Analgesic Effect Of Paracetamol Research Articles

Modern anesthesia in obstetrics as a component of the concept of safe anesthesia

Background. Anesthesia should be selected individually for each labor. Systemic analgesia of labor includes suggestive analgesia, narcotic analgesics, local infiltration and regional blockade, inhalation analgesia. It should be noted that there is no analgesic, sedative or local anesthetic that does not penetrate the placenta, affecting the fetus in any way.
 Objective. To describe modern anesthesia in obstetrics.
 Materials and methods. Analysis of literature sources on this issue.
 Results and discussion. Three groups of antispasmodics are used for analgesia: neurotropic (atropine, scopolamine), myotropic (papaverine, drotaverine) and neuromyotropic (baralgin). The main non-steroidal anti-inflammatory drugs used for this purpose include metamizole sodium, ketorolac tromethamine, diclofenac sodium. Inhalation autoanalgesia with nitrous oxide (N2O) is effective only in 30-50 % of women. When the concentration of N2O exceeds 50 %, the sedative effect increases and oxygenation decreases, which leads to the loss of consciousness and protective laryngeal reflexes. Such analgesia is indicated for low-risk patients who have refused from regional anesthesia. Epidural anesthesia (EDA) is the gold standard of labor anesthesia. The advantages of EDA include the option to change the degree of analgesia, the ability to continue pain relief until the end of labor and the minimal impact on the condition of both child and mother. Before manipulation, be sure to determine the platelet count and heart rate of the fetus. It is recommended to start EDA in the latent stage of labor. In patients with uterine scarring, early EDA is a mandatory component of medical care. The woman’s wish is the main indication for EDA. Indications for early catheterization of the epidural space include the presence of twins, preeclampsia, obesity, respiratory tract with special features. Headache is the most common complication of EDA. The use of pencil-point spinal needles minimizes the frequency of this complication. Adequate analgesia for uncomplicated labor should be performed with minimal concentrations of anesthetics with the least possible motor block. Local anesthetics (lidocaine, bupivacaine (Longocaine, “Yuria-Pharm”), ropivacaine) are used for EDA). Combined spinal-epidural anesthesia provides a rapid effect and long-term analgesia. For this purpose, 0.25 % Longocaine heavy (“Yuria-Pharm”) 2 mg and fentanyl 20 μg are administered intrathecally, followed by 0.225 % Longocaine 10 mg and fentanyl 20 μg epidurally. The technique of epidural dural puncture is a modification of combined spinal-epidural anesthesia. This technique improves the caudal spread of analgesia compared to the epidural technique without the side effects seen with spinal-epidural anesthesia. The ideal local anesthetic should be safe for both mother and fetus, provide sufficient analgesia with minimal motor block, and not affect labor process. A single spinal injection of opioids may be effective, but it should be limited in time. The use of systemic opioids during labor increases the need for resuscitation of newborns and worsens the condition of their acid-base balance compared to basic regional anesthesia. Catheter techniques can be used in case of the increased labor duration. Nalbuphine (“Yuria-Pharm”), which eliminates the side effects of regional anesthesia, can also be successfully used. Analgesic effect of paracetamol (Infulgan, “Yuria-Pharm”) in case of intravenous administration exceeds the analgetic effect of tramadol, and the effect on the newborn condition according to the Apgar scale does not differ (Meenakshi et al., 2015). Paracetamol (Infulgan) is moderately effective for perineal pain on the first day after delivery. The possibility of use during lactation is an another advantage of paracetamol.
 Conclusions. 1. Pain during labor is an extremely stressful factor, so women should have access to quality analgesia and anesthesia. 2. There is no analgesic, sedative or local anesthetic that does not penetrate the placenta, affecting the fetus. 3. EDA is the gold standard of labor anesthesia. 4. Combined spinal-epidural anesthesia provides rapid effect and long-term analgesia. 5. The use of systemic opioids during labor increases the need for resuscitation of newborns and worsens the condition of their acid-base balance. 6. Nalbuphine and Infulgan have been used successfully for labor pain relief.

