Medical Pharmacology Topics   

Pain Management: Non-steroidal Anti-inflammatory Drugs

The non-steroidal anti-inflammatory drugs (NSAIDs, antipyretic analgesics, aspirin-like drugs) are thought to act by blocking at least two types of cyclooxygenases: COX1 and COX2. While COX1 is a constitutive enzyme, trauma can cause the production of COX2, also known as inducible COX, to allow additional production of prostaglandins and thromboxane. NSAIDs agents include the salicylates, para-aminophenols, COX2 selective inhibitors and several other drugs.

The therapeutic effects of NSAIDs include analgesia, antipyresis and anti-iflammation. As analgesics, NSAIDs prevent the hypersensitivization of nociceptive sensory neurons by prostaglandins. As antipyretics, they prevent pyrogen-induced increases in temperature. Except for the para-aminophenols, all NSAIDs seem to have similar anti-inflammatory action.

Side effects of most NSAIDs include GI irritation and ability to cause gastric damage, alterations in platelet function, prolongation of gestation and potential renal damage in patients with renal insufficiency.

Salicylates

Salicylic acid and salicylic acetaldehyde, a.k.a. aspirin, are used in low to moderate intensity pain but may be superior to opiates in pain fro inflammation (ex. post surgical). They also reduce inflammation and pain in arthritis and decrease pain, swelling and fever in rheumatic fever, but do not alter the progress of either disease.

The salicylates are less toxic than opioids, act largely in the peripheral nervous system and tolerance to their effects does not develop. By inhibiting prostaglandin synthesis salicylates also reduce elevated body temperature. Topical application of salicylic acid is used to treat warts.

Aspirin has been shown to reduce the incidence of acute MI and death in patients with unstable angina, and reduce the frequency of ischemic attacks in patients with arteriosclerosis. These cardiovascular effects may be due to long lasting alterations of platelet function. Since the inhibition of COX is irreversible and platelets cannot produce new proteins, the effect lasts until new platelets are generated.

Salicylates stimulate respiration directly by stimulating the respiratory center in the medulla, and indirectly by uncoupling oxidative phosphorylation in skeletal muscle (thus increasing CO2 production, which triggers an increase in respiration). The stimulation of respiration may result in respiratory alkalosis and increased bicarbonate secretion as salicylate derivatives displace bicarbonate. Toxic doses, especially in infants, cause central respiratory paralysis and respiratory acidosis. Higher toxic doses induce further changes that may induce both respiratory and metabolic acidosis. As bicarbonate is depleted from plasma, respiration decreases and CO2 concentrations increase (?).

The cardiovascular effects of salicylates are minimal, except that with toxic concentration circulation is depressed. They inhibit platelet aggregation and may prolong bleeding by blocking thromboxane A2 synthesis. Platelets are especially sensitive to the irreversible COX block since they cannot synthesize new enzyme.

Historically, the salicylates were used as uricosuric agents, but the effect is dose dependent. Low doses decrease urate excretion, antagonize other uricosuric agents and worsen gout. Only at large doses ( 5 g/day) do they increase uric acid excretion.

Aspirin is absorbed in the stomach and intestine with a peak plasma concentration 2 hrs after administration. It distributes to all tissues and is highly bound to plasma proteins. It is removed largely by the liver. At very high toxic concentrations, elimination kinetics may shift from first order to zero order.

In the GI tract, salicylates cause epigastric distress, nausea, vomiting (CNS), gastric ulceration, hemorrhage, exacerbation of ulcers, local irritation and abdominal pain. The mechanism for GI effects is the inhibition of GI prostaglandin (mostly PGF2 and PGE2) that normally inhibit acid secretion.

Some patients are hypersensitive to aspirin, leading to skin eruptions, asthma and anaphylaxis. When used to treat viral fever in children aspirin has been associated with Reye's syndrome. Hepatotoxicity and acute renal toxicity may occur in patients with hepatic or renal disease. Salicylates are contraindicated in patients with severe hepatic damage, vitamin K deficiency, hemophilia, and pregnant woman near term. Patients on anticoagulant therapy should take aspirin with caution to prevent bleeding or drug displacement from plasma proteins.

Aspirin overdose occurs with a relatively high frequency and is more likely to be observed in children. It is also commonly used as a means of suicide. Signs of salicylate intoxication include CNS effects, nausea, vomiting, initial respiratory alkalosis, later respiratory and metabolic acidosis, hyperthermia, dehydration due to excessive sweating, hyperventilation, and in severe cases cardiorespiratory arrest. The CNS symptoms include tinnitis, hearing loss, dimness of vision, headache, dizziness, drowsiness, mental confusion, delirium, convulsions and coma.

Other NSAIDs

Acetaminophen is the prototype para-aminophenol. It is effective as analgesic and antipyretic. Opposite to the salicylates, acetaminophen is not useful as anti-inflammatory, has no uricosuric effects and has a weak effect on platelets.

Acetaminophen does not cause alterations in the acid/base balance nor hypersensitivity reactions, and has minimal effects on the GI at therapeutic doses, thus is the preferred NSAIDs to use in patients with peptic ulcer, aspirin intolerance, on oral anticoagulants, with clotting disorders, with gout or viral infections.

