Paracetamol misusing to dental pain: a case-report and recommandations for treatment

Introduction: The paracetamol is the most widely used painkiller to dental pain. Patients self-medicating with paracetamol for dental pain had 12.8 more times lead to overdose than patients with other pains. The aim of this work was to propose a standardized management in case of paracetamol overdose from a clinical case report. Observation: A 56-year-old man was referred to the General Emergency Department because he had ingested 32 grams of paracetamol in less than 24 hours due to a dental pain. He was in a state of haemodynamic and hypothermic shock. He was placed on the liver transplant list due to fulminant hepatitis. The dental check-up found juxta-pulpal carious lesions on the four wisdom teeth which were removed before the transplantation. Conclusion: Paracetamol overdose is one of the leading causes of liver failure. The estimated toxic dose was 150 mg/kg/day or about 10 g/day. N-acetylcysteine treatment should be leaded early, between 8 and 10 hours after ingestion. The paracetamol-aminotransferase, as a risk prediction tool, reproductibles methods and biomarkers can identify overdoses and lead to a faster medical care. Information campaigns and warning articles on overdosing risk must be continued to strengthen the prevention message for the population.


Introduction
Drug poisoning is a serious public health issue. Pain associated with dental conditions, including acute pulpitis and pericoronitis, is very common in the global population. The pain intensity can lead to analgesic self-medication above the recommended doses. The paracetamol is the analgesic the most widely used in the world in 2016 (49 000 Metrics Tons (MT) in USA, 34 600 MT in China, 48 400 MT in Europe) [1]. This drug was broadly used in mild to moderate pain by self-medication since 2008 and got analgesic and antipyretic effects. It is responsible for 2-7% of all cases of drug poisoning.
After benzodiazepines, it is the second most common drug involved in cases of drug poisoning (2-7%). Its antidote is N-acetylcysteine (NAC) [2].
The aim of this paper is to discuss the epidemiology, triggers, clinical and biological symptoms, as well as the treatment in order to propose a treatment regimen of acute paracetamol overdosing in dentistry.

Observations
A 56-year-old man was referred to the emergency department by his home care worker who found him at the morning in a confused and icteric state in a context of dental pain motivating the intake of 3 boxes of 8 tablets of paracetamol 1g during the night.
The anamnesis highlights: history of myocardial infarction leading to a septo-apical necrosis where angioplasties of the middle anterior interventricular artery and of the right coronary were performed; atrial fibrillation treated with fluindione, acetylsalicylic acid; hypertension treated with bisoprolol, perindopril; hypercholesterolemia treated with a combination of ezetimibe and simvastatin. He was also taking a proton pump inhibitor (lansoprazole).
The patient had risk factors such as active smoking (40 pack-years) and chronic alcoholism (minimum 10 doses of alcohol per day).
On arrival at the emergency room, the patient was in shock (Blood Pressure: 76/40 mmHg; tachycardia: 120 bpm; marbling; polypnea at 30 cycles/minutes; oliguria) and a grade II encephalopathy (flapping and ideomotor slowing). He presented hematemesis and melena. The biological examination showed a hepatocellular insufficiency associated with an acute renal insufficiency and acidosis. The evolution of the biological data is summarized in Table I at three times of the hospitalization: T1 (entry into emergency department), T2 (morning of transplantation), T3 (at discharge).
An N-acetylcysteine protocol was initiated. He was transferred to intensive care. Upon diagnosis of fulminant hepatitis and according to the king's college criterias, the patient was placed on the waiting list for a priority liver transplant according to a national super emergency protocol.
At the time of transplantation, viral status is negative. Wisdoms teeth and 17 were extracted during hospitalization under local anesthesia and under antibiotic prophylaxis and therapy (amoxicillin) for 7 days. A local hemostasis protocol was implemented using collagen sponges and absorbable sutures. A scaling was performed and the 35 was preserved and restored in a conventional way.
The reasons given during anamnesis in supratherapeutic doses were all causes of dental pain (pulp necrosis, acute pulpitis, alveolitis or cellulitis with an apical lesion [4,5,12]. Patients were seen in dental or general emergency departments within 1 to 2 weeks of the appearance of symptoms [5,13]. These patients were classified as relative emergencies, and therefore did not require prompt treatment, which increases the risk of overdose [10].  The main clinical manifestations of overdose are digestive and neurological: abdominal pain, vomiting, or tinnitus [5][6][7]. Biological signs included acute liver failure with elevated transaminases [9,11] and decreased prothrombin (PT) [5] and even hepatic necrosis with paracetamolemia [9,11,12]. In the United Kingdom, paracetamol overdose is one of the leading causes of liver failure [6][7][8]. Georges and Meldrum showed in a survey that one in four patients were unaware of a maximum dose of paracetamol and 36% chose an incorrect amount. [14].

