ArticleLiterature Review

Paracetamol (Acetaminophen) - a Popular and Widely Used Nonopioid Analgesic

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Abstract

For several decades paracetamol has proven its clinical efficacy and safety in the treatment of various acute and chronic pain states. Whereas its pharmacokinetic properties (high oral bioavailability, good penetration into the brain, relative rapid hepatic elimination) are well known, its exact central mode of action remains to be elucidated. According to many international guidelines/recommendations paracetamol is a drug of first choice for relieving mild to moderate pain. It has been successfully combined with opioids for severe pain. Due to its cardiovascular, renal and gastrointestinal safety paracetamol offers several advantages vs. NSAIDs. It should be realized that the maximum daily dose is restricted to 4 g to avoid unnecessary hepatic complications. Keeping this limitation in mind paracetamol still represents a valuable first-line agent in the pharmacological management of pain.

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... Acetaminophen (paracetamol) is a widely used nonprescription drug with analgesic and antipyretic properties that is effective for the symptomatic management of mild to moderate acute and chronic pain of diverse etiology. 1 Many international guidelines recommend acetaminophen for pain management because of its well-established efficacy and safety profiles across diverse patient populations. [1][2][3][4] For example, the American Geriatrics Society guidelines for the management of persistent pain in older adults state that acetaminophen is effective for the management of osteoarthritis pain and that the safety profile of acetaminophen at recommended doses is generally more favorable than that of nonsteroidal anti-inflammatory drugs in older patients. ...
... 1 Many international guidelines recommend acetaminophen for pain management because of its well-established efficacy and safety profiles across diverse patient populations. [1][2][3][4] For example, the American Geriatrics Society guidelines for the management of persistent pain in older adults state that acetaminophen is effective for the management of osteoarthritis pain and that the safety profile of acetaminophen at recommended doses is generally more favorable than that of nonsteroidal anti-inflammatory drugs in older patients. 3 The pharmacokinetic properties of acetaminophen have been studied extensively in various populations. ...
... 5,6 Acetaminophen is eliminated predominantly through hepatic metabolism, with an elimination half-life in adults of between 1.5 and 3.5 hours. 1,2,5,[7][8][9][10] In Mexico, there are currently more than 50 marketed products that contain acetaminophen, either alone or in combination with other drugs, and in different dosages and formulations. 11 However, despite such widespread availability of acetaminophen in Mexico, data on the pharmacokinetic properties of acetaminophen in Mexican populations are quite limited. ...
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Despite widespread availability of acetaminophen in Mexico, data on its pharmacokinetic properties in Mexican populations are limited. This single‐center, single‐blind, randomized, 2‐period, 2‐treatment, crossover, single‐dose‐per‐period, 2‐sequence study evaluated the bioequivalence of a test acetaminophen product available in Mexico compared with a reference 500‐mg acetaminophen product in 28 healthy adults under fasting conditions. Blood samples were collected predose and at specified intervals across a 16‐hour period following administration and were analyzed for acetaminophen using a validated reverse‐phase high‐performance liquid chromatography method. Drug products were considered to be bioequivalent if confidence intervals of natural log‐transformed Cmax, AUC0‐t, and AUC0‐∞ data were within the range of 80% to 125%. Results were inconclusive for Cmax due to high levels of intrasubject variability with this parameter. However, criteria for bioequivalence were met for AUC0‐t and AUC0‐∞. All measured acetaminophen concentrations in this study were within a safe therapeutic range, and no adverse events were reported. The level of Cmax intrasubject variability observed in this study does not have any apparent clinical implications that could affect either safety or efficacy.
... Acetaminophen (APAP) is an effective analgesic and antipyretic (1,2). APAP is safe at therapeutic doses, and higher doses can be provided to patients for short durations (3). ...
... The PYP fraction contains two proteins, PYP1 (10 kDa; an SDS-resistant dimer) and PYP2 (10 kDa) (34). Based on these results, the synthetic peptide PYP1 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) corresponding to the N-terminal 20 residues of PYP1 (ALEGGKSSGGGEATRDPEPT) has been obtained (34). PYP1 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) protects against APAP-induced apoptosis in HeLa (Chang Liver) cells, and has been determined to be the active fraction of PYP (34). ...
... Based on these results, the synthetic peptide PYP1 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) corresponding to the N-terminal 20 residues of PYP1 (ALEGGKSSGGGEATRDPEPT) has been obtained (34). PYP1 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) protects against APAP-induced apoptosis in HeLa (Chang Liver) cells, and has been determined to be the active fraction of PYP (34). ...
Article
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Acetaminophen (APAP) is a widely used analgesic and antipyretic. It is safe at normal treatment doses; however, APAP overdose is a major cause of acute liver and kidney failure. A variety of methods to reduce the damage caused by APAP overdose have previously been evaluated. The protein-rich seaweed Pyropia yezoensis has antioxidant, antitumor and anti-inflammatory activities, and protects against cytotoxicity. However, little is known regarding the protective effects of P. yezoensis peptide against APAP-induced hepatotoxicity. The present study investigated the ability of P. yezoensis peptide (PYP1-4) to ameliorate the damage caused by APAP-induced hepatotoxicity using HepG2 as the model cell line in addition to the signaling pathways involved. Briefly, cell viability, nitric oxide, reactive oxygen species and apoptosis assays were performed in conjunction with western blot analysis and reverse transcription-quantitative PCR. First, the present study revealed the minimum toxic concentration of APAP (15 mM) and the resting concentration of PYP1-4 (0-500 ng/ml). Administration of PYP1-4 to APAP-induced cells decreased the nitric oxide and reactive oxygen species levels, and restored the levels of antioxidant-associated proteins (catalase, heme oxygenase 1, superoxide dismutase 2 and quinone oxidoreductase 1). PYP1-4 increased the translocation of nuclear factor, erythroid 2 like 2 to the nucleus and the activities of glycogen synthase kinase-3β, Akt and AMP-activated protein kinase. In addition, APAP induced apoptosis; however, PYP1-4 inhibited apoptosis by modulating the levels of pro-apoptotic markers (Bad), anti-apoptotic markers (Bcl-2 and BH3 interacting domain death agonist), caspases and poly (ADP-ribose) polymerase 1. Subsequently, the insulin-like growth factor 1 receptor signaling pathway was investigated to determine whether PYP1-4 treatment restored the levels of cell growth-associated factors during APAP-induced hepatotoxicity. PYP1-4 treatment impacted the levels of components of the insulin receptor substrate 1/PI3K/Akt and Ras/Raf/ERK signaling pathways, and promoted cell survival. Therefore, the P. yezoensis peptide PYP1-4 may be useful for preventing APAP-induced hepatotoxicity.
... People worldwide use paracetamol (acetaminophen) more than any other analgesic [1][2][3] ; besides being readily available over-the-counter (OTC), its popularity rests on being generally well tolerated and considered safer than other analgesics when taken as directed, especially in high-risk users such as older people or adults with comorbidities 1-6 . Accordingly, international guidelines and medical experts consistently recommend paracetamol for first-line treatment of acute mild/ moderate pain [6][7][8] . ...
... Paracetamol has antipyretic and analgesic effects ( Figure 1), with complex mechanisms that distinguish it from non-steroidal anti-inflammatory drugs (NSAIDs) and opioids 1,2,6,9 . Its most common everyday uses in adults include headaches, and musculoskeletal, or menstrual pain 7 ; musculoskeletal pain and sprains/injury account for 45% of pain episodes for which adults may use OTC or prescription analgesics (Figure 2) 10 . ...
... However, if NAPQI accumulates faster than it is detoxified (e.g. due to paracetamol overdose or, hypothetically, in glutathione-depleted states) it can cause acute necrotic liver failure 4,6,23,24 . Theoretically, pathologies that affect this pathway could increase the risk of paracetamolinduced hepatotoxicity 25,26 ; for example, hyperglycemia and starvation induce CYP2E1 activity 27 , and malnutrition may deplete hepatic glutathione, potentially abating NAPQI detoxification 23,25 . ...
Article
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Acute pain is among the most common reasons that people consult primary care physicians, who must weigh benefits versus risks of analgesics use for each patient. Paracetamol (acetaminophen) is a first-choice analgesic for many adults with mild to moderate acute pain, is generally well tolerated at recommended doses (≤4 g/day) in healthy adults and may be preferable to non-steroidal anti-inflammatory drugs that are associated with undesirable gastrointestinal, renal, and cardiovascular effects. Although paracetamol is widely used, many patients and physicians still have questions about its suitability and dosing, especially for older people or adults with underlying comorbidities, for whom there are limited clinical data or evidence-based guidelines. Inappropriate use may increase the risks of both overdosing and inadequate analgesia. To address knowledge deficits and augment existing guidance in salient areas of uncertainty, we have researched, reviewed, and collated published evidence and expert opinion relevant to the acute use of paracetamol by adults with liver, kidney, or cardiovascular diseases, gastrointestinal disorders, asthma, or/and who are older. A concern is hepatotoxicity, but this is rare among adults who use paracetamol as directed, including people with cirrhotic liver disease. Putative epidemiologic associations of paracetamol use with kidney or cardiovascular disease, hypertension, gastrointestinal disorders, and asthma largely reflect confounding biases and are of doubtful relevance to short-term use (<14 days). Paracetamol is a suitable first-line analgesic for mild to moderate acute pain in many adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, and/or who are older. No evidence supports routine dose reduction for older people. Rather, dosing for adults who are older and/or have decompensated cirrhosis, advanced kidney failure, or analgesic-induced asthma that is known to be cross-sensitive to paracetamol, should be individualized in consultation with their physician, who may recommend a lower effective dose appropriate to the circumstances.
... Analgesic medicines for pain relief are among the most extensively consumed chemicals classified as ECs (Klotz, 2012). These types of drugs are highly soluble in water and are not completely metabolized in the human body (Boumya et al., 2021), meaning that their use may lead to significant damage to living organisms if contaminated waters are not treated properly (Klotz, 2012). ...
... Analgesic medicines for pain relief are among the most extensively consumed chemicals classified as ECs (Klotz, 2012). These types of drugs are highly soluble in water and are not completely metabolized in the human body (Boumya et al., 2021), meaning that their use may lead to significant damage to living organisms if contaminated waters are not treated properly (Klotz, 2012). It has been reported that ECs like acetaminophen at high concentrations (>1.8 μg/L) would be toxic to aquatic organisms (Klotz, 2012). ...
... These types of drugs are highly soluble in water and are not completely metabolized in the human body (Boumya et al., 2021), meaning that their use may lead to significant damage to living organisms if contaminated waters are not treated properly (Klotz, 2012). It has been reported that ECs like acetaminophen at high concentrations (>1.8 μg/L) would be toxic to aquatic organisms (Klotz, 2012). Therefore, developing methods for treating polluted water remains a challenge since conventional water and wastewater treatment plants (WTPs) are incapable of removing ECs (Daughton, 2014). ...
