In patients with acute stroke, increased body temperature is associated with large lesion volumes, high case fatality, and poor functional outcome. A 1°C increase in body temperature may double the odds of poor outcome. Two randomized double-blind clinical trials in patients with acute ischemic stroke have shown that treatment with a daily dose of 6 g acetaminophen (paracetamol) results in a small but rapid and potentially worthwhile reduction of 0.3°C (95% CI: 0.1–0.5) in body temperature. We set out to test the hypothesis that early antipyretic therapy reduces the risk of death or dependency in patients with acute stroke, even if they are normothermic.
Paracetamol (Acetaminophen) In Stroke (PAIS) is a randomized, double-blind clinical trial, comparing high-dose acetaminophen with placebo in 2500 patients. Inclusion criteria are a clinical diagnosis of hemorrhagic or ischemic stroke and the possibility to start treatment within 12 hours from onset of symptoms. The study will have a power of 86% to detect an absolute difference of 6% in the risk of death or dependency at three months, and a power of 72% to detect an absolute difference of 5%, at a 5% significance level.
This is a simple trial, with a drug that only has a small effect on body temperature in normothermic patients. However, when lowering body temperature with acetaminophen does have the expected effectiveness, 20 patients will have to be treated to prevent dependency or death in one.
Paracetamol (acetaminophen) is recommended in most clinical practice guidelines as the first choice of treatment for low back pain, however there is limited evidence to support this recommendation. The PACE trial is the first placebo controlled trial of paracetamol for acute low back pain. This article describes the statistical analysis plan.
PACE is a randomized double dummy placebo controlled trial that investigates and compares the effect of paracetamol taken in two regimens for the treatment of low back pain. The protocol has been published. The analysis plan was completed blind to study group and finalized prior to initiation of analyses. All data collected as part of the trial were reviewed, without stratification by group, and classified by baseline characteristics, process of care and trial outcomes. Trial outcomes were classified as primary and secondary outcomes. Appropriate descriptive statistics and statistical testing of between-group differences, where relevant, have been planned and described.
A standard analysis plan was developed for the results of the PACE study. This plan comprehensively describes the data captured and pre-determined statistical tests of relevant outcome measures. The plan demonstrates transparent and verifiable use of the data collected. This a priori plan will be followed to ensure rigorous standards of data analysis are strictly adhered to.
Australia and New Zealand Clinical Trials Registry ACTRN12609000966291
Acetaminophen; Back pain; Paracetamol; Statistical analysis plan; Randomised controlled trial
Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect.
Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.
No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period.
Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.
Alternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of a single administration of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children.
Seventy febrile children were randomly allocated to receive either a single oral dose of 10 mg/kg ibuprofen and 15 mg/kg oral acetaminophen after 4 hours, or a similar dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline, 4, 5, 6, 7 and 8 hours later. Endpoints included proportions of afebrile children at 6, 7 and 8 hours, maximum decline in temperature, time to recurrence of fever, and change in temperature from baseline at each time point. Intent-to-treat analysis was planned with statistical significance set at P < 0.05.
A higher proportion of subjects in the intervention group (83.3%) became afebrile at 6 hours than in the control group (57.6%); P = 0.018. This difference was accentuated at 7 and 8 hours (P < 0.001) with a significantly longer time to recurrence of fever in the intervention group (mean ± SD of 7.4 ± 1.3 versus 5.7 ± 2.2 hours), P < 0.001. Odds ratios (95%CI) for defervescence were 5.6 (1.3; 23.8), 19.5 (3.5; 108.9) and 15.3 (3.4; 68.3) at 6, 7 and 8 hours respectively. Two-way ANOVA with repeated measures over time revealed a significantly larger decline in temperature in the intervention group at times 7 (P = 0.026) and 8 (P = 0.002) hours.
A single dose of alternating ibuprofen and acetaminophen appears to be a superior antipyretic regimen than ibuprofen mono-therapy. Further studies are needed to confirm these findings.
Background: Acetaminophen (paracetamol) is recommended as the initial pharmacological treatment for knee or hip osteoarthritis. However, survey and clinical trial data indicate greater efficacy for non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 specific inhibitors.