Diagnosis and treatment
The critical threshold varies between 10 and 15 grams of paracetamol per 24 hours [6,8], or about 150 to 250 mg/kg [9,15]. This threshold was half as high for patients with underlying diseases (cirrhosis, hepatitis) or those at risk (HIV, anorexia, undernutrition, cachexia, liver fibrosis, consumption of hepatotoxic drugs such as carbamazepine, phenobarbital) [8].
In the first prospective study describing the characteristics of paracetamol poisoning, the toxic dose was at least 4 grams within a 24-hour period. Symptoms and consequences of poisoning were dose-dependent [15]. Therefore, any patient who has ingested more than 150 mg/kg/day should be referred promptly to an emergency department.
NAC treatment is leaded when dose of paracetamol is upper or equal of 150 mg/kg in adults and 200 mg/kg in child. This injection could be administered immediately if the patient was seen within the hour [6] or in all cases of ingestion of 2 or more supratherapeutic doses of paracetamol over a period of 8 hours [7]. Compared to acute cases of poisoning involving a single dose, repeated poisonings have a higher mortality rate and a higher incidence of encephalopathy and hepatic and renal damage, despite the lower serum concentrations of paracetamol involved [16]. NAC only protects the liver if the injection takes place within 24 hours of ingestion. It is administered intravenously with an electric syringe at the initial dose of 150 mg/kg in 200 ml of 5% glucose solution for 15 minutes, then 50 mg/kg in 500ml for 4 hours and 100 mg/kg in 1000 ml for 16 hours [12]. Hypersensitivity reactions to NAC occur in 6 to 23% of cases [7] and appear within one hour of injection, ranging from skin rash to anaphylactic shock. Patients were allowed to return home as soon as their liver function had returned to normal [15]. Per os or intraveinous galenics can be used but per os need a longer treatment and can be difficult if vomiting [17]. A part of hepatic metabolism is transformed in a metabolit named N-Acetyl-p-benzoquineimine reacting with glutathione which decreased its rate. The depleting in glutathione leads to oxidative stress can causing centrolobular necrosis hepatic. NAC is the predecessor to glutathione to absorb toxic metabolites of paracetamol to prevent acute poisoning. It restores glutathione concentration by means of hydrolysis of cysteine

Predictor risk of hepatotoxicity
However, Wong and Graudins [18] reported that the use of paracetamol concentration is not a reliable predictor of the risk for this developing hepatotoxicity, unlike the paracetamol- aminotransferase product which is calculated by multiplying the concentration of paracetamol by the aminotransferase activity measured at the same time (APAP x AT). This product does not require any knowledge of the exposure time, its reproducibility is better (laboratory measurements) and has a high sensitivity in the period less than 8 hours after ingestion. The other solution evoked is biomarkers. Biomarkers are sensitive laboratory tests specific to confirm drug-related nature of a liver injury. A hepatotoxicity biomarker is not only the signature of a liver lesion but can also identify the xenobiotic involved or at least one class of chemical entities. They are used to confirm liver damage, severities, prognosis or define the type of liver injury [19]. Two major groups of biomarkers studied in paracetamol overdosing: paracetamol protein adducts (APAP-cys) and liver-specific micro-RNA (miR122-5p defining ALAT value) [18]. They are readily detectable and have better sensivity compared with ALAT and ASAT [20,21]. Nevertheless, higher cost and times requirements of genetic testing limit their use [22].

Conclusion
Based on the literature review and this work, we are proposing a treatment regimen for paracetamol poisoning, which is summarized in Figure 2: Management of involuntary paracetamol poisoning in the context of dental pain.
Patients self-medicating with paracetamol for dental pain had 12,8 more times lead to overdose than patients with other pains [23]. It appears there is a significant lack of knowledge among practitioners about the critical threshold for paracetamol ingestion and drug combinations containing paracetamol, as well as among the general population about the risks of overdose [5,7,8,12]. Information campaigns and warning articles on overdosing risk must be continued in order to strengthen the prevention message for the population.