**2.1 Paracetamol**

*Pain Management - Practices, Novel Therapies and Bioactives*

plus/minus NSAID are most of the time an adequate option.

patient assessment [4, 5].

multimodal analgesia concept.

administration of analgesia may enhance the accuracy of physical examination and

The medications useful in treating acute pain are similar to those used in treating other types of pain [1]. The World Health Organisation (WHO) analgesic ladder (**Figure 1**) developed for treating patients with cancer pain also provides a useful approach to treat acute pain. At the lowest level (mild pain) are recommended nonopioid analgesics such as paracetamol or/plus nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprofen). Such drugs have an analgesic ceiling; above a certain dose, no further analgesia effect is expected [1]. For moderate pain, are recommended combining paracetamol and/or a NSAID with an opioid (a weak opioid). The inclusion of paracetamol limits the amount of opioids that should be used within 24 hour period, with many benefits which will be discussed later in the chapter. For severe level of pain, a strong opioid such as morphine is a better choice; such opioids have no analgesic ceiling. Most postoperative or trauma patients initially respond better to a morphine-equivalent opioid. By the moment the patient is eating, drinking and ready for discharge, a combination of oral analgesics including opioids and paracetamol

Not all types of pain respond equally to the same medication. Usually NSAIDs and steroids are highly effective in controlling soft tissue and bone pain. Bone pain may be helped partially by opioids [1]. But overall, the combination of NSAIDs, paracetamol and opioids is synergistic in treating the most types of pain. Opioid analgesics are useful in controlling somatic and visceral pain. Neuropathic pain, often described as pain with a burning and hyperaesthesia characteristic, which responds well to a diverse group of drugs, called adjuvants, including low dose of antidepressants (amitriptyline), anticonvulsants (carbamazepine and clonazepam), antiarrhythmics (mexiletine), baclofen and alfa-adrenergic agonists (clonidine). Opioids may also be helpful [1]. Most of the time, analgesia is improved after 1–2 days of using adjuvant drugs. Adjuvants were not developed initially as analgesics but recent studies show they poses benefits in a better pain control. Drugs that control pain by different mechanisms of action may be synergistic, when used together. Also, by lower doses of two or more different agents, the patient may have better pain control with fewer side effects. This is the basic background for the

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**Figure 1.**

*WHO analgesic ladder.*

Paracetamol is the first-line agent for the treatment of both acute and chronic pain. It is one of the pain killers with the highest profile of safety and is a first pharmacologic option for controlling pain in children and adults. It has a high toxicto-therapeutic ratio and has very few significant drug interactions compared with other analgesics [2].

It can be given orally, rectally or parentally, has small anti-inflammatory activity, and is an effective analgesic and antipyretic.

Although paracetamol has been in use since 1880, its pharmacologic mechanism of action is not fully known. It has a rapid absorption from the small intestine after oral administration. Paracetamol has lower protein binding than NSAIDs (and hence fewer potential drug interactions) and higher volume of distribution [6].

Paracetamol is the active metabolite of the earlier (more toxic) drugs acetanilide and phenacetin. The recommended dose in adults is 0.5–1 g oral, iv or rectal every 4–6 hours when necessary, without exceeding a total daily dose of 4 g [6].

Paracetamol has a CNS action, where inhibits prostaglandin synthesis. In clinical doses it has insignificant peripheral anti-inflammatory action. Unlike morphine, paracetamol has no apparent biding sites, and unlike NSAIDs it does not inhibit peripheral cyclo-oxygenase activity. But however, his mechanisms of action include, beside central COX-2 inhibition [2, 7], inhibition of a central cyclo-oxygenase, COX-3, that is selectively susceptible to paracetamol, and modulation of descending serotonergic pathways that suppresses spinal cord nociceptive transmission. There is also evidence of agonism at the cannabinoid receptor CB1 [2, 8]. There are, other evidences that paracetamol may inhibit prostaglandin endoperoxidase H2 production at the cellular level, independent of cyclooxygenase activity [2, 6].

The most recent Cochrane review [9] of RCTs of single-dose oral analgesic for acute postoperative pain in adults reported a NNT of 3·6 with 1 g paracetamol, when morphine 10 mg IM has 2.9, ibuprofen 400 mg - 2.4 and codeine 60 mg - 16.7. Efficiency of paracetamol is improved in combinations with other analgesics, such as 400 mg ibuprofen, 60 mg codeine and 10 mg oxycodone (NNT 1·5, 2·2 and 1·8 respectively) [6, 9].

So, paracetamol is an effective analgesic, with potency somewhat less than standard dose of morphine. Paracetamol is an efficient adjunct to opioid analgesia, and regular administration after surgery produce an opioid sparing effect, because reduce opioid requirements by 20–30%. Paracetamol proved to be an integral component of multimodal analgesia in combination with NSAIDs and opioids. Paracetamol has less side effects than the NSAIDs and can be used when the latter are contraindicated.

A significant concern regarding paracetamol use relates to the development of hepatotoxicity; however, current data suggest this is unlikely to develop at therapeutic doses [10]. However, doses of more than 150 mg/kg of paracetamol taken within 24 hours may result in severe liver damage, hypoglycaemia and acute tubular necrosis, especially when associated with dehydration and chronic malnutrition [11]. Individuals taking enzyme-inducing agents are more susceptible. So, important caution should be taken in overdoses due to the risk of liver damage and less frequently renal damage. Nausea and vomiting, the only early features of poisoning, usually settle within 24 hours. Persistence beyond this time, often associated with the onset of a right-side subcostal pain and tenderness, usually indicates development of hepatic necrosis.


