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1.  PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN 74418480] 
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.
PMCID: PMC1208871  PMID: 16109181
2.  Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690] 
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.
PMCID: PMC152640  PMID: 12657165
3.  PACE – the first placebo controlled trial of paracetamol for acute low back pain: statistical analysis plan 
Trials  2013;14:248.
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.
Trial registration
Australia and New Zealand Clinical Trials Registry ACTRN12609000966291
PMCID: PMC3750911  PMID: 23937999
Acetaminophen; Back pain; Paracetamol; Statistical analysis plan; Randomised controlled trial
4.  The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients – a multicenter randomized study 
BMC Medicine  2007;5:13.
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.
PMCID: PMC1894983  PMID: 17537264
5.  Single dose oral paracetamol (acetaminophen) for postoperative pain in adults 
This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way.
To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008.
Selection criteria
Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected.
Main results
Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome.
About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms.
Authors’ conclusions
A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.
PMCID: PMC4163965  PMID: 18843665
Acetaminophen [*administration & dosage; adverse effects]; Analgesics, Non-Narcotic [*administration & dosage; adverse effects]; Pain, Postoperative [*drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
6.  A systematic review of paracetamol for non-specific low back pain 
European Spine Journal  2008;17(11):1423-1430.
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.
PMCID: PMC2583194  PMID: 18797937
Low back pain; Paracetamol; Acetaminophen; Review
7.  Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis 
Annals of the Rheumatic Diseases  2004;63(8):931-939.
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.
PMCID: PMC1755088  PMID: 15082468
8.  Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study [ISRCTN30487061] 
BMC Medicine  2006;4:4.
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.
PMCID: PMC1421419  PMID: 16515705
9.  Short-Term Efficacy of Rofecoxib and Diclofenac in Acute Shoulder Pain: A Placebo-Controlled Randomized Trial 
PLoS Clinical Trials  2007;2(3):e9.
To evaluate the short-term symptomatic efficacy of rofecoxib and diclofenac versus placebo in acute episodes of shoulder pain.
Randomized controlled trial of 7 days.
Rheumatologists and/or general practitioners totaling 47.
Acute shoulder pain.
Rofecoxib 50 mg once daily, diclofenac 50 mg three times daily, and placebo.
Outcome measures:
Pain, functional impairment, patient's global assessment of his/her disease activity, and local steroid injection requirement for persistent pain. The primary variable was the Kaplan-Meier estimates of the percentage of patients at day 7 fulfilling the definition of success (improvement in pain intensity and a low pain level sustained to the end of the 7 days of the study; log-rank test).
There was no difference in the baseline characteristics between the three groups (rofecoxib n = 88, placebo n = 94, and diclofenac n = 89). At day 7, the Kaplan-Meier estimates of successful patients was higher in the treatment groups than in the placebo (54%, 56%, and 38% in the diclofenac, rofecoxib, and placebo groups respectively, p = 0.0070 and p = 0.0239 for placebo versus rofecoxib and diclofenac, respectively). During the 7 days of the study, there was a statistically significant difference between placebo and both active arms (rofecoxib and diclofenac) in all the evaluated outcome measures A local steroid injection had to be performed in 33 (35%) and 19 (22%) patients in the placebo and rofecoxib group respectively. Number needed to treat to avoid such rescue therapy was 7 patients (95% confidence interval 5–15).
This study highlights the methodological aspects of clinical trials, e.g., eligibility criteria and outcome measures, in acute painful conditions. The data also establish that diclofenac and rofecoxib are effective therapies for the management of acute painful shoulder and that they reduce the requirement for local steroid injection.
Editorial Commentary
Background: Shoulder pain is a very common complaint that presents in primary care, and there are many different possible causes. Acute pain would normally be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), supplemented with steroid injections (which are often reserved for the treatment of severe or persistent pain). One NSAID, diclofenac, is used frequently for this condition, but other NSAIDs might also be effective. A subgroup of NSAIDs called the Cox-2 selective inhibitors specifically inhibit one particular enzyme (cyclo-oxygenase, shortened to Cox-2) which is involved in inflammation and pain. These drugs are thought to be less likely to cause stomach irritation than other NSAIDs. Therefore the researchers in this study carried out a short-term, three-way clinical trial comparing diclofenac with one particular Cox-2 inhibitor, rofecoxib, and placebo in patients with acute shoulder pain. However, rofecoxib was withdrawn from the market in September 2004 because of evidence that use of the drug was associated with an increased risk of heart attacks and strokes, and controversy remains regarding the risk of such events among users of other Cox-2 inhibitors.
What this trial shows: The main aim of this trial was to compare the level of pain relief over seven days of treatment with either diclofenac or rofecoxib, as compared to placebo. The primary outcome measure used in the trial was the proportion of patients achieving a 50% or greater decrease in pain levels over the course of the study, measured using a numerical rating scale. A total of 273 participants were recruited into the trial and at day 7 the proportion achieving a 30% decrease in pain was 38% in the placebo arm, 54% in the diclofenac arm, and 56% in the rofecoxib arm. The differences in this outcome measure between diclofenac and placebo and between rofecoxib and placebo were statistically significant; however, the researchers did not carry out a direct comparison between diclofenac and rofecoxib. The rates of adverse events were roughly comparable between all three arms of the trial, although the study was not originally planned to be large enough to detect differences in the rates of such events, so it is not possible to conclude whether there was any true difference.
