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Over-the-counter analgesics and antipyretics: a critical assessment.

BACKGROUND: It is just 100 years since the introduction of aspirin to medicine. Since then, aspirin and its derivatives have been joined by acetaminophen, and the nonsteroidal anti-inflammatory drugs--ibuprofen, naproxen sodium, and ketoprofen--as the only over-the-counter (OTC) agents approved by the US Food and Drug Administration for the short-term treatment of pain, headache, dysmenorrhea, and fever. Recently the prescription use of aspirin has expanded to include a number of antiplatelet indications. OBJECTIVE: The purpose of this paper is to review critically the history, mechanisms of action, efficacy, and tolerability of OTC analgesic and antipyretic products. Relatively new and potential future indications for these drugs are also discussed. CONCLUSION: Although all of the OTC analgesic/antipyretic agents seem to share a common mechanism of prostaglandin inhibition, there are important differences in their pharmacology, efficacy, and side-effect profiles. Considering their often-unsupervised use, the risk-benefit ratio of this class of drugs has been extremely favorable. However, when used inappropriately, even these drugs pose significant risks to certain patient populations.

Analgesics↗

Antipyretics and analgesics in children.

Physicians must carefully consider the appropriate use of antipyretic drugs in children. Despite the ubiquitous presence of acetaminophen and acetylsalicylic acid in the home, there are many factors to weigh prior to their use. The following is a discussion of these factors: efficacy versus toxicity, known effects versus uncertain complications of drug therapy. Acetaminophen and acetylsalicylic acid have equivalent antipyretic effects. Acetysalicylic acid is clearly the better anti-inflammatory drug. Therapeutic misadventures with both drugs have resulted in childhood fatalities. Since these medications are not restricted to prescription order by a physician, instructions as to their safe and appropriate use should become part of 'normal child' counselling by physicians to all parents.

Acetaminophen↗

Pediatric dosing of acetaminophen.

Acetaminophen (paracetamol, APAP) is one of the safest and most widely used analgesic-antipyretics in children. When compared to other analgesic-antipyretics, acetaminophen has been shown in many clinical studies to have equivalent efficacy. Based on available clinical and pharmacokinetic data, acetaminophen should be dosed with single doses in the range of 10-15 mg/kg at 4-hour intervals. However, many dosing schedules recommend inadequate amounts of acetaminophen. Dosing schedules based on weight can be constructed that will accurately keep each dose within the recommended range. Dosing also can be adapted to an age-based schedule, which will provide consistent dosing from infancy to adolescence. The principles used to derive the age-based dosing schedule have potential application for use with other pharmacologic agents, particularly nonprescription drugs.

Acetaminophen↗

Analgesic nephropathy: an underestimated cause of end-stage renal disease.

Addiction and abuse of antipyretic analgesics has been recognized early after the turn of this century. The incidence markedly increased and the syndrome spread over many countries in the first half of the 20th century. The syndrome and its pathology, consisting of renal papillary necrosis and tubulo-interstitial nephritis, was first described in the medical literature in the early 1950's in Switzerland by Spühler and Zollinger, who rightly suspected chronic analgesic (Saridon) intoxication as being the cause in their cases. Clinically the disease is characterized by slowly progressive renal failure with renal colics from passage of necrotic papillae. Death from uremia is common unless dialyzed. The disease has been particularly prevalent in certain areas of Australia, Belgium, Western Germany, in Switzerland and some other countries. The nephrotoxic agents are mixtures of salicylates (aspirin) with phenacetin or acetaminophen. The principal nephrotoxic compound is probably aspirin--the aminophenol derivatives increasing its nephrotoxicity. However, all these components alone may cause--exceptionally--the syndrome. Rarely some newer, nonsteroid analgesics (NSAID's) can also be nephrotoxic. Phenacetin has--in particular in compound mixtures--mood-altering (euphoric) properties, giving rise to craving, addiction and chronic abuse. Addiction has been greatly facilitated by the over-the-counter availability of these cheap analgesic mixtures. Mass addiction--and abuse--may occur in all kinds of communities, in factories or families because of the euphoric effect, taking away fatigue and weariness and increasing productivity. There is a relation between the per capita consumption of antipyretic analgesics and analgesic nephropathy in several countries and in certain districts. The pattern of sales and mass consumption (and the incidence of nephropathy) is substantially promoted by the local presence of production facilities, usually accompanied by vigorous sales and advertising policies. Individual addiction usually occurs in psychoneurotic females often with social and marital problems and mental instability, often with long histories of headaches, backpains, and other, often psychogenic disorders. Analgesic nephropathy is often complicated by anemia, peptic ulcer, premature aging and atherosclerosis and in 8-10% by uro-epithelial carcinoma (the so called analgesic syndrome). The diagnosis depends largely on the history of chronic abuse of analgesics, which is often doggedly denied, hampering the diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Analgesics↗

