Pharmacology of Over-The-Counter Analgesics Used for the Treatment ofHeadache

John Horn, Pharm.D.

INTRODUCTION

Headache is one of the most common disorders affecting humans, and is largely self-treated by patients, asindicated by medication usage studies1 and low consultation rates for both migraine and tension-typeheadache.2,3 When a patient does seek medical advice, the physician in primary care practice is mostfrequently consulted.2,4 Consultation is typically sought when pain becomes intensified, severe or persistent,and may not have been effectively treated with over-the-counter analgesics. Such instances represent anopportunity for the physician to ensure that the patient is taking the medication most likely to offer safe,effective pain relief.

Patient history, potential contraindications, and use of other medications should guide the recommendation ofdrug therapy. Other factors include efficacy data, formulation factors that affect pain relief and side effects,and the potential for adverse effects.5

Aspirin/Salicylates

Aspirin and other salicylates can be effective for treating mild to moderate musculoskeletal pain andheadache, but are not effective for treating visceral pain.6

Mechanism of Action. -Salicylates act peripherally to inhibit prostaglandin-induced sensitization of peripheralpain receptors by blocking cyclooxygenase and preventing conversion of arachidonic acid intoprostaglandins. Some evidence suggests that a central mechanism may also play a role, perhaps related toinhibition of reflex activity in the dorsal horn of the spinal cord.6 The salicylates also have anti-inflammatory andantipyretic action.

Dose. - For mild to moderate pain, the recommended safe and effective adult dose is 325 to 650 mg every 4hours, 325 to 500 mg every 3 hours, or 650 to 1000 mg every 6 hours while symptoms persist. Patientsshould not exceed 4 g in 24 hours.

Therapeutic Considerations.6 -Salicylates exhibit a number of pharmacologic actions that should beconsidered prior to recommendation, including the following.

Impairment of platelet aggregation: Aspirin's effects on platelet aggregation are well appreciated, and may beviewed beneficially or as an adverse effect, depending on the patient. A single dose can irreversibly inhibitplatelet aggregation and double bleeding times for several days. Large doses (more than 6 g per day) willreduce prothrombin concentrations, perhaps by interfering with vitamin K utilization during prothrombinsynthesis.

Effects on uric acid elimination: Low doses (1 to 2 g per day) inhibit renal tubular uric acid secretion but notreabsorption, leading to increased plasma uric acid concentrations. High doses (more than 5 g per day)increase uric acid excretion by inhibiting renal tubular reabsorption.

Gl irritation and bleeding: A small amount of blood loss is common following aspirin ingestion; the amount ofbleeding is dose-dependent. Gastrointestinal side effects occur in about 5% of patients taking salicylatesintermittently, while patients who take them chronically are at greater risk of GI complications.

Hypersensitivity reactions: Allergic reactions to aspirin are rare (less than 0.5%); however, the risk increasesto 20% in patients with asthma, nasal polyps, or urticaria. Cross-reactivity with other nonsteroidalanti-inflammatory drugs is common.

Others: Aspirin should be avoided during pregnancy due to its association with prolonged gestation and laboras well as with increased blood loss at delivery. Because of the link between Reye's syndrome and aspirinuse during viral illness, children and teenagers are advised to avoid aspirin for symptoms of varicella,influenza, or other viral infections.

Drug Interactions.7 - Patient history may reveal the use of other medications-either prescription or nonprescription-that should be avoided by patientstaking salicylates, including those below (see also the Table).

Table 1.-Potential Drug Interactions With OTC Analgesics7 (see text for descriptions of effects).

Aspirin Acetaminophen IbuprofenEthanol Barbituates Anticoagulants

Methotrexate Cholestyramine Antihypertensives

Non-steroidal Ethanol Digoxinanti-inflammatories

Oral anticoagulants Ethanol

Sulfonylureas Lithium

Uricosuric drugs Methotrexate

Valproic acid

Ethanol: The combination of alcohol and salicylates may double the daily GI blood loss from aspirin alone due to the erosiveeffects of both drugs on the GI mucosa and to the potentiation of aspirin's antiplatelet effect. Salicylate-containing productsshould be avoided by patients consuming ethanol.