Article
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Preparing sustainable and highly efficient biochars as adsorbents remains a challenge for organic pollutant management. Herein, a novel nitrogen-doped carbon material has been synthesized via a facile and sustainable single-step pyrolysis method using a wild mixture of microalgae as novel carbon precursor. Phosphoric acid (H3PO4) was employed as activation agent to generate pores in the carbon material. In addition, the effect of melamine (nitrogen source) was evaluated over the biochar properties by the N-doping process. The results showed that the biochar's specific surface area (SSA) increased from 324 to 433 m2 g-1 with the N-doping process. The N-doping process increased the percentage of micropores in the biochar structure. Chemical characterization of the biochars indicated that the N-doping process helped to increase the graphitization process of the biochar and the contents of oxygen and nitrogen groups on the carbon surface. The biochars were successfully tested to adsorb acetaminophen and treat two synthetic effluents, and the N-doped biochar presented the highest efficiency. The kinetics and equilibrium data were well represented by the General-order model and the Liu isotherm model, respectively. The maximum sorption capacities attained were 101.4 and 120.7 mg g-1 for the non-doped and doped biochars, respectively. The acetaminophen adsorption mechanism suggests that the pore-filling was the dominant mechanism for acetaminophen uptake. The biochars could efficiently remove up to 74 % of the contaminants in synthetic effluents.
... treatment of pain and fever in adults and children (Bienert et al. 2012). At therapeutic doses, it is usually safe and well tolerated (Klotz 2012). Therapeutic concentrations for paracetamol range from 5 to 20 lg/mL (Bertolini et al. 2006). ...
... Severe DDIs have been observed between anti-cancer and pain management drugs (Lim et al. 2010;Weise et al. 2009), and also between acetaminophen and other TKIs (Liu et al. 2011;Nassar et al. 2010), resulting in hepatotoxicity due to inhibition of paracetamol glucuronidation and the shared pathway of transport to the liver. The guidelines of SIGN (Scottish Intercollegiate Guidelines Network 2008) and ESMO (European Society of Medical Oncology) (Ripamonti et al. 2011) recommend acetaminophen in cancer pain management, but the FDA (Food and Drug Administration) has expressed concerns about possible toxicity due to its common use (Klotz 2012). ...
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The study aimed to examine the effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite, paracetamol glucuronide. Both drugs share metabolic pathways in the liver, and the drug interactions between sunitinib and paracetamol administered in higher doses were reported. These interactions resulted in hepatotoxicity. The adult New Zealand male rabbits were divided into three groups (6 animals each): rabbits receiving sunitinib and paracetamol (SUN + PC), rabbits receiving sunitinib (SUN), and a control group receiving paracetamol (PC). Sunitinib was administered orally (25 mg) and paracetamol was administrated intravenously (35 mg/kg). Blood samples for sunitinib and SU12662 assays were collected up to 96 h after drug administration and for paracetamol and paracetamol glucuronide up to 300 min after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were analysed before and after drug administration. A number of pharmacokinetic parameters were analysed. There were no differences in the levels of AST, ALT, and bilirubin among the groups at either time point. Significantly higher values of AUC0–t , AUC0–∞ , and C max and lower clearance and volume of distribution of paracetamol were observed in group PC vs. group SUN + PC (p < 0.01). The maximum plasma concentration of paracetamol glucuronide tended to be higher in group PC 213.27 μg/mL (90 % CI 1.06, 1.25; p = 0.0267). Statistically significant differences were revealed for paracetamol glucuronide mean residence time (MRT); MRT was higher in group SUN + PC than in group PC (p = 0.0375). The mean t max of paracetamol glucuronide was similar in both groups: SUN + PC and group PC (15 and 20 min, respectively). The mean t max of sunitinib was different in groups SUN + PC and SUN (10.0 and 7.0, respectively; p = 0.0134). At the studied doses, neither of the drugs, whether administered alone or together, had hepatotoxic effects. The present study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect. Significant differences were observed in some pharmacokinetic parameters of paracetamol.
... Diseases are often associated with acute or chronic pain and fever and the first-line treatment recommended for pain management is paracetamol (acetaminophen, APAP) (7,8). APAP is therefore the analgesic and antipyretic drug the most commonly used in Europe/USA (9)(10)(11) and is considered as safe (7). ...
... Diseases are often associated with acute or chronic pain and fever and the first-line treatment recommended for pain management is paracetamol (acetaminophen, APAP) (7,8). APAP is therefore the analgesic and antipyretic drug the most commonly used in Europe/USA (9)(10)(11) and is considered as safe (7). APAP metabolism in the liver consists mainly in phase II detoxification (up to 90%) by direct sulfate or glucuronide conjugation of APAP. ...
Article
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The use of glutathione (GSH) and sulfate for the detoxification of paracetamol (acetaminophen, APAP) could occur at the expense of the physiological uses of cysteine (Cys). Indeed GSH and sulfate both originate from Cys. Significant APAP-induced Cys loss could generate alterations in GSH and protein metabolisms leading to muscle wasting. The study aimed to investigate the effects of chronic treatment with APAP on whole-body and tissue homeostasis (mass, GSH, proteins, and nitrogen balance) in relation to sulfur losses through APAP-detoxification pathways. Adult male Wistar rats were fed 0% APAP, 0.5% APAP or 1% APAP diets for 17 days. APAP doses were respectively around and largely above the threshold of sulfation saturation for rats. During the last days, the rats were placed in metabolic cages in order to quantify N balance and urinary APAP metabolites. Gastrocnemius muscle mass, protein and GSH contents, N balance and plasma free cyst(e)ine were 8% (P=0.02), 7% (P=0.03), 26% (P=0.01), 37% (P=0.01), and 33% (P=0.003) lower in the 1% APAP group than in the 0% APAP group, respectively. There was no significant difference in these parameters between the 0.5% APAP group and the 0% APAP group. Muscle wasting occurred when the detoxification of APAP through the GSH-dependent pathway was highly activated. Muscle protein synthesis could have been reduced due to a shortage in Cys and/or an increase in protein degradation in response to intra-muscular oxidative stress. Hence, without dietary sulphur amino acid increase, peripheral bioavailability of Cys and muscle GSH are potential players in the control of muscle mass under chronic treatment with APAP, an analgesic medication of widespread use, especially in the elderly.
... Paracetamol (acetaminophen) is a commonly used drug taken to alleviate pain and reduce fever [13]. It acts on several mechanisms, for instance, by lowering prostaglandins (e.g., inhibiting their cyclooxygenase-mediated production), activating descending serotonergic pathways, and modulating cannabinoid signaling (e.g., conjugating with the arachidonic acid to inhibit the reuptake of the anandamide, an endogenous ligand of CB1 receptors, from the synaptic cleft, hence increasing cannabinoid receptor activation on the post-synaptic membrane) [14]. ...
... Albeit being one of the most prescribed medications today [13], the CNS effects of paracetamol in vivo remain poorly understood. For example, some rodent evidence indicates that paracetamol may modulate emotional behavior [15]. ...
Article
Typically triggered by stress, anxiety disorders are most common and widespread mental illnesses. The zebrafish (Danio rerio) is rapidly becoming an important aquatic model species in stress research and central nervous system (CNS) drug screening. Paracetamol is currently the most prescribed medication for pain and fever, and is among the most commonly used drugs globally. However, its CNS effects, especially on anxiety in clinical and animal studies, remain poorly understood. Capitalizing on zebrafish as a powerful model system, here we evaluate the effects of paracetamol on anxiety-like behavior in adult fish, and its changes following an acute stress exposure. Overall, we report an anxiolytic-like profile of acute paracetamol, and its alleviation of stress-evoked anxiety, in adult short-fin wild type zebrafish. Collectively, these findings suggest complex neuroactive effects of paracetamol, and reinforce the growing importance of zebrafish models for drug screening, including the search for novel anti-stress therapies.
... Paracetamol is a valuable first-line drug for relieving mild to moderate pain and has been successfully combined with opioids for the management of severe pain. [1][2][3] Dose administration aids (DAAs) are used to manage medications for patients in their homes and for residents in aged care and other facilities. The level and type of care often determines which medicines are repacked and the type of DAAs used. ...
Article
Background Paracetamol tablets are often repackaged into dose administration aids (DAAs) for prn use. Pharmacists have limited information regarding the long-term stability of prn medicines stored in DAAs for extended periods due to infrequent dosing. According to current guidelines, in the absence of specific data, medicines should not be stored in a DAA for longer than 8 weeks.AimTo determine the physicochemical stability of paracetamol tablets repackaged into DAAs and stored for 12 months.Method Paracetamol (Panamax) tablets were removed from primary packaging, repackaged into DAAs (Multi Dose Webster-pak) and stored under ambient (25 °C; 60% relative humidity) and accelerated (40 °C; 75% relative humidity) conditions for 12 months. Physical characteristics of the tablets, such as appearance, weight uniformity, thickness, hardness, friability, disintegration and dissolution rates were evaluated at baseline, 3, 6 and 12 months. Chemical stability was confirmed by high performance liquid chromatography.ResultsAll compendial requirements for physical stability were met for tablets stored under ambient and accelerated conditions over the 12-month period. Chemical stability was confirmed, with paracetamol content in the tablets within the British Pharmacopoeial range of 95% to 105% of the labelled amount.Conclusion This study provides data on the stability of paracetamol tablets repackaged into DAAs and stored under ambient and accelerated conditions for 12 months. Pharmacists will be able to make risk-benefit assessments and recommend a 12-month expiry on paracetamol prn DAAs.
... Paracetamol is a valuable first-line drug for relieving mild-to-moderate pain and has been successfully combined with opioids for the management of severe pain. [1][2][3] Dose administration aids (DAAs) are used to safely manage medication for patients in their homes and for residents in aged care. The level and type of care often determines which medicines are repacked and the type of DAAs used. ...
... Acetaminophen (APAP) is commonly used as an analgesic and antipyretic agent (1)(2)(3), and is considered safe at therapeutic doses (4). It is readily available, and high doses of APAP may be provided to patients over a short time-period. ...
Article
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Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Generally, the therapeutic dose of APAP is clinically safe, however, high doses of APAP can cause acute liver and kidney injury. Therefore, the majority of previous studies have focussed on elucidating the mechanisms of APAP‑induced hepatotoxicity and nephrotoxicity, in addition to examining ways to treat these conditions in clinical cases. However, few studies have reported APAP‑induced intoxication in human stem cells. Stem cells are important in cell proliferation, differentiation and repair during human development, particularly during fetal and child development. At present, whether APAP causes cytotoxic effects in human stem cells remains to be elucidated, therefore, the present study aimed to investigate the cellular effects of APAP treatment in human stem cells. The results of the present study revealed that high‑dose APAP induced more marked cytotoxic effects in human mesenchymal stem cells (hMSCs) than in renal tubular cells. In addition, increased levels of hydrogen peroxide (H2O2), phosphorylation of c‑Jun N‑terminal kinase and p38, and activation of caspase‑9/‑3 cascade were observed in the APAP‑treated hMSCs. By contrast, antioxidants, including vitamin C reduced APAP‑induced augmentations in H2O2 levels, but did not inhibit the APAP‑induced cytotoxic effects in the hMSCs. These results suggested that high doses of APAP may cause serious damage towards hMSCs.
