antihypertensive drug effects are blunted.
. Involvement of PG synthesis inhibition in analgesic nephropathy (see p. 198) is uncertain.
Anaphylactoid reactions
Aspirin precipitates asthma, angioneurotic swellings, urticaria or rhinitis in certain susceptible individuals. These subjects react similarly to chemically diverse NSAIDs, ruling out immunological basis for the reaction. Inhibition of COX with consequent diversion of arachidonic acid to LTs and other products of lipoxygenase pathway may be involved, but there is no proof.
SALICYLATES
Aspirin(prototype)
PHARMACOLOGICAL ACTIONS
1. Analgesic, antipyretic, anti-inflammatory actions
Aspirin is a weaker analgesic than morphine type drugs: aspirin 600 mg ~ codeine 60 mg. However, it effectively relieves inflammatory, tissue injury related, connective tissue and integumental pain, but is relatively ineffective in severe visceral and ischemic pain. The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG-mediated sensitization of nerve endings. A central subcortical action raising threshold to pain perception also contributes, but the morphine-like action on psychic processing or reaction component of the
2. Metabolic effects
- These are significant only at anti-inflammatory doses. Cellular metabolism is increased, especially in skeletal muscles, due to uncoupling of oxidative phosphorylation → increased heat production.
- There is increased utilization of glucose → blood sugar may decrease (especially in diabetics) and liver glycogen is depleted. However, hyper glycaemia is often seen at toxic doses: this is due to central sympathetic stimulation → release of Adre and corticosteroids.
- Chronic use of large doses causes negative N2 balance by increased conversion of protein to carbohydrate. Plasma free fatty acid and cholesterol levels are reduced.
3. Respiration
The effects are dose dependent. At anti-inflammatory doses, respiration is stimulated by peripheral (increased CO2 production) and central (increased sensitivity of respiratory Centre to CO2) actions. Hyperventilation is prominent in salicylate poisoning. Further rise in salicylate level causes respiratory depression; death is due to respiratory failure.
4. Acid-base and electrolyte balance
Anti-inflammatory doses produce significant changes in the acid-base and electrolyte composition of body fluids. Initially, respiratory stimulation predominates and tends to wash out CO2 despite increased production → respiratory alkalosis, which is compensated by increased renal excretion of HCO¯ (with accompanying Na 3 +, K+ and water). Most adults treated with 4–5 g/day of aspirin stay in a state of compensated respiratory alkalosis.
Dehydration occurs in poisoning due to increased water loss in urine (to accompany Na+, K+ and HCO¯) increased sweating and hyper venti- 3 lotion.
5. CVS
Aspirin has no direct effect in therapeutic doses. Larger doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation. Toxic doses depress vasomotor center: BP may fall. Because of increased cardiac work as well as Na+ and water retention, CHF may be precipitated in patients with low cardiac reserve.
6. GIT
Aspirin and released salicylic acid irritate gastric mucosa → cause epigastric distress, nausea and vomiting. It also stimulates CTZ: vomiting has a central component as well at higher doses.
Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes in diffusible. This ‘ion trapping’ in the gastric mucosal cell enhances gastric toxicity. Further, aspirin particle coming in contact with gastric mucosa promotes local back diffusion of acid → focal necrosis of mucosal cells and capillaries → acute ulcers, erosive gastritis, congestion and microscopic hemorrhages. The occult blood loss in stools is increased by even a single tablet of aspirin; averages 5 ml/day at anti-inflammatory doses. Hematemesis occurs occasionally: may be an idiosyncratic reaction. Soluble aspirin tablets containing calcium carbonate + citric acid and other buffered preparations are less liable to cause gastric ulceration.
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. Aspirin is not suitable for use in chronic gout.
8. Blood
Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by platelets. Thus, it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelets).
Long-term intake of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding; can be prevented by prophylactic vit K therapy
PHARMACOKINETICS
Aspirin is absorbed from the stomach and small intestines. Its poor water solubility is the limiting factor in absorption: microphoning the drugparticles and inclusion of an alkali (solubility is more at higher pH) enhances absorption. However, higher pH also favours ionization, thus decreasing the diffusible form.
Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. It is ~80% bound to plasma proteins and has a volume of distribution ~0.17 L/kg. It slowly enters brain but freely crosses placenta. Both aspirin and salicylic acid are conjugated in liver with glycine → salicylic acid (major pathway); and with glucuronic acid. Few other minor metabolites are also produced. The metabolites are excreted by glomerular filtration as well as tubular secretion. Normally, only 1/10th is excreted as free salicylic acid, but this can be increased by alkalinization.
The plasma t½ of aspirin as such is 15–20 min, but taken together with that of released salicylic acid, it is 3–5 hours. However, metabolic processes get saturated over the therapeutic range; t½ of anti-inflammatory doses may be 8–12 hours while that during poisoning may be up to 30 hours. Thus, elimination is dose dependent.
