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).
The two COX isoforms differ in their regulation of expression and tissue distribution. COX-1 is expressed constitutively at detectable levels in most tissues, including blood vessels, interstitial cells, smooth muscle cells, platelets and mesothelial cells. Although COX-1 is considered as a constitutively expressed isoform, two splice variants of COX-1 gene exists, with the recently discovered variant COX-1b denoted as COX-3, that are differentially regulated by growth factors and cytokines. COX-2 is the isoform inducible by multiple stimuli, such as growth factors, proinflammatory agents, endotoxins or mitogens, and often undetectable at basal levels. However, recent data indicate that COX-2 can be also expressed constitutively in parenchymal cells of various tissues, such as vascular endothelium, and that COX-2-derived prostaglandins can maintain vascular homeostasis (5). In addition to its involvement in pathophysiology of inflammation and pain, COX-2 is also associated with pro-atherogenic states due to its upregulation in macrophages infiltrating atherosclerotic lesions (6). Moreover, some functional differences between COX-1 and COX-2 have been identified, as only COX-2 can use ester and amide derivatives of AA as substrates (7).
Based on the selectivity, NSAIDs can be divided into three subcategories that differ in terms of efficacy and type/extent of side effects: i) selective COX-1 inhibitors (e.g. acetylsalicylic acid, or aspirin); ii) non-selective COX inhibitors (e.g. ibuprofen and naproxen); and iii) relatively or highly selective COX-2 inhibitors – COXIBs (e.g. celocoxib and rofecoxib) (3). Numerous studies have addressed the tolerability and relative efficacy, especially in reducing severity of pain, delaying time to maximum pain intensity, and prolonging duration of analgesic effect, of different NSAIDs. It appears that the type, formulation, method of delivery, as well as patients’ status all affect the overall efficacy as well as pharmacokinetic properties of NSAIDs. For example, rofecoxib (selective COX-2 inhibitor commonly known as VIOXX) had a superior analgesic efficacy in comparison to diclofenac sodium (8), celecoxib (9, 10) or codeine/acetaminophen (11, 12), but similar efficacy to ibuprofen and naproxen sodium, in patients after oral surgery or in postoperative dental pain. In a series of studies comparing derivatives of ibuprofen with different pharmacokinetic characteristics, ibuprofen arginate and ibuprofen sodium dehydrate have been consistently shown to provide better pain relief then ibuprofen in subjects suffering from postoperative dental pain (13 -16). Evidence that the formulation per se also affects the efficacy of NSAIDs has been provided for example by comparative studies using solubilized liquigel ibuprofen, ibuprofen suspension and solid ibuprofen tables. The latter had a significantly delayed absorption and lower mean peak concentration (Cmax), and thus a diminished overall analgesic efficacy. Extensive studies have also examined pharmacokinetic characteristics of traditional NSAIDs (tNSAIDs) and selective COX-2 inhibitors, including bioavailability following different routes of administration, and excretion mechanisms. These studies often provide invaluable information on potential drug interactions, available combinatorial treatments or effects on fetus and infants. tNSAIDs distribute mostly to the sites of inflammation where they often maintain effective concentrations for long periods of time. However, the effective concentrations in the bloodstream, gastrointestinal mucosa and kidney can be only achieved by tNSAIDs with half life above 12h. Interestingly, the bioavailability and solubility of tNSAID can be improved by co-administration with antacids, as has been shown for a combination of ibuprofen and magnesium-based antacid suspension (17). Among COX-2 selective inhibitors, following oral administration, celocoxib has a relatively low bioavailability (20-40%) with Tmax of 2-4h, whereas lumiracoxib and etoricoxib have good oral bioavailability ranging between 74-100% (18, 19). In addition, patient-associated factors influence the extent of absorption of NSAIDs, and thus should be taken into account prior to administration. These include age, race, renal and hepatic function (19), but not polymorphism within CYP2C9 gene, encoding for the cytochrome P450 enzyme that metabolizes celocoxib and diclofenac (20). It has been suggested that selective COX-2 inhibitors have a longer duration of action as compared to traditional NSAIDs. In general, half-life of COXIBs vary between 5-8h (e.g. lumiracoxib) to 19-32h (e.g. etoricoxib). Prior to elimination, all COXIBs are extensively metabolised by hepatic metabolism involving mostly CYP2C9 and CYP3A4, and are excreted via renal and faecal routes (21). On the molecular level, NSAIDs are often excreted into urine via organic anion transporter 3 (OTA3) and/or tetracycline transporter-like protein (TETRAN) (22). Although many analgesics are also secreted into breast milk and/or can traverse the placental barrier, short-term treatments with selected NSAIDs (e.g. low-dose aspirin) are compatible with breast feeding (23).
