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Nonprescription analgesics and their use in solid-organ transplantation: a review.

OBJECTIVE: To review the pharmacology, adverse events, drug interactions, and use of the nonprescription analgesics in solid-organ transplant recipients. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating nonprescription analgesics in solid-organ transplantation were considered for evaluation. English-language studies were selected for inclusion. DATA SYNTHESIS: Nonprescription analgesics (aspirin, choline salicylate, magnesium salicylate, sodium salicylate, ibuprofen, ketoprofen, naproxen sodium, and acetaminophen) are the most commonly purchased over-the-counter agents in the United States. These agents, although generally considered safe, have been associated with a number of toxicities. The salicylates and nonsteroidal anti-inflammatory drugs have been associated with gastrointestinal damage, hematologic changes, liver and kidney dysfunction, and breathing difficulties. Acetaminophen has been shown to induce hematologic changes and liver and renal dysfunction. CONCLUSION: A closer look at the nonprescription analgesics reveals their potential for harm when used by solid-organ transplant recipients. In this patient population, the salicylates and nonsteroidal anti-inflammatory drugs should generally be avoided if possible, because of their potential toxicities, especially renal dysfunction. Low-dose aspirin, for the prevention of cardiovascular and cardiocerebral events, appears to be safe, but patients must still be followed closely. Acetaminophen is generally considered the nonprescription analgesic and antipyretic of choice in transplant recipients because of its favorable toxicity profile. However, it is imperative that patients and transplant practitioners are aware that this agent is not without toxicities and proper monitoring is advised.

Analgesics↗

Nonsteroidal anti-inflammatory agents in neonates.

The use of NSAIDs has become routine for adults and children in the management of pain. NSAIDs (other than aspirin [acetylsalicylic acid]) are also enjoying greater popularity as antipyretics since the recognition of Reye's syndrome's putative association with aspirin. In neonates, NSAIDs have been used for many years in an attempt to pharmacologically close the ductus arteriosus. This review examines the various NSAIDs and their potential and real applications in the neonatal population. For completeness, acetaminophen (paracetamol), which has weak NSAID activity and is a widely used analgesic and antipyretic in this patient group, was also included. The prostaglandin system is important for healthy development, and conversely there are unique risks posed by pharmacologic interference with this system in the neonatal period. The prostanoid system in neonates has the capacity to modulate nociception, but comes at the expense of interfering with nearly every organ system. Physiologic effects of inhibition of prostaglandin synthesis applicable to neonates include disruption of the sleep cycle, increased risk of pulmonary hypertension, alterations in cerebral blood flow, decreased renal function, disrupted thermoregulation, and alterations in hemostasis balance, among others. Prostaglandins are also important for the normal development of the central nervous, cardiovascular, and renal systems, and there is evidence that the proper genesis of these systems may be adversely effected by NSAID exposure in utero and in the neonatal period. Gastrointestinal adverse effects have provided the impetus for the development and marketing of selective cyclo-oxygenase type 2 (COX-2) inhibitors. These agents' reputation for safety in adults may not be applicable to neonates. COX-2 is involved in the development of several organ systems, and its inhibition may induce a prothrombotic state. The advent of parenteral formulations of cyclo-oxygenase inhibitors, including COX-2-selective agents, increases the therapeutic flexibility of NSAIDs. However, objective data on the safety of these agents have not kept pace with their clinical availability.

Anti-Inflammatory Agents, Non-Steroidal↗

[Pharmacologic profile of a new compound with antiinflammatory activity: 2-(4-dimethylvinylphenyl)propionic acid (Gx 258)].

Gx 258, a new phenylalkanoic acid derivative, was shown in animal tests to possess potent antiinflammatory, analgesic and antipyretic activity. Its antiinflammatory activity was not mediated via the pituitary-adrenal axis, since it was also effective in adrenalectomized rats. Since large doses of Gx 258, 9-83 times greater than those showing antiinflammatory activity, were required to produce gastrointestinal lesions in rats, Gx 258 appears to have a very good therapeutic index. Its therapeutic index as an antiinflammatory and analgesic agent was 2.3-20.5 times greater than that of the parent compound ibuprofen. Gx 258, like ibuprofen, inhibited the biosynthesis of prostaglandins in vitro.