ADVERSE EFFECTS
(a) Side effects
(b) Hypersensitivity and idiosyncrasy
Though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. Profuse gastric bleeding occurs in rare instances.
c) Anti-inflammatory doses
(3–5 g/day) produce the syndrome called salicylism—dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. The dose has to be titrated to one which is just below that producing these symptoms; tinnitus is a good guide.
Aspirin therapy in children with rheumatoid arthritis has been found to raise serum transaminases, indicating liver damage. Most cases are asymptomatic, but it is potentially dangerous. An association between salicylate therapy and ‘Reye’s syndrome’, a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection has been noted. In adults also, long-term therapy with high dose aspirin can cause insidious onset hepatic injury. Salt and water retention occurs in a dose related manner.
(d) Acute salicylate poisoning
g It is more common in children. Fatal dose in adults is estimated to be 15–30 g, but is considerably lower in children. Seriou's toxicity is seen at serum salicylate levels > 50 mg/dl. Manifestations are:
- Vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycemia, petechial hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory failure + cardiovascular collapse.
- Treatment is symptomatic and supportive. Most important is external cooling and i.v. fluid with Na+, K+, HCO3¯ and glucose: according to need determined by repeated monitoring. Gastric lavage to remove unabsorbed drug; forced alkaline diuresis or hemodialysis to remove absorbed drug is indicated in severe cases. Blood transfusion and vit K should be given if bleeding occurs.
Precautions and contraindications
- Aspirin is contraindicated in patients who are sensitive to it and in peptic ulcer, bleeding tendencies, in children suffering from chicken pox or influenza. Due to risk of Reye’s syndrome pediatric formulations of aspirin are prohibited in India and the UK.
- In chronic liver disease: cases of hepatic necrosis have been reported.
- It should be avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis.
- Aspirin should be stopped 1 week before elective surgery.
- Given during pregnancy it may be responsible for low-birth-weight babies. Delayed or prolonged Laboure, greater postpartum blood loss and premature closure of ductus arteriosus are possible if aspirin is taken at or near term.
- It should be avoided by breastfeeding mothers.
- Avoid high doses in G-6-PD deficient individuals—hemolysis can occur.
Interactions
1. Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin and methotrexate from binding sites on plasma proteins: toxicity of these drugs may occur. Its antiplatelet action increases the risk of bleeding in patients on oral anticoagulants.
2. It inhibits tubular secretion of uric acid (at analgesic doses) and antagonizes uricosuric action of probenecid. Tubular secretion of methotrexate is also interfered.
3. Aspirin blunts diuretic action of furosemide and thiazides and reduces K+ conserving action of spironolactone. Competition between amrinone (active metabolite of spironolactone) and aspirin for active transport in proximal tubules has been demonstrated.
4. Aspirin reduces protein bound iodine levels by displacement of thyroxine; but hypothyroidism does not.
USES
1. As analgesic
For headache (including mild migraine), backache, myalgia, joint pain, pulled muscle, toothache, neuralgias and dysmenorrhea; it is effective in low doses (0.3–0.6 g 6–8 hourly). Analgesic effect is maximal at ~ 1000 mg (single dose).
2. As antipyretic
It is effective in fever of any origin; dose is same as for analgesia. However, paracetamol, being safer, is generally preferred. Antipyretics are not useful in fever due to heat stroke, only external cooling lowers body temperature.
3. Acute rheumatic fever
Aspirin is the first drug to be used in all cases; other drugs are added or substituted only when it fails or in severe cases (corticosteroids act faster). In a dose of 4–5 g or 75–100 mg/kg/day (in divided portions producing steady state serum salicylate concentration 15–30 mg/dl) it brings about marked symptomatic relief in 1–3 days. Dose reduction may be started after 4–7 days and maintenance doses (50 mg/kg/day) are continued for 2–3 weeks or till signs of active disease (raised ESR) persist. Withdrawal should be gradual over the next 2 weeks.
Granulomatous lesions, nodules, cardiac complications, valvular defects, chorea and duration of disease are not altered by salicylate therapy.
4. Rheumatoid arthritis
Aspirin in a dose of 3–5 g/day is effective in most cases; produces relief of pain, swelling and morning stiffness, but progress of the disease process is not affected. Since large doses of aspirin are poorly tolerated for long periods, it is rarely used now; other NSAIDs are preferred.
5. Osteoarthritis
It affords symptomatic relief only; may be used on ‘as and when required’ basis, but paracetamol is the first-choice analgesic for most cases.
6. Post myocardial infarction and poststroke patients
By inhibiting platelet aggregation aspirin lowers the incidence of reinfarction. TXA2 synthesis in platelets is inhibited at low doses. It has been argued that high doses can reverse the beneficial effects by concurrently inhibiting PGI2 (antiaggregatory and vasodilatory) synthesis in vessel wall. Large studies have demonstrated that aspirin 60–100 mg/day reduces the incidence of myocardial infarction (MI): it is now routinely prescribed to post-infarct patients; many recommend it for primary prophylaxis as well. ‘New onset’ or ‘sudden worsening’ angina is associated with high infarction rate. This can be reduced to half by 100–150 mg aspirin per day for 12 weeks.
