From the Guidelines
Paracetamol exerts its useful effects of analgesia and antipyrexia primarily through inhibition of prostaglandin production within the central nervous system and within peripheral tissues, as demonstrated in recent studies 1. The mechanism of paracetamol's analgesic action remains largely unknown, but it is believed to involve the inhibition of cyclooxygenase (COX) enzymes, particularly COX-2 and a variant called COX-3. This inhibition reduces the production of prostaglandins, which are key mediators of pain and fever.
- In the brain, paracetamol decreases prostaglandin synthesis in the hypothalamus, the body's temperature regulation center, which helps lower fever.
- For pain relief, paracetamol works by reducing prostaglandin production in the central nervous system rather than in peripheral tissues, which explains why it has minimal anti-inflammatory effects compared to NSAIDs.
- Paracetamol also interacts with the endocannabinoid and serotonergic systems, which may contribute to its pain-relieving properties. The standard adult dosage is 500-1000 mg every 4-6 hours, not exceeding 4000 mg in 24 hours, though lower maximum doses (3000 mg) are often recommended to reduce liver toxicity risk, as suggested by various guidelines, including the EULAR recommendations 1. It is essential to use paracetamol cautiously in patients with liver disease or alcohol use disorder, as it is metabolized primarily in the liver and excessive doses can lead to hepatotoxicity.
From the Research
Mechanism of Action of Paracetamol
The mechanism of action of paracetamol is complex and involves multiple pathways, including:
- Inhibition of cyclooxygenases (COX-1, COX-2, and COX-3) 2, 3, 4
- Involvement in the endocannabinoid system and serotonergic pathways 2, 5, 4
- Influence on transient receptor potential (TRP) channels and voltage-gated Kv7 potassium channels 4
- Inhibition of T-type Cav3.2 calcium channels 4
- Impact on L-arginine in the nitric oxide (NO) synthesis pathway 5, 4
Analgesic and Antipyretic Effects
The analgesic and antipyretic effects of paracetamol are thought to be mediated by:
- Inhibition of COX-1 and COX-2, which reduces the production of prostaglandins and other pro-inflammatory mediators 2, 3
- Activation of the endocannabinoid system, which modulates pain perception and inflammation 2, 4
- Modulation of the serotonergic pathway, which regulates pain transmission and mood 2, 5
Safety Concerns
While paracetamol is generally well-tolerated, there are safety concerns associated with its use, including:
- Hepatotoxicity, which can occur with overdosing or prolonged use 5, 3, 6
- Gastrointestinal side effects, such as nausea and vomiting 5
- Potential interactions with other medications, such as opioids and NSAIDs 3, 6
Clinical Use
Paracetamol is a suitable first-line analgesic for mild to moderate acute pain in many adults, including those with liver, kidney, or cardiovascular disease, gastrointestinal disorders, asthma, or who are older 6. However, dosing should be individualized and monitored by a physician to minimize the risk of adverse effects.