Animals↗

Pharmacological properties of a new non-steroidal anti-inflammatory drug: flunoxaprofen.

The anti-inflammatory, analgesic and antipyretic activities of S-(+)-2(4-fluorophenyl)-alpha-methyl-5 benzoxazole acetic acid (flunoxaprofen: Flu), a new non-steroidal anti-inflammatory drug, were compared with those of indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) in experimental animals. Flu showed strong inhibitory activity on acute and subacute inflammation tests in rats, such as carrageenin hind paw oedema (oral: 6-25 mg/kg; rectal: 50-100 mg/kg); pellet-induced granuloma formation (5-20 mg/kg/day) and adjuvant-induced arthritis (10 mg/kg/day). Its potency was comparable with that of indomethacin (I) and higher than that of acetyl salicylic acid (ASA), ibuprofen (IBU) or phenylbutazone (P). The analgesic activity of Flu, evaluated by the hot plate method and tail pinching in mice, was slightly lower than that of I but higher than that of ASA and IBU. In pyretic rabbits Flu showed an antipyretic activity higher than that of ASA and IBU. The ability of Flu to affect platelet aggregation, mucopolysaccharide synthesis by fibroblasts and the proteolytic action of trypsin was also investigated.

Animals↗

Pharmacology of the potent new non-steroidal anti-inflammatory agent aceclofenac.

Aceclofenac (2-[(2,6-dichlorophenyl) amine]phenylacetoxyacetic acid; CAS 89796-99-6) is a new orally effective non-steroidal anti-inflammatory agent of the phenylacetic acid group which showed remarkable anti-inflammatory, analgesic, and antipyretic properties. Hence, aceclofenac possesses a potent inhibitory activity in several models of acute and chronic inflammation in rodents, and resembles indometacin and diclofenac in its pharmacodynamic profile, being superior to naproxen and phenylbutazone. In addition, aceclofenac was found to be highly active against sodium urate-induced synovitis in dogs and adjuvant-induced polyarthritis in rats, both prophylactically and therapeutically. The analgesic effect of aceclofenac on the pain elicited by chemical and mechanical stimuli was nearly equal to or slightly better than that of indometacin and diclofenac. Fever induced by brewer's yeast injection in rats was also markedly suppressed by aceclofenac. In contrast, the acute gastric ulcerogenic activity of aceclofenac was about 2, 4 and 7-fold lesser than that of naproxen, diclofenac, or indometacin, respectively. As a consequence of its high anti-inflammatory activity and lower potential for gastric damage aceclofenac exhibited the most favourable therapeutic ratio in comparison with indometacin, diclofenac, naproxen, and phenylbutazone. These data indicate that aceclofenac could be a potent anti-inflammatory and analgesic agent with a wide margin of safety in clinical practice.

Animals↗

[Non-antibiotic treatments for community-acquired pneumonia in children].

Besides antibiotic therapy (when warranted), treatment of acute pneumonia in children usually requires only simple measures, including: fractionated feeding, analgesic and antipyretic medications and detection of hypoxemia. There is no evidence that physical chest therapy, bronchial mucus modificators and corticosteroid therapy are really useful. The best prevention relies upon vaccinations, suppression of passive smoking, and hygiene and nutritional improvements.

Acute Disease↗

[Combined use of bucolome and pyrazolone derivatives (1). Pharmacological activities and blood concentration].

A combination of two or more drugs may exert a drug-drug interaction, in which case the effect can be potentiated or antagonized. Such synergistic effects are well known in the case of pyrabital (barbital + aminopyrine) or irgapyrine (phenylbutazone + aminopyrine). Bucolome (BCP), a non-steroidal anti-inflammatory agent, has the chemical structure of a barbiturate and also resembles the formula of pheylbutazone. Thus the influence of BCP combination on the pharmacological activities of various pyrazolone derivatives was examined. BCP potentiated the analgesic and antipyretic effects of 4-aminoantipyrine (4A), methylaminoantipyrine (MA), aminopyrine (AM) and isopropylaminoantipyrine (IPA), which were substituted by the alkylamino group at 4-position of the pyrazolone ring. This potentiation occurred when the dose of BCP exceeded that of the pyrazolones, and was especially marked when combination ratio of BCP exceeded that of the pyrazolones, and was especially marked when combination ratio of BCP and pyrazolone was 2:1 mola. The analgesic effects of antipyrine (AN), isopropylantipyrine (IP) and aminopropylone (AP), which were substituted by alkyl group or aminoacylamino group at 4-position, were not potentiated by BCP in any combination ratio. Most pyrazolones showed additive acute toxicity in their combination with BCP, but acute toxicities of 4A and AM, which were potentiated in analgesic effects, were decreased and antagonized when combined with BCP. The plasma concentration of AM was increased and prolonged by BCP, while that of IP remained much the same. These results suggest that the pharmacological activities are associated with certain molecular interactions between BCP and pyrazolones, which are substituted by the alkylamino group at 4-position of the pyrazolone ring.