Design: Two randomised, double blind, placebo controlled, crossover multicentre clinical trials, Patient Preference for Placebo, Acetaminophen or Celecoxib Efficacy Studies (PACES).
Patients: Osteoarthritis of knee or hip.
Intervention: "Wash out" of treatment; randomisation; 6 weeks of celecoxib 200 mg/day, acetaminophen 1000 mg four times a day, or placebo; second "wash out;" crossover to 6 weeks of second treatment.
Measurements: Western Ontario McMaster Osteoarthritis Index (WOMAC), visual analogue pain scale, patient preference between two treatments.
Results: Celecoxib was more efficacious than acetaminophen in both periods in both studies; WOMAC and pain scale scores differed at p<0.05 in period II and both periods combined of PACES-a and in periods I and II and both periods combined in PACES-b, but not in period I of PACES-a. Acetaminophen was more efficacious than placebo, generally p<0.05 in PACES-b, and >0.05 in PACES-a. Patient preferences were 53% celecoxib v 24% acetaminophen in PACES-a (p<0.001) and 50% v 32% in PACES-b (p = 0.009); 37% acetaminophen v 28% placebo in PACES-a (p = 0.340) and 48% v 24% in PACES-b (p = 0.007). No clinically or statistically significant differences were seen in adverse events or tolerability among the three treatment groups.
Conclusions: Greater efficacy was seen for celecoxib v acetaminophen v placebo, while adverse events and tolerability were similar. Variation in results and statistical significance in the two different trials are of interest.
During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their functional outcome. Previously, we studied the effect of high dose (6 g daily) and low dose (3 g daily) paracetamol (acetaminophen) in a randomised placebo-controlled trial of 75 patients with acute ischemic stroke. In the high-dose paracetamol group, mean body temperature at 12 and 24 hours after start of treatment was 0.4°C lower than in the placebo group. The effect of ibuprofen, another potent antipyretic drug, on body-core temperature in normothermic patients has not been studied.
The aim of the present trial is to study the effects of high-dose paracetamol and ibuprofen on body temperature in patients with acute ischaemic stroke, and to study the safety of these treatments.
Seventy-five (3 × 25) patients with acute ischaemic stroke confined to the anterior circulation will be randomised to treatment with either: 400 mg ibuprofen, 1000 mg acetaminophen, or with placebo 6 times daily during 5 days. Body-temperatures will be measured with a rectal electronic thermometer at the start of treatment and after 24 hours. An infrared tympanic thermometer will be used to monitor body temperature at 2-hour intervals during the first 24 hours and at 12-hour intervals thereafter. The primary outcome measure will be rectal temperature at 24 hours after the start of treatment. The study results will be analysed on an intent-to-treat basis, but an on-treatment analysis will also be performed. No formal interim analysis will be carried out.
Considering that protocols of postoperative pain management would be planned regarding the facilities of each center or region and the importance of its proper management to reduce its related complication and improve patient's satisfaction, in this study we compared the effect of orally administrated tramadol and acetaminophen-codeine in this regard.
Materials and Methods:
In this prospective randomized double-blind clinical trial, 136 (68 in tramadol and 68 in acetaminophen codeine groups) ASA I and II patients scheduled for open cholecystectomy under general anaesthesia were enrolled. They randomly allocated to receive oral tramadol (50 mg capsule) or acetaminophen-codeine (325/10 mg) 1 hour before surgery. After surgery they evaluated for postoperative pain using VAS score, analgesic consumption and vomiting.
Mean of postoperative pain score during 24 hours after surgery was 2.1 ± 1.0 and 3.8 ± 2.0 in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). Mean of analgesic consumption (morphine) during 24 hours after surgery was 6.2 ± 4.4 mg and 12.9 ± 5.7 mg in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). Mean of vomiting during 24 hours after surgery was 1.2 ±0.9 and 0.4 ± 0.5 in tramadol and acetaminophen-codeine groups, respectively (P < 0.05).
The findings of current study indicated that in lower dose of tramadol (50 mg) and acetaminophen/codeine (325 mg/10 mg) the analgesic effect of tramadol is better and its side effects are higher than acetaminophen/codeine, which limit its use for mentioned purpose. It seems that administration of each of studied agents it depends on patients’ tolerance and decision of the physician.
