Journal of Clinical Pharmacy and Therapeutics (2010) 35, 617–638 doi:10.1111/j.1365-2710.2009.01143.x REVIEW ARTICLE What do we (not) know about how paracetamol (acetaminophen) works? K. Toussaint* PharmD,X.C.Yang*PharmD, M. A. Zielinski* PharmD,K.L.Reigle* PharmD,S.D.Sacavage*PharmD, S. Nagar PhD and R. B. Raffa PhD Temple University School of Pharmacy, Philadelphia, PA, USA SUMMARY BACKGROUND What is known and background: Although parac- etamol (acetaminophen), N-(4-Hydroxyphe- The recent (June, 2009) convening of an FDA joint nyl)acetamide, is one of the world’s most widely meeting of the drug safety and risk management used analgesics, the mechanism by which it pro- advisory committee with the anaesthetic and life duces its analgesic effect is largely unknown. This support drugs advisory committee and the non- lack is relevant because: (i) optimal pain treatment prescription drugs advisory committee, which had matches the analgesic mechanism to the as its primary topic area for discussion the safe use (patho)physiology of the pain and (ii) modern drug of acetaminophen (acetaminophen: para-acetylam- discovery relies on an appropriate screening assay. inophenol; paracetamol: para-acetylaminophenol; Objective: To review the clinical profile and pre- Tylenol: para-acetylaminophenol; APAP: N-acetyl- clinical studies of paracetamol as means of gain- para-aminophenol) and a recent article (1) and ing insight into its mechanism of analgesic action. accompanying commentary (2) in this journal Methods: A literature search was conducted of about the relative risk of paracetamol vs. aspirin, clinical and preclinical literature and the infor- resurrect the following interesting fact: the mech- mation obtained was organized and reviewed anism of action of paracetamol, one of the world’s from the perspective of its contribution to an most widely used analgesics, is not fully known. understanding of the mechanism of analgesic action of paracetamol. Modern pain therapy Results: Paracetamol’s broad spectrum of analge- sic and other pharmacological actions is pre- In contrast to the older view in which pain was cat- sented, along with its multiple postulated egorized according to its subjective ‘degree’ (using mechanism(s) of action. No one mechanism has terms such as mild, moderate, severe, etc.), the more been definitively shown to account for its anal- modern view categorizes pain according to its gesic activity. mechanistic ‘type’, i.e. according to the underlying What is new and conclusion: Further research is (patho) physiology (e.g. nociceptive, inflammatory, needed to uncover the mechanism of analgesic neuropathic, etc.) and the biochemical mediators action of paracetamol. The lack of this knowledge (e.g. prostaglandins, substance P, glutamate, etc.) (3). affects optimal clinical use and impedes drug In many painful conditions, the underlying injury is discovery efforts. actually multi-faceted and the pain is transmitted by multiple primary and secondary afferent pathways Keywords: acetaminophen, mechanism of action, and by a variety of neurotransmitters and modula- paracetamol tors (‘mixed’ pains). The pain can result from Received 11 September 2009, Accepted 12 October 2009 increased activity in excitatory pathways involving, Correspondence: R. B. Raffa, Temple University School of for example substance P, glutamate, etc. decreased Pharmacy, 3307 N. Broad Street, Philadelphia, PA 19140, USA. activity in inhibitory pathways involving, for Tel.: +1 215 707 4976; fax: +1 215 707 5228; example noradrenaline or serotonin (5-HT) or both e-mail: [email protected] mechanisms (4). In addition, the underlying pain *These authors contributed equally to this work. Ó 2010 The Authors. JCPT Ó 2010 Blackwell Publishing Ltd 617 618 K. Toussaint et al. (patho)physiology may be time-variant, i.e. the type and toxicity of paracetamol and preclinical inves- can change from one to another because of the tigations of its mechanism of analgesic action. development of central or peripheral sensitization Several comprehensive reviews of the early litera- (or both) or other such phenomena. The modern ture were obtained, as well as an extensive collec- view of pain is better able to explain the otherwise tion of primary literature. In addition, valuable seemingly contradictory clinical observation that recent reviews of mechanism of action were avail- addition of a so-called ‘weak’ analgesic [such as an able, as well as data from one of the author’s (RBR) non-steroidal anti-inflammatory drug (NSAID) or laboratory. paracetamol] to a so-called ‘strong’ analgesic (such as an opioid) can sometimes achieve superior pain Analysis relief. According to the new view of pain, optimal pain treatment results from matching the type of Each of