**4. Paracetamol/acetaminophen**

Paracetamol, also commonly referred to as acetaminophen, was first synthesized in 1878 by Morse, a researcher at Johns Hopkins Hospital [11]. It was not until 15 years later that paracetamol's antipyretic effects were first noted and a medical implication was suggested [11, 12]. The current consensus is that paracetamol is the first‐line agent for both acute pain and chronic pain [1, 6, 11]. This is not because paracetamol is a more potent analgesic, but because it has a much better side effect profile than that of other nonopioid analgesics [1, 11].

Even though it has been well over a hundred years since its synthesis, not much is known about the mechanism of action of paracetamol and several have been proposed to explain paracetamol's antipyretic and analgesics effects [11–13]. One in particular is that it indirectly inhibits the cyclooxygenase (COX) enzymes. The COX isoenzymes are responsible for con‐ verting arachidonic acid to prostaglandins, thromboxanes and prostacyclins. Prostaglandins are thought to be a primary mediator of pain, fever and inflammation both centrally and peripherally. Paracetamol is thought to only inhibit a certain isoenzyme of COX (COX‐3) in the brain which is why many believe that it has minimal anti‐inflammatory effects in periph‐ eral tissues [11, 14]. While there are high concentrations of COX‐1 and COX‐2 in peripheral tissue, the proposed COX‐3 enzyme is thought to have higher concentrations in the brain. It is through the inhibition of COX‐3 that paracetamol may have its primary mechanism of action causing analgesic and antipyretic effects while exerting minimal anti‐inflammatory effects [11, 12]. While this is a popular hypothesis, it does not explain the small amount of peripheral anti‐inflammatory activity some researchers have found.

upon the type of pain being treated and may not follow the originally proposed WHO's step‐

Several recommendations have been suggested for the alteration of the WHO's stepwise approach to pain [9]. The first is that when dealing with acute pain, it is sometimes necessary to start at a higher step than the first step of the ladder. This means that opposed to starting with a nonopioid agent alone, it may be necessary to start therapy with a weak, moderate or even strong opioid in addition to a nonopioid agent. However, because most acute pain resolves or markedly improves in a short period of time, there should be an emphasis on early alteration of the analgesic regimen. Rarely are opioids needed for longer than 7 days to treat acute pain [6]. The one major stipulation to treating acute pain in this way (skipping steps on the WHO's ladder) is that the provider is encouraged to rapidly step down the ladder or de‐ escalate therapy as pain diminishes or side effects are too severe. This requires a practitioner to have very close follow‐up and may not be appropriate in all settings. This recommendation is not originally recommended by the WHO, but it is feasible when considering the acute pain

process and the need to wean patients from regimens containing strong opioids [9].

As the patient transitions from an acute pain process to a chronic pain state (1–3 months), it is import to reassess the analgesic regimen. If de‐escalation has not been performed, it should be done at this point to ensure that the patient is only prescribed the minimal amount of medi‐ cations required to control their pain. When escalating in a stepwise manner, the cause and type of pain should be considered. The pain regimen should focus on nonopioid analgesics with nonsteroidal anti‐inflammatories (NSAIDs) if the pain is caused or exacerbated by an inflammatory process. Adjuvant medications targeting neuropathic pain should be initiated and optimized at this time if there is a component of neuropathic pain [9]. Only when nono‐ pioids and adjuvant medications have been fully optimized, an opioid should be scheduled at a fixed interval. Nonpharmacologic and nonopioid medications are preferred for chronic pain [6]. If the pain requires opioids, a weak opioid should be trialed first before escalating to a moderate or strong opioid [8, 9]. To appropriately escalate therapy, it is necessary to under‐ stand the specific attributes of each analgesic medication (nonopioids, opioids and adjuvants) so that the patient receives the maximum benefit while minimizing the potential for harm and

Paracetamol, also commonly referred to as acetaminophen, was first synthesized in 1878 by Morse, a researcher at Johns Hopkins Hospital [11]. It was not until 15 years later that paracetamol's antipyretic effects were first noted and a medical implication was suggested [11, 12]. The current consensus is that paracetamol is the first‐line agent for both acute pain and chronic pain [1, 6, 11]. This is not because paracetamol is a more potent analgesic, but because it has a much better side effect profile than that of other nonopioid analgesics [1, 11]. Even though it has been well over a hundred years since its synthesis, not much is known about the mechanism of action of paracetamol and several have been proposed to explain

wise approach [9].