... Acetaminophen (APAP) is widely used clinically as an antipyretic and analgesic medicine (1)(2)(3). Generally, APAP is considered to be safe when used within the therapeutic dose range; however, APAP overdose can cause liver and renal damage (4)(5)(6). Because APAP is cheap and readily available, patients may overdose easily, leading to reports of self-poisoning in numerous countries (7)(8)(9). ...
Article
Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide anti‑inflammatory, anti‑microbial, anti‑oxidative and anti‑diarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAP‑induced renal cell damage. In the present study, extracts from guavas were obtained and added to APAP‑treated renal tubular endothelial cells. The present results demonstrated that APAP induces cytotoxicity in renal tubular endothelial cells, while guava extracts inhibited this cytotoxicity. In addition, the study demonstrated that the protective effects of guava extracts against APAP‑induced cytotoxicity may be associated with inhibition of oxidative stress and caspase‑3 activation.
... [59] Acetaminophen is an alternative that can be considered as it does not increase the risk of GI ulcers and has been shown to have a more favorable side effect profile compared to NSAIDs while reducing opioid consumption and pain scores in patients undergoing bariatric surgery. [60][61][62] NMDA antagonists, including ketamine and magnesium, have been shown to reduce morphine consumption without increasing pain scores in patients undergoing bariatric surgery. [63,64] However, further research is necessary to determine whether postoperative pulmonary complications can be reduced with their use. ...
Article
The prevalence of patients with obesity continues to rise worldwide and has reached epidemic proportions. There is a strong correlation between obesity and sleep-disordered breathing (SDB), and, in particular, obstructive sleep apnea (OSA). OSA is often undiagnosed in the surgical population. Bariatric surgery has been recognized as an effective treatment option for both obesity and OSA. Laparoscopic bariatric procedures, particularly laparoscopic sleeve gastrectomy (LSG), have become the most frequently performed procedures. OSA has been identified as an independent risk factor for perioperative complications and failure to recognize and prepare for patients with OSA is a major cause of postoperative adverse events, suggesting that all patients undergoing bariatric surgery should be screened preoperatively for OSA. These patients should be treated with an opioid-sparing analgesic plan and continuous positive airway pressure (CPAP) perioperatively to minimize respiratory complications. With the number of bariatric surgical patients with SDB likely to continue rising, it is critical to understand the best practices to manage this patient population.
... It inhibits cyclooxygenase (COX) in the arachidonic acid pathway. The central inhibition of the COX-1 and COX-2 isoforms gives an analgesic effect [10][11][12]. Ayoub et al. [13] proved that paracetamol reduced the concentration of PGE 2 prostaglandins in the brain. Pickering et al. [14] proved that paracetamol affected the serotonergic system by connecting it with 5-HT3 receptors. ...
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Background and Objective Sorafenib is an oral, multikinase inhibitor with established single-agent activity in several tumor types. Sorafenib was moderately transported by P-glycoprotein (P-gp) and more efficiently by breast cancer resistance protein. The constitutive androstane receptor (CAR) is a ligand-activated transcription factor involved in P-gp regulation in the brain microvasculature. Paracetamol is a CAR activator. The purpose of this study was to investigate the effect of paracetamol on the brain uptake of sorafenib and sorafenib N-oxide.Methods The rats were assigned to two groups—rats receiving oral paracetamol 100 mg/kg and sorafenib 100 mg/kg (n = 42, ISR+PA) and rats receiving oral vehicle and sorafenib 100 mg/kg (n = 42, IISR). The sorafenib and sorafenib N-oxide concentrations in blood plasma and brain tissue were determined by a high-performance liquid chromatography method with ultraviolet detection. Brain-to-plasma partition coefficient (Kp) was calculated as a ratio of the area under the curve from zero to 24 h (AUC) in the brain and plasma. A drug targeting index (DTI) was estimated as the group ISR+PA Kp to group IISR Kp ratio.ResultsPharmacokinetic analysis revealed increased brain exposure to sorafenib and sorafenib N-oxide after co-administration of paracetamol. The brain maximum concentration (Cmax) and the AUC of the parent drug in the ISR+PA group compared with the IISR group were greater by 49.5 and 77.8%, respectively, and the same parameters for the metabolite were higher by 51.4 and 50.9%. However, the Kp values of sorafenib and sorafenib N-oxide did not differ significantly between the two animal groups and the DTI values were close to 1.Conclusion Paracetamol increases exposure to sorafenib and sorafenib N-oxide in the brain, likely due to increased exposure in plasma.
... PA was one of the eighteen PPCPs found in a Shallow lake-China, while both MF and PA were of the thirteen PPCPs found in the red-sea water 33,34 . In addition, PA consumption is expected to increase enormously as it had been recommended to treat the symptoms of the COVID-19 pandemic [35][36][37][38][39] . Natural clay is a safe and low-cost material, making it a suitable alternative to nano-sorbents if it has an adequate adsorption capacity. a natural clay NC was collected from the Eldoushain area, Nile river state, Sudan (16°45′43.1″N ...
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Natural clays are considered a safe, low-cost, and sound sorbent for some pharmaceutical and body care products from water. Metformin (MF) and paracetamol (PA) are of the most consumable drugs worldwide. A portion of natural clay was treated with distilled water, and another part was treated with hydrochloric acid. The water-treated clay (WTC) and the acid-treated clay (ATC) were characterized by scanning electron microscopy-energy dispersive spectroscopy, X-ray diffraction, Fourier transforms infrared spectroscopy, and nitrogen adsorption isotherm. Batch experiments were employed to investigate the influence of contact time and solution parameters on the adsorption of PA and MF on WTC and ATC. 30 min attained the equilibrium for all sorbent-sorbate systems. Both sorbents fitted the pseudo-second-order kinetic model with a preference to the nonlinear fitting, and the mechanism of adsorption partially fitted the liquid-film diffusion model. The PA and MF adsorption on WTC and ATC fitted the Freundlich model in preference to nonlinear fitting. The adsorption of pollutants on both sorbents was spontaneous, exothermic, and physisorption in nature. Even at low concentrations, both WTC and ATC showed efficiency above 80% in removing PA and MF from tab water, groundwater, and Red seawater. These findings nominated natural clay as an alternative to the costly nanomaterials as sorbents for removing pharmaceutical contaminants from water.
... 69 Acetaminophen, or paracetamol, can be considered to have a more favorable side-effect profile compared with NSAIDs because it is well-established that it does not increase the risk of GI ulcers or renal insufficiency. 70 Multiple studies have shown Copyright r 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes. ...
... acetaminophen (also known as paracetamol) is one of the widely used over the counter and prescribed medicines for curing pain and fever around the world for many decades. This is also the drug choice in children under 12 years of age as an antipyretic and analgesic drug (Klotz 2012;Marzuillo et al. 2014;Jóźwiak-Bebenista and Nowak 2014). Acetaminophen's mechanism of action has not completely been elucidated. ...
Article
Jelly candy is a novel and promising method for advanced drug delivery, especially among children due to the enjoyable taste of candy products. The anti-fever and analgistic properties of acetaminophen in the effective treatment of mild to moderate pain has been well-studied over the past few decades. This study aims to prepare a novel dosage form of acetaminophen nanoparticles jelly candies that are suitable for children to consume. Polyethylene glycol 6000 was dissolved in distilled water and then acetaminophen powder dissolved in ethanol, added rapidly to the stirring solution of polyethylene glycol 6000. Gelling agents consisting of gelatin and starch were added to the nanoparticle solution. The final solution was stirred well and allowed to dry at refrigerator temperature for 24 h. Characterization tests such as DSC, FT-IR spectroscopy, surface electron microscopy (SEM) and transmission electron microscopy (TEM) imaging, and release profiles of both nanoparticles and jelly candies were done. FT-IR results confirmed the formation of nanoparticles. The size of the synthesized nanoparticles was about 38–50 nm. Cumulative drug release of the nanoparticles in the jelly candies was about 74% after 24 h, the the nanoparticles’ release profile obeys the Hixon–Crowell model, and the jelly candies show first-order release profiles. The oral jelly candies loaded with nanoparticles can be the next generation of novel dosage forms of acetaminophen because of their ease of consumption and higher compliance among children than the conventional oral tablets. Further studies are needed to confirm these findings.
... Acetaminophen has an established record of safety when taken according to the recommended therapeutic dose range [9]. However, the use of acetaminophen at levels exceeding the maximum daily dose is a well-document leading cause of hepatotoxicity and acute liver failure [7,10]. ...
Article
Abstract Objective A narrative review of randomized, blinded, controlled studies assessing the antipyretic effect of ibuprofen versus acetaminophen or combined or alternating treatment in children was conducted. Methods Searches of the PubMed and Embase literature databases were conducted to identify relevant articles. Selected articles were limited to studies published in English that investigated OTC oral tablet and syrup formulations of acetaminophen and ibuprofen; there were no publication date limits. Open-label studies, nonrandomized studies, and those evaluating intravenous or suppository formulations of acetaminophen or ibuprofen were excluded. Variations in designs, endpoints, methods, and patient populations precluded our ability to conduct a formal systematic review. Results At physician-directed dosing (acetaminophen 15 mg/kg vs ibuprofen 10 mg/kg), no significant differences in antipyretic effects from 0‒6 hours and between 0‒6, ‒12, ‒24, or ‒48 hours, with single or multiple-doses, respectively, were observed. Tolerability profiles at physician dosing were similar. In 14 over-the-counter dose comparisons (acetaminophen, 10–15 mg/kg; ibuprofen, 2.5–10 mg/kg), antipyresis favored ibuprofen in 6, was similar between groups in 7, and favored acetaminophen (15 mg/kg vs ibuprofen 5 mg/kg) in 1 comparison. Both medications were well tolerated. Efficacy favored combination over individual components in 3 of 4 studies; alternating use results were mixed. All combination or alternating treatments were well tolerated. Conclusions Antipyretic effects of ibuprofen and acetaminophen are similar at physician-directed doses; ibuprofen may be modestly superior at over-the-counter doses.
... Research, Society and Development, v. 10, n. 11, e30101119308, 2021 (CC BY 4. Research, Society and Development, v. 10, n. 11, e30101119308, 2021 (CC BY 4. Research, Society and Development, v. 10, n. 11, e30101119308, 2021 (CC BY 4. Research, Society andDevelopment, v. 10, n. 11, e30101119308, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i11.19308 12 Kartikasari, Suryajaya,Sintoro, 2020 (2011) com Rosa centifolia, Rosa damascena, sálvia, gerânio e Hur, Lee, Seong e Lee (2012) associando com sálvia, manjerona, canela e gerânio. Torna-se importante ressaltar, que neste último o uso da combinação de OEs foi comparado com o Paracetamol, medicamento de primeira escolha no alívio de dores leves a moderadas, como cefaleias, dores musculares, estados gripais, dores leves de artrite, dor de dente, cólicas menstruais e redução da febre, sendo eficaz em todas as idades e que há anos vem provando sua eficácia clínica e segurança como analgésico (Klotz, 2012), mesmo assim, como resultado, a combinação de OEs se mostrou mais eficiente. ...
