Paracetamol Overdose
NICE BNF Treatment summaries. Poisoning, emergency treatment. Paracetamol poisoning.
Background information added accordingly.
Date: 13/11/25
Background Information
Pathophysiology
Normal metabolism of paracetamol (under normal therapeutic dosing)
- Main site: liver
- ~90% of paracetamol ungoes conjugation (glucuronidation / sulfation) to form inactive, water-soluble metabolites
- ~10% of paracetamol undergoes oxidation via CYP450 (mainly CYP2E1) to form NAPQI (a highly toxic metabolite)
- NAPQI is usually rapidly neutralised by conjugation with glutathione, therefore is of minimal significance
In paracetamol overdose, the main conjugation pathway (glucuronidation and sulfation) becomes saturated
- More paracetamol is shunted down the oxidation (CYP450) pathway → excessive NAPQI production
- With excessive NAPQI, glutathione stores become depleted
- Excess NAPQI binds covalently to hepatocellular proteins and lipids → oxidative stress, mitochondrial dysfunction, and cell necrosis
The antidote, N-acetylcysteine, acts by replenishing glutathione and directly detoxifying NAPQI.
Clinical Presentation
The key impact of paracetamol overdose is acute hepatocellular necrosis leading to potentially fatal acute liver failure
There are 3 main stages: [Ref1][Ref2]
| Time from ingestion | Clinical manifestation | Laboratory results |
|---|---|---|
| 0-24 hours | Asymptomatic or mild non-specific symptoms
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| 24-72 hours | Hepatic injury occurs at this point:
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| 72-96 hours | Maximal liver toxicity occurs at this point
The most common stage for death to occur due to acute liver failure and subsequent multisystem organ failure
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If the patient survives stage 3, the recovery phase begins by day 4 and completes by day 7.
Classification
Paracetamol overdose can be classified by the timing of ingestion, which guides management:
| Type | Definition |
|---|---|
| Acute overdose | Ingestion of all the paracetamol tablets within 1 hour |
| Staggered overdose | Ingestion of the paracetamol tablets over more than 1 hour |
| Therapeutic excess | Ingestion of potentially toxic paracetamol dose with the intent to treat pain / fever and without self-harm intent |
Diagnosis
Investigation and Diagnosis
Gold standard test: serum paracetamol concentration
- For an accurate result, the sample should be taken at least 4 hours post-ingestion, allowing for complete absorption and reliable risk stratification.
- The test is most valid in cases of a single, acute overdose
- See the management section below for details on when and in whom to measure the serum paracetamol concentration
Key laboratory features include (see clinical presentation section above regarding timing of manifestation):
| Hepatitis |
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| Liver synthetic dysfunction (from acute liver failure) |
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| Systemic / secondary effects |
|
Standard blood work for paracetamol overdose:
- Blood gas
- FBC, U&E
- LFT
- Clotting profile
- Glucose level
- Serum paracetamol concentration
Management
Essential information to obtain from the history of ANY drug overdose cases:
- Elicit the agent involved
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Elicit the dose
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Elicit the intent
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Pattern of use (acute or staggered?)
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Time of ingestion
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Presence of co-ingestants
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Presence of comorbid conditions or medications (e.g. Gilbert disease, alcohol use, antiepileptic drugs)
Antidote of choice for paracetamol overdose is N-acetylcysteine (standard 21-hour regimen, 3 consecutive IV infusions over 1 hour, 4 hours and 16 hours).
- Prevents or reduces the severity of liver damage if given up to 24 hours after ingestion (possibly beyond 24 hours)
- Most effective when given within 8 hours of ingestion, its effectiveness declines after
Guidelines regarding paracetamol overdose are complicated, therefore the author presented 2 approaches: 1) a list of indications to give N-acetylcysteine immediately, 2) management depending on the type of overdose. It is recommended to go over both and consolidate the content.
Indications to Give N-acetylcysteine Immediately
The most important and commonly examined indication to give N-acetylcysteine is if serum paracetamol concentration falls on or above the treatment line on the paracetamol treatment graph (nomogram)
However, there are separate indications where N-acetylcysteine should be given immediately (without waiting to measure serum paracetamol concentration or plot on the nomogram)
- Staggered overdose (all patients)
- Unclear / unknown timing of ingestion (all patients)
- Selected patients in acute overdose
- <8 hours of ingestion of >150 mg/kg + if there will be a ≥8 hours delay in obtaining paracetamol concentration
- 8-24 hours after ingestion + >150 mg/kg / unknown dose / symptomatic with jaundice or hepatic tenderness
- >24 hours after ingestion + >150 mg/kg / unknown dose / jaundice or hepatic tenderness / detectable paracetamol concentration
- Biochemical tests suggest acute liver injury (e.g. ↑ ALT or INR >1.3)
Management by Type of Overdose
Unknown Ingestion Timing
Give N-acetylcysteine immediately (do not wait to measure serum paracetamol concentration or plot on the nomogram)
- NB that paracetamol concentration should still be taken but only to guide continuation or cessation of N-acetylcysteine, NOT to decide whether to start treatment
The paracetamol overdose nomogram (Rumack–Matthew nomogram) is only valid for a single, acute ingestion of paracetamol, where the exact time of ingestion is known.
It is not valid for:
- Unknown ingestion timing, or
- Staggered / repeated ingestions (i.e. taken over >1 hour period)
Staggered Overdose
Give N-acetylcysteine immediately (do not wait to measure serum paracetamol concentration or plot on the nomogram)
- NB that paracetamol concentration should still be taken but only to guide continuation or cessation of N-acetylcysteine, NOT to decide whether to start treatment
The paracetamol overdose nomogram (Rumack–Matthew nomogram) is only valid for a single, acute ingestion of paracetamol, where the exact time of ingestion is known.
It is not valid for:
- Unknown ingestion timing, or
- Staggered / repeated ingestions (i.e. taken over >1 hour period)
Acute Overdose
Consider activated charcoal if the patient presents within 1 hour of ingesting paracetamol (>150 mg/kg).
Acute overdose is a bit more complicated, with 5 main scenarios:
| Scenario | Management |
|---|---|
| Ingested <4 hours ago | Wait until 4 hours after ingestion, then measure serum paracetamol concentration, and
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| Ingested <8 hours ago | Give N-acetylcysteine immediately (without waiting for paracetamol concentration) if
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| Ingested 8-24 hours ago | Give N-acetylcysteine immediately (without waiting for paracetamol concentration) if there is ANY of the following:
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| Ingestion >24 hours | Give N-acetylcysteine if any of the following:
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| Biochemical tests suggest acute liver injury (e.g. ↑ ALT, INR >1.3 in the absence of other causes) | Give N-acetylcysteine (even if paracetamol concentration is BELOW the treatment line) |
Therapeutic Excess
If there are any clinical features of hepatic injury (e.g. jaundice / RUQ tenderness) → give N-acetylcysteine immediately