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Viewpoint Indian Pediatrics 2003; 40:541-544 |
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Rational Use of Antipyretics |
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Fever is body’s response to mostly an infection though a variety of other factors may induce similar reactions. It results from an immune response mediated through action of cytokines on thermoregulatory center of brain. Peripheral mechanisms play a role by either conserving heat through vasoconstriction manifesting as chills or generating heat by active muscular contractions presenting as rigors Suppression of fever may not be harmful: It is important to realize that fever is a beneficial response in favor of the host. The question that then arises is whether fever should be ever suppressed and would it be harmful to do so. Few studies have suggested that suppression of fever may lead to persistence of viral shedding or malarial parasitemia leading to prolongation of illness and delayed recovery. However, most of the studies have not been able to substantiate such a conclusion. No studies have documented adverse effects of suppression of fever on immune functions(1). While it may not be harmful to suppress fever the question remains whether it is necessary to do so. It may be prudent to suppress fever only when it reaches beyond a certain degree: Fever is beneficial though beyond a certain degree, it may lead to a reasonable discomfort and at times to febrile convulsion. In general, fever up to 102ºF may be considered beneficial, safe and not discomforting and so may not be intervened. Fever between 102ºF and 104ºF may be beneficial but discomforting and hence reduction of fever to a level below 102ºF may be ideal to comfort the child. It could be achieved by simple measures. However, if fever rises beyond 104º F, it may be harmful and hence should definitely be brought down by prompt action. Reduction of fever may not necessarily be useful: Feeling of comfort is subjective and hence may be unpredictable in spite of reduction of fever. Though febrile convulsion occurs commonly at higher degree of fever, mere reduction of fever does not guarantee against such an event. However, as fever phobia is a universal phenomenon, attempt to reduce fever offers moral confidence to the parents and physicians alike. Fever may be suppressed by use of antipyretics or physical cooling methods:It is customary to use an oral antipyretic for its convenience and acceptance. Paracetamol, Ibuprofen and Nimesulide are some of the drugs used to suppress fever. Physical cooling methods include tepid water sponging, bath or fanning. Comparative studies have shown no distinct superiority of any method over another. In fact, controlled double blind trials with placebo have demonstrated equal beneficial effects with either of the methods. It is clear that cause of fever decides the response to an antipyretic and hence it is not a surprise that even a placebo may be as effective in controlled trials. Choice of antipyretic is unfortunately debatable: It is the safety that should decide the choice, as all antipyretics are equally efficacious. Aspirin is not used for fear of Reye’s syndrome, besides the risk of maetabolic acidosis and coma. Paracetamol is traditional considered to be safe based on large clinical experience over long time. It has a wide therapeutic window, has a short duration of action and hence the drug can be repeated every 4-6 hourly. Ideally a drug used merely for symptomatic relief should be short acting so that it can be repeated frequently as per the need and paracetamol is a perfect fit. Most of the adverse effects of paracetamol cited in western literature have been ascribed to overdosing either intentional or accidental(2). Such adverse effects are nor reported in India. It has been shown that metabolism of paracetamol in Indain population is similar to that found in western population and hence potential for liver toxicity should also be similar(3). Metabolism of paracetamol has been shown to have circadian rhythm in healthy subjects and hence liver toxicity may be related to timing of the dose as well(4). Hypersensitivity to paracetamol is very rare(5). Paracetamol has been considered to be safe in right dose even in liver diseases. Ibuprofen is considered safe in children though it may lead to dyspepsia, nausea, vomiting and at times gastrointestinal bleeding. It can be repeated every 6-8 hourly and not 4-6 hourly as in case of paracetamol. It can be considered as an alternative to paracetamol. Nimesulide has a disadvantage of long duration of action and hence ideally should be repeated 12 hourly. Its therapeutic dose is small (5 mg/kg/day) as compared to paracetamol (60 mg/kg/day) and has small therapeutic window. These facts result in easy overdosing by negligence or ignorance, leading to adverse effects. Being a potent antipyretic, return of fever to normal often makes physician complacent about the status of the disease. In clinical practice, serious infections may be easily missed once fever is controlled, till organ dysfunction manifests, as happens