Analgesics↗

Synthesis and pharmacological evaluation of 5H-[1]benzopyrano[4,3-d]pyrimidines effective as antiplatelet/analgesic agents.

Synthesis and pharmacological screening of new 2-methylthio/2-methanesulfonyl/2-methoxy-5H-[1]benzopyrano[4,3-d]pyrimidines were planned in order to study the effects of the 5-substitution with alkoxy/phenoxy/alkylthio and phenylthio groups both on in vitro antiplatelet and in vivo antinociceptive activities. Antiplatelet activity was assessed in vitro against ADP, Arachidonic acid and U46619 induced aggregation, in rabbit plasma. Anti-inflammatory, analgesic and antipyretic activities were tested in rat paw edema, mouse writhing test and LPS induced rat fever, respectively. Amongst test compounds, 2-methylthio derivatives displayed an ASA-like antiplatelet activity whereas 2-methoxy and, particularly, 2-methanesulfonyl derivatives showed a broad spectrum of antiplatelet action, inhibiting both the ADP- and the AA- and U46619-induced aggregation. With regard to the in vivo pharmacological activities, mainly the 2-methoxy derivatives showed a significant analgesic effect comparable to that of indomethacin. SAR considerations, also in comparison with a number of previously described compounds, were performed.

Analgesia↗

Comparative analgesia, cardiovascular and renal effects of celecoxib, rofecoxib and acetaminophen (paracetamol).

Comparisons are made between the specific COX-2 inhibitors, celecoxib and rofecoxib, and acetaminophen. The specific COX-2 inhibitors are a significant advance in therapy because their anti-inflammatory, analgesic and antipyretic activities are associated with a high degree of gastrointestinal safety. Acetaminophen is often not considered to be a potent inhibitor of COX-2 but it is a potent inhibitor of prostaglandin synthesis in intact cells after stimulation by cytokines. Its weak activity on the pathway of prostanoid synthesis involving COX-1 is shown by its weak anti-platelet activity and good gastrointestinal safety. The specific COX-2 inhibitors and acetaminophen are analgesic after dental surgery, orthopedic surgery and in osteoarthritis although acetaminophen appears to be a slightly weaker agent. The apparent analgesic activity of both the COX-2 inhibitors and acetaminophen may, in part, be due to their anti-inflammatory properties. Both groups of drugs also decrease the urinary excretion of prostacyclin metabolites consistent with inhibition of the systemic and renal activity of the COX-2 system. During repeated dosage with the specific COX-2 inhibitors, the 24 hour urinary excretion of sodium is only inhibited for the first day of treatment while the excretion of sodium is still decreased over the first 3 hours after the individual doses. Therapeutic doses of the COX-2 inhibitors and overdoses of acetaminophen have been associated with the development of occasional cases of acute renal failure. Acetaminophen also may decrease the excretion of sodium and the reason for its greater renal safety at therapeutic doses is unclear. Myocardial infarction has also been attributed to the specific COX-2 inhibitors from meta-analysis of large scale clinical trials and examination of reports of adverse drug reactions although this is still a topic of considerable discussion. No such associations have been made with acetaminophen, possibly because it is a weak inhibitor of COX-1 in platelets.

Acetaminophen↗

Synthesis and antiinflammatory activity of 3-chloro-4-cyclopropylmethoxyphenylacetic acid and its alpha-methyl homologue.