Acetaminophen codeine; postoperative pain; tramadol
The objective of this study was to assess the efficacy of paracetamol (acetaminophen) in the treatment of pain and disability in patients with non-specific low back pain. We conducted a systematic review of randomized controlled trials to assess the efficacy of paracetamol in the treatment of pain and disability in patients with non-specific low back pain. A search for randomized controlled trials was conducted using the Medline, Embase and CINAHL databases. Trials were eligible if they were randomized controlled trials comparing paracetamol to no treatment, placebo or another treatment in patients with non-specific low back pain. Two of the authors independently assessed trials for methodological quality on the PEDro Scale and extracted data. Continuous pain and disability data were converted to a common 0–10 scale; ordinal data were dichotomized (e.g., no pain, pain). The data was analyzed using the MIX version 1.61 meta-analysis software. Out of 205 unique articles found in the searches, 7 eligible trials were identified. The trials enrolled a total of 676 participants with 5 investigating acute low back pain, 1 investigating chronic low back pain and 1 investigating both. No trial provided data comparing paracetamol to placebo and only one trial compared paracetamol to no treatment. In general the trials were small (only 1 trial had >25 subjects per group) and of low methodological quality (only 2 had a score above 6 on the quality scale). All but one of the trials provided imprecise estimates of the effects of treatment with confidence intervals spanning clinically important beneficial and also harmful effects of paracetamol. No trial reported a statistically significant difference in favor of paracetamol. There is insufficient evidence to assess the efficacy of paracetamol in patients with low back pain. There is a clear need for large, high quality randomized controlled trials evaluating paracetamol, to provide reliable evidence of paracetamol’s effectiveness in patients with low back pain and to establish the validity of the recommendations in clinical guidelines.
Low back pain; Paracetamol; Acetaminophen; Review
Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States.
Children six weeks through nine months of age were randomized 1∶1 to receive up to five doses of acetaminophen (10–15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal temperature ≥38°C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo.
A temperature ≥38°C was recorded for 14% (25/176) of children randomized to acetaminophen compared with 22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40–1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24%) (RR, 0.42; 95% CI, 0.25–0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI, 0.11–0.83) than those randomized to placebo. In age-stratified analyses, among children ≥24 weeks of age, there was a significantly lower risk of temperature ≥38°C in the acetaminophen group (13% vs. 25%; p = 0.03).
The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness.
Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.
This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.
EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity
A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms.
Transient symptoms including myalgia and pyrexia have been reported post-infusion of IV bisphosphonates, typically starting the day after infusion and resolving within several days. The cause is unknown but may be related to transient cytokine elevations. Statins’ potential to block release of these cytokines has been hypothesized. This study was aimed to evaluate efficacy of acetaminophen and fluvastatin in preventing/reducing post-dose symptoms following ZOL 5 mg infusion.
Randomized, double-blind, placebo-controlled study of efficacy of acetaminophen or fluvastatin in preventing increases in body temperature or use of rescue medication (ibuprofen) following a single ZOL infusion. Bisphosphonate-naive postmenopausal women with low bone mass (N = 793) were randomized into three treatment groups and given 650 mg acetaminophen or 80 mg fluvastatin or placebo 45 min before ZOL infusion. The acetaminophen group continued taking 650 mg acetaminophen every 6 h over the next 3 days, and the other two groups took matching placebo according to the same schedule. Subjects recorded body temperature, symptoms in a diary. Inflammatory cytokines and C-reactive protein (CRP) were measured at baseline, 24, and 72 h in a study subset.
Acetaminophen four times/day significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. Single-dose fluvastatin 80 mg prior to ZOL infusion did not prevent/reduce post-dose symptoms. Cytokine levels increased by 24 h and returned towards baseline by 72 h, similar to the pattern for post-infusion symptoms. CRP levels increased from baseline to 72 h.
Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion.