Aspirin reduces ‘transient ischemic attacks’ and lowers incidence of stroke in such patients. But the risk of stroke in post-MI patients is not reduced.
7. Other less well-established uses of aspirin are:
- Pregnancy-induced hypertension and pre-eclampsia: imbalance between TXA2 and PGI2 is believed to be involved: aspirin 80–100 mg/day benefits many cases by selectively suppressing TXA2 production.
- Patent ductus arteriosus: aspirin can bring about closure and avoid surgery.
- Familial colonic polyposis: aspirin and other NSAIDs suppress polyp formation and afford symptomatic relief in this rare disorder.
- Prevention of colon cancer: incidence of colon cancer among regular aspirin users is much lower. Colonic tumor's express large quantities of COX-2. However, the rofecoxib trial (APPROVE) was prematurely terminated and the drug withdrawn due to increased incidence of cardiovascular events. The Adenoma Prevention with Celecoxib (APC) trial has also been terminated due to 2.5-fold increase in risk of major fatal/nonfatal cardiovascular events.
- To prevent flushing attending nicotinic acid ingestion, which is due to PGD2 release in the skin.
ASPIRIN 350 mg tab, COLSPRIN 100, 325, 650 mg tabs, ECOSPRIN 75, 150, 325 mg tabs, DISPRIN 350 mg tab, LOPRIN 75, 162.5 mg tabs.
An injectable preparation has been made available recently.
BIOSPIRIN: Lysine acetylsalicylate 900 mg + glycine 100 mg/vial for dissolving in 5 ml water and i.v. injection.Other salicylates (salicylamide, benorilate, diflunisal) are seldom if ever used.
PROPIONIC ACID DERIVATIVES
Ibuprofen was the first member of this class to be introduced in 1969 as a better tolerated alternative
to aspirin. Many others have followed. All have similar pharmacodynamic properties but differ considerably in potency and to some extent in duration of action (Table 14.2)
The analgesic, antipyretic and anti-inflammatory efficacy is rated somewhat lower than high dose of aspirin. All inhibit PG synthesis, naproxen being the most potent; but they're in vitro potency for this action does not closely parallel in vivo anti-inflammatory potency. Inhibition of platelet aggregation is short-lasting with ibuprofen, but longer lasting with naproxen.
Adverse effects
Ibuprofen and all its congeners are better tolerated than aspirin. Side effects are milder, and their incidence is lower.
Gastric discomfort, nausea and vomiting, though less than aspirin or indomethacin, are still the most common side effects. 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 phenomena are infrequent. However, these drugs precipitate aspirin-induced asthma.
Fluid retention is less marked than that with phenylbutazone. They are not to be prescribed to pregnant women and should be avoided in peptic ulcer patient.
Pharmacokinetics and interactions
All are well absorbed orally, highly bound to plasma proteins (90–99%), but displacement interactions are not clinically significant—dose of oral anticoagulants and oral hypoglycemic's need not be altered. Because they inhibit platelet function, use with anticoagulants should, nevertheless, be avoided. Similar to other NSAIDs, they are likely to decrease diuretic and antihypertensive action of thiazides, furosemide and β blockers.
All propionic acid derivatives enter brain, synovial fluid and cross placenta. They are largely metabolized in liver by hydroxylation and glucuronide conjugation and excreted in urine as well as bile.
Uses
1. Ibuprofen is used as a simple analgesic and antipyretic in the same way as low dose of aspirin. It is particularly effective in dysmenorrhea in which the action is clearly due to PG synthesis inhibition. It is available as an ‘over-the-counter’ drug.
2. Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, especially where pain is more prominent than inflammation.
3. They are indicated in soft tissue injuries, fractures, vasectomy, tooth extraction, postpartum and postoperatively: suppress swelling and inflammation.
Ibuprofen
has been rated as the safest conventional NSAID by the spontaneous adverse drug reaction reporting system in U.K. Ibuprofen (400 mg) has been found equally or more efficacious than a combination of aspirin (650 mg) + codeine (60 mg) in relieving dental surgery pain.
Concurrent treatment with ibuprofen has been found to prevent irreversible COX inhibition by low dose aspirin. Thus, it may antagonize the antiplatelet and cardioprotective effect of low dose aspirin.
Naproxen
is particularly potent in inhibiting leucocyte migration—may be more valuable in acute gout: dose 750 mg stat followed by 250 mg 8 hourly till attack subsides. It is also recommended for ankylosing spondylitis. Dose should be reduced in the elderly.
Naproxen is marketed as active single S(–) enantiomer preparation, which poses less renal burden. However, some R(+) enantiomer is formed in vivo due to inversion.
Ketoprofen
An additional action to stabilize lysosomes and inhibit LOX has been demonstrated with ketoprofen, though anti-inflammatory efficacy is similar to other NSAIDs.
Flurbiprofen
more effective than ibuprofen, but gastric side effects are also more. It is used as an ocular anti-inflammatory as well.