Comparative anti-inflammatory, analgesic, and antipyretic activities of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one and 5-chlorosalicylic acid in rats.

Evidence is presented which indicates that 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b) (1,3)-benzoxazin-9-one (I) and 5-chlorosalicylic acid, its major metabolic end-product, are equally effective as anti-inflammatory and antipyretic agents, while the former is a somewhat more effective analgesic than its metabolite in the rat. However, at the equimolar doses used in this study, I is not ulcerogenic, while 5-chlorosalicylic acid does possess this untoward effect in the fasted rat. Moreover, the LD50 for 5-chlorosalicylic acid (261.0 mg/kg) is approximately 6.5 times less than that of I (1710.0 mg/kg) in the nonfasted rat. These results support the postulation that 5-chlorosalicylic acid is most likely responsible for the pharmacological activity displayed by I; i.e., the latter acts as a carrier or delivery system, allowing attenuation of the toxic properties of its active metabolite.

Analgesics↗

Antipyretic and analgesic activities of Caesalpinia bonducella seed kernel extract.

Ethanolic extract (70%) of Caesalpinia bonducella seed kernel has been subjected for its antipyretic and antinociceptive activities in adult albino rats or mice of either sex at 30, 100 and 300 mg/kg orally. The extract demonstrated marked antipyretic activity against Brewer's yeast-induced pyrexia in rats. The extract had significant central analgesic activity in hot plate and tail flick methods. It also exhibited marked peripheral analgesic effect in both acetic acid-induced writhing test in mice and Randall-Selitto assay in rats. It also significantly inhibited the formalin-induced hind paw licking in mice. In conclusion, the present study suggests that the ethanolic extract of Caesalpinia bonducella seed kernel possesses potent antipyretic and antinociceptive activities and thus, validates its use in the treatment of pain and pyretic disorders.

Acetic Acid↗

Relationship between enkephalinase inhibition of thiorphan in vivo and its analgesic activity.

The relationship between enkephalinase inhibition by thiorphan in vivo and analgesic activity in nociceptive tests was studied. The analgesic activity of thiorphan in various nociceptive tests was compared with that of a narcotic analgesic, morphine and antipyretic analgesic, antipyrine. Tail-flick test revealed that thiorphan applied intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) in rats markedly potentiated the analgesic activity of [D-Ala2, Met5]-enkephalin administered i.c.v. The amount of thiorphan in the mouse brain and the fragments of Met-enkephalin degraded by brain homogenate were assayed after intraperitoneal administration of 300 mg/kg thiorphan. The concentration of thiorphan in the brain arised to 18.2 +/- 2.4 nmol/g brain 30 min after intraperitoneal administration of thiorphan and then it quickly disappeared from the brain. As to the fragments of Met-enkephalin degraded by brain homogenate after i.p. administration of thiorphan, the concentration of tyrosine and tyrosyl-glycine (Tyr-Gly) was the same as that of the vehicle control, whereas only the amount of tyrosyl-glycyl-glycine (Tyr-Gly-Gly) decreased to 21.5% of the control value after 30 min, and then it recovered to 75% after 180 min. Thus, thiorphan inhibited enkephalinase activity alone demonstrating selective activity. Thiorphan at doses of 30-300 mg/kg demonstrated analgesic activity in the nociceptive tests of acetic acid writhing, hot-plate and tail-flick, whereas it did not have any activity in the tail-pinch test. Morphine showed analgesic activity in the four nociceptive tests employed. Antipyrine showed analgesic activity in three nociceptive tests but not in the tail-flick test. The dose response curves for morphine and antipyrine were parallel. The slope of the dose response curve for thiorphan, however, was shallower than those for two reference analgesics used. The role of main enkephalin degrading enzymes in the brain was discussed with respect to the analgesic action of thiorphan and its concentration in the brain.