Cytokines; Fluvastatin; Inflammatory biomarkers; Osteoporosis; Post-dose symptoms; Zoledronic acid
The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 400 mg, or placebo. Active control with ibuprofen was used to determine model sensitivity. Pain relief (scale, 0-4) and pain intensity (scale, 0-3) were reported at 30 minutes after the dose and then hourly for 8 hours. Total pain relief over 8 hours (TOTPAR8) and the sum of pain intensity differences (SPID8) were calculated from the hourly scores. Time to onset of pain relief was determined by the double-stopwatch technique, and patients were advised to wait at least 2 hours before taking supplemental analgesia. Patients assessed overall efficacy (scale, 1-5) upon completion. In all, 1197 patients (age range, 16-46 years) were evaluable for efficacy; treatment groups in each study were similar at baseline. Pain relief was superior to placebo (P < or = .0001) for all treatments. Pain relief provided by tramadol/ APAP was superior to that of tramadol or APAP alone, as shown by mean TOT-PAR8 (12.1 vs 6.7 and 8.6, respectively, P < or = .0001) and SPID8 (4.7 vs 0.9 and 2.7, respectively, P < or = .0001). Estimated onset of pain relief was 17 minutes (95% CI, 15-20 minutes) for tramadol/APAP compared with 51 minutes (95% CI, 40-70 minutes) for tramadol, 18 minutes (95% CI, 16-21 minutes) for APAP, and 34 minutes (95% CI, 28-44 minutes) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (P < .05) for the tramadol/APAP group (302 minutes and 3.0, respectively) than for the tramadol (122 minutes and 2.0) or APAP (183 minutes and 2.7) monotherapy groups. A new combination analgesic, tramadol/APAP, is superior to tramadol or APAP alone with respect to pain relief and duration of action. It is also superior to tramadol alone with respect to time to onset.
To quantify the effect of acetaminophen at therapeutic doses on serum ALT in subjects who use ethanol, using data from all randomized placebo-controlled trials (RCT).
A systematic review and meta-analysis of RCTs identified in a comprehensive literature search of PubMed EMBASE, International Pharmaceutical Abstracts and the Cochrane Registry of Clinical Trials. The search included multiple terms for “acetaminophen” combined with multiple terms for “ethanol”.
Patients We included RCT that enrolled subjects who had consumed ethanol either during or just prior to study entry, and who were administered up to 4 g daily of acetaminophen.
The primary outcome was the change in serum ALT activity from baseline compared to placebo.
184 unique articles were identified; six articles met all criteria. Five of the six articles reported ALT values at study day 4 for 551 acetaminophen-treated and 350 placebo-treated subjects; thus the changes in ALT from baseline to study day 4 were used for the meta-analysis. The difference in mean change from baseline ALT values between the acetaminophen and placebo groups on study day 4 was 0.0 IU/L (95%CI: −0.2 to 0.1 IU/L). There were no reports of liver dysfunction, failure or death in any of the prospective trials.
In published randomized, placebo controlled trials of subjects who consume ethanol, there was no elevation of ALT on study day four when subjects ingest 4g/day of acetaminophen.
Muscle injuries are one of the commonest injuries affecting athletes. It often leads to significant pain and disability causing loss of training and competition time. With current treatment, the duration to return-to-play ranges form six weeks to never, depending on injury severity. Recent researches have suggested that autologous platelet-rich plasma (PRP) injection into the injured site may hasten soft tissues healing. To-date, there has been no randomised clinical trials to evaluate the effects of PRP on muscle healing. The aim of this study is to examine the effects of autologous PRP on duration to return-to-play after muscle injury.
Methods and design
A randomised, single blind controlled trial will be conducted. Twenty-eight patients aged 18 years and above with a recent grade-2 hamstring injury will be invited to take part. Participants will be randomised to receive either autologous PRP injection with rehabilitation programme, or rehabilitation programme only. Participants will be followed up at day three of study and then weekly for 16 weeks. At each follow up visit, participants will be assessed on readiness to return-to-play using a set of criteria. The primary end-point is when participants have fulfilled the return-to-play criteria or end of 16 weeks.
The main outcome measure of this study is the duration to return-to-play after injury.
This study protocol proposes a rigorous and potential significant evaluation of PRP use for grade-2 hamstring injury. If proven effective such findings could be of great benefit for patients with similar injuries.
Current Controlled Trials ISCRTN66528592
Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are widely used in the treatment of tension headache. The objective of this study was to evaluate and compare the efficacy and safety of single doses of acetaminophen and NSAIDs using meta-analysis of randomized placebo-controlled trial studies.
