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PubMed2001

Pain control with paracetamol from a sustained release formulation and a standard release formulation after third molar surgery: a randomised controlled trial.

OBJECTIVE: To compare the analgesic efficacy and safety of a sustained release (SR) paracetamol formulation (Panadol Extend) with a standard immediate release (IR) formulation (Panadol) after third molar surgery. DESIGN: A multi-centre, double-blind, randomised clinical trial. METHODS: Patients received either a single oral dose of SR paracetamol or IR paracetamol for pain after the removal of at least one impacted third molar requiring bone removal under general anaesthesia. Post-operative pain and pain relief assessments were undertaken at time intervals up to 8 hours. Global assessments of effectiveness were made at 4 and 8 hours. Any adverse events were also recorded. RESULTS: Of 627 randomised patients, 314 were treated with SR paracetamol and 313 with IR paracetamol. In the per protocol population at 4 hours, 35.1% of the 252 patients on SR paracetamol rated the study medication as very good or excellent compared with 27.7% of the 258 patients on IR paracetamol. There were few statistically significant differences among the secondary parameters but where they did occur they favoured SR paracetamol. Trends in favour of SR paracetamol were observed among the secondary parameters and these tended to emerge at the later time points. For example, while there was no statistically significant difference in time to re-medication between the treatment groups, the estimated time to re-medication was longer for patients treated with SR paracetamol (4 hr 5 min) compared with IR paracetamol (3 hr 10 min). The high rate of re-medication observed is consistent with that reported for IR paracetamol using the post-operative dental pain model(4,6). No difference was observed between the SR paracetamol and IR paracetamol treatment groups in distribution, incidence or severity of adverse events. CONCLUSIONS: SR paracetamol and IR paracetamol are clinically and statistically equivalent. While SR paracetamol and IR paracetamol were similar in terms of both onset of analgesia and peak analgesic effect, SR paracetamol had a longer duration of activity than IR paracetamol. The safety profiles of SR paracetamol and IR paracetamol were found to be very similar.

Acetaminophen↗

PubMed2000

Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain.

BACKGROUND: Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Paracetamol (acetaminophen) is an important non-opiate analgesic, commonly prescribed, as well as being available for retail sale. This review seeks to examine the efficacy of paracetamol alone and in combination with codeine, and also considers adverse effects. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single dose of oral paracetamol (acetaminophen) alone and in combination with codeine for moderate to severe postoperative pain. SEARCH STRATEGY: Published trials were identified from: Medline (1966 to May 1996), Embase (1980 to 1996), Cochrane Library (Issue 2 1996) and the Oxford Pain Relief Database (1950 to 1994). Additional trials were identified from reference lists of retrieved studies. Date of most recent searches: July 1998. SELECTION CRITERIA: Inclusion criteria were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared paracetamol with placebo or a combination of paracetamol and codeine with either placebo or the same dose of paracetamol alone. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief over 4 to 6 hours compared with placebo. Adverse effects were used to calculate relative risk and number-needed-to-harm (NNH). MAIN RESULTS: We found 40 trials of paracetamol against placebo (4171 patients), 22 trials of paracetamol plus codeine against placebo (1407 patients) and 12 trials of paracetamol plus codeine against the same dose of paracetamol (794 patients). In postoperative pain paracetamol 1000 mg had an NNT of 4.6 (3.8-5.4) for at least 50% pain relief when compared with placebo, and paracetamol 600/650 mg had an NNT of 5.3 (4.1-7.2). Paracetamol 600/650 mg plus codeine 60 mg had an NNT of 3. 6 (2.9-4.5). Comparing paracetamol plus codeine 60 mg with the same dose of paracetamol alone gave an NNT of 7.7 (5.1-17) for at least 50% pain relief. Adverse effects: Relative risk estimates for paracetamol 600/650 mg plus codeine 60 mg versus placebo showed a significant difference for 'drowsiness'/somnolence (NNH 11 (7.5- 0)) and dizziness (NNH 27 (15-164)) but no significant difference for nausea/vomiting. REVIEWER'S CONCLUSIONS: Paracetamol is an effective analgesic with a low incidence of adverse effects. The addition of codeine 60 mg to paracetamol produces additional pain relief even in single oral doses, but may be accompanied by an increase in drowsiness and dizziness.