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey.

We previously demonstrated that paracetamol has to be metabolised in the brain by fatty acid amide hydrolase enzyme into AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) to activate CB1 receptors and TRPV1 channels, which mediate its analgesic effect. However, the brain mechanisms supporting paracetamol-induced analgesia remain unknown. The effects of paracetamol on brain function in Sprague-Dawley rats were determined by functional MRI. Levels of neurotransmitters in the periaqueductal grey (PAG) were measured using in vivo 1 H-NMR and microdialysis. Analgesic effects of paracetamol were assessed by behavioural tests and challenged with different inhibitors, administered systemically or microinjected in the PAG. Paracetamol decreased the connectivity of major brain structures involved in pain processing (insula, somatosensory cortex, amygdala, hypothalamus, and the PAG). This effect was particularly prominent in the PAG, where paracetamol, after conversion to AM404, (a) modulated neuronal activity and functional connectivity, (b) promoted GABA and glutamate release, and (c) activated a TRPV1 channel-mGlu5 receptor-PLC-DAGL-CB1 receptor signalling cascade to exert its analgesic effects. The elucidation of the mechanism of action of paracetamol as an analgesic paves the way for pharmacological innovations to improve the pharmacopoeia of analgesic agents.

Analgesic effect of paracetamol as an adjuvant to lignocaine in upper limb surgeries under intravenous regional anaesthesia (IVRA)

Materials and methods: A total 120 cases belong to ASA grade I or II, between age group 21-60 years undergoing upper limb surgeries were divided into two groups. Group A administered with 2% lignocaine (10 ml) with paracetamol (30 ml) and group 2 administered with 10ml 2% lignocaine with normal saline (30ml). Onset of motor and sensory blockade and recovery duration, intraoperative pain assessment by using 10 cm visual analogue scale, utilization of intra operative analgesia and need of post-operative analgesia, Post-operative patient satisfaction were evaluated.

The Accuracy of Increased Blood Concentration of Prostate-Specific Antigen to Prostate Malignancy

Background: Circumcision is the most widely minor surgery in the world, whether done by doctors, paramedics, or by traditional. Circumcision that removes part or all of the penis prepuce with the aim of removing smegma (dirt). Society circumcised their children at the age of 5-12 years. Analgesics may be given to patients, for instance, paracetamol, nonsteroidal anti-inflammatory drug (NSAIDs) such as aspirin and opioid groups such as tramadol. Objective: The aim of this study was to compare the effectiveness of paracetamol analgesics and tramadol in circumcised patients given prior to the act of circumcision. Methods: This study was a quasi-experimental study to determine different analgesic effects of paracetamol and tramadol administration, prior to circumcision. The subjects of this study are children aged 5-12 years as many as 36 children, which is divided into 2 groups of paracetamol and tramadol group. One hour before circumcision, subjects were given group-appropriate analgesics, then the Visual Analog Scale (VAS) was measured 1 hour after circumcision. The data obtained were made intopercentage on the scale of VAS 5. Results: Â In the paracetamol group, there were 5 children (27.8%) with VAS 1-3 (mild pain), 13 children (72.2%) with moderate pain (VAS value 4-7). In the tramadol group, there were 15 children (83.3%) with mild pain (VAS score 1-3), and the remaining 3 children (16.7%) had moderate pain. No side effects of both analgesic drugs were found. Conclusion: Patients with mild pain complaints were more likely found in the tramadol group than in paracetamol group. Tramadol gave stronger preemptive analgesic results in circumcision compared to paracetamol.

Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context

Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro-drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in naive animals, a far cry from the clinical pathologic context of paracetamol use. Moreover, FAAH is a ubiquitous enzyme expressed both in the central nervous system and in the periphery. Thus, we explored: (i) the involvement of FAAH in the analgesic action of paracetamol in a mouse model of inflammatory pain; and (ii) the contributions of central versus peripheral FAAH in this action. The analgesic effect of paracetamol was evaluated in thermal hyperalgesia, mechanical allodynia and hyperalgesia induced by an intra-plantar injection of carrageenan (3%) in FAAH knock-out mice or their littermates. Moreover, the contribution of the central and peripheral enzymes was explored by comparing the effect of a global FAAH inhibitor (URB597) to that of a peripherally restricted FAAH inhibitor (URB937) on paracetamol action. Here, we show that in a model of inflammatory pain submitted to different stimuli, the analgesic action of paracetamol was abolished when FAAH was genetically or pharmacologically inhibited. Whereas a global FAAH inhibitor, URB597 (0.3 mg/kg), reduced the anti-hyperalgesic action of paracetamol, a brain-impermeant FAAH inhibitor, URB937 (0.3 mg/kg), had no influence. However, administered intracerebroventricularly, URB937 (5μg/mouse) reduced the action of paracetamol. These results demonstrate that the supra-spinally-located FAAH enzyme is necessary for the analgesic action of paracetamol.

Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review.

In contemporary post-operative pain management, patients are most often treated with combinations of non-opioid analgesics, to enhance pain relief and to reduce opioid requirements and opioid-related adverse effects. A diversity of combinations is currently employed in clinical practice, and no well-documented 'gold standards' exist. The aim of the present topical, narrative review is to provide an update of the evidence for post-operative analgesic efficacy with the most commonly used, systemic non-opioid drugs, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs)/COX-2 antagonists, glucocorticoids, gabapentinoids, and combinations of these. The review is based on data from previous systematic reviews with meta-analyses, investigating effects of non-opioid analgesics on pain, opioid-requirements, and opioid-related adverse effects. Paracetamol, NSAIDs, COX-2 antagonists, and gabapentin reduced 24 h post-operative morphine requirements with 6.3 (95% confidence interval: 3.7 to 9.0) mg, 10.2 (8.7, 11.7) mg, 10.9 (9.1, 12.8) mg, and ≥ 13 mg, respectively, when administered as monotherapy. The opioid-sparing effect of glucocorticoids was less convincing, 2.33 (0.26, 4.39) mg morphine/24 h. Trials of pregabalin > 300 mg/day indicated a morphine-sparing effect of 13.4 (4, 22.8) mg morphine/24 h. Notably, though, the available evidence for additive or synergistic effects of most combination regimens was sparse or lacking. Paracetamol, NSAIDs, selective COX-2 antagonists, and gabapentin all seem to have well-documented, clinically relevant analgesic properties. The analgesic effects of glucocorticoids and pregabalin await further clarification. Combination regimens are sparsely documented and should be further investigated in future studies.

The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings

Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.

Intraocular pressure-lowering effect of oral paracetamol and its in vitro corneal penetration properties

BackgroundSeveral studies have confirmed the ability of cannabinoids to reduce intraocular pressure. Experimental data recently demonstrated unequivocally that the analgesic effect of paracetamol is due to its indirect action on cannabinoid receptors. The question then arises as to whether paracetamol can reduce intraocular pressure via its effect on intraocular cannabinoid receptors.MethodsA 2-week, prospective, randomized, controlled, single-center, parallel-group pilot study was carried out to determine the efficacy and safety of paracetamol 1 g orally administered every 6 hours in adult patients with primary or secondary open angle glaucoma as compared with topical levobunolol 0.5% twice a day. Patient well-being was closely monitored throughout the study and focused on hepatic safety in accordance with Drug-Induced Liver Injury Network criteria. The in vitro diffusion kinetics of acetaminophen in a phosphate-buffered solution in rabbit and human corneas was also investigated, with the view to a topical application.ResultsEighteen adult patients were enrolled in the study, with nine in the topical levobunolol group and nine in the oral paracetamol group. In the levobunolol group, the mean reduction in intraocular pressure at day 7 was 7.5 mmHg (P < 0.008) and at day 14 was 9.1 mmHg (P < 0.005), from a mean baseline intraocular pressure of 29.6 mmHg. The corresponding figures for the paracetamol group were 8.8 mmHg (P < 0.0004) at day 7 and 6.5 mmHg (P < 0.004) at day 14, from a mean baseline intraocular pressure of 29.4 mmHg. Both study regimens were well tolerated. No serious treatment-related adverse events were reported in either of the treatment groups. Liver function tests, systolic/diastolic blood pressure, or heart rate remained unchanged in both groups during the 2 weeks of the study. In the laboratory study, paracetamol 1 mg/mL in phosphate-buffered solution (pH 7.4) showed acceptable flux rates. Steady-state levels were achieved within 12 hours, thus confirming that paracetamol penetrates the cornea well.ConclusionParacetamol 1 g taken orally every 6 hours reduced open angle glaucoma and/or angle recession glaucoma in both groups of patients, in a way comparable with that achieved by a topical beta-adrenergic receptor antagonist.