We searched MEDLINE, EMBASE, CINAHL, Cochrane, KMbase, KoreaMed, RiCH, National Assembly Library, Riss4u, and DBPIA for studies released through 27th July 2010. Two authors independently extracted the data. To assess the risk of bias, the Cochrane Collaborations risk of bias tool was used. Review Manager 5.0 was used for statistics.
We identified 6 studies. The relative benefit of the NSAIDs group compared to the acetaminophen group for participants with at least 50% pain relief was 1.18 (95% confidence interval [CI], 0.99 to 1.39; I2 = 85%). We did subgroup analysis based on allocation concealment versus non-allocation concealment, and low-dose NSAIDs versus high-dose NSAIDs. The relative benefit of the low-dose NSAIDs subgroup to the acetaminophen group was 0.98 (95% CI, 0.91 to 1.06; I2 = 0%). However, the heterogeneity of other subgroup analysis was not settled. The relative risk for using rescue medication of the NSAIDs group compared to the acetaminophen group was 0.84 (95% CI, 0.64 to 1.12; I2 = 47%). The relative risk for adverse events was 1.31(95% CI, 0.96 to 1.80; I2 = 0%).
In this meta-analysis, there was no difference between low-dose NSAIDs and acetaminophen in the efficacy of the treatment for tension type headache. The results suggested that high-dose NSAIDs have more effect but also have more adverse events. The balance of benefit and harm needs to be considered when using high-dose NSAIDs for tension headache.
Tension-type Headache; Non-steroidal Anti-inflammatory Drugs; Acetaminophen; Meta-analysis
Background and aim
As non‐randomised studies have suggested that surgical decompression may reduce mortality in patients with space occupying hemispheric infarction, randomisation may be considered unethical in controlled trials testing this treatment strategy. We studied differences in recall of information and in appreciation of the informed consent procedure between representatives included in the Hemicraniectomy After Middle cerebral artery infarction with Life‐threatening Edema Trial (HAMLET) and representatives of patients participating in the randomised trial of Paracetamol (Acetaminophen) In Stroke (PAIS).
1 year after study inclusion, we contacted 30 consecutive representatives who had given informed consent for participation of their relative in HAMLET, and 30 for PAIS. Recall of trial details and appreciation of the informed consent procedure were investigated using standardised questionnaires and compared between the two groups.
All 30 PAIS representatives and 28 HAMLET representatives were interviewed. Participation of their relative in a clinical trial was remembered by 86% of HAMLET and 40% of PAIS representatives (p<0.001). HAMLET representatives remembered more trial details (effect of the treatment under study (61% vs 3%, p<0.001); randomised treatment allocation (71% vs 0%, p<0.001)). With respect to appreciation of the informed consent procedure, we found no differences between the groups: in each trial, four representatives (14% vs 13%) had considered the question of randomisation unacceptable.
Participation of patients in a randomised controlled trial of surgical decompression for space occupying infarction is generally considered acceptable by their representatives, and recall of trial details is better than in a trial in which less vital issues are at stake.
The purpose of this paper was to evaluate the contribution of low dosages of codeine and caffeine when added to acetaminophen. Subjects were dental outpatients undergoing oral surgery involving bone removal. This was a single-dose, parallel group, double-blind assay evaluting 99 subjects. The treatment groups were acetaminophen 1000 mg, acetaminophen 1000 mg + codeine 16 mg + caffeine 30 mg and placebo. The results demonstrated that both active treatments were superior to placebo. Overall, the combination was slightly better than acetaminophen alone. The advantage of the combination appeared more evident in the “severe” baseline pain group.