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Esta revisão tem como objetivo reunir evidências para identificar os possíveis benefícios do uso de OEs associado à fisioterapia para o alívio da dor na dismenorreia. Para a definição da questão de pesquisa de forma estruturada foi utilizado o formato do acrônimo PICO e o processo de busca de publicações apropriadas foi totalmente documentado pelos itens de Relatórios Preferenciais para Revisões Sistemáticas e Meta-Análise (PRISMA). Os artigos selecionados estudaram a utilização de variados OEs, sejam sozinhos ou em associação. Além da massagem como principal técnica, também foi encontrada a utilização de compressas quentes associadas a OEs para o alívio da dor. De maneira geral, os manuscritos revisados encontraram resultados positivos, mostraram que os OEs apresentam grandes benefícios no tratamento da DP. O uso dos OEs associado à fisioterapia, potencializa o tratamento e ameniza o quadro álgico nas mulheres acometidas por DP. Por outro lado, nenhum dos estudos mencionou ou apresentou dados a respeito da DS.
... Headache is a common side effect of AVA and paracetamol (PAR) is the most widely used analgesic drug. 55,56 The proposed method was also showed good resolution between AVA and paracetamol as a co-administered analgesic drug in spiked plasma (Fig. 10B). The interference of excipients that present in the pharmaceutical preparations (e.g. ...
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A sensitive voltammetric technique for the determination of avanafil (AVA) has been investigated at a carbon paste electrode modified with Zinc oxide nanoparticles and multi-walled carbon nanotubes (ZnO-NPs/MWCNT/CP). The study investigated the electrochemical behavior of AVA, and the morphology of the modified electrode was evaluated by transmission electron microscopy, scanning electron microscopy, and X-ray diffraction patterns. The influence of different electrodes and the content of ZnO-NPs on the voltammetric behavior of AVA were evaluated. Square wave voltammetry was studied and a linear correlation resulted within the range of (1.3–16 μg ml⁻¹) with correlation coefficient 0.999, LOD 0.342 μg ml⁻¹ and LOQ 1.141 μg ml⁻¹. The proposed procedure was applied successfully for the determination of AVA with good recovery in commercial dosage form and human plasma. The technique was validated and found to be accurate and reproducible according to the ICH guidelines.
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Background/Aims: Acetaminophen (APAP) effects on intestinal barrier properties are less investigated. APAP may lead to a changed bioavailability of a subsequently administered drug or diet in the body. We investigated the influence of APAP on enterocytic cell membrane properties that are able to modify the net intestinal absorption of administered substances across the Caco-2 barrier model. Methods: The effect of APAP on cytotoxicity was measured by LDH assay, TER value and cell capacitance label-free using impedance monitoring, membrane permeability by FITC-dextrans, and efflux transporter MDR1 activity by Rh123. APAP levels were determined by HPLC analysis. Cell membrane topography and microvilli were investigated using SEM and intestinal alkaline phosphatase (Alpi) and tight junction protein 1 (TJP1) expression by western blot analysis. Results: APAP changed the apical cell surface, reduced the number of microvilli and protein expression of Alpi as a brush border marker and TJP1, increased the membrane integrity and concurrently decreased cell capacitance over time. In addition, APAP decreased the permeability to small molecules and increased the efflux transporter activity, MDR1. Conclusion: APAP alters the Caco-2 cell membrane properties by different mechanisms and reduces the permeability to administered substances. These findings may help to optimize therapeutic implications. © 2013 S. Karger AG, Basel.
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Acetaminophen (APAP), is a safe analgesic and antipyretic drug at therapeutic dose, and is widely used in the clinic. However, high doses of APAP can induce hepatotoxicity and nephrotoxicity. Most studies have focused on high‑dose APAP‑induced acute liver and kidney injury. So far, few studies have investigated the effects of the therapeutic dose (1/10 of the high dose) or of the low dose (1/100 of the high dose) of APAP on the cells. The aim of this study was to investigate the cellular effects of therapeutic- or low‑dose APAP treatment on hepatoma cells and kidney fibroblasts. As expected, high‑dose APAP treatment inhibited while therapeutic and low‑dose treatment did not inhibit cell survival of kidney tubular epithelial cells. In addition, therapeutic-dose treatment induced an increase in the H2O2 level, activated the caspase‑9/‑3 cascade, and induced cell apoptosis of hepatoma cells. Notably, APAP promoted fibroblast proliferation, even at low doses. This study demonstrates that different cellular effects are exerted upon treatment with different APAP concentrations. Our results indicate that treatment with the therapeutic dose of APAP may exert an antitumor activity on hepatoma, while low‑dose treatment may be harmful for patients with fibrosis, since it may cause proliferation of fibroblasts.
Article
Rezeptfreie Analgetika gehören zu den am häufigsten verkauften Arzneimitteln. Sie werden zur akuten symptomatischen Behandlung von leichten bis mäßig starken Schmerzen und Fieber eingenommen. Welche Vorteile haben Fixkombinationen mit ASS, Paracetamol und/oder Coffein? Wann sind sie indiziert? Die Autoren haben zur Beantwortung dieser Fragen relevante klinische Studien herangezogen.
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NF-E2 p45-related factor 2 (Nrf2) is a cap ‘n’ collar (CNC) basic region-leucine zipper (bZIP) transcription factor that imparts cellular defence against xenobiotic and oxidative stress evoked responses by inducing an array of cytoprotective genes. Essential factors that regulate Nrf2 activity and stability during analgesic nephropathy are incompletely understood. In this study, we demonstrate that acetaminophen (a classic analgesic) posit nephrotoxicity both in vitro and in vivo via PHLPP2 activation. Enhanced PHLPP2 levels down regulate p-Akt by dephosphorylating it at Ser473 residue leading to Gsk3β activation. APAP subsided Nrf2 nuclear accumulation by activating Gsk3β which phosphorylates Fyn kinase. p-Fyn kinase translocates into the nucleus and phosphorylates Nrf2 (Tyr 568) leading to its nuclear export, ubiquitination and degradation. Therefore, poor prognosis prevails during analgesic nephrotoxicity because of the defects in Akt-1/Gsk3β/Fyn-Nrf2 signaling pathway. Morin, a bioflavonoid given as co- and pre-treatment with acetaminophen significantly prevented the toxicity induced damage by constitutively stabilizing Nrf2 nuclear retention. Diminished Nrf2 levels by APAP overdose imposed severe proximal tubular damage leading to apoptotic cell death. Morin, as a potent Nrf2 inducer accorded protection against acetaminophen induced renal damages by its molecular intervention with Akt-1/Gsk3β/Fyn kinase pathway via PHLPP2 de-activation.
Article
Myriad of therapeutic drugs used in clinical practice have led to hepatotoxicity reporting more than 1,100 pharmaceutical and chemical products with liver injury. Drug-induced liver damage reports for 7% of adverse reactions, 2% jaundice, 1% acute liver failure, and more acute hepatitis and account for approximately 40,000 deaths per annum in 17 countries. Considering the prominence of drug-induced hepatotoxicity, this review focuses on providing an overview of the plausible mechanisms of action of various intrinsic and idiosyncratic hepatotoxic drugs that involve various molecular and cellular elements in hepatotoxicity and cell death. Also, we discussed their hepatotoxicity control treatments.
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Background: Selective cyclooxygenase-2 (COX-2) inhibitors, conventional non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen have been adopted for the relief of mild to moderate acute and chronic pain. However, it remains unclarified whether the therapeutic differences in pain sensation exist among these agents. The aim of this study was to compare the efficacy of different types of analgesic agents for postoperative acute pain management. Methods: A single-center, randomized, controlled study was performed in consecutive patients who underwent the second-look procedure with removal of internal fixation after anterior cruciate ligament reconstruction or arthroscopic meniscal repair/meniscectomy. Celecoxib (400 mg for the first dose and then 200 mg), loxoprofen (60 mg), or acetaminophen (600 mg) was orally administered from postoperative 3 h. The pain intensity on a 100-mm VAS scale and subjective assessment of therapeutic pain-relief were compared among these three treatment groups until postoperative 2 days. The acquired data were analyzed according to the per-protocol analysis principle. Results: A total of 432 patients were screened, and 160 were enrolled. The VAS score tended to decrease over time in all groups. There was a significant improvement in the pain score both at rest and on movement, and subjective impression in the celecoxib-treated group compared with acetaminophen at postoperative 2 days. On the other hand, loxoprofen resulted in the benefit only in the pain score at rest in comparison with acetaminophen. Any comparisons between celecoxib and loxoprofen showed insignificant differences throughout observations. No adverse effects were confirmed in each group. Conclusions: These obtained findings in our dose setting conditions suggest that celecoxib and loxoprofen treatments were superior to acetaminophen in pain-relief, though the superiority of loxoprofen over acetaminophen was modest. Overall, selective COX-2 inhibitors including conventional NSAIDs seem to have a possible advantage in acute pain management of relatively less invasive surgery.
Article
The interaction of N-(2-hydroxyphenyl)acetamide with methyl(organyl)dichlorosilanes RMeSiCl2 (R = Me, Vinyl, Ph) lead to the formation of 5-membered silaheterocyclic benzoxazasiloles 1a-3a. According to data of NMR and FTIR spectra these compounds exist in equilibrium with 7-membered cyclic benzodioxazasilepines 1b-3b which have the imidate structure. The structure of compound 1a was proved by X-ray analysis. Compounds 1a-3a are hydrolyzed to form silanols 4–6. 3-Acetyl-2,2-dimethyl-2,3-dihydro-1,3,2-benzoxazasilole 1a react with methanol and isopropanol and transform into silanes 7 and 8.
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While being a safe over the counter drug, paracetamol has also proved to be a cytotoxic agent for cultured hepatocellular carcinoma cells (HepG2). In order to understand the biochemical mechanisms underlying its cytotoxic ability, molecular docking of paracetamol with cyclin dependent kinase 2 protein (CDK2) and breast cancer type 2 susceptibility protein (BRCA2) plus cyclooxygenase 1 (COX1) enzyme protein was undergone. Computational simulation was performed using Schrödinger software to describe the details of binding between atoms of the active sites and paracetamol. All COX1, CDK2 and BRCA2 proteins showed binding scores with paracetamol. Their G-scores were -5.32, -5.61 and -6.08 respectively leading to selective inhibition of these proteins and loss of their cell cycle related activity. The binding strength of COX1 and CDK2 with paracetamol was mainly dependent on the hydrophobic residues, while that of BRCA2 was contributed to charged residues. Binding is responsible for the subsequent loss of activity of these cell cycle related proteins and eventual cancer cell death via apoptosis.