Paroxetine Augments while Naloxone Abolishes the Analgesic Effect of Paracetamol in Acute Nociceptive Pain in Mice

The mechanism(s) of analgesic action of paracetamol (acetaminophen; N-acetyl-p-aminophenol) remains controversial. Previous studies on rats suggested that the antinociceptive action of paracetamol might involve the central descending inhibitory pain pathways recruiting both a serotoninergic and an opioidergic system. This study explores this issue in mice using paroxetine, the most potent selective serotonin re-uptake inhibitor, and the nonselective opioid pure antagonist naloxone. Animals were divided into two main groups for two separate experiments, each subdivided into 3 subgroups. In both experiments; the first group served as control, the second group received paracetamol (200 mg/kg, i.p). In one experiment, the third group received paroxetine (20 mg/kg p.o for 7 days) before paracetamol. In the other experiment, animals of the third group were pretreated with naloxone (5 mg/kg, i.p) 30 min before paracetamol. The antinociceptive effect of paracetamol was tested using the hot plate test. Paracetamol displayed a significant antinociceptive activity that was augmented by pretreatment with paroxetine as was shown by maintenance of its effect beyond that shown by paracetamol alone. On the other hand, pretreatment with naloxone abolished paracetamol’s antinociceptive activity in the hot-plate test. These results extended the previous observation in rats that the antinociceptive effect of paracetamol involved activation of a central descending pain inhibitory pathway with serotonin and opioidergic peptides being potential mediators recruited.

Characterization of the analgesic effect of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat.

The analgesic activities of paracetamol (100, 178, 316 and 562 mg kg-1), caffeine (10, 18, 32 and 56 mg kg-1) and combinations of these doses were tested on a pain-induced functional impairment model in the rat. Dysfunction of the right hind limb was induced by an intra-articular injection of 30% uric acid in the knee. Drugs were given orally and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol alone induced a dose-dependent analgesic effect whereas caffeine alone did not show any activity at the assayed doses. Combinations of 316 mg kg-1 paracetamol with either 10, 18, 32 or 56 mg kg-1 caffeine yielded analgesic effects significantly greater than that of paracetamol alone. The highest potentiation was observed with a paracetamol-caffeine mixture of 316-32 mg kg-1. Caffeine coadministration, however, did not significantly change paracetamol plasma levels. No potentiation was obtained with other combinations. Paracetamol plasma levels and analgesic effect observed with administration of 316 mg kg-1 paracetamol alone or 316-32 mg kg-1 of paracetamol-caffeine were fitted to the sigmoidal Emax model according to the Hill equation. The curves obtained were parallel, but that of the combination was shifted to the left. It is concluded that caffeine is able to potentiate the analgesic effect of paracetamol by a pharmacodynamic mechanism, but this only occurs at certain dose combinations.