OBJECTIVE: To evaluate the effects of acetaminophen on the incidence of adverse effects to, and the immunogenicity of, whole-virus influenza vaccine in health care workers. DESIGN: Prospective, randomized, double-blind placebo-controlled trial. SETTING: Health Sciences Centre, an acute care teaching hospital in Winnipeg. PARTICIPANTS: Of 474 hospital personnel who agreed to undergo influenza vaccination during the 1990-91 season 262 volunteered to participate in the study. INTERVENTIONS: A dose of 0.5 mL of inactivated trivalent whole-virus influenza vaccine was injected into the deltoid muscle. Volunteers were randomly assigned to ingest two capsules of acetaminophen in a half dose (162.5 mg per capsule) or a full dose (325 mg per capsule) or two identical placebo capsules. Capsules were to be taken at vaccination and at 4, 8 and 12 hours afterward. Subjects were asked to answer questions regarding six symptoms in a diary for the 3 days after vaccination and to record their ingestion of the study medication. MAIN OUTCOME MEASURES: Incidence of local (sore arm) and systemic (headache, fever, muscle ache, nausea and diarrhea) side effects as well as serum titres of hemagglutination inhibition (HAI) antibody to vaccine antigens before vaccination and 2 weeks and 6 months afterward. RESULTS: A total of 87, 87 and 88 subjects received the half dose, full dose and placebo respectively; 96% returned the diaries, 83% ingested all four doses of medication, and 87% volunteered all blood samples. Compared with the placebo group the incidence of sore arm was 25% to 28% lower in the half-dose and full-dose groups respectively at 24 hours after vaccination, and the rate of nausea was 90% lower in the full-dose group. The HAI titres were similar among the groups at the three test times. CONCLUSIONS: The full dose of acetaminophen significantly reduced the incidence of sore arm and nausea without affecting the antibody response. Acetaminophen use may increase the acceptance of influenza vaccine by health care workers in whom concern about side effects is an impediment to vaccination.
Many pediatricians recommend, and many parents administer, alternating or combined doses of ibuprofen and acetaminophen for fever. Limited data support this practice with standard US doses.
This study compared the antipyretic effect of 3 different treatment regimens in children, using either ibuprofen alone, ibuprofen combined with acetaminophen, or ibuprofen followed by acetaminophen over a single 6-hour observation period.
Febrile episodes from children aged 6 to 84 months were randomized into the 3 treatment groups: a single dose of ibuprofen at the beginning of the observation period; a single dose of ibuprofen plus a single dose of acetaminophen at the beginning of the observation period; or ibuprofen followed by acetaminophen 3 hours later. Ibuprofen was administered at 10 mg/kg; acetaminophen at 15 mg/kg. Temperatures were measured hourly for 6 hours using a temporal artery thermometer. The primary outcome was temperature difference between treatment groups. Adverse-event data were not collected in this single treatment period study.
Sixty febrile episodes in 46 children were assessed. The mean (SD) age of the children was 3.4 (2.2) years, and 31 (51.7%) were girls. Differences among temperature curves were significant (P < 0.001; the combined and alternating arms had significantly better antipyresis compared with the ibuprofen-alone group at hours 4 to 6 (hour 4, P < 0.005; hours 5 and 6, P < 0.001). All but one of the children in the combined and alternating groups were afebrile at hours 4, 5, and 6. In contrast, for those receiving ibuprofen alone, 30%, 40%, and 50% had temperatures >38.0°C at hours 4, 5, and 6, respectively (hour 4, P < 0.002; hours 5 and 6, P < 0.001).
During a single 6-hour observation period for these participating children, combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than ibuprofen alone at 4 to 6 hours.
fever; antipyretic; acetaminophen; ibuprofen
Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects.
Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT.
A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 ± 45 IU/L and 55 ± 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group.
Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.
Cesarean section is one of the common surgeries of women. Acute post-operative pain is one of the recognized post-operative complications.
This study was planned to compare the effects of suppositories, indomethacin, diclofenac and acetaminophen, on post-operative pain and opioid usage after cesarean section.
Materials and Methods:
In this double-blind clinical trial study, 120 candidates of cesarean with spinal anesthesia and American Society of Anesthesiologists (ASA) I-II were randomly divided into four groups. Acetaminophen, indomethacin, diclofenac, and placebo suppositories were used in groups, respectively, after operation and the dosage was repeated every 6 h and pain score and opioid usage were compared 24 h after the surgery. The severity of pain was recorded on the basis of Visual Analog Scale (VAS) and if severe pain (VAS > 5) was observed, 0.5 mg/kg intramuscular pethidine had been used.