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The optimisation of nutritional support for the growing number of older individuals does not usually take into account medication. Paracetamol (acetaminophen; APAP) is the first intention treatment of chronic pain that is highly prevalent and persistent in the elderly. Detoxification of APAP occurs in the liver and utilises sulfate and glutathione (GSH), both of which are issued from cysteine (Cys), a conditionally indispensable amino acid. The detoxification-induced siphoning of Cys could reduce the availability of Cys for skeletal muscle. Consequently, APAP could worsen sarcopenia, an important component of the frailty syndrome leading to dependency. The present review provides the rationale for the potential pro-sarcopenic effect of APAP then recent results concerning the effect of chronic APAP treatment on muscle mass and metabolism are discussed. The principal findings are that chronic treatments with doses of APAP comparable with the maximum posology for humans can increase the requirement for sulfur amino acids (SAA), reduce Cys availability for muscle, reduce muscle protein synthesis and aggravate sarcopenia in animals. One clinical study is in favour of an enhanced SAA requirement in the older individual under chronic treatment with APAP. Few clinical studies investigated the effect of chronic treatment with APAP combined with exercise, in nutritional conditions that probably did not affect Cys and GSH homeostasis. Whether APAP can aggravate sarcopenia in older individuals with low protein intake remains to be tested. If true, nutritional strategies based on enhancing Cys supply could be of prime interest to cut down the pro-sarcopenic effect of chronic treatment with APAP.
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Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation ( α ), conversion of healthy to stressed cells ( β ) and further sensitization of stressed cells towards necrotic pathways ( γ ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α / β (fast proliferation), combined with a large γ / β (slow death) have the lowest probabilities of tissue survival. At large α / β , tissue fate can be described by a critical γ / β* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N . Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.
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Aufgrund hoher Verordnungszahlen und der häufigen Selbstmedikation mit rezeptfrei erhältlichen Nichtopioidanalgetika ist die Berücksichtigung dieser Arzneistoffgruppe bei der Beurteilung der gesamten Medikation eines individuellen Patienten von Bedeutung. Dieser Beitrag beschreibt grundlegende pharmakologische Kenngrößen und charakteristische Nebenwirkungen dieser Analgetika. Eine weitere Einteilung der Nichtopioide kann anhand der zusätzlich zur Analgesie zu erreichenden Effekte erfolgen. Eine antipyretische und antiphlogistische Wirkung weisen dabei Acetylsalicylsäure in analgetischer Dosierung, die traditionellen nichtsteroidalen Analgetika/Antiphlogistika sowie die Coxibe auf. Metamizol und Paracetamol sind Analgetika mit antipyretischer Wirkung, wobei Metamizol zusätzlich spasmolytisch wirkt. Rein analgetisch wirken Capsaicin und das intrathekal zu applizierende Ziconotid.
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The advantage of paracetamol (acetaminophen) is that it can be administered via the oral, intravenous or rectal routes. The last mentioned differs from the oral route in the slow and irregular absorption of the active substance. At therapeutic concentrations, the pharmacokinetics of paracetamol are linear - that is, independent of the dose, and constant with repeated administration. The efficacy of paracetamol has been demonstrated in a wide variety of acute or chronic painful syndromes. In adults, the optimum unit dose is 1g. The maximum daily dosage is 4g, consistent with the decline in analgesic activity, which is usually over 6 hours. With effervescent tablets, drug absorption and onset of action are more rapid than with conventional tablets. However, there is no direct correlation between serum concentrations of paracetamol and its analgesic or antipyretic effect. Paracetamol is the non-opiate analgesic of choice in elderly persons or patients with chronic renal insufficiency, and it is usually not necessary to reduce the dosage in such individuals, even though clearance is reduced. Although the bioavailability of paracetamol is not impaired in patients with chronic, benign liver diseases, the agent is contraindicated in those with hepatic insufficiency. It can be used during pregnancy and lactation. The very low level of paracetamol binding to plasma proteins, together with its hepatic metabolism, mainly through glucuronide or sulphate conjugation, account for the low risk of drug interactions with paracetamol, particularly with antivitamin K. When added to a traditional non-steroidal anti-inflammatory drug, paracetamol enhances the analgesic effect or allows the use of lower doses. It is more difficult to define the ideal dosage of paracetamol in children, because of the influence of age on its pharmacokinetics, and the relatively erratic bioavailability of suppositories. An oral dose of 15 mg/kg every 4 hours, up to a total of 60 mg/kg/day, is usually sufficient to achieve the desired analgesic or antipyretic effect.
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To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age. After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM. One hundred and fifty-nine blood samples from 33 children aged 1.8-15 yr, weight 13.7-56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V(1) (central volume of distribution), Q (inter-compartmental clearance), and V(2) (peripheral volume of distribution) were: 16.51×(WT/70)(0.75), 28.4×(WT/70), 11.32×(WT/70)(0.75), and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V(1) and V(2) in litres). In children aged 1.8-15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V(1), V(2)).
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Acetylcysteine has been utilized successfully in the treatment of acetaminophen overdose since the 1970s. Although prospective trials as to efficacy and safety of acetylcysteine were conducted, there were no randomized controlled trials. This commentary addresses the reasons for this, and the background to choice of dose of acetylcysteine utilized in the oral and IV dosing regimens. Nomograms to predict possible hepatotoxicity based upon time of ingestion of acetaminophen were developed from a relatively arbitrary definition of toxicity as an aspartate aminotransferase/alanine aminotransferase (ALT/AST) greater than 1000 IU/L. While these have proved generally useful, patients still continue to develop hepatic damage after acetaminophen overdose, particularly if they present late after ingestion. The optimum management of these patients remains unclear, and one area of uncertainty is the dose and duration of acetylcysteine in various circumstances. This article discusses the issues that need to be elucidated to better target changes in acetylcysteine dose. The potential for measurements of other markers to improve treatment selection is the subject of further research.
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TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1(-/-) mice. The electrophilic metabolites N-acetyl-p-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-p-benzoquinoneimine metabolite L-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1(-/-) mice. Intrathecal injection of a non-electrophilic cannabinoid, Δ(9)-tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. Our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.
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The aims of this report are to quantify and compare competing risks associated with the use of non-prescription analgesics (daily doses of acetaminophen ≤ 4000 mg, aspirin ≤ 4000 mg, ibuprofen ≤ 1200 mg, naproxen ≤ 660 mg and ketoprofen ≤ 75 mg) and identify research needs. Literature was searched and organized by medication, adverse effect and direction of effect. Causality was determined using structured consensus, using IOM and GRADE nomenclature. Magnitude of risk data were extracted from primary sources. Structured consensus were used to construct a list of research priorities. The available data favor acceptance of a causal relationship between each of the five analgesics studied and at least one specific form of harm. Dosing in excess of the non-prescription limits is associated with increased risk. Existing data do not support precise estimates of population or individual patient attributable risks for most analgesic and organ system combinations, and as a result competing risks cannot be adequately assessed. The highest priority research needs included understanding 'real world' dosing and how co-morbidities and prodromal symptoms modify exposure. Although generally safe, all non-prescription analgesics are associated with some harm, particularly when recommended dosing limits are exceeded. Research to quantify the competing risks of different analgesic strategies is urgently needed.
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Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings. We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment. This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary.
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To evaluate the evidence surrounding the use of combinations of paracetamol and ibuprofen in the treatment of fever. Systematic narrative review of randomised controlled trials using the UK Economic and Social Research Council guidance on the conduct of narrative synthesis. Inpatient, outpatient and home care. Children with fever. The effect of combination treatments of paracetamol and ibuprofen on fever and comfort, and identification of side effects. Seven studies were identified, six of which provided useful data for the evaluation of the effect of treatment on temperature. Overall these studies showed limited benefit from the combined treatment until around 4 h, after which there was a statistically but only marginally clinically significant benefit. Two studies contained data directly relating to comfort; these suggest a marginal benefit from the combined treatment, but the clinical significance of this was limited. There was no evidence of greater side effects or toxicities associated with the combined treatment. However, it is important to note that these studies were small, short term, and not conducted in the normal setting in which these treatments are given. There is little evidence of any benefit or harm from the combined treatment compared with the use of each drug alone. In the absence of such benefit, there is little to recommend the unnecessary use of polypharmaceutical methods to treat a symptom that does not require treatment, when effective monotherapies exist.
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Prescription of non-steroidal anti-inflammatory drugs (NSAIDs) should be based on the assessment of both gastrointestinal (GI) and cardiovascular (CV) risk for the individual patient. We aimed to assess the GI/CV risk profile and the pharmacological management of patients with osteoarthritis (OA) in clinical practice. We conducted a cross-sectional, multicentre, observational study of consecutive OA patients that visited 1,760 doctors throughout the Spanish National Health System (NHS) in a single day. The presence of GI risk factors, CV histories, hypertension and current pharmacological treatments was recorded. Of the 60,868 patients, 17,105 had a diagnosis of OA and were evaluable. The majority (93.4%) had more than one GI risk factor and 60.3% were defined to be at high-GI risk. Thirty-two percent had a history of CV events, 57.6% were treated with anti-hypertensive therapy and 22.6% had uncontrolled hypertension. One-fifth of patients were treated with non-NSAID therapies, whereas the remaining patients received NSAIDs. Non-selective NSAIDs (nsNSAID) plus proton pump inhibitor (PPI) or cyclooxigenase-2 (COX-2)-selective NSAIDs alone were more frequently prescribed in patients at increased GI risk. Patients with a positive CV history received nsNSAIDs or COX-2-selective NSAIDs in 41.3% and 31.7% of cases, respectively. When both the GI and CV histories were combined, 51% of the overall population was being prescribed drugs that were either not recommended or contraindicated. Over 90% of patients with OA are at increased GI and/or CV risk. In over half of these patients, the prescription of NSAIDs was not in accordance with current guidelines or recommendations made by regulatory agencies.
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Chronic pain is a significant public health burden. Several international guidelines and influential reviews recommend the use of paracetamol (acetaminophen) as the first-line analgesic of choice for the management of chronic pain. These recommendations are based largely on the balance of evidence, which favorably demonstrates the efficacy, safety, and low cost of paracetamol relative to other analgesics.A decade ago, March et al suggested that because of the dangers associated with conventional nonsteroidal antiinflammatory (NSAID) use, particularly in the elderly, they should ideally not be used without an individual n-of-1 trial to show that they are more effective than paracetamol. Today, the results of our investigations into the individualization of pain management options continue to support this suggestion. Based on the data available to date, it still seems prudent to use NSAIDs only in those patients in whom there is good evidence of improved efficacy over paracetamol. In patients with chronic pain, paracetamol can play an important role as an NSAID sparer, with resultant benefits in terms of reduced adverse effects and cost savings.
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Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.
