The committee's two main conclusions were that sufficient evidence is absent to associate nonphenacetin combined analgesics with nephropathy and that new studies should be done to provide appropriate data for resolving the question.

Although more experimental and long-term data would be desirable to show possible mechanisms of dependence and to offer unequivocal proof of safety, the committee concluded that the available evidence does not support the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.

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.

Individual groups of nephrologists - in their responsibility for their patients - initiated a most controversial discussion whether or not caffeine - coformulated to analgesics - might initiate or sustain analgesic overdosing. The original sources (data) of such suspicion have got lost during the debate of the last two decades. Therefore, it seemed to be appropriate to investigate the original data background and the reasons why nephrologists started to suspect caffeine as a stimulant of analgesic overdosing by employing a systematic and exhaustive review of primary nephrological publications. Their selection followed a precise selection plan, including all epidemiological studies on analgesic-associated nephropathy, the original papers of all groups having been involved in those studies, further originals from the mainly involved countries (academically, politically), and any literature thereof cited as a proof. The following results emerged from the investigation: (i) The epidemiological studies warranted no conclusion about a role of caffeine in prompting excessive analgesic use. (ii) The identified groups of nephrologists provided not substantial data to advocate the said suspicion, except for the observation of a preferential choice of phenacetin-containing combinations, especially powder preparations. (iii) Only two cited original data sources revealed drug-seeking behaviour with phenacetin-containing preparations which subsided, after phenacetin was banned from the respective markets. Conclusively, it appears that there is no substantial data to support a pivotal role of caffeine in initiating or sustaining analgesic overdosing. However, there is strong data that phenacetin, by its psychotropic properties, may have caused drug-seeking behaviour and thus led to analgesic overdosing. This conclusion is convincingly supported by thorough pharmacokinetic investigations. Note: All caffeine-related statements within the reviewed literature have been collected in tables (referred to as Table SX) which are provided in full text for check on the following website: http://www.blackwellpublishing.com/products/journals/suppmat/FCP/FCP174/FCP174sm.htm

No abstract