Statistical Analysis Used:
The data were analyzed in SPSS software version 15 and analytical statistics such as ANOVA, Chi-square, and Tukey's honestly significant difference (HSD) post-hoc.
Pain score was significantly higher in control group than other groups, and also pain score in acetaminophen group was higher than indomethacin and diclofenac. The three intervention groups received the first dose of pethidine far more than control group and the distance for diclofenac and indomethacin were significantly longer (P < 0.001). The use of indomethacin, diclofenac, and acetaminophen significantly reduces the amount of pethidine usage in 24 h after the surgery relation to control group.
Considering the significant decreasing pain score and opioid usage especially in indomethacin and diclofenac groups rather than control group, it is suggested using of indomethacin and diclofenac suppositories for post-cesarean section analgesia.
Acetaminophen; cesarean section; diclofenac; indomethacin; opioid
N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen related acute liver failure.
In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and randomly assigned to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.
A total of 173 patients received NAC (n=81) or placebo (n=92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (one-sided p=0.283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; one-sided p=0.043). The benefits of transplant-free survival appeared to be confined to the 114 patients with coma grade I–II who received NAC (52% compared with 30% for placebo; one-sided p=0.010); transplant-free survival for the 59 patients with coma grade III–IV was 9% in those given NAC and 22% in those given placebo (one-sided p=0.912). The transplantation rate was lower in the NAC group but not significantly different between groups (32% vs. 45%; p=0.093). Intravenous NAC was generally well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs. 4%; p=0.031).
Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation. (ClinicalTrials.gov number NCT00004467)
Randomized clinical trials are blinded to prevent knowledge of treatment assignment from influencing outcomes and their assessments, thus protecting the trial’s scientific integrity. Trials involving a warfarin treatment arm are difficult to blind due to the need to continuously adjust dose.
We sought to examine the effectiveness of blinding secondary stroke prevention trials with a warfarin treatment arm in which the blinding system incorporates use of placebo warfarin dose modification schedules for patients in the placebo warfarin arm.
We examined treatment assignment guesses of 569 patients or their next of kin as well as study coordinators and principal neurologists at the clinical sites in a multicenter, randomized, double-dummy, double-blinded clinical trial of warfarin and aspirin using dose adjustment schedules for management of placebo warfarin.
Overall, the crude rates of correct responses are 60% for patient/proxy, 66% for study coordinator, and 56% for principal neurologist. Several indices were used to assess the consistency of guesses with what would be expected if the guessing were done completely at random, and all measures indicate adequate blinding.
Comparison to other trials using warfarin is difficult due to limited data and differences in assessment of blinding. However, results compared favorably to one existing trial.
Placebo warfarin dose adjustment schedules can protect blinding adequately in trials involving warfarin.
Objective To investigate whether paracetamol (acetaminophen) plus ibuprofen are superior to either drug alone for increasing time without fever and the relief of fever associated discomfort in febrile children managed at home.
Design Individually randomised, blinded, three arm trial.
Setting Primary care and households in England.
Participants Children aged between 6 months and 6 years with axillary temperatures of at least 37.8°C and up to 41.0°C.
Intervention Advice on physical measures to reduce temperature and the provision of, and advice to give, paracetamol plus ibuprofen, paracetamol alone, or ibuprofen alone.
Main outcome measures Primary outcomes were the time without fever (<37.2°C) in the first four hours after the first dose was given and the proportion of children reported as being normal on the discomfort scale at 48 hours. Secondary outcomes were time to first occurrence of normal temperature (fever clearance), time without fever over 24 hours, fever associated symptoms, and adverse effects.
Results On an intention to treat basis, paracetamol plus ibuprofen were superior to paracetamol for less time with fever in the first four hours (adjusted difference 55 minutes, 95% confidence interval 33 to 77; P<0.001) and may have been as good as ibuprofen (16 minutes, −7 to 39; P=0.2). For less time with fever over 24 hours, paracetamol plus ibuprofen were superior to paracetamol (4.4 hours, 2.4 to 6.3; P<0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P=0.008). Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone but no faster than ibuprofen alone (−3 minutes, 18 to −24; P=0.8). No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.
Conclusion Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours.
Trial registration Current Controlled Trials ISRCTN26362730.
The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.