From Volume 44, Issue 5, May 2017 | Pages 409-414
Paracetamol (acetaminophen) is a commonly used analgesic; its ‘over the counter’ availability, low cost and popularity amongst patients often make it the first choice for dental pain. It is in this that its potential toxicity, made more complicated by the ever extending range of paracetamol-containing products, make the understanding of this medication key to the safe management of patients presenting to surgery with dental pain.
Indicated for use in the treatment of mild to moderate pain and fever, and available as an ‘over the counter’ medication, paracetamol (acetaminophen) is widely used as the analgesic of choice in the management of dental pain in the UK.1 Indeed, the 2007 Cochrane review by Weil et al concluded that paracetamol was a safe, effective drug for the treatment of post-operative pain following the surgical removal of lower third molars.2
Being an inexpensive and freely available drug, coupled with the ever extending range of paracetamol-containing preparations, can leave patients with misunderstandings regarding its safety, resulting in cases of unintentional overdose compounding a visit to the dental surgery.3
Unfortunately, the risk of overmedication before presentation is complicated by the prevalence of dental anxiety and the current emergency dental care provisions.4,5 In this, dental pain has been highlighted as a risk factor for paracetamol overdose, with a clinically significant number of patients attending A&E with overuse of non-prescription analgesics secondary to dental pain.4,6 To contextualize, a case series encompassing 116 admissions of unintentional paracetamol overdose to the Medical Assessment Unit at the Northern General Hospital, Sheffield, revealed that 41% were secondary to a cause associated with dental pain.7
In this vein it is essential that all dental practitioners can extract a detailed analgesic history, have a working understanding of paracetamol pharmacology and knowledge of their role as gatekeepers in the management of a suspected overdose.
Paracetamol is both an effective analgesic and antipyretic with peripheral and centrally acting analgesic effects.8 The drug is also known to have a synergistic effect when taken with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and opiates.9
The exact mechanism of action of paracetamol is not known, but it is felt that the antipyretic and analgesic properties share a number of common features with NSAIDs due to the main mechanism of action resulting in suppression of prostaglandin synthesis.10,11 However, paracetamol differs from NSAIDs in that it does not possess anti-inflammatory properties, nor does it cause the gastro-intestinal or renal side-effects when taken at recommended doses.11
NSAIDs typically provide peripheral analgesia, which is one reason why the mechanism of action of paracetamol appears more complex. Not only does it provide peripheral analgesia, but also acts centrally via the serotonergic descending neuronal pathway, L-arginine/Nitric Oxide (NO) pathway and cannabinoid system as well as providing central cyclo-oxygenase inhibition.11,12
The recommended maximum dose of paracetamol is 4 g (or 75 mg/kg, 60 mg/kg if weight <50 kg) in 24 hours for a standard adult. Any ingestion >75 mg/kg/24hours is considered overdose.
Most cases of overdose presenting to the dental surgery will be of a supra-therapeutic nature, defined as more than one ingestion of paracetamol to a total >75 mg/kg within 24 hours.13
Staggered overdose is slightly different in nature, this is where multiple doses of paracetamol have been ingested over a period of >1 hour. Typically, excess paracetamol use can happen over days to weeks in these patients. Owing to the greater time scale, paracetamol level assays are ineffective in these cases and the history may be imprecise, therefore medical admission units will almost always intervene medically in a staggered overdose.13
Acute single overdose is that of ingestion of paracetamol >4 g or >75 mg/kg in a period of <1 hour. This would be a very unlikely case to present to the dental surgery and hence its management will not be discussed further, however, it is prudent to note that, should this be encountered, the patient should be sent to the local A&E immediately.
There are some additional special cases which should be contemplated when considering overdose (Table 1).
| Special Cases | Toxic Dose |
|---|---|
| Pregnant patients | The toxic dose is calculated based on the patient‧s pre-pregnancy weight |
| Obese patients | The toxic dose is calculated based on a maximum of 110 kg instead of the patient‧s actual weight |
| Children | Assessed by weight |
One of the challenges to the detection of paracetamol overdose is that, within the first 24 hours of ingestion of a toxic dose, patients are often asymptomatic. Early non-specific signs can be present, are often vague, and may include: nausea, vomiting, anorexia and abdominal discomfort. Suspicion of combined overdose should be brought to mind in all patients who present with reduced levels of consciousness.
