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Analysis of analgesic tablet

The pain management therapy is based on the careful consideration of patients' physiological status, severity of pain, and the disease type. Advances in understanding of biomolecular mechanisms of chronic pain continue to assist in the development of novel analgesics, which include non-opioid drugs (paracetamol, non-steroidal anti-inflammatory drugs - NSAIDs) and opioid drugs. According to WHO, management of the mild pain should involve using non-opioid drugs, followed by administration of mild and strong opioids (alone or with non-opioid drugs plus adjuvant drugs) for the management of moderate and severe pain, respectively. Treatment should be adjusted on a single-step basis according to increasing or decreasing pain severity, reaction to previously administered analgesics, profile of side effects and/or expected drug interactions.

Paracetamol and NSAIDs are the most commonly used remedies to provide pain relief in rheumatic and urologic diseases, headache, toothache, acute postoperative pain or upper respiratory tract infections. It is now well established that both therapeutic and side effects of NSAIDs depend on inhibition of cyclooxygenase (COX), also known as prostaglandin-endoperoxide synthase (PTGS) (1). Paracetamol also acts through COX, particularly in some brain areas, but its effects can be also ascribed to an active metabolite p-aminophenol, which upon conjugation with arachidonic acid (AA) forms AM404 that interacts with cannabinoid receptors (2). Up to date, two isoforms of COX have been identified, COX-1 and COX-2, which have very similar amino acid sequence (60% identity), homologous three-dimensional structures, and similar catalytic activity (3). Biochemically, COX enzymes act as dioxygenases and peroxidases, and catalyse a two-step conversion of AA into prostaglandin (PG) G2 and next into PGH2. The latter is subsequently converted into a number of biologically active molecules, including prostaglandins D2, E2, F2α or I2, by terminal prostaglandin synthases. PGE2 and PGI2 are the main mediators of pain, acting via their plasma membrane receptors to induce intracellular cascades of protein kinase signaling, resulting in sensitisation of nerve cells (4). The process occurs both at the site of injury (peripheral sensitisation) and at the synapses in the spinal cord (central sensitisation).

Another group of analgesics that was used for the treatment of pain already in ancient Egypt are opioids. They are commonly administered to treat acute pain and/or in palliative care, for instance in the management of chronic metastatic pain in cancer patients. Chemically, this group of analgesics is divided into phenanthrenes (eg. Morphine, codeine), benzomorphans, phenylpiperidines (eg. fentanyl), and diphenylheptanes (36). The mechanism of action of opioids is based on antagonistic, partially antagonistic or agonistic interaction with receptors OP1 (δ), OP2 (κ), and OP3 (µ) (36). Although the majority of clinically relevant opioids act mostly at OP3 receptors, it is suggested that strong opioids can actually interact with different sub-populations of opioid receptors. Tramadol is a unique opioid with catecholamine, serotonergic and central GABA activities in addition to partial OP3 agonist action. Most of the side effects of opioids are ascribed to products of their metabolism, which occurs in the liver by glucuronidation or by P450 (CYP) system (e.g. CYP2D6, CYP3A4, CYP2C8). Importantly, opioids differ significantly in terms of the pharmacokinetics, with half-life ranging from 10-12h (e.g. morphine) to 70-120h (e.g. methadone). Numerous hepatic drug interactions influence concentration/efficacy of opioids, including erythromycin-mediated enhancement of opioid effects, or decreased conversion of codeine to morphine by Quinine. Methadone is particularly prone to drug interactions, with erythromycin, barbiturates, several anti-retroviral drugs, or carbamazepine decreasing its blood levels. On the other hand, venlafaxine, CYP3A4 inhibitors (e.g. ciprofloxin), azole antifungals or tricyclin antidepressants can increase levels of methadone. The side effects of opoids are widely recognised mostly due to physical and/or psychological drug addiction. Indeed, as opioids act on central and peripheral nervous systems, their clinical application is severely limited by numerous side effects, such as respiratory and cardiovascular decline, constipation, drowsiness or vomiting. Therefore, combinatorial treatments with NSAIDs, palliative radiation or local anaesthetics can often be used in combination with opioids to achieve greater pain relief while reducing narcotic requirements compared with opioids administered alone (37). Still, there are discrepancies between the studies with regards to the efficacy and safety of NSAIDs in combination with opioids for the treatment of cancer pain (38). Opioid rotation has been also suggested to restore pain relief and improve tolerability.

Other drugs are used as adjuncts to NSAIDs and opioid analgesics, such as inflammation-reducing corticosteroids, for both cancer and non-cancer pain. Recently, innovative drug-delivery methods have been introduced, such as rapidly dissolving solid dispersion systems (39) or complexation with beta-cyclodextrins (40), and appear advantageous in improving the pharmacological activity of NSAIDs (41). Alternatives to standard pharmacological approaches, such as immersive virtual reality (VR) distraction analgesia (42), electrical stimulation of brain to modulate pain perception (43), or continuous peripheral nerve blocks (44), have also been tested. Overall, irrespectively on the type of analgesics used, mechanism-based treatment of pain, novel drug formulations and advanced patient-tailored therapy should improve pain relief while reducing possible side effects.

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