Amino Acids, Sulfur↗

Changing patterns of therapeutic agents in the elderly: a ten-year overview.

Drug use patterns in a large ambulatory elderly population were studied cross-sectionally over a 10-year period. There were 24192 drug histories obtained on 4509 individuals during the period from 1 August 1978 to 31 July 1988. The average number of drugs used per person increased from 3.22 in 1978-9 to 3.94 in 1987-8. Prescribed drug use increased by 0.52 per person compared with an increase of 0.21 for nonprescribed medication. Analysis of two mutually exclusive groups of participants from 1978-9 and 1987-8 revealed a significant (p less than 0.0001) increase in the use of nonprescribed medication but no significant increase in the use of prescribed medication after adjusting for age and sex effects. The four most frequently used therapeutic classes of drugs in 1978-9 as a percentage of all drugs used were antihypertensives (10.8%), analgesic-antipyretics (6.4%), antirheumatic (6.4%), and cathartics (5.4%) compared with the antihypertensives (9.5%), analgesic-antipyretics (5.9%), anticoagulants (5.5%), and antirheumatic (4.6%) for the 1987-8 period.

Age Factors↗

Next generation of everyday analgesics.

Pain is the leading symptom of most diseases. Humans have always tried to overcome pain using physical and chemical means, and it is believed that opioids and salicylates present in natural products have been used since prehistoric times. The development of the sciences, in particular chemistry and medicine, in the 19th century led to the discovery of the active ingredients of poppy and willow bark (morphine and salicylic acid). Shortly after, synthetic chemistry provided substitutes produced from coal tar (ie, acetaminophen, aspirin, phenazone, and pethidine). These represent the two main types of analgesics commonly used to treat mild and serious pain: the opioids (pethidine) and the antipyretic analgesics, which may be further divided into the aspirin-derived (acidic) nonsteroidal anti-inflammatory drugs (eg, ibuprofen) and the phenazone and acetaminophen-like (nonacidic) antipyretic analgesics (which have little anti-inflammatory activity). Chemical modifications and broad-spectrum screening provided medicine with thousands of pharmacologic analogs that broadened the therapeutic spectrum but did not supplant the original compounds developed in the 19th and early 20th century. Recently, molecular biology and genomics have led to the development of new target-selective chemical entities for use in pain relief. These include selective cyclooxygenase (COX)-2 inhibitors, substance P, blockers or agonists of cannabinoid and vanilloid receptors, inhibitors of tetradotoxin-resistant Na channels, and many more. Most of these selective compounds did not succeed in everyday pain treatment. Some look promising, including the COX-2 selective inhibitors, but doubts remain about the superiority of these new compounds in everyday use. This is particularly the case with the generation of selective COX-2 inhibitors currently in clinical use.

Analgesics↗

[An experimental observation on the analgesic and antipyretic effects and toxicity of Acanthopanax giraldii Harms].

Experimental data indicate that EtOH extract of Acanthopanax giraldii (EAGH) has pronounced analgesic action and reduces not only high temperature induced by proteinic jelly, but also normal body temperature in rabbits. However no effect was observed on the fever induced by choleraic vaccine in rabbits. The acute ip LD50 of EAGH in mice was 73.34 +/- 7.29 g/kg (crude drug). In prolonged toxicity test on rats no harmful effects on body weight, blood picture, liver and kidney functions were observed.

Animals↗