OCUFLUR, FLUR, FLURBIN, 0.03% eyedrops, 1 drop 6 hourlies.Mathematic acid
An analgesic, antipyretic and weaker anti-inflammatory drug, which inhibits COX as well as antagonizes certain actions of Pgs. Mehinovic acid exerts peripheral as well as central analgesic action.
Adverse effects
Diarrhea is the most important dose-related side effect. Epigastric distress is complained, but gut bleeding is not significant. Skin rashes, dizziness and other CNS manifestations have occurred. Hemolytic Anamia is a 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 t½ is 2–4 hours.
Uses
Mathematic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is not needed. It is quite effective in dysmenorrhea. It may be useful in some cases of rheumatoid and osteoarthritis but has no distinct advantage.
Dose: 250–500 mg TDS; MEDOL 250, 500 mg cap; MEFTAL 250, 500 mg tab, 100 mg/5 ml susp. PONSTAN 125, 250, 500 mg tab, 50 mg/ml syrupARYL-ACETIC ACID DERIVATIVES
Diclofenac sodium
An analgesic-antipyreticantiinflammatory drug, similar in efficacy to naproxen. It inhibits PG synthesis and is somewhat COX-2 selective. The antiplatelet action is short lasting. Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced.
It is well absorbed orally, 99% protein bound, metabolized and excreted both in urine and bile. The plasma t½ is ~2 hours. However, it has good tissue penetrability and concentration in synovial fluid is maintained for 3 times longer period than in plasma, exerting extended therapeutic action in joints.
Adverse effects
of diclofenac are generally mild: epigastric pain, nausea, headache, dizziness, rashes. Gastric ulceration and bleeding are less common. Reversible elevation of serum aminotransferases has been reported more commonly; kidney damage is rare.
Diclofenac is among the most extensively used NSAID; employed in rheumatoid andosteoarthritis, bursitis, ankylosing spondylitis, toothache, dysmenorrhea, post-traumatic and postoperative inflammatory conditions—affords quick relief of pain and wound edema.
Dose: 50 mg TDS, then BD oral, 75 mg deep i.m.VOVERAN, DICLONAC, MOVONAC 50 mg enteric coated tab, 100 mg S.R. tab, 25 mg/ml in 3 ml amp. for i.m. inj. DICLOMAX 25, 50 mg tab, 75 mg/3 ml inj.Diclofenac potassium: VOLTAFLAM 25, 50 mg tab, ULTRA-K 50 mg tab; VOVERAN 1% topical gel. DICLONAC, VOVERAN OPHTHA 0.1% eye drops.Aceclofenac
A somewhat COX-2 selective congener of diclofenac having similar properties. Enhancement of glycosaminoglycan synthesis may confer chondroprotective property.
Dose: 100 mg BD; ACECLO, DOLOKIND 100 mg tab, 200 mg SR tabOXICAM DERIVATIVES
Piroxicam
It is a long-acting potent NSAID with anti-inflammatory potency similar to indomethacin and good analgesic-antipyretic action. It is a reversible inhibitor of COX; lowers PG concentration in synovial fluid and inhibits platelet aggregation—prolonging bleeding time. In addition, it decreases the production of IgM rheumatoid factor and leucocyte chemotaxis. Thus, it can inhibit inflammation in diverse ways.
Pharmacokinetics
It is rapidly and completely absorbed: 99% plasma protein bound; largely metabolized in liver by hydroxylation and glucuronide conjugation; excreted in urine and bile; enterohepatic cycling occurs. Plasma t½ is long— nearly 2 days. Steady-state concentrations are achieved in a week. Single daily administration is sufficient.
Adverse effects
The g.i. side effects are more than ibuprofen, but it is better tolerated and less ulcerogenic than indomethacin or phenylbutazone; causes less fecal blood loss than aspirin. Rashes and pruritus are seen in < 1% patients. Edema and reversible azotemia have been observed.mg), paracetamol (600 mg) and equivalent to ibuprofen (400 mg). Continuous use for more than 5 days is not recommended. It should not be used for preanesthetic medication or for obstetric analgesia.
KETOROL, ZOROVON, KETANOV, TOROLAC 10 mg tab, 30 mg in 1 ml amp. KETLUR, ACULAR 0.5% eye drops; 1–2 drops 2–4 times a day for noninfective ocular inflammatory conditions.INDOLE DERIVATIVE
Indomethacin Indomethacin
It is a potent anti-inflammatory drug with prompt antipyretic action. Indomethacin relieves only inflammatory or tissue injury related pain. It is a highly potent inhibitor of PG synthesis and suppresses neutrophil motility. In toxic doses it uncouples oxidative phosphorylation (like aspirin).
Pharmacokinetics
Indomethacin is well absorbed orally; rectal absorption is slow but dependable. It is 90% bound to plasma proteins, partly metabolized in liver to inactive products and excreted by kidney. Plasma t½ is 2–5 hours.
Adverse effects
Gastric irritation, nausea, anorexia, gastric bleeding and diarrhea are prominent.