Clinical features of hepatotoxicity usually develop 2–3 days post acute overdose ingestion, and often centre themselves around: right upper abdominal pain, nausea and vomiting, bleeding, low blood sugar levels and confusion. Patients may also become clinically jaundiced during this period.14
Metabolism of paracetamol's toxic metabolites are determined by the function of the liver's CYP450 enzyme pathway. Therefore, specific attention should also be paid to medical conditions and patient medications that affect hepatic function via CYP450 induction, inhibition and glutathione level reduction (Tables 2 and 3).
| Carbamazepine |
| Rifampicin |
| Alcohol (chronic)* |
| Phenytoin |
| Griseofulvin |
| Tobacco* |
| Pirimidone |
| St John's Wort |
| Sulphonylureas |
| Ritonavir |
| Malnourishment |
| Nutritional deficiency states |
| Anorexia nervosa |
| Bulimia nervosa |
| Cystic fibrosis |
| AIDS |
| Alcoholism |
| Hepatitis C |
| Other liver diseases |
Following ingestion of a therapeutic dose of paracetamol (<75 mg/kg/24 hours), the drug undergoes two main forms of hepatic metabolism: glucuronidation via the glycoronyl transferase enzymes (50%–60%) and sulfation via the phenolsulphotransferase enzyme pathway (25%–30%)15 (Figure 1). The non-toxic conjugates formed are then excreted harmlessly in the urine. In addition to the two main metabolic pathways, around 5% of a therapeutic dose is broken down by the cytochrome P450 system, the most prominent enzyme involved being CYP2E1, to the potentially toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). With therapeutic doses of paracetamol NAPQI then combines with intracellular glutathione to form paracetamol-glutathione conjugates which are further broken down and excreted in the urine as non-toxic cysteine and mercapturic acid conjugates.11
When taken in overdose, hepatic conjugation pathways become inundated, forcing paracetamol to be metabolized by the CYP450 pathway. The increased activity of this pathway results in excess NAPQI formation, which exceeds the availability of glutathione. The end result is the of binding of NAPQI to hepatic cellular structures and ultimately hepatic necrosis (Figure 1).
It is important to note that it is essential to ascertain the timing of the overdose as this will allow it to be categorized into: supra-therapeutic, staggered or acute, and thus affect subsequent management.
Figure 2 gives a management algorithm.
Patients seen in A&E as a result of oral supra-therapeutic paracetamol overdose which meets the threshold for management are treated with N-acetylcysteine (NAC). This drug increases intracellular levels of glutathione in an attempt to mop-up excess NAPQI, preventing its binding to cellular structures and hence hepatocyte death (Figure 1).
It is reported that almost all patients treated within 8 hours of acute ingestion (>75 mg/kg in <1 hour), regardless of dose, are spared hepatic injury.16 Patients are discharged when the INR is ≤1.3 and the alanine aminotransferase (ALT) is <2 x upper limit of normal, with advice to return to hospital if vomiting or abdominal pain ensues.13
Occasionally, patients enter fulminant hepatic failure, the King's College Criteria (pH<7.3 or Lactate >3.5 after early fluids or all 3 of: Kidney injury: Creatinine >300; Bleeding: INR >6.5; Coma: Encephalopathy Grade III/IV) is used to identify those patients who warrant liver transplant.
Paracetamol is a very commonly used drug in the management of dental pain. Its ‘over the counter’ availability and the lay lack of understanding around its potential potency all too often lead to patients presenting having exceeded the maximum dose. It is hoped that this article cements a general understanding of the drug, raises awareness of patient education around the use of paracetamol and provides a useful algorithm of what to do should a patient present to the dental surgery with a supra-therapeutic oral overdose.