Strengths and limitations: The randomization procedures used in the study minimize the possibility of bias in assigning patients to treatment arms. Bias in assessment of outcomes was also minimized by ensuring that steps were taken to prevent investigators and patients from knowing which drugs a particular patient received until the end of the trial. A key limitation of the study is the short follow-up, only seven days, and it is therefore unclear whether efficacy and safety of these drugs would continue for the much longer periods of time (weeks or even months) for which these patients might need pain relief. Finally, patients randomized to the placebo arm received no treatment for the seven days of the study other than acetaminophen or steroid injections (which would result in withdrawal from the trial). This design does not limit interpretation of the data but could be criticized because of concern over whether the patients receiving placebo received adequate pain relief.
Contribution to the evidence: This study provides some data on the efficacy of diclofenac and rofecoxib, as compared to placebo in treatment of this condition. Given that rofecoxib is now withdrawn, the efficacy of this drug is no longer relevant. However, the information from this trial should help in designing future studies of NSAIDs in shoulder pain, for example to define appropriate trial outcomes, sample size, and other aspects of study design.
PMCID: PMC1817652  PMID: 17347681
10.  Pre emptive analgesia for reducing pain after cholecystectomy: Oral tramadol vs. acetaminophen codeine 
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.
PMCID: PMC3732874  PMID: 23930257
Acetaminophen codeine; postoperative pain; tramadol
11.  The Effect of Acetaminophen on Serum Alanine Aminotransferase Activity in Subjects Who Consume Ethanol: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials 
Pharmacotherapy  2012;32(9):784-791.
Study Objective
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.
Main Results
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.
PMCID: PMC3561770  PMID: 22851428
12.  Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP) 
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.
Trial registration
EudraCT number 2009-017800-10, IdentifierNCT01050270
PMCID: PMC3626543  PMID: 23556549
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity
13.  PISA. The effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute stroke: Protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690] 
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.
PMCID: PMC101394  PMID: 11918829
14.  A randomized, double-blind, placebo-controlled, multiple-dose, parallel-group clinical trial to assess the effects of teduglutide on gastric emptying of liquids in healthy subjects 
BMC Gastroenterology  2014;14:25.
Teduglutide, a recombinant analog of human glucagon-like peptide (GLP)-2, is a novel therapy recently approved for the treatment of adult patients with short bowel syndrome who are dependent on parenteral support. Previous studies assessing the effect of GLP-2 on gastric emptying in humans have yielded inconsistent results, with some studies showing no effect and others documenting a GLP-2–dependent delay in gastric emptying. The primary objective of this study was to assess the effect of teduglutide on gastric emptying of liquids in healthy subjects, as measured by the pharmacokinetics of acetaminophen.
This double-blind, parallel-group, single-center study enrolled and randomized 36 healthy subjects (22 men, 14 women) to receive subcutaneous doses of teduglutide 4 mg or placebo (2:1 ratio; 23:13) once daily on Days 1 through 10 in the morning. Gastric emptying of a mixed nutrient liquid meal was assessed by measuring acetaminophen levels predose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, and 14 hours after administration of 1000 mg acetaminophen on Days 0 and 10. The primary study endpoint was a pharmacokinetic analysis of acetaminophen absorption in subjects receiving teduglutide or placebo.
No significant differences in gastric emptying of liquids (acetaminophen area under the concentration [AUC] vs time curve from time 0 to the last measurable concentration, AUC extrapolated to infinity, maximum concentration [Cmax], and time to Cmax) were observed on Day 10 in subjects receiving teduglutide 4 mg versus subjects receiving placebo. There were no serious adverse events (AEs), deaths, or discontinuations due to an AE reported during the study.
Teduglutide 4 mg/day for 10 days does not affect gastric emptying of liquids in healthy subjects as measured by acetaminophen pharmacokinetics. No unexpected safety signals were observed.
Trial registration
This study was registered at, identifier NCT01209351.
PMCID: PMC3928318  PMID: 24517114
Teduglutide; Gastric emptying; Pharmacokinetics; Pharmacodynamics
15.  Can Biomarkers Identify Women at Increased Stroke Risk? The Women's Health Initiative Hormone Trials 
PLoS Clinical Trials  2007;2(6):e28.
The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT).
The hormone trials were randomized, double-blind, and placebo controlled.
The Women's Health Initiative trials were conducted at 40 clinical centers in the United States.
The trials enrolled 27,347 postmenopausal women, aged 50–79 y.
We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
Outcome Measures:
Stroke was ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03).
Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance.