The very action that confers therapeutic effects of NSAIDs can also lead to deleterious and dose-restricting side effects. Prostaglandins (PG) synthesised from AA by COX induce pain perception by indirect and direct sensitization of nociceptors, such as irritant transient receptor potential A1 (TRPA1) (24). However, prostaglandins also control a number of physiological processes. COX-1-mediated prostaglandin synthesis is critical for the reduction of gastric acid secretion and maintenance of gastrointestinal system integrity. Therefore, administration of nonselective or COX-1-selective NSAIDs can lead to serious gastrointestinal complications, ranging from dyspepsia and abdominal pain to gastric injury, ulceration and bleeding (25). Combinatorial treatments with gastroprotective agents, such as misoprostol, that neutralise the detrimental effects of inhibited prostaglandin synthesis can be of benefit, but reportedly may induce additional toxicity, as well as problems with pharmacokinetics and patients’ compliance. Although specific COX-2 inhibitors have a significantly reduced gastrointestinal toxicity, including lower incidence of endoscopically visualised gastrointestinal ulcers, these compounds may have serious cardiovascular and renal side effects (26). Indeed, it has been shown that COX-2 inhibitors selectively reduce production of vascular prostacyclins which can predispose to hyper-tension and atherosclerosis, and can reduce synthesis of COX-2-formed renal medullar prostacyclin and prostaglandin PGE2. Placebo-controlled clinical trials have indicated that 3 chemically distinct coxibs (celecoxib, rofecoxib and valdecoxib) increase the risk of myocardial infraction and stroke (27). In addition, prostaglandins produced upon COX-2 stimulation have vital regulatory roles in osteoclasts and osteoblasts, affecting bone repair and normal bone homeostasis (28). Although clinical data on the effects of selective COX-2 inhibitors on bone repair are still limited, it is postulated that they may delay fracture healing. NSAIDs are also associated with drug-induced liver injury, and some (eg. diclofenac) represent a paradigm for hepatic toxicity. Finally, controversies surround the effects of NSAID on the risk of hematological malignancies, and apparently the effects depend on the type of NSAID used, frequency/period of administration, and type of malignancy (29).
Apart from restrictive side effects of single-agent NSAID regimens, it is vital to consider potential detrimental drug interactions that lead to reduced analgesic action of NSAIDs or reduced efficacy/enhanced toxicity of co-administered drugs. Such adverse interactions have indeed been reported from in vitro studies in human cell lines, in vivo studies using animal models, as well as from clinical trials. Leon-Reyes and co-workers have recently reported that a sulfonylurea antidiabetic drug, glibendamide, negatively affects pharmacodynamics of diclofenac (30), and many groups have suggested that high-doses of aspirin counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors (31). Moreover, low-dose aspirin combined with rofecoxib may lead to increase in gastrointestinal ulceration, and some NSAIDs reduce the natriuretic effect of furosemide and thiazides. In addition, NSAIDs can decrease renal lithium clearance, leading to elevated plasma lithium levels. There is also an increasing knowledge on the molecular mechanisms behind the reported interactions. For example, most NSAIDs are excreted into urine via organic anion transporter 3 (OAT3), and thus compete with other substrates of this transporter such as the antifolate drug methotrexate (32), leading to increased methotrexate serum concentrations and toxicity. Noteworthy, a number of advantageous drug interactions involving NSAIDs have also been reported, including improved cancer chemoprevention by a combination of low-dose statins and NSAIDs (33), and enhanced cancer cell killing by a combination of aspirin and histone deacetylase inhibitors (HDIs) (34) or TRAIL agonists (35).
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.