The most serious problem associated with acetaminophen is fatal hepatic necrosis with acute overdose. Initial symptoms are gastrointestinal, followed perhaps by a period of apparent recovery and then appearance of jaundice. An oxidizing metabolite of acetaminophen has been formed in sufficient quantity to exceed the availability of glutathione to inactivate it before causing cell death and necrosis. This condition is managed with N-acetylcysteine (NAC), which can stimulate GSH synthesis, enhance glutathione-S-transferase activity, promote detoxification, and act directly on reactive oxidant radicals.

Other side effects of acetaminophen include skin rash, mucosal lesions and rarely leukopenia.

Several other NSAIDs have mostly the same profile of effects and side effects as aspirin: indole/indene acetic acids, heteroaryl acetic acids, acylpropionic acids, enolic acids and pyrazolon derivatives. Their therapeutic efficacy and toxicity can vary, and the choice of agent is largely empirical and depends on the patient.

The indole/indene acetic acids include indomethacin and sulindac. The use of indomethacin is limited due to toxicity. Sulindac is a prodrug metabolized to the active sulfide and is less toxic than indomethacin.

Indomethacin is used as an antipyretic especially in fever from Hodgkin's disease or when non-responsive to other agents. Indomethacin as marked anti-inflammatory action, and although not uricosuric, it is used in acute gout to decrease inflammation. 35-50% of patients experience toxicity, including nausea, anorexia, vomiting, abdominal pain, diarrhea, ulcerative GI lesions, headache, dizziness, mental confusion, neutropenia, thrombocytopenia,rarely aplastic anemia, and acute asthma.

The acylpropionic acid derivatives like ibuprofen and naproxen have less GI toxicity than salicylates. Ibuprofen is available over-the-counter. Naproxen is administered only twice daily.

The only enolic acid currently available in the US is piroxicam, a long-lasting, single dose agent. The pyrazolon derivatives phenylbutazone and oxyphenbutazone are linked to a relatively high incidence of serious toxicity and should be used only as a last resort. The heterocyclic acetic acids include tolmecin and ketorolac.

Arthritis Treatment

COX2 selective inhibitors such as celecoxib, rofecoxib and valdecoxib, are primarily indicated for rheumatoid arthritis or osteoarthritis. Rofecoxib i also indicated for short-term pain relief (5 days) after minor surgery, and for dysmenorrhea. Valdecoxib is also approve for primary dysmenorrhea.

In general, COX2 inhibitors have less side effects than other NSAIDs. Some side effects are similar to other NSAIDs (GI, renal) but with a lesser incidence. They have no significant effect on platelet aggregation. celecoxib contains a reactive sulfur molecule that may cause allergic reactions in patients allergic to sulfonamides.

In addition to the NSAIDs and glucocorticoids, a number of other dugs are used to treat rheumatoid arthritis and osteoarthritis. Because rheumatoid arthritis appears to be an autoimmune disease, a number of immunosupressive and/or antineoplastic drugs are used to relieve symptoms: azathioprine, hydroxychloroquine, leflunomide, methotrexate, penicillamine and anakinra. These drugs are only used in severe rheumatoid arthritis that is unresponsive to conventional therapy. They can cause numerous side effects including fever, chills, anorexia, nausea, vomiting, hepatotoxicity, agranulocytosis, leukopenia, anemia, ad thrombocytopenia.

Gold salts are used in the management of progressive rheumatoid arthritis that is unresponsive to traditional therapies. Agents include auranofin, aurothioglucose and gold sodium thiomalate. Gold salts relieve pain and stiffness and in some patients may arrest the progression of joint degeneration. These drugs do not reverse damage that has already occurred. Side effects limit their use, and include metallic taste, stomatitis, and diarrhea with abdominal pain and cramping. Some patients develop a rash, dermatitis, thrombocytopenia, aplastic anemia, agranulocytosis and acute tubular necrosis.

Gout Treatment

Acute gout is a severe attack of acute pain, maybe limited to a specific joint It is caused by deposition of urate crystals in the joint. As leukocytes ingest the crystals, they release pain mediators. Chronically, these patients have increased plasma uric acid (hyperuricemia). I asymptomatic, is not always necessary to lower urate levels, although crystals may precipitate in the kidneys and develop into stones. Gout is treated using cochicine, probenecid, sulfinpyrazone, and allopurinol.

Cochicine inhibits migration of granulocytes t the affected area, thus lessening the inflammatory response. Although not urisuric, cochicine is useful in relieving and preventing acute gout attacks. Major side effects include nausea, vomiting, diarrhea and abdominal pain. Long term administration increases the incidence of blood dyscrasias.

Probenecid and sulfinpyrazone increase excretion of uric acid by decreasing its reabsorption. The patient must drink lots of water and the urine should be alkalinized to prevent ppt (?, transport?) of uric acid in the renal tubules.

Allopurinol reduces formation of uric acid by inhibiting xanthine oxidase.

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