Acetaminophen↗

PubMedDate not supplied

Effect of polysaccharide peptide (PSP) on in vivo sulphation and glucuronidation of paracetamol in the rat.

The effect of polysaccharide peptide (PSP), an immunomodulator isolated from Coriolus versicolor COV-1, on the disposition of paracetamol was investigated in the rat. PSP (100 and 200 mg/kg, i.v.) was administered 30 min before a moderate dose (100 mg/kg, i.v.) of paracetamol was given. Plasma and bile concentrations of paracetamol, paracetamol glucuronide and paracetamol sulphate were measured by high performance liquid chromatography. The pharmacokinetics of paracetamol (100 mg/kg) alone was consistent with those reported previously, using a one-compartment model. PSP (200 mg/kg) significantly (P < 0.05) increased the clearance (controls, 19.06 +/- 2.74 ml/min/kg: PSP treated, 26.22 +/- 0.84 ml/min/kg) and volume of distribution (controls, 1.35 +/- 0.11 l/kg: PSP treated, 1.61 +/- 0.04 l/kg) of paracetamol by 37% and 21%, respectively. These changes were associated with concomitant increases in the glucuronide and sulphate metabolites in plasma, with significant increases in the Cmax and Tmax for both metabolites. The biliary excretion rate of paracetamol glucuronide and paracetamol sulphate were also measured. The Cmax values of paracetamol sulphate were significantly (P < 0.01) increased by 2.4-fold from 907.8 +/- 157.7 micrograms/ml (controls) to 3061 +/- 331 micrograms/ml after PSP treatment. The lower dose of PSP (100 mg/kg) had no significant effect on the disposition of paracetamol in this study, which agreed with previous reports that a low dose of PSP (100-200 mg/kg, i.p.) was less effective in the protection against paracetamol-induced hepatotoxicity. The time course of the increase in paracetamol sulphate in plasma and bile in this study coincided with the transient perturbation of glutathione (GSH) turnover by a similar dose range of PSP previously described, such that more cysteine was available for oxidation to inorganic sulphate. This increase in sulphate conjugation by PSP would, in part, contribute to the increase in disposition of paracetamol and may be related to the ability of PSP to decrease the covalent binding of paracetamol to microsomal proteins previously reported. Further studies are necessary to understand the mechanism(s) involved in the PSP-induced increases in paracetamol glucuronide and paracetamol sulphate formation and biliary excretion.

Acetaminophen↗

PubMed2000

Paracetamol, alcohol and the liver.

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with 'therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol-alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic. The paracetamol-alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol-ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical. In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion-ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.

Acetaminophen↗

PubMed2002

Effect of ethanol and pH on the adsorption of acetaminophen (paracetamol) to high surface activated charcoal, in vitro studies.