**Table 1.** *Paracetamol side effects.*

Paracetamol is metabolised in the liver primarily through conjugation to sulphate or glucuronides [2]. A minor pathway for the oxidative metabolism of paracetamol produces the toxic metabolite N-acetyl-P-benzoquinone (NAPQI) [2]. NAPQI requires glutathione for detoxification and elimination. Hepatic toxicity can occur when glutathione pathways are overwhelmed by an increase in NAPQI or decrease in glutathione.

Paracetamol is generally well tolerated with rare side effects when the right doses are prescribed (**Table 1**) [2, 4].

#### **2.2 Interactions**

It is associated with several important drug interactions. Many anticonvulsants, including phenytoin, barbiturates and carbamazepine induces hepatic microsomal enzymes. Increased conversion of paracetamol to its toxic metabolite may occur in patients who are taking anticonvulsants, but this rarely leads to concerning consequences in the context of the usual doses for pain management [2, 6].

Although uncommon, drug interaction resulting in an increased INR is reported for patients taking both paracetamol and warfarin, particularly among patients taking high doses of paracetamol (> 9 g/week) [2, 12, 13]. Long term use of paracetamol should be avoided in patients with hepatic or renal impairment. Patients with a history of salicylate hypersensitivity characterised by urticaria have a 11% cross-reactivity to paracetamol, and the agent should be used with caution in this group [2, 7].

#### **3. Nonsteroidal anti-inflammatory drugs**

The NSAIDs share several properties with aspirin and may be considered together. NSAIDs are particularly used for the treatment of patients with chronic disease accompanied by pain and inflammation.

Some of them are also used for acute pain management and in the short-term treatment of mild to moderate pain including transient musculoskeletal pain. They are also suitable for the pain control in dysmenorrhoea and to release pain caused by secondary bone tumours, many of which produce lysis of bone and increase prostaglandins synthesis. Many of the NSAIDs are also used for postoperative analgesia as part of the multimodal analgesia strategy. Selective inhibitors of COX2 may be used in preference to non-selective NSAIDs for patients at high risk of developing serious gastro-intestinal side-effects.

There are some limited and low quality evidences against the use of NSAIDs in bone pathology, suggesting that prostaglandins promote bone formation and that NSAID might impair this process [14, 15], theory not proven through properly

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*Analgesics*

*DOI: http://dx.doi.org/10.5772/intechopen.94319*

after fracture is detrimental to healing [2].

saturated fatty acids that include leukotrienes [6].

monitoring the incidence of NSAID-renal damage is low.

the potency of the COX inhibition [2].

*3.1.2 Cyclo-oxygenase isoenzymes*

cal enzymes kinetics.

*3.1.1 Prostaglandin synthesis inhibition*

**3.1 Mechanism of action**

conducted studies. There is no evidence that NSAIDs administration on short term

These agents inhibit cyclooxygenase (COX) and, as result, the synthesis of prostaglandin, a key mediator of inflammation, in the peripheral tissues, CNS and nerves – leading to an effective raise in the threshold of nociceptors stimulation. Aspirin acetylates and irreversibly inhibits cyclo-oxygenase, while NSAIDs work by competitive inhibition, being reversible. The prostaglandins are part of the eicosanoid's family, oxygenated metabolites of arachidonic acid and other polyun-

The rate of prostaglandin synthesis is usually low, being regulated by trauma and tissue stimuli, which activates phospholipases to free arachidonic acid, from which prostaglandins are produced. Prostaglandins have several physiological roles, including gastric mucosal protection, bronchodilation and maintenance of renal tubular function, renal vasodilatation, regulation of tubular electrolytes and modulation the action of renal hormones [2, 6]. The side effects on the renal system of chronic NSAIDs is well known. In certain clinical settings when there are high plasma concentration of the vasoconstrictors rennin, noradrenaline, angiotensin and vasopressin, intrarenal vasodilators including prostacyclin are produced and renal function can be affected by NSAIDs administration [2]. The concomitant use of other potential nephrotoxic drugs, such as gentamicin, can worsen the renal effect of these drugs [2]. Nevertheless, with careful patient selection and closed

Triggering bronchospasm is a recognised phenomenon in patients with asthma, rhinitis and nasal polyps [2]. Such "aspirin induce asthma" can be severe, and goes up to 10–15% as incidence with a feature cross sensitivity with NSAIDs. A known history of aspirin induce asthma should band the administration of NSAIDs perioperatively. The mechanism is unclear, but practice shown the reaction increases with

Endothelial released prostacyclin induces vasodilatation and prevents platelet adhesion, and platelet thromboxane produces aggregation and vasospasm. In addition to prostaglandins, cyclooxygenase induces prostacyclin synthesis, a vasodilator that also increases GI mucosal perfusion. Also, in the gastric tissue, COX-1 increases mucus and bicarbonate production, valuable feature for stomach mucosal protection [2]. Inhibition of COX-1 is affecting this protection, predisposing to ulcerations and bleeding, which

Two subtypes of cyclo-oxygenase enzyme have been identified. These are constitutional COX-1 and inducible COX-2, the last one triggered by inflammation and trauma. The COX-1 is present in all cells and regulates various roles in homeostatic function. NSAIDs, like aspirin, are non-selective cyclo-oxygenase inhibitors that act on both COX-1 and COX-2, which results in multiple beneficial effects (reduction in

These two COX isoenzymes have 75% aminoacid homology, with almost identi-

COX-1 is a membrane bound haemoglycoprotein found in the endoplasmic reticulum of prostaglandin-inducing cells. The COX active site is a long hydrophobic

can be exacerbated by concomitant NSAID-induced platelet dysfunction [2].

inflammation, pain and fever) but also some important side effects.

conducted studies. There is no evidence that NSAIDs administration on short term after fracture is detrimental to healing [2].