the sources was reviewed for its relevance pain with the drug that has the appropriate mecha- to the mechanism of analgesic action of paraceta- nism of analgesic action. Recent advances in the mol. In many cases, the information was obtained understanding of pain transmission pathways, from studies that did not have investigation of the genetic polymorphisms (5) and analgesic pathways mechanism as the primary outcome, but the results suggest that future pharmacotherapy might be able were determined to either reflect on the mechanism to target a patient’s unique pain with the fewest or to suggest further avenues of investigation. adverse effects. Until that time, clinicians are faced with the ‘analgesic challenge’ – namely, trying to Assessment treat pain with the currently available drugs. As novel, more targeted analgesics are awaited, the cli- Each item was evaluated for its relevance and nician can optimize treatment of pain by using strength of the evidence. In at least one case, an individual drugs, or combinations, which incorpo- author (authority) was contacted with a series of rate the appropriate mechanism(s) of action. questions that shed additional light on a particular mechanistic hypothesis that originally seemed to be only weakly supported. Implications of not knowing drug mechanism The search for a new drug that represents an RESULTS improvement of an existing drug such as paraceta- mol requires a mechanistic assay for screening com- Paracetamol is an aniline (a.k.a. phenylamine, pounds (derived from combinatorial chemistry, aminobenzene, C6H7N aromatic amine) derivative. molecular modelling or other source) or for testing It is an active metabolite of two other anilines the activity of such compounds. Without knowledge [Greek for ‘black’], acetanilide and phenacetin, and of the molecular target of the drug, it is impossible to this played a role in the history of its use. Acetan- setupsuchanassay.Likewise,withoutknowledgeof ilide was first synthesized in 1852 and serendipi- thedrug’smechanism, it isimpossibletodetermine if tously found to have antipyretic effects by Cahn the new drug works the same way as the existing one. and Hepp (6). While studying the effect of naph- Therefore, until the mechanism of action of paracet- thalene on intestinal parasites, Cahn and Hepp amolisknown,drug-discoveryeffortsarestalledand requested naphthalene from the local pharmacy, a great deal of effort and money will be expended but were inadvertently sent the incorrect material. studying and trying to address paracetamol’s They noted that the delivered substance (acetani- adverse effects rather than finding a replacement. lide) behaved differently than expected and had antipyretic properties. The mistake was soon real- ized and taken advantage of. Acetanilide was METHODS marketed as an antipyretic under the clever trade name ANTIFEBRIN. Unfortunately, acetanilide Identification of studies was soon discovered to be quite toxic (causing Computerized literature searches were conducted cyanosis due to methemglobinenia), prompting a using keywords related to clinical use, attributes search for a safer substitute. Ó 2010 The Authors. JCPT Ó 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 617–638 Paracetamol’s analgesic mechanism? 619 Phenacetin and paracetamol, both derivatives of and it was introduced to the UK in 1956 as pre- acetanilide, were studied during the 1880s and scription only PANADOL (7). Found to be ade- 1890s (7, 8). During this period, Hinsberg and quately safe at therapeutic doses and free of the Treupel (9) showed that paracetamol was as effec- gastrointestinal bleeding side effects associated tive as phenacetin as an antipyretic, but von Mer- with acetylsalicylic acid, paracetamol gained over- ing (7, 9) concluded that paracetamol was more the-counter status in the US in 1960 (12) and was toxic, so phenacetin began to be used. By the early added to the British Pharmacopoeia in 1963 (7). 1900s, phenacetin’s analgesic effects were recog- By the mid-1960s, paracetamol use increased nized and it began to be used as an analgesic for dramatically overtaking the use of acetylsalicylic mild to moderate pain in addition to its use as an acid (7). Combination products containing parac- antipyretic (7). etamol were also introduced at this time. In 1978, In the 1940s, Brodie and Axelrod at the National paracetamol sales surpassed those of acetylsalicylic Institutes of Health (NIH) (10, 11) and Smith and acid in the UK (8). Paracetamol gained further Williams (9) at St Mary’s Hospital in London, popularity in the 1980s when acetylsalicylic acid studied the metabolism of phenacitin and acetani- was associated with Reye’s syndrome in children lide. Both groups found that acetanilide and with viral