186 Pain Relief - From Analgesics to Alternative Therapies

side effects.

**4. Paracetamol/acetaminophen**

Another proposed hypothesis postulates that paracetamol inhibits COX isoenzymes in a unique manner and explains the mild anti‐inflammatory effects it may have. Unlike NSAIDs, this hypothesis suggests paracetamol does not bind to the active site of COX to cause inhibi‐ tion [11]. It instead reduces COX from its active form (Fe4+) to its inactive form (Fe3+) and in turn prevents the conversion of arachidonic acid to prostaglandins. Paracetamol's reducing effects are blocked by locally acting peroxides. This explains why paracetamol may be inacti‐ vated in the periphery where there are high levels of peroxides in the setting of cell damage, but not centrally where levels are significantly lower.

Side effects of paracetamol are relatively benign with the most worrisome being hepatotox‐ icity caused by toxic levels of its metabolite N‐acetyl‐p‐benzoquinineimine (NAPQI) [11, 14]. Close to 40% of all acute liver failure cases in the United States and United Kingdom can be attributable to paracetamol intoxication. Approximately 90% of paracetamol is metabolized in the liver through glucuronidation or sulfation. The remainder of the drug's metabolism through the liver is through the cytochrome P450 (CYP450) system. The spe‐ cific subfamily that has been implicated in the majority of this process is CYP2E1. As the glucuronidation and sulfation pathways are saturated, the metabolism through the CYP450 system proportionately increases and more NAPQI is produced. NAPQI then exerts its toxic effects by binding covalently to macromolecules of hepatocytes. Total daily doses of paracetamol alone or in combination with other analgesics should not be greater than 4 g a day with most regimens being 325–650 mg given every 4–6 h [1, 11, 15]. However, recent increases in the use of paracetamol‐containing combination products have brought concern to overdose risk. Due to this, some clinicians recommend a maximum daily dose of 2.4–3.2 g a day, especially in the elderly [16–18]. Of note, paracetamol is commonly combined with opioid analgesics and is found to have additive analgesic effects when done so. The risk for overdose is increased in this setting due to patients taking paracetamol alone in addition to the combination product. In 2011, the Food and Drug Administration (FDA) of the United States limited the amount of paracetamol to 325 mg in combination products due to this increased risk.

Other patient populations at risk for toxicity include those that are malnourished, those tak‐ ing CYP450 inducers (isoniazid, anticonvulsants) and those with heavy alcohol consumption [11, 14]. Chronic alcoholism is especially worrisome for patients taking high doses of paracetamol on a daily basis. Chronic alcohol intake causes hepatotoxicity through a completely indepen‐ dent pathway as well as increasing CYP450 activity and depleting glutathione stores. Both of these increase the production of NAPQI. Therefore, in alcoholics, total daily doses should be limited to 2 g [18].

Other less common, but notable side effects of paracetamol therapy include hypersensitiv‐ ity reactions and elevations in international normalized ration (INR) [11, 18, 19]. When patients were given 4 g of paracetamol a day for 14 days, there was a mild increase in INR as well as a mild decrease in vitamin K‐dependent clotting factors. This supports closer monitoring when patients are being co‐administered warfarin and paracetamol for long periods of time. Intravenous doses of 1 g have been shown to cause very minor decreases in platelet aggregation, but overall paracetamol should be considered safe to use in the setting of an elevated bleeding risk. It is because of the lack of side effects and relative tolerability of paracetamol that it is recommended as the first‐line agent in treating acute and chronic pains.