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Acetaminophen, the active ingredient in Tylenol, is a widely used drug that is well known for its analgesic and antipyretic properties. Acetaminophen is a commonly used alternative to nonsteroidal anti-inflammatory drugs, which have recently been demonstrated to increase mortality after acute myocardial infarction (AMI). The safety and potential cardioprotective properties of acetaminophen in the setting of AMI have recently been investigated; however, the results from these studies have been inconclusive. Using both large (ovine) and small (rabbit) collateral-deficient animal models, we studied the effects of acetaminophen in the setting of reperfused AMI. In both species we studied the effects of acetaminophen on myocardial salvage and ventricular function. Additionally, we studied the effects of acetaminophen on myocardial perfusion in sheep and on myocyte apoptosis in rabbits. Sixteen sheep and twenty-two rabbits were divided into two groups and administered acetaminophen or a vehicle before undergoing ischemia and reperfusion. The ischemic period was 60 min in sheep and 30 min in rabbits. All animals were reperfused for 3 h. There were no significant differences observed in myocardial perfusion, myocyte apoptosis, or infarct size in acetaminophen-treated animals. Acetaminophen increased cardiac output and mean arterial pressure before ischemia in sheep but had no effect on any other hemodynamic parameter. In rabbits, no effect on cardiac output or blood pressure was detected. These results support the role of acetaminophen as a safe drug in the postmyocardial infarction setting; however, no significant cardioprotective effect of the drug could be demonstrated.
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Acetaminophen (APAP) is a popular analgesic. In the present study, we characterized the pharmacokinetics and pharmacodynamics of APAP in the Japanese. Five healthy volunteers were administered 1000 mg of APAP orally. Five patients with chronic pain were administered the optimal oral dose of APAP ranging from 600 to 1000 mg to allow for an adequate analgesic effect. Plasma APAP and APAP metabolite concentrations were measured in the volunteers, plasma APAP concentrations and pain scores using a visual analog scale were measured in the patients with chronic pain. Patient data were fitted to a first-order absorption one-compartment model with delayed effects accounted for by an effect compartment. A sigmoid Emax model was used as the pharmacodynamic model. Acetaminophen-cysteine metabolites, which are conjugates of the toxic metabolite N-acetyl-p-benzoquinone-imine, were detected in the plasma at levels lower than 0.2 microg/ml, but no side effects were observed. The pharmacokinetic and pharmacodynamic parameter (mean+/-S.D.) estimates were as follows: clearance, 18.7+/-4.7 l/h; distribution volume, 30.9+/-6.8 l; absorption rate constant, 2.4+/-1.3 h(-1); rate constant for the elimination of APAP from the effect compartment, 1.3+/-0.5 h(-1); maximum pain relief score, 4.6+/-2.2 units; effect compartment concentration at 50% maximum, 2.0+/-1.2 microg/ml; and sigmoid factor, 1.3+/-0.7. These results suggest that these parameters can be used to determine an effective APAP dosage regimen for Japanese patients with chronic pain.
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To reassess the prevalence of aspirin induced asthma and other issues related to the syndrome. Biosis, SciSearch (1990 to March 2002), Embase (1974 to March 2002), Medline (1966 to March 2002), Toxline, Derwent Drug File (1964 to March 2002), Conference Papers Index and Inside Conferences, Int'l Pharmaceutical Abstracts, Pharma-Online (1978 to March 2002). Study type, patient population, and outcome measures. Review was restricted to respiratory responses to analgesics available without prescription. The prevalence of aspirin induced asthma was highest when determined by oral provocation testing (adults 21%, 95% confidence interval 14% to 29%; children 5%, 0% to 14%) than by verbal history (adults 3%, 2% to 4%; children 2%, 1% to 3%). Cross sensitivity to doses of over the counter non-steroidal anti-inflammatory drugs was present in most patients with aspirin induced asthma: ibuprofen, 98%; naproxen, 100%; and diclofenac, 93%. The incidence of cross sensitivity to paracetamol among such patients was only 7%. Aspirin induced asthma in adults is more prevalent than previously suggested. When there is a clinical necessity to use aspirin or a non-steroidal anti-inflammatory drug and there is uncertainty about safety, oral provocation testing should be performed.
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The possibility of liver intoxication at therapeutic doses of paracetamol (maximal dailydose of 4 x 1 g) is supported by retrospective, but not by controlled prospective studies. Intended orsuicidal overdosages are frequently misjudged in retrospektive reports. Malnutrition, ethanol consumption, and drugs inducing hepatic metabolism are no established riskfactors at therapeutic dose levels. Dose adaptation in existing liver disease is recommended for longer-term use.Transient increases in transaminase values (> 3 x upper limits of normal) after regulardoses of paracetamol are not proof of hepatic damage unless associated with corresponding symptoms or laboratory changes indicative of compromised hepatic function (total bilirubin, INR). There is insufficient evidence of liver injury by paracetamol at regular dose levels.
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Acetaminophen injection is an antipyretic and analgesic agent recently marketed in the United States as Ofirmev. Five published trials directly compare acetaminophen injection to drugs available in the United States. For management of pain in adults, acetaminophen injection was at least as effective as morphine injection in renal colic, oral ibuprofen after cesarean delivery, and oral acetaminophen after coronary artery bypass surgery. In children (3 to 16 years old), single-dose acetaminophen injection was similar to meperidine intramuscular (i.m.) for pain after tonsillectomy; readiness for discharge from the recovery room was shorter with acetaminophen injection (median 15 minutes) compared with meperidine i.m. (median 25 minutes), P = .005. In children (2 to 5 years old) postoperative adenotonsillectomy or adenoidectomy, the time to rescue analgesia was superior with high-dose acetaminophen rectal suppository (median 10 hours) compared with acetaminophen injection (median 7 hours), P = .01. One published trial demonstrated acetaminophen injection is noninferior to propacetamol injection for fever related to infection in pediatric patients. Dosing adjustments are not required when switching between oral and injectable acetaminophen formulations in adult and adolescent patients. Acetaminophen injection represents another agent for multimodal pain management.
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The major clinical guidelines recommend the use of acetaminophen (acetyl-para-aminophenol [APAP]) for the treatment of mild-to-moderate symptoms of osteoarthritis (OA) and only recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) after APAP failure. This recommendation is based on the efficacy of APAP in treating OA and its relatively benign side-effect profile compared with NSAIDs. NSAIDs are associated with a high risk of adverse events, particularly those of the gastrointestinal (GI) tract. A large number of studies in OA have compared APAP with a variety of selective and nonselective NSAIDs and typically found greater efficacy with NSAIDs. This advantage, however, is mainly the result of increased efficacy in patients with more severe disease, and is viewed as a relatively small analgesic advantage in some studies and meta-analyses. Many of these same studies have reported little or no difference in safety between APAP and NSAIDs, but these results are typically based on short-term studies. Results from meta-analyses on the safety of NSAIDs almost unanimously confirm elevated risk of GI complications. The analgesic mechanism of APAP is still not well understood. However, the notion that APAP has no anti-inflammatory effect has been challenged in recent years with increasing data that suggest it may have an effect on inflammation distinct from that seen with NSAIDs. A variety of mechanistic hypotheses have been proposed.
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There is limited information about the safety of chronic nonsteroidal anti-inflammatory drugs (NSAIDs) in hypertensive patients with coronary artery disease. This was a post hoc analysis from the INternational VErapamil Trandolapril STudy (INVEST), which enrolled patients with hypertension and coronary artery disease. At each visit, patients were asked by the local site investigator if they were currently taking NSAIDs. Patients who reported NSAID use at every visit were defined as chronic NSAID users, while all others (occasional or never users) were defined as nonchronic NSAID users. The primary composite outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Cox regression was used to construct a multivariate analysis for the primary outcome. There were 882 chronic NSAID users and 21,694 nonchronic NSAID users (n = 14,408 for never users and n=7286 for intermittent users). At a mean follow-up of 2.7 years, the primary outcome occurred at a rate of 4.4 events per 100 patient-years in the chronic NSAID group, versus 3.7 events per 100 patient-years in the nonchronic NSAID group (adjusted hazard ratio [HR] 1.47; 95% confidence interval [CI], 1.19-1.82; P=.0003). This was due to an increase in cardiovascular mortality (adjusted HR 2.26; 95% CI, 1.70-3.01; P<.0001). Among hypertensive patients with coronary artery disease, chronic self-reported use of NSAIDs was associated with an increased risk of adverse events during long-term follow-up.
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Intravenous paracetamol (N-acetyl-paraminophenol, acetaminophen) is a widely used nonopioid analgesic which has become popular in the treatment of pain in many patient groups, including the elderly. Although intravenous paracetamol has been studied widely in clinical analgesia studies, there is little information on its pharmacokinetics in the elderly. We designed this study to determine the pharmacokinetics of intravenous paracetamol in very old patients and to compare them with that of younger patients. We also considered the effect of adenosine triphosphate-binding cassette G2 protein (ABCG2) genotype and renal function on paracetamol pharmacokinetics in these patients. We compared the pharmacokinetics of intravenous paracetamol in four groups of ten patients, aged 20-40, 60-70, 70-80 and 80-90 years, undergoing orthopaedic surgery. Paracetamol 1000 mg was given by infusion over 15 minutes. Plasma concentrations of paracetamol and its glucuronide and sulphate conjugates were measured for 24 hours with a high-performance liquid chromatographic method and ABCG2 genotype was determined. Glomerular filtration rate (GFR) was estimated from age, sex and serum creatinine of the patient. In the group aged 80-90 years, the mean value of the area under the plasma concentration-time curve extrapolated to infinity (AUC(∞)) of paracetamol was 54-68% higher than in the two youngest groups. Paracetamol clearance showed a statistically significant dependence on age group, whereas volume of distribution during elimination and elimination half-life were associated with age group and sex, respectively. Based on mean AUC(∞) of paracetamol glucuronide and paracetamol sulphate, the oldest patients had 1.3- to 1.5-fold greater exposure to these metabolites than patients aged 20-40 years. ABCG2 genotype did not affect paracetamol pharmacokinetics. There was a linear correlation between the values of AUC(∞) of paracetamol, its glucuronide and sulphate metabolites and GFR. Age and sex are important factors affecting the pharmacokinetics of paracetamol. The higher the age of the patient, the higher is the exposure to paracetamol. Female sex is associated with increased paracetamol concentrations but ABCG2 genotype does not seem to affect paracetamol pharmacokinetics. Trial registration number (EudraCT): 2006-001917-14.
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In response to the April 2010 U.S. Food and Drug Administration's (FDA's) revision of warning labeling for over-the-counter (OTC) acetaminophen, or N-acetyl-p-aminophenol (APAP), products, the authors reviewed APAP's potential for liver toxicity. The authors reviewed the literature in which investigators examined data related to the epidemiology of APAP-related liver toxicity, studies in which the investigators evaluated the risk factors for its occurrence and case reports. They included articles that were used by the FDA as the basis for establishing the new labeling requirements. Findings from the literature in which investigators have examined the relationship between APAP and liver toxicity indicate several key risk factors. Foremost are the extensive use of one or more APAP-containing compounds (particularly combinations with opioid agents) and the small margin of safety between the therapeutic and toxic doses. Both of these factors lead to unintentional or intentional drug overdose. Concurrent use of alcohol may contribute to hepatotoxicity, but it may be related to behavior rather than biochemical mechanisms involved in liver damage. The widespread use of APAP has contributed to a substantial increase in the number of cases of acute liver toxicity in the United States. Since APAP is a component of many prescription and OTC medications, unintentional overdose can occur. APAP has numerous applications in dentistry, but if it is used conjointly for other conditions, the risk of the patient's experiencing an overdose increases. In the context of recent FDA concerns about the increased incidence of APAP-related liver toxicity, the authors provide recommendations for safe prescribing practices for APAP. Practitioners should caution patients to follow recommended dosage instructions and avoid taking multiple APAP-containing products.