in case of pneumonia and meningitis. Occasionally, nimesulide may cause lowering of body temperature to even subnormal levels that can be harmful. It has bot been marketed in many countries of the world and few countries have withdrawn the drug after initial introduction. It has been found to have serious side effects(6-8), Maternal ingestion of nimesulide has been shown to result in end-stage renal failure in a neonate(9). Currently, there is a fierce debate in India and the views expressed need cautious analysis(10). It is ironical that most of the cited studies in the literature come from India and manufacturing firms have sponsored most of them(11). It appears that if the drug is used in proper doses, it may not be harmful but as it is rare to have fever controlled for as long as 12 hours, frequent dosing is inevitable and it is definitely dangerous. All antipyreties are equally efficacious if proper dose is used: Equipotent single dose of paracetamol, ibuprofen and nimesulide is 10-15 mg/kg, 8-10 mg/kg and 2.5 mg/kg, respectively. Dose must be reduced in pre-terms proportionate to the post-conceptional age(12). Besides wide variation in ideal dose, frequency of administration also varies a great deal. While paracetamol can be safely repeated every 4-6 hours, nimesulide is ideally used only in two doses a day. Thus, in clinical situation, underdosing of paracetamol and overdosing of nimesulide is inadvertently practiced and hence parents and physicians feel that paracetamol does not work while nimesulide is always successful. This has resulted in overuse of nimesulide, which has nearly replaced paracetamol in clinical practice. Strong and often unethical marketing practices have contributed to such a scenario. Considering practical issues beyond pharmacological parameters, nimesulide as an antipyretic is best avoided. Alternating two different antipyretics is not an ideal practice(13): With increasing use of nimesulide that cannot be repeated earlier than 8 hours, there has been a tendency to use another antipyretic such as paracetamol or ibuprofen in between doses of nimesulide. Need arises to use such an alternate drug regime because fever may rise again much before next dose of nimesulide is due. It is best therefore to use short-acting antipyretic, which can be safely repeated every 4-6 hours, as commonly, fever may rise with 4 hours of administering previous dose. This is one more good reason to use paracetamol as the first drug of choice. Fixed dose combination of antipyretics is beyond doubt irrational:It amounts to doubling the dose of a single antipyretic, expecting better response. However, as each of the antipyretic is ideally administered in different frequency, rationality is totally flouted. Studies have shown no advantage in combining antipyretics. Combining an antipyretic drug with any other such as metoclopromide is intended to enhance its effect but is not based on evidence. Route of administration of an antipyretic has no significant difference in its effect: Rectal route has been tried and paracetamol has been used in double the dose with good tolerability. But there is no advantage of rectal route over oral route as far as its antipyretic efficacy is concerned(14). There is a need to change the mindset of parents and physicians: Fever is a friend and not the enemy. It rarely kills but what is most important to treat is the cause that leads to fever. Merely reverting fever to normal does not change the disease state and at times may be misleading to a physician. Unfortunately, every one expects an antipyretic to bring down fever to normal while ideally an antipyretic is intended not to allow fever to rise to a dangerous level thereby protecting a child without disturbing body’s immune response. With the use of potent antipyretics, present day physician has lost an opportunity to follow progress of underlying disease, which often gives a clue to correct diagnosis. In summary, use of an antipyretic drug should be restricted merely for symptomatic relief and to prevent fever from rising to a dangerous degree. It should not be used just to bring down fever to normal. In view of its comparable antipyretic efficacy, but superior tolerability profile, paracetamol when used appropriately with age-adapted formulations, should remain the first-line therapy in the treatment of childhood fever. There are not enough pharmacokinetic studies on cox-2 inhibitors in children though they are considered safe in adults(15). Paracetamol is the time tested safe drug and it should be the first drug of choice in most of the conditions. Physical cooling measures are equally effective and may replace use of antipyretic drug. Though evidence based conclusions are lacking in support of benefits of reduction of fever(16), as the community psychologically prefers use of a drug to physical measures, it is quite rational to accept paracetamol in preference to physical cooling measures and no attempt should be made to change the perception of the community though scientific evidence may support placebo as equally effective. Y.K. Amdekar,
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