A Safety Assessment of Fixed Combinations of Acetaminophen and Acetylsalicylic Acid, Coformulated with Caffeine

Abstract

Overuse and abuse of phenacetin-containing mixed analgesics has contributed to end-stage renal disease. Combination analgesics, especially those coformulated with caffeine, have been implicated as imparting a greater risk of analgesic-associated nephropathy (AAN) than single or coformulated analgesics without caffeine. This has led to a recommendation that the sale of "two plus caffeine" analgesic mixtures be reclassified from over-the-counter to prescription only availability. There is a rational basis for coformulating acetylsalicylic acid (ASA) and acetaminophen (paracetamol) as this reduces the dose of each, without altering efficacy. The coformulation of caffeine with these analgesics has a significant adjuvant effect and increases analgesic efficacy 1.4-1.6-fold. Currently available animal and human data do not support the notion that the nephrotoxic risk from coformulated ASA and acetaminophen is higher than the risk from either ASA or acetaminophen alone, in equivalent analgesic doses. There are no epidemiological data that implicate caffeine in AAN, and only limited evidence that links excessive acetaminophen usage to renal disease. There is no evidence that caffeine increases analgesics papillotoxicity directly. The presence of caffeine in mixtures of analgesics are no more addictive than other sources of caffeine. There is no evidence to suggest that adding caffeine to analgesic mixtures enhances the potential for promoting analgesic misuse in the general population. Thus distinct therapeutic benefits of ASA, acetaminophen and caffeine appear to outweigh any known risk. It is doubtful if preventing the availability of these products will significantly affect the role of analgesic abuse/overuse in end-stage renal disease. Better risk management would come from a focused educational program, developed in a close collaboration between industry, healthcare professionals and consumer organizations, such a program must warn against the potential dangers of analgesic and non-steroidal anti-inflammatory drug misuse.

The analgesic effect of decursinol

“…Therefore, several attempts to reduce the adverse effects of APAP or ASA have been conducted (Buckley et al, 1999;Kalabis and Wells, 1990;Prescott and Critchley, 1983;van Bree et al, 1989;van de Straat et al, 1987;Wu et al, 2008) in which treatment of APAP or ASA in combination with other compounds such as caffeine or codeine has been suggested for increasing analgesic potency and decreasing the risks of complications (Bach et al, 1998;Engelhardt and Homma, 1996;Engelhardt et al, 1997). In this regard, we also examined the effects of decursinol, which previously had been announced as having a potent analgesic property, on ASA and APAP-induced analgesia, respectively.…”

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

“…This is highly surprising, as three detailed analyses of the epidemiological studies [67-69] upon which the allegations of an increased risk of developing nephropathy were based showed, independently of one another, that these data do not conclusively establish a causal link between use of specific analgesics and chronic renal failure [68]. Bach et al specify that the currently available animal and human data do not support the notion that the nephrotoxic risk from coformulated ASA or acetaminophen is higher than the risk from either ASA or acetaminophen alone, in equivalent analgesic doses.…”

Comparison of analgesic effects of nimesulide, paracetamol, and their combination in animal models

“…Hence, it would also be necessary to test the combination on human subjects, both on experimental pain in healthy volunteers as well as clinical pain, before commenting on the appropriateness of this combination. Many studies have compared the analgesic efficacy of nimesulide and paracetamol with other NSAIDs;[12–14] however, there is no such study, which compares individual drugs with the combination. Usually, the fixed dose combinations are introduced in the market to generate prescriptions and make profit with no consideration of the rationality.…”