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Paracetamol (acetaminophen) is a worldwide used analgesic and antipyretic drug. It is metabolised via several metabolic pathways, including glucuronidation, sulfation, oxidation, hydroxylation, and deacetylation: Hepatic and other organ damage may occur, especially in overdose, because of the accumulation of a toxic metabolite. Intersubject and ethnic differences have been reported in paracetamol metabolism activation, suggesting possible differences in susceptibility to toxicity and in pain alleviation, linked to different pharmacogenetic profiles. This article aims at reviewing, in the literature, the links between paracetamol metabolism and enzyme genotypes in the context of toxic side effects and efficacy of paracetamol in therapeutics.
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Concern exists about the potential for liver injury with therapeutic dosing of acetaminophen in children. We systematically reviewed the medical literature to determine the rate at which liver injury has been reported for children prescribed therapeutic doses of acetaminophen (≤75 mg/kg per day orally or intravenously or ≤100 mg/kg per day rectally). We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials to locate all studies in which acetaminophen was administered to a defined pediatric population for ≥24 hours and for all case reports of liver injury after therapeutic acetaminophen dosing. Trained reviewers extracted data from each report. Major and minor hepatic adverse events (AEs) were defined prospectively. Causality was assessed by using the Naranjo algorithm. A total of 62 studies that enrolled 32,414 children were included. No child (0% [95% confidence interval: 0.000-0.009]) was reported to have exhibited signs or symptoms of liver disease, to have received an antidote or transplantation, or to have died. Major or minor hepatic AEs were reported for 10 children (0.031% [95% confidence interval: 0.015-0.057]). The highest transaminase value reported was 600 IU/L. Naranjo scores (2-3) suggested "possible" causation. Twenty-two case reports were identified. In 9 cases, the Naranjo score suggested "probable" causation (5-6). Hepatoxicity after therapeutic dosing of acetaminophen in children is rarely reported in defined-population studies. Case reports suggest that this phenomenon may occur, but few reports contain sufficient data to support a probable causal relationship.
Article
Acetaminophen has unique analgesic and antipyretic properties. It is globally recommended as a first-line agent for the treatment of fever and pain due to its few contraindications. Acetaminophen lacks the significant gastrointestinal and cardiovascular side effects associated with nonsteroidal anti-inflammatory drugs and narcotics. An intravenous formulation of acetaminophen is available in Europe and is currently undergoing extensive clinical development for use in the United States. This use may have important implications for management of postoperative pain and fever. This review summarizes recent clinical trial experiences with intravenous acetaminophen for the treatment of postoperative pain and fever in adult and pediatric subjects.
Article
WHAT IS KNOWN AND BACKGROUND: Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts.
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The possible association between acetaminophen use during pregnancy and childhood asthma has been a subject of interest based on the theory that acetaminophen metabolism may deplete glutathione in the developing lung, leading to oxidative damage and inflammation. Epidemiology studies from eight centers have reported conflicting results. In some cases, end points of these studies have included wheezing in very young children, which is a poor predictor of asthma. Other study problems have included the common use of acetaminophen as the analgesic and antipyretic of choice during pregnancy. Because acetaminophen use may be a marker for infectious or inflammatory disorders, the results of the epidemiology studies may be influenced by confounding by indication. A placebo-controlled randomized trial of acetaminophen use during pregnancy would be helpful in resolving the question of whether acetaminophen use causes childhood asthma. At present, the evidence is inconclusive that any such association is causal.
Article
What is already known about this subject: Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are widely used analgesics in the prescription and non-prescription settings. Although both classes of drug are generally well tolerated, they can lead to well-characterized adverse effects. Both drugs are widely co-prescribed and it is of interest to understand better safety outcomes when the two drugs are taken concomitantly. WHAT THIS STUDY ADDS?: Relative rates and hazard ratio patterns of safety outcomes were broadly similar for patients prescribed ibuprofen alone, paracetamol alone and concomitant ibuprofen and paracetamol. The risks of the various safety outcomes examined do not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone. Aims: To evaluate and compare the risk of specific safety outcomes in patients prescribed ibuprofen and paracetamol concomitantly with those in patients prescribed ibuprofen or paracetamol alone. The outcomes were evaluated according to dose, duration and exposure. Methods: The study used a retrospective longitudinal cohort design with data from the UK General Practice Research Database (GPRD). The study population included patients aged 18 years or over who were prescribed ibuprofen alone, paracetamol alone or concomitant ibuprofen and paracetamol (tablets or capsules only). The safety outcomes evaluated were upper gastrointestinal events, myocardial infarction, stroke, renal failure (excluding chronic), congestive heart failure, intentional or accidental overdose, suicidal behaviour and mortality. Time-dependent Cox regression was used to estimate relative rates for the safety outcomes, by treatment group. A further analysis evaluated whether the hazard rates (i.e. absolute risks) varied over time with changes in drug exposure. Results: The study population included 1.2 million patients. There was considerable heterogeneity in both patient and exposure characteristics. When comparing with past users, for most safety outcomes, current users of concomitant paracetamol and ibuprofen had relative rates between those for current users of ibuprofen alone and paracetamol alone. The hazard rates were generally proportional over time, from current to past exposure, following a prescription for concomitant paracetamol and ibuprofen compared with ibuprofen alone or paracetamol alone. Conclusions: The known risk of the safety outcomes examined does not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone.
Article
Tramadol/paracetamol 37.5mg/325mg (Tramacet®, Zaldiar®, Ixprim®, Kolibri®) is an orally administered fixed-dose combination of the atypical opioid tramadol and paracetamol, which is indicated in the EU for the symptomatic treatment of moderate to severe pain. This article reviews the pharmacological properties, clinical efficacy and tolerability of tramadol/paracetamol in adults with moderate to severe pain. Fixed-dose tramadol/paracetamol is a rapidly-acting, longer-duration, multi-modal analgesic, which is effective and generally well tolerated in patients with moderate to severe pain. In several well designed, clinical studies, single- or multiple-dose tramadol/paracetamol was effective in providing pain relief in adult patients with postoperative pain after minor surgery, musculoskeletal pain (acute, subacute or chronic), painful diabetic peripheral neuropathy or migraine pain. It was also effective as an add-on analgesic in patients who were experiencing moderate to severe musculoskeletal pain (e.g. osteoarthritis or rheumatoid arthritis pain) despite ongoing NSAID and/or disease-modifying antirheumatic drug therapy. Moreover, in patients with postoperative pain, ankle sprain pain or subacute lower back pain, the analgesic efficacy of tramadol/paracetamol was better than that of paracetamol, generally similar to, or better than that, of tramadol, and generally similar to that of ibuprofen or the fixed-dose combinations hydrocodone/paracetamol, codeine/paracetamol and codeine/paracetamol/ibuprofen. In addition, the analgesic efficacy of tramadol/paracetamol did not differ significantly from that of gabapentin in patients with chronic pain associated with diabetic peripheral neuropathy. Tramadol/paracetamol had no additional tolerability issues relative to its components and, overall, the tolerability profile of tramadol/paracetamol was generally similar to that of other active comparators (fixed-dose combinations or single-agents); however, incidences of some adverse events were lower in tramadol/paracetamol than in active comparator recipients. Although additional comparative and long-term studies would help to definitively position tramadol/paracetamol with respect to other analgesics, available clinical data suggest that tramadol/paracetamol is a useful treatment option for providing multimodal analgesia in patients with moderate to severe pain.
Article
Paracetamol is widely used in the management of acute and chronic pain. The purpose of this review is to give anesthesiologists answers to some of the most common questions about paracetamol, specifically the following questions. What is the mechanism of action of paracetamol? Is paracetamol a NSAID? Which endogenous analgesic systems are influenced by paracetamol? Are the perceived concerns about paracetamol use real? What new research is there into paracetamol-induced liver failure? Is paracetamol safe for use by patients with liver disease or those taking anticoagulants? How effective is paracetamol for the management of postoperative pain? Does paracetamol have any opioid-sparing effects? Which formula has the best analgesic efficacy? Which route of administration has the better pharmacokinetic profile? Is the concentration of paracetamol in blood or cerebrospinal fluid relevant to the analgesic effect? Which starting dose should be administrated in intravenous infusion?
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NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.
Article
This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly. Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events. We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update. Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults. Two authors assessed trial quality and extracted data. The area under the "pain relief versus time" curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo.Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups. This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
Article
This article is a review of the peri-operative use of paracetamol. It reviews the pharmacology of paracetamol, highlighting new information about the mechanism of action, and examines its therapeutic use in the peri-operative period, focusing on efficacy, route of administration, and the use of a loading dose to improve early postoperative analgesia.
Article
To determine, on the basis of published studies, the efficacy of rectal vs oral acetaminophen as treatment of fever and pain. MEDLINE, PubMed, and the Cochrane database as well as major pharmacologic textbooks and the references of all included studies were searched for studies comparing oral and rectal administration of acetaminophen. Randomized and quasi-randomized controlled studies comparing rectal and oral administration of acetaminophen were included. Reviews, letters, and studies that compared combined treatments or additional drugs were excluded. Main Exposure Oral vs rectal acetaminophen. Standardized measures of temperature and pain reduction. For temperature reduction, 4 studies met the inclusion criteria. The decline in temperature 1 hour after administration of acetaminophen was no different between rectal and oral administration (weighted mean difference [WMD], -0.14 degrees C; 95% confidence interval [CI], -0.36 degrees C to 0.08 degrees C; P for heterogeneity = .49). There was no difference in the decline of temperature 3 hours after administration (WMD, -0.10 degrees C; 95% CI, -0.41 degrees C to 0.21 degrees C; P = .84), the maximum decline in temperature (WMD, -0.10 degrees C; 95% CI, -0.24 degrees C to 0.04 degrees C; P > .99), or the average time to temperature reduction of 1 degrees C (WMD, -0.06 degrees C; 95% CI, -1.34 degrees C to 1.23 degrees C; P < .001). We did not perform a meta-analysis comparing rectal and oral acetaminophen for pain reduction because only 1 study fulfilled the inclusion criteria. Rectal and oral acetaminophen are comparable with respect to temperature reduction. The American Academy of Pediatrics recommendation to refrain from rectal acetaminophen in children should possibly be revised.