Frontal headache (very common), dizziness, ataxia, mental confusion, hallucination, depression and psychosis can occur. Leukopenia, rashes and other hypersensitivity reactions are also reported.
Increased risk of bleeding due to decreased platelet aggregability.
It is contraindicated in machinery operators, drivers, psychiatric patients, epileptics, kidney disease, pregnant women and in children.
Dose: 25–50 mg BD-QID. Those not tolerating the drug orally may be given nightly suppository.
IDICIN, INDOCAP 25 mg cap, 75 mg SR cap, ARTICID 25, 50 mg cap, INDOFLAM 25, 75 mg caps, 1% eye drop. RECTICIN 50 mg suppository.Uses
Because of prominent adverse effects, indomethacin is used as a reserve drug in conditions requiring potent anti-inflammatory action like ankylosing spondylitis, acute exacerbations of destructive arthropathies, psoriatic arthritis and acute gout that are not responding to better tolerated NSAIDs.
Malignancy associated fever refractory to other antipyretics may respond to indomethacin. It has been the most common drug used for medical closure of patent ductus arteriosus: three 12 hourly doses of 0.1–0.2 mg/kg achieve closure in majority of cases.
Bartter’s syndrome responds dramatically, as it does to other PG synthesis inhibitors.
PYRAZOLONES
Antipyrine (phenazone) and amidopyrine (aminopyrine) were introduced in 1884 as antipyretic and analgesic. Their use was associated with high incidence of agranulocytosis are banned in many countries, including India. Phenylbutazone was introduced in 1949 and soon its active metabolite oxyphenbutazone was also marketed. These two are potent anti-inflammatory drugs, inhibit COX, but have slow onset, weak analgesic and antipyretic action. Their gastric toxicity is high; edema due to Na+ and water retention is frequent and CNS side effects, hypersensitivity reactions, hypothyroidism are reported. They are banned in many countries and rarely used in others due to residual risk of bone marrow depression and other toxicity. Two other pyrazalone's available in India—metamizole and propyphenazone are primarily used as analgesic and antipyretic.
Metamizole (Dipyrone)
In contrast to phenylbutazone, this derivative of amidopyrine is a potent and promptly acting analgesic and antipyretic but poor anti-inflammatory and not uricosuric. It can be given orally, i.m. as well as i.v, but gastric irritation, pain at injection site occurs. Occasionally, i.v. injection produces precipitous fall in BP.
Few cases of agranulocytosis were reported and metamizole is banned in the USA and some European countries. However, it has been extensively used in India and other European countries. Adverse reaction data collected over four decades shows that risk of serious toxicity with this drug is lower than with aspirin or many other NSAIDs. However, its fixed dose combination with antispasmodics is banned in India.
Dose: 0.5–1.5 g oral/i.m./i.e., ANALGIN 0.5 g tab; NOVALGIN, BARALGAN 0.5 g tab, 0.5 g/ml in 2 ml and 5 ml amps; ULTRAGIN 0.5 g/ml inj in 2 ml amp and 30 ml vial.Propyphenazone
- Another pyrazoline, similar in properties to metamizole; claimed to be better tolerated. Agranulocytosis has not been reported. Dose: 300–600 mg TDS; marketed only in combination in several ‘over-the-counter’, preparations—in SARIDON, ANAFEBRIN: propyphenazone 150 mg + paracetamol 250 mg tab.
- DART: propyphenazone 150 mg + paracetamol 300 mg + caffeine 50 mg tab.
- PREFERENTIAL COX-2 INHIBITORS
Nimes Lide
- This newer NSAID is a relatively weak inhibitor of PG synthesis and there is some evidence to indicate relative COX-2 selectivity. Anti-inflammatory action may be exerted by other mechanisms as well, e.g. reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and TNFα release, free radical scavenging, inhibition of metalloproteinase activity in cartilage. The analgesic, antipyretic and anti-inflammatory activity of nestlike has been rated comparable to other NSAIDs. It has been used primarily for short-lasting painful inflammatory conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis, low backache, dysmenorrhea, postoperative pain, osteoarthritis and for fever.
- Nimes Lide is almost completely absorbed orally, 99% plasma protein bound, extensively metabolized and excreted mainly in urine with a t½ of 2–5 hours.
- Adverse effects of nestlike are gastrointestinal (epigastralgia, heart burn, nausea, loose motion), dermatological (rash, pruritus) and central (somnolence, dizziness). Gastric tolerability of mikeside is better, though an Italian study has shown that ulcer complications are as prevalent as with other NSAIDs. There is also no proof that renal complications are missing: hematuria is reported in few children. Instances of fulminant hepatic failure have been associated with Nimes Lide and it has been withdrawn in Spain and Turkey; use in children is banned in Portugal and Israel. However, a Finish committee for proprietary medicinal products has concluded that hepatic reactions to mikeside are similar to other NSAIDs. Considering that it has not been marketed in many countries like the UK, USA, Australia, Canada, the overall safety of this drug, especially in children, has been questioned. However, most asthmatics and those who develop bronchospasm or intolerance to aspirin and other NSAIDs do not cross react with mikeside. Its specific usefulness appears to be only in such patients.