The Analgesic Effect of Paracetamol When Added to Lidocaine for Intravenous Regional Anesthesia

The Analgesic Effect of Paracetamol When Added to Lidocaine for Intravenous Regional Anesthesia

The Analgesic Effect of Paracetamol When Added to Lidocaine for Intravenous Regional Anesthesia

In this study, we evaluated the effect of paracetamol on sensory and motor block onset time, tourniquet pain, and postoperative analgesia, when added to lidocaine in IV regional anesthesia (IVRA). Sixty patients undergoing hand surgery were randomly and blindly divided into three groups. All groups received IVRA lidocaine (3 mg/kg) diluted with saline to a total volume of 40 mL. Group 1 received IVRA lidocaine plus IV saline, Group 2 received IVRA lidocaine and paracetamol (300 mg) admixture plus IV saline, and Group 3 received IVRA lidocaine plus IV paracetamol (300 mg). Sensory and motor block onset time, tourniquet pain, and analgesic use were assessed during operation. After tourniquet deflation, visual analog scale (VAS) scores at 1, 2, 4, 6, 12, and 24 h, the time to first analgesic requirement, total analgesic consumption in first 24 h, and side effects were noted. Onset of motor block was shorter and recovery of motor and sensory block was significantly longer in Group 2 (P < 0.05). Intraoperative VAS scores at intraoperative 20, 30, and 40 min were significantly lower in Group 2 (P < 0.05). Intraoperative fentanyl consumption (78 +/- 12, 58 +/- 14, 78 +/- 11 microg, respectively) and the number of patients who required fentanyl for tourniquet pain (13 patients, 3 patients, 9 patients, respectively) were significantly less in Group 2 (P < 0.05). Time to postoperative fentanyl administration was also prolonged (15 +/- 6, 25 +/- 5, 15 +/- 4 min, respectively) in Group 2 (P < 0.05). The quality of surgical anesthesia was better in Group 2 (P < 0.05). Postoperative VAS scores and time of initial analgesic requirement were similar among groups; however, the total amount of diclophenac use was less in Group 2 (P < 0.05). The addition of paracetamol during IVRA with lidocaine decreased tourniquet pain, increased anesthesia quality, and decreased postoperative analgesic consumption.

The synergistic interaction between rilmenidine and paracetamol in the writhing test in mice

The aim of the study was to ascertain antinociceptive effects of rilmenidine, a second-generation imidazoline-alpha-2-adrenoreceptor agonist, and to see whether rilmenidine was able to increase the analgesic effects of paracetamol in the writhing test in mice. An acetic acid (0.7%) solution was injected into the peritoneal cavity and the number of writhes was counted. The influence on locomotor performance was tested using the rotarod test. Rilmenidine, paracetamol, and rilmenidine-paracetamol fixed-ratio combinations produced dose-dependent antinociceptive effects. ED(50) values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical additive ED(50) value for the rilmenidine-paracetamol combination was 109.23 +/- 35.05 mg/kg. This value was significantly greater than the observed ED(50) value which was 56.35 +/- 20.86 mg/kg, indicating a synergistic interaction. Rilmenidine did not impair motor coordination, as measured by the rotarod test, at antinociceptive and higher doses.

Reflecting on tragedy: A commentary on deaths of children in restraints

Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro-drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in naive animals, a far cry from the clinical pathologic context of paracetamol use. Moreover, FAAH is a ubiquitous enzyme expressed both in the central nervous system and in the periphery. Thus, we explored: (i) the involvement of FAAH in the analgesic action of paracetamol in a mouse model of inflammatory pain; and (ii) the contributions of central versus peripheral FAAH in this action. The analgesic effect of paracetamol was evaluated in thermal hyperalgesia, mechanical allodynia and hyperalgesia induced by an intra-plantar injection of carrageenan (3%) in FAAH knock-out mice or their littermates. Moreover, the contribution of the central and peripheral enzymes was explored by comparing the effect of a global FAAH inhibitor (URB597) to that of a peripherally restricted FAAH inhibitor (URB937) on paracetamol action. Here, we show that in a model of inflammatory pain submitted to different stimuli, the analgesic action of paracetamol was abolished when FAAH was genetically or pharmacologically inhibited. Whereas a global FAAH inhibitor, URB597 (0.3 mg/kg), reduced the anti-hyperalgesic action of paracetamol, a brain-impermeant FAAH inhibitor, URB937 (0.3 mg/kg), had no influence. However, administered intracerebroventricularly, URB937 (5 μg/mouse) reduced the action of paracetamol. These results demonstrate that the supra-spinally-located FAAH enzyme is necessary for the analgesic action of paracetamol.