Article
Pain is commonly experienced after surgical procedures, and is not always well controlled. This review assessed data from fifty-one studies and found that paracetamol provided effective pain relief for about half of participants experiencing moderate to severe pain after an operation, including dental surgery for a period of about four hours. There were no clear differences between doses of paracetamol typically used. These single dose studies did not associate paracetamol with any serious side effects.
Article
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of peptic ulcer complications, but it is not clear whether some drugs are more likely than others to cause such complications. We compared previous use of NSAIDs in 1144 patients aged 60 and older admitted to hospitals in five large cities with peptic ulcer bleeding and in 1126 hospital controls and 989 community controls matched for age and sex. Peptic ulcer bleeding was strongly associated with use of non-aspirin NSAIDs of any type during the 3 months before admission (411 cases, 351 controls; odds ratio 4.5 [95% CI 3.6 to 5.6]). The odds ratios for peptic ulcer bleeding were lowest for ibuprofen (2.0 [1.4-2.8]) and diclofenac (4.2 [2.6-6.8]), and intermediate for indomethacin, naproxen, and piroxicam (11.3 [6.3-20.3], 9.1 [5.5-15.1], and 13.7 [7.1-26.3]). Azapropazone and ketoprofen carried the highest risks (31.5 [10.3-96.9] and 23.7 [7.6-74.2]). Risks also increased with drug dose (low dose 2.5 [1.7-3.8], intermediate 4.5 [3.3-6.0], and high 8.6 [5.8-12.6]) for all drugs combined. Appropriate clinical strategies could prevent many episodes of peptic ulcer bleeding: NSAIDs should be used only in patients who do not respond to other analgesics; the lowest possible doses should be used; and the least toxic NSAIDs should be selected.
Article
The acute administration of acetaminophen to isolated, perfused guinea pig hearts appears to have cardioprotective effects against the injury/mechanical dysfunction caused by global, low-flow, myocardial ischemia and reperfusion. In the current study we selected ischemia/reperfusion and administration of sodium pentobarbital as perturbations of the electrical stability of the myocardium. We investigated their ability to induce ventricular arrhythmias and changes in the characteristics of monophasic action potentials in the absence and presence of acetaminophen (0.35 mmol/l). The numbers of ventricular premature beats and ventricular salvos encountered in the presence of pentobarbital were significantly (P < 0.05) reduced by acetaminophen. The combined frequency of these arrhythmias was 0.14+/-0.06/min vs 0.03+/-0.01/min (P < 0.05) in the absence and presence of acetaminophen, respectively. The incidence of ventricular salvos increased steadily in vehicle-treated hearts after administration of pentobarbital. No such trend was seen with acetaminophen. After 10 min of global, low-flow myocardial ischemia, MAP50 and MAP90 (monophasic action potentials at 50 and 90% repolarization, respectively) decreased without acetaminophen (e.g. MAP50, 31+/-4 ms) but did not change during the same time interval with acetaminophen (e.g. MAP50, 57+/-6 ms)(P < 0.05). During ischemia and reperfusion, acetaminophen attenuated the release of hydroxyl radicals and peroxynitrite. Collectively these data reveal cardioprotective, antioxidant behavior of acetaminophen. Under selected conditions (e.g. those causing release of free radicals and other oxidants) such behavior might also prevent ventricular arrhythmias.
Article
Data concerning metabolism of paracetamol in infants are scant. Previous studies have examined urinary metabolite recovery rates after a single dose of paracetamol in either neonates (<6 weeks) or children (3-9 years). There are no studies investigating infants. Infants ( n=47) undergoing major craniofacial surgery were given paracetamol 19-45 mg/kg 6-, 8-, or 12-hourly as either elixir or suppository formulation for postoperative analgesia, after a loading dose of 33-59 mg/kg rectally during the operation. Serum was assayed for paracetamol concentration in 40 of these infants at 5, 8, 11, 14, 17 and 20 h postoperatively. Urine samples were collected every 3 h for 24 h in 15 of these infants. The clearances of paracetamol to glucuronide and sulphate metabolites as well as the urinary clearance of unmetabolised paracetamol were estimated using non-linear, mixed-effects models. Mean (+/-SD) age and weight of the patients were 11.8+/-2.5 months and 9.1+/-1.9 kg. Clearances of paracetamol to paracetamol-glucuronide (%CV) and to paracetamol-sulphate were 6.6 (11.5) l/h and 7.5 (11.5) l/h respectively, standardised to a 70-kg person using allometric "1/4 power" models. Glucuronide formation clearance, but not sulphate formation, was related to age and increased with age from a predicted value in a neonate of 2.73 l/h/70 kg to a mature value of 6.6 l/h/70 kg with a maturation half-life of 8.09 months. Urine clearance of paracetamol-glucuronide, paracetamol-sulphate and unchanged paracetamol (%CV) were, respectively, 2.65, 3.03 and 0.55 (28) l/h/70 kg. The urine clearance of unchanged paracetamol and metabolites was related to urine volume flow rate. Clearance attributable to pathways other than these measured in urine was not identifiable. The glucuronide/sulphate formation clearance ratio was 0.69 at 12 months of age. Sulphate metabolism contributed 50% towards paracetamol clearance. Glucuronide formation clearance increases with age in the infant age range but sulphate formation does not. Renal clearance of paracetamol and its metabolites increases with urine flow rate. This and other studies show that paracetamol metabolism to glucuronide appears to be similar in infants and children, but in adults is increased in comparison with children. Oxidative pathways were undetectable in this infant study and may explain, in part, the reduced incidence of hepatotoxicity in infants.
Article
Acetaminophen has been used safely and effectively for many years to manage pain and/or fever in patients of all ages. It is commonly recommended as first-line therapy for a variety of patients and conditions, including the elderly, children with viral illnesses, and patients with osteoarthritis, gastrointestinal conditions, bleeding disorders, cardiovascular disease, or renal disease. However, its use is often avoided in patients with chronic liver disease. The perception that acetaminophen should be avoided in such patients arose from awareness of the association between massive acetaminophen overdose and hepatotoxicity, combined with a lack of understanding of the metabolism of acetaminophen in patients with liver disease. There are various theoretical mechanisms of acetaminophen hepatotoxicity in chronic liver disease including: altered metabolism and depleted glutathione stores that would be expected to increase accumulation of the hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). Available studies in patients with chronic liver disease, however, have shown that although the half-life of acetaminophen may be prolonged, cytochrome P-450 activity is not increased and glutathione stores are not depleted to critical levels in those taking recommended doses. Furthermore, acetaminophen has been studied in a variety of liver diseases without evidence of increased risk of hepatotoxicity at currently recommended doses. Therefore, acetaminophen can be used safely in patients with liver disease and is a preferred analgesic/antipyretic because of the absence of the platelet impairment, gastrointestinal toxicity, and nephrotoxicity associated with nonsteroidal antiinflammatory drugs.
Article
Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by tropisetron, a 5-hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans. Twenty-six rapid metabolizers of tropisetron were included in this double-blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self-evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0-4 hours) (mean +/- SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction. The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time [% x min]) (2145 +/- 2901 % x min) was totally inhibited by both tropisetron (89 +/- 1747 % x min, P = .007) and granisetron (45 +/- 2020 % x min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309). These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.
Article
Establishing the dose-response relationship for clinically useful doses of aspirin, ibuprofen and paracetamol has been difficult. Indirect comparison from meta-analysis is compromised by too little information at some doses. A systematic review of randomized, double-blind trials in acute pain comparing different doses of aspirin, ibuprofen and paracetamol was therefore undertaken. Fifty trials were found. Numerical superiority of higher over lower dose was found by the original authors in 37/50 trials (74%) and statistical superiority in 11/50 (22%). Twenty-eight trials had design, quality and data reporting characteristics to allow pooling of common doses; in 3/28 (11%) of the individual trials our calculations showed statistical superiority of higher over lower dose. Pooled comparison of 1000/1200 mg aspirin over 500/600 mg was statistically superior, with a number-needed-to-treat (NNT) for higher over lower dose of 16 (8 to > 100). Pooled comparison of 400 mg ibuprofen over 200 mg was statistically superior, with an NNT for higher over lower dose of 10 (6-23). Pooled comparison of 1000 mg paracetamol over 500 mg was statistically superior, with an NNT for higher over lower dose of 9 (6-20). Use of trials making direct comparison of two different doses of target drugs revealed the underlying dose-response curve for clinical analgesia.
Article
Lower gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) are much more poorly characterized than upper gastrointestinal effects. To determine if NSAIDs increase lower gastrointestinal adverse effects and if the risk with non-selective NSAIDs is greater than with cyclooxygenase-2-selective inhibitors (coxibs). Computerized databases were searched to identify studies of NSAID use reporting on lower gastrointestinal integrity (e.g. permeability), visualization (e.g. erosions, ulcers) and clinical events. Designs in 47 studies were randomized (18), case-control (14), cohort (eight) and before-after (seven). Non-selective-NSAIDs had significantly more adverse effects vs. no NSAIDs in 20 of 22 lower gastrointestinal integrity studies, five of seven visualization studies, seven of 11 bleeding studies (OR: 1.9-18.4 in case-control studies), two of two perforation studies (OR: 2.5-8.1) and five of seven diverticular disease studies (OR: 1.5-11.2). Coxibs had significantly less effect vs. non-selective-NSAIDs in three of four integrity studies, one endoscopic study (RR mucosal breaks: 0.3), and two randomized studies (RR lower gastrointestinal clinical events: 0.5; haematochezia: 0.4). An increase in lower gastrointestinal injury and clinical events with non-selective-NSAIDs appears relatively consistent across the heterogeneous collection of trials. Coxibs are associated with lower rates of lower gastrointestinal injury than non-selective-NSAIDs. More high-quality trials are warranted to more precisely estimate the effects of non-selective-NSAIDs and coxibs on the lower gastrointestinal tract.
Article
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.
Article
The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single-dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher, strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose-dependent differences were detected in fCL of thiol metabolites formed via cytochrome P4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose-dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time-dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short-term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults.
Article
The mechanism of the analgesic action of acetaminophen involves the serotonergic system. This study explores how acetaminophen interferes with serotonergic descending pain pathways. Eighteen rapid metabolizers of tropisetron were included in this double-blind cross-over study. After ethical approval, the healthy volunteers took 1 g oral acetaminophen (A) or placebo (p) combined with either the 5-HT3 antagonist tropisetron (T) (5 mg) or saline, intravenously, at weekly intervals. Mechanical pain thresholds, determined before and after a cold pressor test (CPT), were repeated seven times during the three post-dosing hours, and area under the concentration-time curves (AUCs) of the three treatments were compared. After CPT, AUC (%*min) of Ap (1,561+/-429) was larger than before CPT (393+/-382, P<0.05); these effects were totally inhibited by tropisetron. Acetaminophen reinforces descending inhibitory pain pathways; it suggests a supraspinal target for acetaminophen's antinociceptive action. This study also confirmed that there is a central serotonergic mechanism of action for acetaminophen that is not stimulus-dependent.