Methotrexate (MTX): MTX concentrations may be increased by salicylate-induced reduction in MTX renal clearance.Increased MTX toxicity may result, particularly in patients receiving immuno-suppressive MTX doses. Patients on MTX therapyshould be warned not to self-medicate with any form of salicylate.

Nonsteroidal anti-inflammatory drugs (NSAIDs): The risk of combining NSAIDs with aspirin may not be well appreciated, butcan cause a dramatic increase in GI ulceration. Patients using NSAIDs for arthritis are at particular risk.

Oral anticoagulants: Aspirin increases the risk of bleeding due to its antiplatelet and gastric erosion effects. Large doses(more than 3 g per day) have some intrinsic hypoprothrombinemic effects and may decrease anticoagulant protein binding.Patients taking oral anticoagulants should be cautioned to avoid aspirin products.

Sulfonylureas: Salicylate doses of more than 2 g per day appear to increase insulin secretion in response to hyperglycemia,thereby enhancing the hypoglycemic effect of sulfonylureas. Patients taking these drugs should avoid the chronic ingestion oflarge doses of salicylates.

Uricosuric drugs: Salicylates may inhibit the uricosuric effect of probenecid and sulfinpyrazone, leading to the worsening ofhyperuricemia and possibly, the exacerbation of gout.

Valproic acid: Aspirin may displace valproic acid from its binding site and decrease its clearance. Patients taking valproic acidshould avoid salicylates; signs of valproic acid toxicity may result from the combined use.

Acetaminophen

Mechanism of Action. - The exact mechanism of acetaminophen's analgesic action is not clearly understood. It appears towork by inhibiting prostaglandin production centrally, as opposed to the peripheral action of salicylates. In contrast tosalicylates, its anti-inflammatory effect is weak.6

Dose. - Recommended adult dosage is 325 to 650 mg every 4 hours, 325 to 500 mg every 3 hours, or 650 to 1000 mg every6 hours, not to exceed a total of 4 g in 24 hours.

Therapeutic Considerations.6-Unlike the salicylates, acetaminophen has no effect on platelet aggregation, uric acidelimination, or prothrombin synthesis, and it produces less GI bleeding and irritation. When aspirin is contraindicated becauseof the considerations listed above, acetaminophen is an appropriate alternative for noninflammatory indications.

Drug Interactions.7 -One should caution against concurrent use of acetaminophen with the drugs indicated below (see alsothe Table).

Barbiturates: The induction of hepatic enzymes by barbiturates leads to the production of hepatotoxic acetaminophenmetabolites following large acetaminophen doses.

Cholestyramine: Administration of cholestyramine may reduce the gastrointestinal absorption of acetaminophen, resulting inreduced plasma concentrations and efficacy.

Ethanol: The hepatotoxicity associated with excessive acetaminophen doses may be worsened by chronic ethanol-inducedliver enzyme induction, leading to an increased formation of hepatotoxic acetaminophen metabolites.

Ibuprofen

Mechanism of Action. - Ibuprofen's analgesic action is similar to, though more potent than aspirin, occuring as a result ofcyclooxygenase blockage and the subsequent inhibition of prostaglandin synthesis. It has antipyretic and anti-inflammatoryaction as well.5

Dose. - Adult nonprescription dose is 200 to 400 mg every 4 to 6 hours, not to exceed 1200 mg in 24 hours.

Therapeutic Considerations5. - Patients with aspirin hypersensitivity or intolerance, as well as pregnant women in theirthird trimester, should avoid ibuprofen. Other pharmacologic actions exhibited by ibuprofen that should be consideredprior to recommending it include:

GI effects: These are the most frequent adverse effects of ibuprofen administration, and include dyspepsia, heartburn,nausea, anorexia, and epigastric pain. GI bleeding is usually less than that seen with aspirin.

Platelet aggregation: Ibuprofen doses of 600 to 1800 mg per day inhibit platelet aggregation and increase bleeding time,though these effects reverse within 24 hours of discontinuing ibuprofen.