Dose: 100 mg BD; NIMULID, NIMEGESIC, NIMODOL 100 mg tab, 50 mg/5 ml susp
Meloxicam.
This newer congener of piroxicam has a COX-2/COX-1 selectivity ratio of about 10. Since measurable inhibition of platelet TXA2 production (a COX-1 function) occurs at therapeutic doses of meloxicam, it has been labelled ‘preferential COX-2 inhibitor’. Efficacy of meloxicam in osteo- and rheumatoid arthritis is comparable to piroxicam. In short-term studies, gastric changes with the lower dose (7.5 mg/day) were found to be similar to placebo, but at the higher dose (15 mg/day) they were intermediate between placebo and piroxicam. Gastric side effects of meloxicam are milder, but ulcer complications (bleeding, perforation) have been reported on long-term use. Thus, there is no convincing evidence that meloxicam is safer than other NSAIDs.
Dose: 7.5–15 mg OD; MELFLAM, MEL-OD, MUVIK, MCAM 7.5 mg, 15 mg tabs.Norboletone
It is a prodrug—generates an active metabolite (6-MNA) and is a relatively more potent COX-2 than COX-1 inhibitor. It possesses analgesic, antipyretic and anti-inflammatory activities, effective in the treatment of rheumatoid and osteoarthritis as well as soft tissue injury. Nifurmerone has caused a lower incidence of gastric erosions, ulcers and bleeding, probably because the active COX inhibitor is produced in tissues after absorption. However, abdominal cramps and diarrhea can occur and there is no firm evidence of its relative safety compared to traditional NSAIDs.
NABUFLAM 500 mg tab; 1 tab ODSELECTIVE COX-2 INHIBITORS (Coils)
Because of the theoretical advantage of inhibiting COX-2 without affecting COX-1 function, some highly selective COX-2 inhibitors have been introduced over the past decade. They cause little gastric mucosal damage; occurrence of peptic ulcer and ulcer bleeds is clearly lower than with traditional NSAIDs. They do not depress TXA2 production by platelets (COX-I dependent); do not inhibit platelet aggregation or prolong bleeding time but reduce PGI2 production by vascular endothelium.
Currently, 3 selective COX-2 inhibitors (also called coils) Celecoxib, Etoricoxib and Parecoxib are available in India; Lumiracoxib is marketed in Europe, while Forecoxae and Valdecoxib have been withdrawn for increasing cardiovascular (CV) risk.
It has been concluded that selective COX-2 inhibitors should be used only in patients at high risk of peptic ulcer, perforation or bleeds. If selected, they should be administered in the lowest dose for the shortest period of time. Moreover, they should be avoided in patients with history of ischemic heart disease/hypertension/cardiac failure/cerebrovascular disease, who are predisposed to CV event.
Concerns, other than cardiovascular, have also been expressed about selective COX-2 inhibitors.
Celecoxib
The COX-2 selectivity of celecoxib is modest (6–20 fold). It exerts anti-inflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac, without affecting COX-1 activity in gastroduodenal mucosa. Platelet aggregation in response to collagen exposure remained intact in celecoxib recipients and serum TXB2 levels were not reduced. Though tolerability of celecoxib is better than traditional NSAIDs, still abdominal pain, dyspepsia and mild diarrhea are the common side effects. Rashes, edema and a small rise in BP have also been noted.
Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized primarily by CYP2C9 with a t½ of ~10 hours. It is approved for use in osteo- and rheumatoid arthritis in a dose of 100–200 mg BD.
CELACT, REVIBRA, COLCIBRA 100, 200 mg capsEtoricoxib
This newer COX-2 inhibitor has the highest COX-2 selectivity. It is suitable for oncea-day treatment of osteo/rheumatoid/acute gouty arthritis, dysmenorrhea, acute dental surgery pain and similar conditions, without affecting platelet function or damaging gastric mucosa. The t½ is ~ 24 hours. Side effects are dry mouth, aphthous ulcers, taste disturbance and paresthesia.Dose: 60–120 mg OD; ETODY, TOROCOXIA, ETOXIB, NUCOXIA 60, 90, 120 mg tabs.Parecoxib
It is a prodrug of valdecoxib suitable for injection, and to be used in postoperative or similar short-term pain, with efficacy similar to ketorolac.
Dose: 40 mg oral/i.m./i.v., repeated after 6–12 hours. REVALDO, VALTO-P 40 mg/vial inj, PAROXIB 40 mg tab.PARA-AMINO PHENOL DERIVATIVES
Phenacetin introduced in 1887 was extensively used as analgesic-antipyretic but is now banned because it was implicated in analgesic abuse nephropathy.
Paracetamol (acetaminophen) the demethylated active metabolite of phenacetin, was also introduced in the last century but has come into common use only since 1950.