BACKGROUND: Paracetamol (acetaminophen) intoxication often in combination with ethanol, is seen commonly in overdose cases. Doses of several grams might be close to the maximum adsorption capacity of the standard treatment dose (50g) of activated charcoal. The aim of this study was to determine the maximum adsorption capacity for paracetamol for two types of high surface-activated charcoal [Carbomix and Norit Ready-To-Use (not yet registered trademark in Denmark) both from Norit Cosmara, Amersfoort, The Netherlands] in simulated in vivo environments: At pH 1.2 (gastric environment), at pH 7.2 (intestinal environment), and with and without 10% ethanol. METHODS: Activated charcoal, at both gastric or intestinal pHs, and paracetamol were mixed, resulting in activated charcoal-paracetamol ratios from 10:] to 1:1. In trials with ethanol, some of the gastric or intestinal fluid was replaced with an equivalent volume of ethanol, resulting in an ethanol concentration of 10% v/v. After incubation, the concentration of unabsorbed paracetamol was analyzed by high-performance liquid chromatography. The maximum adsorption capacity of paracetamol to activated charcoal was calculated as mg paracetamol adsorbed/g activated charcoal, using Langmuir's isotherm. RESULTS: Carbomix [95% confidence limits are shown in square brackets]: 623.7 [612.8;634.5] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 626.2 [611.6;640.9] mg paracetamol adsorbed/g activated charcoal (pH 7.2); Norit Ready-To-Use: 693.6 [676.8;710.5] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 722.6 [687.4;757.9] mg paracetamol adsorbed/g activated charcoal (pH 7.2). For experiments with ethanol (10% v/v) the results with Carbomix were 465.7 [449.2;482.2] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 498.6 [481.8;515.6] mg paracetamol adsorbed/g activated charcoal (pH 7.2); with Norit Ready-To-Use: 617.2 [606.6;627.7] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 640.6 [624.9;656.4] mg paracetamol adsorbed/g activated charcoal (pH 7.2). CONCLUSION: Under conditions simulating immediate treatment with charcoal, a standard dose of 50 g of either of the two tested activated charcoals adsorbed a sufficient amount of paracetamol to be beneficial in the treatment of the majority of overdoses of this drug. For both types of activated charcoal, with or without ethanol, there was no significant difference in the adsorption of paracetamol at pH 1.2 and 7.2. Norit Ready-To-Use had a larger maximum adsorption capacity than Carbomix, and was not as sensitive as Carbomix to environmental changes (pH and ethanol). The presence of 10% ethanol lowered the adsorption capacity of the two tested activated charcoal preparations by an amount that might be clinically relevant in cases of intoxications by high-gram doses.

Acetaminophen↗

PubMed2004

The role of cytochrome-P450 inhibitors in the prevention of hepatotoxicity after paracetamol overdose in rats.

Despite the understanding that some cytochrome P450 isoforms are responsible for activation of paracetamol to the hepatotoxic metabolite, N-acetyl-p-benzoquinineimine (NAPQI), the use of enzyme inhibitors for prevention and/or treatment of paracetamol hepatotoxicity is still not well researched. Here, a mixture of ketoconazole, isoniazid and caffeine (inhibitor solution), known inhibitors of CYP3A, CYP2E1 and CYP1A2, was investigated for prevention of hepatotoxicity after paracetamol over-dose in rats. The appropriate doses of paracetamol (1000 mg/kg/day) and the 'inhibitor solution' (ketoconazole 5 mg/kg, isoniazid 5 mg/kg and caffeine 10 mg/kg; =KIC-5-50), were selected in preliminary experiments. Thereafter, two groups of 15 male Sprague-Dawley rats each were treated with the toxic dose of paracetamol intraperitoneally to induce severe hepatotoxicity. But one of the two groups was treated with the KIC-5-50 intraperitoneally 5 min after administration of paracetamol. Five rats were killed at 24, 48 and 72 hours after paracetamol administration. Plasma concentrations of paracetamol were determined by the polarization fluorescent immunoassay and a piece of liver was sent for histopathology examination. Liver function tests at 48 hours were higher in the 'paracetamol only' treated group than in the 'KIC-5-50 + paracetamol' treated group' (P < 0.05), i.e., median (range) AST 2025 (530-4329) i.u./L, ALT 1174 (662-2395) i.u./L versus AST 194 (81-494) i.u./L, ALT 311 (201-945) i.u./L, respectively. The corresponding plasma concentrations of paracetamol were 0.26 (0.13-1.02) microg/mL for the 'paracetamol only' treated group versus 0.17 (0.07-0.33) microg/ml for the 'KIC-5-50 + paracetamol' treated group. Centrilobular necrosis, the pathogmonomic feature of paracetamol hepatotoxicity, was demonstrated only in the 'paracetamol only' treated group. In conclusion, coadministration of paracetamol with inhibitors of cytochrome P450 prevented the development of paracetamol-induced hepatotoxicity in rats, and this calls for research for enzyme inhibitors that may be of therapeutic value.