Renal blood flow: The drug's inhibition of renal prostaglandin synthesis may cause decreased renal blood flow andglomerular filtration rate. This effect may be more common in patients with preexisting renal impairment, congestiveheart failure, hypertension, and diabetes, as well as for patients taking diuretics.

Drug Interactions.7 - Anticoagulants: Ibuprofen's effects on platelet aggregation and GI mucosa increase the risk ofbleeding in anticoagulated patients.

Antihypertensive drugs: Ibuprofen may antagonize the blood pressure-lowering effects of diuretics, beta blockers, andangiotensin-converting enzyme inhibitors. Ibuprofen's effects are usually limited and require several weeks of chronicdosing to produce significant changes in blood pressure control.

Digoxin: Ibuprofen may increase plasma digoxin concentrations, though the clinical significance of this is uncertain.Patients with a history of congestive heart failure should not self-medicate with ibuprofen.

Ethanol: As with salicylates, alcohol ingestion increases ibuprofen-induced prolongation of bleeding time. Patientstaking ibuprofen should avoid alcohol.

Lithium: A week of chronic ibuprofen administration has been reported to increase plasma lithium concentrations andthe risk of lithium toxicity. The effects of intermittent dosing are unknown but likely to be limited.

Methotrexate (MTX): Limited clinical evidence suggests that ibuprofen reduces the renal elimination of MTX and maycause MTX toxicity (see also the Table).

Caffeine

Caffeine has long been added to prescription and nonprescription medications to enhance the analgesic effect, but ithas only recently been formally recognized by the FDA as an effective analgesic adjuvant when combined with aspirinor with aspirin and acetaminophen combinations. Little data exists to support an analgesic effect of caffeine alone,8 butits adjuvant effect is well documented, though perhaps underappreciated.

Pharmacological Actions. - The pharmacology of caffeine and its chemical congeners, the methylxanthines, is complex.For a thorough review of caffeine's pharmacology and mechanisms of action, see Sawynok and Yaksh 1993.8

Adenosine Receptor Antagonist: Caffeine is a competitive inhibitor of adenosine, a compound that facilitates painresponse.8 Caffeine has a number of other pharmacologic actions, including inhibition of phosphodiesterase and5'-nucleoti-dase. However, the inhibition of adenosine is considered to be the mechanism responsible for its analgesicadjuvancy.

The central nervous system effects of caffeine (particularly its mood elevation effects) may also be a factor in its role asa facilitator of pain relief.

Gastric Absorption: Caffeine's stimulation of parietal cells lowers gastric acidity and may facilitate the diffusion acrossthe gastric mucosa of some drugs, such as aspirin, that require a lower pH for optimal absorption.8 This may result in a20% increase in the peak concentration of aspirin when the two agents are coadministered.

Drug Interactions. - A variety of drugs may lead to increased plasma concentrations of caffeine by impairing itselimination. Examples are oral contraceptives,11,12 cimetidine,13,14 disulfiram,15 and quinolones, including enoxacinand ciprofloxacin.7 Conversely, smoking and rifampin may stimulate caffeine clearance.14,16,17

Combination Products

Over-the-counter preparations that combine one or more analgesics with caffeine have been shown in several studies toproduce enhanced relief in headache pain models as well as other pain states.8,18 Products containing both aspirinand acetaminophen may produce greater efficacy than the individual components, perhaps due to the different sites ofaction (peripheral vs. central prostaglandin inhibition).19 When increased efficacy is desired, caffeine-analgesiccombinations may be worthwhile in light of the increased analgesic efficacy and relative safety of caffeine as ananalgesic adjuvant. Based on published literature, it would appear that a caffeine dose of 65 mg for

325 to 500 mg of aspirin or acetaminophen will augment the analgesia,

SUMMARY

The primary care physician must consider all therapeutic consequences of OTC analgesics in making arecommendation to the patient with headache. These include the analgesic's pharmacologic actions, adversereactions, and potential interactions with concurrently administered drugs. Combination products containingone or more analgesics plus an accepted adjuvant, such as caffeine, should also be considered.

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