Paracetamol: new vistas of an old drug.

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.

The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB 1 receptors

The mechanism of the analgesic activity of paracetamol (acetaminophen), one of the most widely used drugs for the treatment of pain, is still not clear. Here we show that in rats, using the hot plate test, the analgesic effect of paracetamol is prevented by two antagonists at cannabinoid CB 1 receptors (AM281 and SR141716A) at doses that prevent the analgesic activity of the cannabinoid CB 1 agonist HU210. Our present results suggest that paracetamol-induced antinociception involves the cannabinoid system.

Mechanism of Action of Paracetamol

Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.

The effect of paracetamol on peritoneal reflex after single and multiple grapefruit ingestion

In the last few years, more attention has been paid to the influence of grapefruit juice on metabolism on many drugs. It has been reported that grapefruit juice increases the plasma concentrations of orally administrated drugs, that undergo metabolism in liver. However, all these experiments were done with a single dose of grapefruit juice. The primary aim of this study was to evaluate if the chronical ingestion of grapefruit juice could also cause these effects. Paracetamol is metabolized by reactions of oxidation and conjugation to nontoxic ineffective metabolites. These reactions, partly catalyzed by cytochrome P450 izoenzymes, take place in liver. The analgesic effect of paracetamol was examined by Writhing tests, where we used acetic acid as an irritating agent. We used three groups of male mice: the control group, the group which was administrated 0.2 mL of grapefruit juice per os 10 days (GPOch) and the group which was administrated single dose of 0.5 mL grapefruit juice per os 90 min. before the experiment (GPOac). Dose of 50 mg/kg of paracetamol was applicated s.c. 5 min. before i.p. application of 3 % acetic acid. The writhing phenomenon was observed in periods of 5-15 min. and 15-30 min. after the application of paracetamol. The results show that paracetamol in GPOch group significantly decreases irritant effect of acetic acid in the period of 15-30 min. after the application in relation to the control group. However, the acetic acid shows stronger irritant effect in GPOch group than in the control group and less irritant effect in GPOac group than in the control group. In the period of 5-15 min. after the application, paracetamol shows analgesic effect neither in the control nor in the other groups.

Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol.

Since the antipyretic and probably the analgesic effects of paracetamol are, at least in part, centrally mediated, its plasma and cerebrospinal fluid (CSF) concentrations were measured in 43 patients with nerve-root compression pain. Each subject was given a short i.v. infusion of 2 g propacetamol, a prodrug which is hydrolysed to paracetamol within 7 min. Single blood and CSF samples were drawn concomitantly in each patient at intervals between 20 min and 12 h. Maximum CSF drug concentrations were observed at the 4th hour, subsequent concentrations exceeding those in plasma. The elimination half-life of paracetamol calculated from pooled data was shorter in plasma (2.4 h) than in CSF (3.2 h). The time-course of paracetamol in CSF may parallel that of analgesic effect.

Paracetamol hepatotoxicity: A built-in antidote?

The analgesic effect, toxicity and kinetics of oral paracetamol were compared with those of paracetamol + l-methionine (5:1). The analgesic effect of paracetamol, studied in the Randall-Selitto test in rats, was not changed by methionine: ED50 was 94.6 mg/kg without methionine and 94.1 mg/kg with it. However, methionine reduced the acute toxicity (LD50) of paracetamol by 50% (p &lt; 0.05) in non-fasted, fasted and phenobarbital-pre-treated mice. In a randomized cross-over study in 10 human volunteers the pharmacokinetics of paracetamol (1,500 mg) was not affected by methionine (300 mg). The absorption of methionine from the combination tablets was rapid, peak concentrations occurred in plasma at 30 min and were 3-4 times higher than after paracetamol tablets not containing methionine. Methionine in products containing paracetamol should increase their safety and be the simplest way to reduce the high mortality in paracetamol overdosage.