Acetaminophen↗

PubMed2003

Paracetamol and metabolite pharmacokinetics in infants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Acetaminophen↗

PubMed2001

Measuring plasma paracetamol concentrations in all patients with drug overdose or altered consciousness: does it change outcome?

OBJECTIVE: To assess whether measuring plasma paracetamol concentrations in all patients with drug overdose or collapse (altered consciousness) changes outcome. METHOD: A retrospective survey was performed of all patients attending the Accident and Emergency Department at Guy's Hospital, London over a 12 month period who had plasma paracetamol concentrations measured (it is hospital policy that patients presenting after any drug overdose, or with a collapse/altered consciousness have a plasma paracetamol concentration). RESULTS: A total of 440 patients were identified who had plasma paracetamol concentrations measured, of whom 411 were eligible for the study. Altogether 115 patients presented after a collapse and paracetamol was detected in four of these. A total of 296 patients presented after a drug overdose-136 denied overdose with a paracetamol containing product and paracetamol was not detected in any of these 136 cases. Of the remaining 160 patients who gave a positive history for overdose with paracetamol, 122 presented within 24 hours and 94 had detectable paracetamol values with 16 cases above the treatment line, 12 presented more than 24 hours after ingestion, and 26 presented with a staggered overdose. One patient died as a result of paracetamol overdose. CONCLUSIONS: This is the first study in the United Kingdom to evaluate the clinical value of routine paracetamol levels in patients presenting to the emergency department after any overdose or a collapse. Taking blood samples for plasma paracetamol estimation in patients who deny taking paracetamol is of little clinical value. However, there is the potential for missing significant paracetamol poisoning in patients presenting with collapse and so screening with a plasma paracetamol concentration is clinically justified in these patients. Such an approach can only be justified in a country in which paracetamol poisoning is prevalent, such as the United Kingdom.

Acetaminophen↗

PubMed1995

[Paracetamol poisoning].

Administration of paracetamol (acetaminophen) has analgetic and antipyretic effect. After trauma paracetamol has an anti-inflammatory activity. It was presumed that paracetamol in therapeutic doses had fewer and more acceptable side-effects than other analgetic drugs such as acetylsalicylic acid and NSAID-drugs. However, in toxic concentrations, paracetamol is more life-threatening. The toxic effects of paracetamol most often occur in the liver and kidneys. Phosphate and lactate turn-over can also be impaired. Paracetamol poisoning can induce temporary liver dysfunction or even irreversible liver failure with liver transplantation as the only therapeutic possibility. Chronic alcoholics are especially at risk, as liver damage may occur following paracetamol even in recommended doses. When intoxication with paracetamol is presumed, administration of N-acetylcysteine is vital. N-acetylcysteine therapy should be initiated not later than 15 hours after paracetamol intake. Moreover, the antitoxic effect has been observed even when N-acetylcysteine therapy is initiated 24-36 hours after presumed paracetamol intake. Measures of preventing further absorbtion of paracetamol from the gastrointestinal tract should be taken. Activated charcoal should be given if less than two hours have passed since paracetamol intake. Between two and four hours following paracetamol intake gastric lavage should be performed. During the last 10 years the incidence of paracetamol self-poisoning has increased, but death following paracetamol poisoning is relatively constant at around nine per year in Denmark. It is suggested that the incidence of serious cases of paracetamol poisoning could be reduced by simple measures. Special attention should be paid to the risk-group of chronic alcoholics.

Acetaminophen↗

PubMed1995

[Paracetamol poisoning].