The synthesis of 3-chloro-4-cyclopropylmethoxyphenylacetic acid (I) from 3-chloro-4-hydroxyacetophenone (III) by the etherification with cyclopropylmethyl bromide and by the Willgerodt reaction is described. The alpha-methyl homologue (II) was also prepared from 4-benzyloxy-3-chlorophenylacetate (VIII). The antiinflammatory, analgesic and antipyretic activities of the lysine salts of (I) (ISF 2508) and (II) (ISF 2606) were tested in comparison with alclofenac and phenylbutazone. The new ocmpounds compare favourably with the standards; in particular ISF 2508 was selected for further pharmacological studies.

Analgesics↗

Influence of antipyretic drugs on the labeling of blood elements with technetium-99m.

Acetaminophen (AAP), acetylsalicylic acid (ASA) and dipyrone (DIP) are antipyretic and analgesics drugs that have wide use in health sciences. Some drugs can modify the labeling of blood elements with technetium-99m (99mTc). This work has evaluated the effect of AAP, ASA and DIP on the labeling of the blood elements with 99mTc. Blood was incubated with different concentrations of the drugs before the 99mTc-labeled process. Plasma (P), blood cells (BC), insoluble (IF-P, IF-BC) and soluble (SF-P, SF-BC) fractions were separated and percentage of radioactivity (%ATI) in each fraction was determined. Data have shown that the antipyretic drugs used in this study did not significantly modify the fixation of 99mTc on the blood elements when the experiments were carried out with the doses usually used in human beings. Although the experiments were carried out with rats, it is possible to suggest that AAP, ASA or DIP should not interfere with the procedures in nuclear medicine involving the labeling of blood elements with 99mTc.

Acetaminophen↗

Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used antipyretic agents that most probably exert their antifever effect by inhibiting cyclooxygenase (COX)-2. Thus, COX-2-selective drugs or null mutation of the COX-2 gene reduce or prevent fever. Acetaminophen is antipyretic and analgesic, as are NSAIDs, but it lacks the anti-inflammatory and anticoagulatory properties of these drugs. This has led to the speculation that a COX variant exists that is inhibitable by acetaminophen. An acetaminophen-inhibitable enzyme is inducible in the mouse J774.2 monocyte cell line. Induction of acetaminophen-inhibitable prostaglandin E(2) synthesis parallels induction of COX-2. Thus, inhibition of pharmacologically distinct COX-2 enzyme activity by acetaminophen may be the mechanism of action of this important antipyretic drug.

Acetaminophen↗

AHR-10037, a non-steroidal anti-inflammatory compound of low gastric toxicity.

AHR-10037 is an anti-inflammatory compound possessing analgesic and antipyretic properties and a high therapeutic index. AHR-10037 was comparable to indomethacin in suppressing acute (Evans blue-carrageenan pleural effusion) and chronic (adjuvant-induced arthritis) inflammation. There was a delayed onset of antipyresis (yeast-induced hyperthermia in rats), analgesia (acetylcholine-induced abdominal constriction in mice) and inhibition of caster oil-induced diarrhea in rats. Antipyresis occurred 3 hours after administration of AHR-10037, 4 mg/kg, PO. vs 1 hour after administration of acetylsalicylic acid, 100 mg/kg, PO; maximum analgesic activity (ED50 = 4.1 mg/kg) occurred at 4 hours. AHR-10037 was inferior to indomethacin in suppressing castor oil-induced diarrhea in rats. The therapeutic index of AHR-10037 (relating acute anti-inflammatory potency to gastric toxicity potency relative to indomethacin) ranged from 56-91. The pharmacological profile suggests that AHR-10037 is a prodrug converted in vivo to a cyclooxygenase inhibitor.

Acetamides↗

[Paracetamol prenatal toxicity].

Paracetamol is common used over-the-counter (OTC) nonnarcotic analgesic and antipyretic drug during pregnancy. Several animal and human studies on reproductive effect of paracetamol have been done and the overall results do not implicate paracetamol as a teratogen. However, there are some dates that paracetamol administration during pregnancy may have an effect on lowering body birth weight and length.

Abnormalities, Drug-Induced↗

Antiinflammatory effect of petroleum ether extract of leaves of Litchi chinensis Gaertn. (Sapindaceae).