Paracetamol has negligible anti-inflammatory action. It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in the brain. One explanation offered for the discrepancy between its analgesic-antipyretic and anti-inflammatory actions is its inability to inhibit COX in the presence of peroxides which are generated at sites of inflammation but are not present in the brain. The ability of paracetamol to inhibit COX-3 (an isoenzyme so far located in dog brain) could also account for its analgesic-antipyretic action.
In contrast to aspirin, paracetamol does not stimulate respiration or affect acid-base balance; does not increase cellular metabolism. It has no effect on CVS. Gastric irritation is insignificant— mucosal erosion and bleeding occur rarely only in overdose. It does not affect platelet function or clotting factors and is not uricosuric.
Pharmacokinetics Paracetamol is well absorbed orally, only about 1/4th is protein bound in plasma and it is uniformly distributed in the body. Metabolism occurs mainly by conjugation with glucuronic acid and sulfate: conjugates are excreted rapidly in urine. Plasma t½ is 2–3 hours. Effects after an oral dose last for 3–5 hours.
Adverse effects In isolated antipyretic doses paracetamol is safe and well tolerated. Nausea and rashes occur occasionally, leukopenia is rare.
Analgesic nephropathy occurs after years of heavy ingestion of analgesics; such individuals probably have some personality defect. Pathological lesions are papillary necrosis, tubular atrophy followed by renal fibrosis. Urine concentrating ability is lost and the kidneys shrink. Because phenacetin was first implicated, it went into disrepute, though other analgesics are also liable to produce similar effects.
Acute paracetamol poisoning
It occurs especially in small children who have low hepatic glucuronide conjugating ability. If a large dose (> 150 mg/kg or > 10 g in an adult) is taken, serious toxicity can occur. Fatality is common with > 250 mg/kg.
ing, abdominal pain and liver tenderness with no impairment of consciousness. After 12–18 hours centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypo glycaemia that may progress to coma. Jaundice starts after 2 days. Further course depends on the dose taken. Fulminating hepatic failure and death are likely if the plasma levels are above the line joining 200 μg/ml at 4 hours and 30 μg/ml at 15 hours. If the levels are lower recovery with supportive treatment, is the rule.
Mechanism of toxicity
y N-acetyl-p-benzoquinone mine (NABQI) is a highly reactive arylating minor metabolite of paracetamol which is detoxified by conjugation with glutathione. When a very large dose of paracetamol is taken, glucuronidation capacity is saturated, more of the minor metabolite is formed—hepatic glutathione is depleted, and this metabolite binds covalently to proteins in liver cells (and renal tubules) causing necrosis. Toxicity thus shows a threshold effect manifesting only when glutathione is depleted to a critical point.
In chronic alcoholics even 5–6 g/day taken for a few days can result in hepatotoxicity because alcoholism induces CYP2E1 that metabolizes paracetamol to NABQI.
Paracetamol is not recommended in premature infants (< 2 kg) for fear of hepatotoxicity.
Treatment
If the patient is brought early, vomiting should be induced, or gastric lavage done. Activated charcoal is given orally or through the tube to prevent further absorption. Other supportive measures, as needed, should be taken.
Specific: N-acetylcysteine (MUCOMIX, ANTIFEN 200 mg/ml inj in 2, 5 ml amps)150 mg/kg should be infused i.v. over 15 min, followed by the same dose i.v. over the next 20 hours. Alternatively, 75 mg/kg may be given orally every 4–6 hours for 2–3 days. It replenishes the glutathione stores of liver and prevents binding of the toxic metabolite to other cellular constituents.
Uses Paracetamol is one of the most commonly used ‘over-the-counter’ analgesic for headache, mild migraine, musculoskeletal pain, dysmenorrhea, etc. but is relatively ineffective when inflammation is prominent. Paracetamol is recommended as first choice analgesic for osteoarthritis by many professional bodies. It is one of the best drugs to be used as antipyretic, especially in children (no risk of Reye’s syndrome).
Dose to dose it is equally efficacious as aspirin for noninflammatory conditions. It is much safer than aspirin in terms of gastric irritation, ulceration and bleeding (can be given to ulcer patients), does not prolong bleeding time. Hypersensitivity reactions are rare; 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 and in patients in whom aspirin is contraindicated. It does not have significant drug interactions. Thus, it may be preferred over aspirin for most minor conditions.
Dose: 0.5–1g TDS; infants 50 mg; children 1–3 years 80– 160 mg, 4–8 years 240–320 mg, 9–12 years 300–600 mg. CROCIN 0.5, 1.0 g tabs; METACIN, PARACIN 500 mg tab, 125 mg/5 ml syrup, 150 mg/ml paed. drops, ULTRAGIN, PYRIGESIC, CALPOL 500 mg tab, 125 mg/ 5 ml syrup, NEOMOL, FEVASTIN, FEBRINIL 300 mg/2 ml inj., CROCIN PAIN RELIEF: 650 mg + Caffeine 50 mg tab.BENZOXAZOCINE DERIVATIVE
Nefopam
m It is a nonopioid analgesic which does not inhibit PG synthesis and acts rapidly in traumatic and postoperative pain. Favour able results have been obtained in short-lasting musculoskeletal pain.
