Caffeine as a promoter of analgesic‐associated nephropathy – where is the evidence?

Abstract

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

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

“…A detailed analysis of the original publications behind the numerous literature citations shows that the epidemiological studies do not provide convincing evidence for a role of caffeine in prompting excessive analgesic use. Moreover, the identified groups of nephrologists did not provide substantial data to advocate the said suspicion, except for the observation of a preferential choice of phenacetin-containing combinations, especially powder preparations [ 77 ]. The fact that phenacetin, which was used exclusively in the form of combination analgesics (often in conjunction with caffeine), is the sole antipyretic analgesic to be accorded with a drug seeking or craving behaviour, as described by Murray [78 and 79], has often been overlooked.…”

“…The fact that phenacetin, which was used exclusively in the form of combination analgesics (often in conjunction with caffeine), is the sole antipyretic analgesic to be accorded with a drug seeking or craving behaviour, as described by Murray [78 and 79], has often been overlooked. Moreover, this effect was no longer observed once it had been replaced with paracetamol [ 77 ]. It was phenacetin rather than caffeine that induced overuse/abuse of combination analgesics and phenacetin, but paracetamol does not have this psychotropic potential, as Fox pointedly concluded [ 80 ].…”

A Risk-Benefit Assessment of Paracetamol (Acetaminophen) Combined with Caffeine

“…We also present an analysis of the risks of the combined treatment of paracetamol and caffeine. It has been established that caffeine does not contribute to nephrotoxicity [35][36][37]. The hepatotoxicity of overdoses of paracetamol results from its oxidative metabolism.…”

Case-control study on analgesics and nephropathy (SAN): protocol

“…Although an additional Expert Meeting on Caffeine found no evidence for such an effect [7], and although a further special review did not reveal any substantial data to support a pivotal role of caffeine [8], the new study was intended to provide information on the role of caffeine in risk development.…”