Pharmacological studies were conducted with the petroleum ether extract of leaves of the plant Litchi chinensis Gaertn. (Sapindaceae) on experimental animals. The extract was found to possess antiinflammatory, analgesic and antipyretic activity. Acute toxicity studies revealed that the extract, up to a dose of 1 g/kg intraperitoneally, was nontoxic. The extract did not inhibit arachidonic acid-induced paw inflammation thus indicating that it may inhibit the cyclooxygenase pathway of arachidonic acid metabolism. The extract also enhanced peritoneal cell exudate along with macrophage significantly.

Analgesics↗

Warfarin-acetaminophen drug interaction revisited.

Physicians and pharmacists routinely advise patients receiving warfarin to take acetaminophen for pain or fever because of its relative safety; however, a recent study questioned the safety of such practice. A comprehensive search of MEDLINE and IPA for human studies and case reports from 1966-1999 revealed evidence that acetaminophen may potentiate the effect of warfarin by a mechanism that has yet to be elucidated. Due to lack of a safer alternative, acetaminophen still should be the analgesic and antipyretic of choice in patients taking warfarin, as long as excessive amounts and prolonged administration (> 1.3 g acetaminophen/day for > 2 wks) are avoided. With the high degree of interpatient variability and the unpredictability of various drug-drug interactions with warfarin, close and frequent monitoring of international normalized ratios is the key for safe oral anticoagulation therapy.

Acetaminophen↗

Nitric oxide-releasing NSAIDs: a review of their current status.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide owing to their anti-inflammatory, antipyretic and analgesic properties. However, their use is hampered by gastrointestinal (GI) toxicity, the most common drug-related serious adverse event in industrialised nations. Nitric oxide (NO)-releasing NSAIDs, a recently described class of drugs, are generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NO-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in animals, thus the abbreviation NO-NSAIDs used here refers to the latter group of NSAID derivatives. NO-NSAIDs retain the anti-inflammatory and antipyretic activity of original NSAIDs, although they exhibit markedly reduced gastrointestinal toxicity. NO-NSAIDs are nonselective cyclo-oxygenase (COX) inhibitors, and they also exert COX-independent activities that are NO-dependent. Indeed, NO-NSAIDs suppress production of the cytokines interleukin (IL)-1beta, IL-18 and interferon-gamma by causing the S-nitrosilation/inhibition of caspase-1. In acute and chronic animal models of inflammation, it has been demonstrated that NO-NSAIDs abrogated prostaglandin E2 as well as thromboxane B2 generation. In a murine model, NO-naproxen was approximately 10-fold more potent than naproxen in reducing animal writhing after intraperitoneal injection of acetic acid. Similar data have been obtained in chronic models of pain such as rat adjuvant arthritis. In vivo and in vitro studies suggest that NO-aspirin (acetylsalicylic acid) exerts more potent antithrombotic action than aspirin, probably by coupling the ability to inhibit COX-1 with the anti-adhesive effect of NO. Moreover, in a model of renal injury NO-flurbiprofen not only has been demonstrated to be devoid of nephrotoxicity but also to ameliorate renal function. Finally, in an animal model of chronic neurodegenerative disease, NO-flurbiprofen and NO-aspirin attenuated the brain inflammatory response. The GI toxicity of NO-flurbiprofen and NO-naproxen is currently being investigated in healthy individuals.

Animals↗

Pharmacokinetics of common analgesics, anti-inflammatories and antipyretics in children.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a major component of paediatric therapeutics. This paper summarises the clinical pharmacology and pharmacokinetics of some commonly used NSAIDs as well as paracetamol (acetaminophen), which has very weak anti-inflammatory activity. Available information is reviewed in an attempt to evaluate the basis for paediatric dosing recommendations and to underline known or likely differences in drug disposition that result from diseases and changes in developmental physiology. Clinically important general considerations are stressed, including areas in which age-appropriate pharmacological information is needed but unavailable. The review is not exhaustive, as only the following selected drugs are surveyed: paracetamol, ibuprofen, indomethacin, diclofenac, naproxen and sulindac. Some compounds of interest, including salicylates (e.g. aspirin, salsalate), recently introduced drugs (e.g. ketoprofen, nimesulide) and those withdrawn (e.g. zomepirac, benoxaprofen), are not included. Non-NSAID analgesics (e.g. dextropropoxyphene, narcotics) are also not included.

Adolescent↗