Administration of paracetamol (acetaminophen) has analgetic and antipyretic effect. After trauma paracetamol has an anti-inflammatory activity. It was presumed that paracetamol in therapeutic doses had fewer and more acceptable side-effects than other analgetic drugs such as acetylsalicylic acid and NSAID-drugs. However, in toxic concentrations, paracetamol is more life-threatening. The toxic effects of paracetamol most often occur in the liver and kidneys. Phosphate and lactate turn-over can also be impaired. Paracetamol poisoning can induce temporary liver disfunction or even irreversible liver failure with liver transplantation as the only therapeutic possibility. Chronic alcoholics are especially at risk, as liver damage may occur following paracetamol even in recommended doses. When intoxication with paracetamol is presumed, administration of N-acetylcysteine is vital. N-acetylcysteine therapy should be initiated not later than 15 hours after paracetamol intake. Moreover, the antitoxic effect has been observed even when N-acetylcysteine therapy is initiated 24-36 hours after presumed paracetamol intake. Measures of preventing further absorption of paracetamol from the gastrointestinal tract should be taken. Activated charcoal should be given if less than two hours have passed since paracetamol intake. Between two and four hours following paracetamol intake gastric lavage should be performed. During the last 10 years the incidence of paracetamol self-poisoning has increased, but death following paracetamol poisoning is relatively constant at around nine per year in Denmark. It is suggested that the incidence of serious cases of paracetamol poisoning could be reduced by simple measures. Special attention should be paid to the risk-group of chronic alcoholics.

Acetaminophen↗

PubMed1996

Paracetamol and its metabolites in saliva and plasma in chronic dialysis patients.

1. Many pharmacokinetic studies on paracetamol are based on saliva paracetamol concentrations. The utility of saliva in patients with chronic renal failure is unclear. In this study, concentrations of saliva and plasma paracetamol and its major metabolites, sulphate and glucuronide conjugates were determined at 0.5, 1, 2 and 3 h after the ingestion of 1 g paracetamol in 20 patients with endstage renal failure. Ten haemodialysis patients were studied on a non-haemodialysis day and during a haemodialysis session. The other 10 patients were on chronic ambulatory peritoneal dialysis. 2. The plasma paracetamol concentrations attained in all groups were not different from those reported previously in healthy subjects. Mean +/- s.d. plasma paracetamol concentrations at 0.5 h in haemodialysis patients on a non-haemodialysis day, during haemodialysis and in those on chronic ambulatory peritoneal dialysis were 15.3 +/- 8.2, 21.5 +/- 10.9 and 18.2 +/- 12.3 micrograms ml-1 respectively. 3. The saliva paracetamol concentrations were highly variable and unpredictable. Saliva paracetamol concentrations at 1, 2 and 3 h after ingestion in the haemodialysis group during haemodialysis were 31.5 +/- 20.1, 14.1 +/- 10.4 and 7.3 +/- 3.8 micrograms ml-1 respectively, significantly (P < 0.05; paired t-test) higher than the corresponding plasma paracetamol concentrations which were 11.0 +/- 2.8, 6.5 +/- 2.8 and 3.2 +/- 0.9 micrograms ml-1 respectively. 4. Correlation coefficients between saliva and plasma paracetamol concentrations in haemodialysis patients on a non-haemodialysis day and during haemodialysis and in chronic ambulatory peritoneal dialysis patients were poor; r = 0.58 (P < 0.0002); r = 0.40 (P < 0.02); and r = 0.13 (P = 0.49) respectively. 5. Three hours after paracetamol ingestion, plasma paracetamol, sulphate and glucuronide concentrations were significantly (P < 0.05) reduced in haemodialysis patients during haemodialysis when compared with the same patients on a non-haemodialysis day (paired t-test) and to the chronic ambulatory peritoneal dialysis group (Kruskal-Wallis ANOVA) except for plasma glucuronide. This indicates the effective removal of paracetamol and metabolites by haemodialysis. In contrast, chronic ambulatory peritoneal dialysis seemed to remove glucuronide only. 6. In the light of the poor correlation between saliva and plasma paracetamol in dialysis patients in this study, we would like to caution against using saliva paracetamol concentrations for pharmacokinetic studies in this group of patients.

Acetaminophen↗

PubMed2001

Cisapride raises the bioavailability of paracetamol by inhibiting its glucuronidation in man.