Nefopam produces anticholinergic (dry mouth, urinary retention, blurred vision) and sympathomimetic (tachycardia, nervousness) side effects, and nausea is often dose limiting. It is contraindicated in epileptics. Dose: 30–60 mg TDS oral, 20 mg i.m. 6 hourlies.
NEFOMAX 30 mg tab, 20 mg in 1 ml amp.Topical NSAIDs
Many NSAIDs have been marketed in topical formulations (mostly as gels) for application over painful muscles or joints. These preparations are being used for osteoarthritis, sprains, sports injuries, tenosinovitis, backache, spondylitis and other forms of soft tissue rheumatism. It is believed that the drug would penetrate to the subjacent tissues attaining high concentrations in the affected muscles/joints, while maintaining low blood levels. Consequently the g.i. and other. Systemic adverse effects would be minimized and first pass hepatic metabolism would also be avoided.
While there is no doubt about their safety, doubt has been raised about their actual efficacy over and above a strong placebo effect of local application, massaging and that due to presence of counter irritants like menthol, methyl salicylate, etc. in most of them. Often they are used in addition to oral NSAID medication; the benefit of topical application per se is difficult to assess.
Measurement of drug concentration attained in tissues underlying the site of application, as well as concurrent blood levels has shown that systemic absorption from topical NSAID preparations is slow taking ~10 times longer time to attain peak concentration compared to oral dosing. Highest blood levels remain below 15% of the same dose given orally. This is consistent with their lack of systemic toxicity. Local concentrations are high unto a depth of 4–6 mm, i.e. in dermis, but at 25 mm depth in muscles, the concentration is low and nearly the same as in blood. Marked variation has been noted in the concentration attained in muscles and joints depending on the type of formulation, depth and distance from site of application and among different individuals. Reports on the clinical efficacy of topical NSAIDs are even more variable (range 18–92% response). Better responses have generally been obtained in short lasting musculoskeletal pain. Contribution of the NSAID present in the formulation to the beneficial effect, when elicited, is uncertain.
Choice of nonsteroidal anti-inflammatory drug
NSAIDs have their own spectrum of adverse effects. They differ quantitatively among themselves in producing different side effects and there are large inter-individual differences. At present NSAIDs are a bewildering array of strongly promoted drugs. No single drug is superior to all others for every patient. Choice of drug is inescapably empirical.
escapable empirical. The cause and nature of pain (mild, moderate or severe; acute or chronic; ratio of pain: inflammation) along with consideration of risk factors in the given patient govern selection of the analgesic. Also to be considered are the past experience of the patient, acceptability and individual preference. Patients differ in their analgesic response to different NSAIDs. If one NSAID is unsatisfactory in a patient, it does not mean that other NSAIDs will also be unsatisfactory. Some subjects ‘feel better’ on a particular drug, but not on a closely related one. It is in this context that availability of such a wide range of NSAIDs may be welcome. Some guidelines are:
1. Mild-to-moderate pain with little inflammation: paracetamol or low-dose ibuprofen.
2. Postoperative or similar acute but short-lasting pain: ketorolac, a propionic acid derivative, diclofenac, Nimes Lide or aspirin.
3. Acute musculoskeletal, osteoarthritic, injury associated pain: paracetamol, a propionic acid derivative or diclofenac.
4. Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever: naproxen, piroxicam, indomethacin, high dose aspirin.
5. Gastric intolerance to traditional NSAIDs or predisposed patients: a selective COX-2 inhibitor or paracetamol
6. Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs: Nimes Lide, COX-2 inhibitor.
7. Pediatric patients: only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in children — should be preferred in them. Due to risk of Reye’s syndrome, aspirin should be avoided.
8. Pregnancy: paracetamol is the safest; low-dose aspirin is probably the second best. 9. Hypertensive, diabetic, ischemic heart disease, epileptic and other patients receiving long-term regular medication: possibility of drug interaction with NSAIDs should be considered.
Analgesic combinations
Combination of aspirin and paracetamol is additive (not supra-additive) and a ceiling analgesic effect is obtained when the total amount of aspirin + paracetamol is ~ 1000 mg. The same is true of combinations of paracetamol with other NSAIDs like ibuprofen, diclofenac, etc. There is no convincing evidence that such combinations are superior to single agents, either in efficacy or in safety. If at all used, such combinations should be limited to short periods.
Combination of codeine (an opioid analgesic) with aspirin or paracetamol is also additive, but in this case combination provides additional analgesia beyond the ceiling effect of aspirin/ paracetamol. The mechanisms of pain relief by these two classes of drugs are different. Such combination can be considered rational for providing greater analgesia. Adequate clinical data supports use of such combination for pain refractory to single agent.
To obviate inadvertent misuse and chance of producing dependence, fixed dose combinations of analgesics with hypnotics/sedatives/anxiolytics is banned in India.
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