The effect of cisapride on plasma concentrations of paracetamol was investigated with respect to hepatic metabolism. Paracetamol (1 g) together with cisapride (7.5 mg) or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and its glucuronide and sulfate conjugates were measured by HPLC. The pharmacokinetic variables were calculated from the plasma concentration-time curves of each volunteer. The area under the plasma paracetamol concentration-time curve from 0 to 180 min (mean +/- s.d.) increased from 1875.0 +/- 112.8 micrg min mL(-1) (placebo coadministration) to 2238.8 +/- 125.8 microg min mL(-1) (cisapride coadministration) (P < 0.01). The mean maximum plasma paracetamol concentration(18.2 microg mL(-1))with placebo was reached 30 min after administration, whereas mean maximum plasma paracetamol concentration (21.2 microg mL(-1)) with cisapride occurred 45 min after administration. The plasma paracetamol concentrations with cisapride were significantly greater at 45 to 120 min after administration compared with placebo. Plasma paracetamol glucuronide conjugate concentrations with cisapride were decreased at 15 to 60 min compared with placebo (P< 0.05), whereas plasma paracetamol sulfate conjugate concentrations did not change significantly. Hence the coadministration of paracetamol with cisapride reduced plasma paracetamol glucuronide concentrations and increased plasma paracetamol concentrations, presumably due to inhibition of paracetamol metabolism via paracetamol glucuronyltransferase. Thus, care is necessary when paracetamol and cisapride are coadministered.

Acetaminophen↗

PubMed1995

High resolution NMR spectroscopic studies on the metabolism and futile deacetylation of 4-hydroxyacetanilide (paracetamol) in the rat.

Paracetamol (4-hydroxyacetanilide, acetaminophen) was synthesized with the acetyl group labelled with C2H3 (paracetamol-C2H3), and dosed to rats i.p. at 25 mg/kg (N = 5) and 40 mg/kg (N = 3) body weight. Paracetamol, with a 13CH3 in the acetyl group (paracetamol-13CH3) was also synthesized and dosed to rats i.p. at 40 mg/kg (N = 3). The metabolism and excretion of the 2H-labelled compound was followed in the rat using 600 MHz 1H and 92.1 MHz 2H NMR spectroscopy of urine collected 0-8, 8-24, 24-32 and 32-48 hr post-dosing. The metabolism of paracetamol-13CH3 was also monitored using 600 MHz 1H NMR spectroscopy of urine collected 0-8, 8-24 and 24-48 hr post-dosing. For paracetamol-C2H3 the total recovery of the sulphate, glucuronide and N-acetyl cysteinyl metabolites via the urine accounted for 61.2 +/- 14.1% of the 25 mg/kg dose and 61.4 +/- 8.8% of the 40 mg/kg dose. For paracetamol-13CH3 the recovery was 102.7 +/- 3.7% indicating that the low % urinary recovery with the C2H3-labelled drug is the result of isotope effects on the disposition of paracetamol. In the case of the paracetamol-C2H3, quantitative 1H NMR analysis of urine showed that 13.3 +/- 0.5 and 10.0 +/- 1.2 mole % (25 and 40 mg/kg, respectively) of the urinary paracetamol sulphate recovered following dosing of the deuterium labelled drug had the C2H3 acetyl groups replaced by C1H3 acetyl groups from endogenous sources. In the case of the paracetamol-13CH3 8.9 +/- 0.7 mole % of the sulphate conjugate had also been transacetylated to paracetamol-12CH3. There was no significant difference between the level of futile deacetylation observed for the deuterated and 13C-labelled drug. Overall these data indicate a high level of deacetylation followed by reacetylation (i.e. futile deacetylation) prior to excretion of paracetamol via the nephrotoxic intermediate 4-aminophenol. The level of deacetylation is much higher than has previously been thought which may cast new light on the role of 4-aminophenol in the development of paracetamol induced nephrotoxicity.

Acetaminophen↗

PubMed1997

Paracetamol with and without codeine in acute pain: a quantitative systematic review.

In order to assess the analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain, we conducted a systematic review of randomised controlled trials. We found 31 trials of paracetamol against placebo with 2515 patients, 19 trials of paracetamol plus codeine against placebo with 1204 patients and 13 trials of paracetamol plus codeine against the same dose of paracetamol with 874 patients. Pain relief information was extracted, and converted into dichotomous information (number of patients with at least 50% pain relief). Wide variations in responses to placebo (0-72%) and active drug (3-89%) were observed. In postoperative pain states paracetamol 1000 mg alone against placebo had an number-needed-to-treat (NNT) of 3.6 (3.0-4.4) and paracetamol 600/650 mg alone an NNT of 5.0 (4.1-6.9). Paracetamol 600/650 mg plus codeine 60 mg against placebo had a better NNT of 3.1 (2.6-3.8), with no overlap of 95% confidence intervals with paracetamol 600/650 mg alone. In direct comparisons of paracetamol plus codeine with paracetamol alone the additional analgesic effect of 60 mg of codeine added to paracetamol was 12 extra patients in every 100 achieving at least 50% pain relief. In indirect comparisons of each with placebo it was 14 extra patients per 100. This was an NNT for adding codeine 60 mg of 9.1 (5.8-24). The results confirm that paracetamol is an effective analgesic, and that codeine 60 mg added to paracetamol produces worthwhile additional pain relief even in single oral doses.

Acetaminophen↗

PubMed2001

Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study.

OBJECTIVE: To evaluate the effects on suicidal behaviour of legislation limiting the size of packs of paracetamol and salicylates sold over the counter. DESIGN: Before and after study. SETTING: UK population, with detailed monitoring of data from five liver units and seven general hospitals, between September 1996 and September 1999. SUBJECTS: People who died by suicidal or accidental overdose with paracetamol or salicylates or who died of undetermined causes; patients admitted to liver units with hepatic paracetamol poisoning; patients presenting to general hospitals with self poisoning after taking paracetamol or salicylates. MAIN OUTCOME MEASURES: Mortality from paracetamol or salicylate overdose; numbers of patients referred to liver units or listed for liver transplant; numbers of transplantations; numbers of overdoses and tablets taken; blood concentrations of the drugs; prothrombin times; sales to pharmacies and other outlets of paracetamol and salicylates. RESULTS: Numbers of tablets per pack of paracetamol and salicylates decreased markedly in the year after the change in legislation on 16 September 1998. The annual number of deaths from paracetamol poisoning decreased by 21% (95% confidence interval 5% to 34%) and the number from salicylates decreased by 48% (11% to 70%). Liver transplant rates after paracetamol poisoning decreased by 66% (55% to 74%). The rate of non-fatal self poisoning with paracetamol in any form decreased by 11% (5% to 16%), mainly because of a 15% (8% to 21%) reduction in overdoses of paracetamol in non-compound form. The average number of tablets taken in paracetamol overdoses decreased by 7% (0% to 12%), and the proportion involving >32 tablets decreased by 17% (4% to 28%). The average number of tablets taken in salicylate overdoses did not decrease, but 34% fewer (2% to 56%) salicylate overdoses involved >32 tablets. After the legislation mean blood concentrations of salicylates after overdose decreased, as did prothrombin times; mean blood concentrations of paracetamol did not change. CONCLUSION: Legislation restricting pack sizes of paracetamol and salicylates in the United Kingdom has had substantial beneficial effects on mortality and morbidity associated with self poisoning using these drugs.

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PubMed2006

Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure.

BACKGROUND: Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen-activated protein kinase family and is a key intracellular signalling molecule involved in controlling the fate of cells. AIM: To examine the role of JNK in paracetamol-induced acute liver failure (ALF). METHODS: A previously developed mouse model of paracetamol poisoning was used to examine the role of JNK in paracetamol-induced ALF. RESULTS: Paracetamol-induced hepatic JNK activation both in human and murine paracetamol hepatotoxicity and in our murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity, with a significant reduction in hepatic necrosis and apoptosis. In addition, delayed administration of the JNK inhibitor was more effective than N-acetylcysteine after paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride-mediated or anti-Fas antibody-mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic tumour necrosis foctor alpha (TNF alpha) production after paracetamol poisoning. CONCLUSIONS: These data demonstrated a central role for JNK in the pathogenesis of paracetamol-induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity.

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PubMed1997

Use of paracetamol for suicide and non-fatal poisoning in the UK and France: are restrictions on availability justified?

OBJECTIVE: To investigate the relationship between the availability of paracetamol and its use for overdose and suicide. DESIGN: Analysis of routinely collected information on time trends for paracetamol suicides, non-fatal overdoses, and sales. SETTING: England and Wales and France. RESULTS: There were strong correlations between trends in paracetamol sales in the UK and trends in non-fatal paracetamol overdose in Oxford between 1976 and 1993 (Spearman's r = 0.86; 95% confidence interval (CI) 0.54, 0.96) and between paracetamol sales and non-fatal overdoses in France between 1974 and 1990 (r = 0.99; 95% CI 0.97, 1.00). Sales figures were also correlated with paracetamol related suicides in both England and Wales, 1983-91 (r = 0.72; 95% CI 0.11, 0.94) and France, 1974-90 (r = 0.79; 95% CI 0.50, 0.92). Similarly strong relationships were observed between trends in non-fatal overdoses and suicide by paracetamol poisoning in England and Wales (r = 0.85; 95% CI 0.61, 0.95) and France (r = 0.79; 95% CI 0.50, 0.92). It is estimated that approximately 32,000 overdoses involving paracetamol occur annually in England and Wales. Fatality rates from paracetamol overdose were four times as high in England and Wales (0.4%, 95% CI 0.38, 0.46) as in France (0.1%, 95% CI 0.06, 0.17). CONCLUSION: Trends towards greater availability of paracetamol are paralleled by increases in its use for both non-fatal overdose and suicide. Paracetamol related morbidity and mortality seem to be less frequent in France where the quantity of paracetamol in a single purchase is limited. Although not conclusive, these data add to a body of evidence which suggests that restrictions in the quantity of paracetamol available as a single purchase in the UK may reduce suicide and liver failure related to paracetamol.

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PubMed2002

No clinically relevant drug interaction between paracetamol and phenprocoumon based on a pharmacoepidemiological cohort study in medical inpatients.

OBJECTIVE: A recent case control study suggests that paracetamol at a dosage above 1300 mg/day increases the anticoagulant effects of warfarin. In many European countries, phenprocoumon and not warfarin is used as an anticoagulant. However, the effects of paracetamol on the anticoagulant effects of phenprocoumon have so far not been evaluated. METHODS: This study is based on the data recorded prospectively between 1996 and 1998 in two Swiss teaching hospitals in the pharmacoepidemiological database of the SAS/CHDM project. As a first step, all phenprocoumon-treated patients with at least one international normalized ratio (INR) determination at least 4 days after cohort entry were selected and evaluated concerning paracetamol co-administration. The "paracetamol group" included only patients receiving at least 1300 mg/day paracetamol on the 3 days preceding the INR determination, whereas the comparison group contained only patients without paracetamol exposure during hospital stay. Thereafter, INR values of the paracetamol and the comparison groups were compared. RESULTS: The paracetamol and the comparison groups included 54 and 180 patients, respectively. Patients' characteristics in both groups were comparable. Patients in the paracetamol group received on average 2220 +/- 651 mg/day paracetamol. The median duration of paracetamol exposure was 5 days. The median difference in INR values between the paracetamol and the comparison groups was -0.3 (with a 99% confidence interval of -0.6, 0.1). CONCLUSIONS: These results suggest that paracetamol co-administration at a dosage of 2000-2500 mg/day for 3 days has no clinically relevant effects on the anticoagulant effects of phenprocoumon.

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