Editorial Commentary
Background: The Women's Health Initiative hormone trials originally set out to evaluate whether postmenopausal hormone therapy (HT, estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced the risk of heart attacks and strokes, as compared to placebo. The trials were stopped early, and the investigators found that both estrogen alone, as well as estrogen plus progestin increased the risk of stroke amongst women participating in the trials. As part of a secondary analysis of data from these trials, the investigators aimed to explore possible associations between various biological markers (such as variants in particular genes, and levels of particular lipids, proteins, and other markers in blood), and the risk of a woman experiencing a stroke in the trials. Specifically, they wanted to evaluate whether there was any evidence for particular markers being associated with the risk of a stroke; and then whether that risk was modified by whether a woman took HT in the trials.
What the trial shows: In this study, the researchers collected early cases of ischemic stroke in the trials (combining cases among women taking estrogen with those for women taking both estrogen and progestin), and matched these to control individuals, or women participating in the trials who did not experience a stroke. Two hundred five women who experienced a stroke were compared to 878 control individuals. The markers analyzed included those for which there was already some evidence for an association with stroke. Several clinical characteristics and some biomarkers, as measured at the start of the trial, but none of the gene variants, were linked with later risk of stroke. However, none of these clinical characteristics or gene variants specifically identified women who were at greater risk of experiencing a stroke within the HT arms of the trial. High levels of two biomarkers, IL-6 and PAP, did seem to identify women who were at lower risk of experiencing a stroke within the HT arms of the trial. This finding is interesting, because high levels of these markers had previously been suggested as being associated with a higher risk of stroke. Levels of several biomarkers changed during the trial, but for only one biomarker, D-dimer, did the change (an increase in levels) seem to predict higher risk of stroke amongst women receiving HT.
Strengths and limitations: A particular strength of this study includes the nesting of a case-control study within the Women's Health Initiative trials, in which HT or placebo was randomly assigned. This design minimizes the chance that individuals taking HT differ in their stroke risk from individuals taking placebo. However, the power of this study to detect anything other than large associations is limited; together with the limitation of multiple statistical testing, the findings here must be interpreted as hypotheses for further study and not definitive conclusions.
Contribution to the evidence: This study adds data relating to possible predictive risk markers for stroke among users of HT. The hypotheses raised here remain to be tested in further studies.
PMCID: PMC1891725  PMID: 17571161
16.  Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies 
Most patients with episodic tension-type headache treat headache episodes with over-the-counter medication. Combination analgesics containing caffeine may be more effective and as well tolerated as monotherapy. The aim of this study was to evaluate the efficacy of the combination of acetylsalicylic acid, acetaminophen (paracetamol) and caffeine in episodic tension-type headache using recently recommended endpoints.
Four randomized, controlled trials of identical design in 1,900 patients with episodic tension-type headache comparing acetylsalicylic acid, acetaminophen and caffeine vs. acetaminophen or placebo were pooled. Analysis populations were ‘all headache episodes’ and those with ‘severe pain at baseline’. Post-hoc defined primary endpoint: headache episodes pain-free at 2 h. Secondary endpoints: headache episodes pain-free at 1 h, headache response at 2 h (mild or no pain), degree of interference with daily activities.
6,861 headache episodes were treated, including 2,215 severe headache episodes. The proportion of headache episodes pain-free at 2 h was significantly higher with the triple combination (28.5%) vs. acetaminophen (21.0%) and placebo (18.0%) (p < 0.0001), and similarly for those severe at baseline (20.2% vs. 12.1% and 10.8%; p ≤ 0.0003). A similar pattern of superiority was observed for secondary endpoints. The triple combination was generally well tolerated.
The combination of acetylsalicylic acid, acetaminophen and caffeine is effective and well tolerated in episodic tension-type headache, and significantly superior to acetaminophen with regard to being pain-free at 2 h, headache response at 2 h and ability to return to daily activities, even in those with pain rated severe at baseline.
PMCID: PMC4256978  PMID: 25406671
Acetaminophen; Acetylsalicylic acid; Caffeine; Episodic tension-type headache; Severe pain; Triple combination
17.  Update of the Preventive Antibiotics in Stroke Study (PASS): statistical analysis plan 
Trials  2014;15(1):382.
Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes.
The primary outcome is the score on the modified Rankin Scale (mRS), assessed by ordinal logistic regression analysis according to a proportional odds model. Secondary analysis of the primary outcome is the score on the mRS dichotomized as a favorable outcome (mRS 0 to 2) versus unfavorable outcome (mRS 3 to 6). Secondary outcome measures are death rate at discharge and 3 months, infection rate during hospital admission, length of hospital admission, volume of post-stroke care, use of antibiotics during hospital stay, quality-adjusted life years and costs. Complications of treatment, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported as safety outcomes.
The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection and will be analyzed according to this pre-specified SAP.
Trial registration
Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.
PMCID: PMC4195873  PMID: 25269598
stroke; infection; antibiotics; randomized clinical trial; statistical analysis plan
18.  Effects of Suppository Acetaminophen, Bupivacaine Wound Infiltration, and Caudal Block With Bupivacaine on Postoperative Pain in Pediatric Inguinal Herniorrhaphy 
Anesthesiology and Pain Medicine  2012;1(4):243-247.
The control of postoperative pain is important in children, and poor pain control leads to organ dysfunction and behavioral problems.
We compared the analgesic effects of suppository acetaminophen, bupivacaine wound infiltration, and caudal block with bupivacaine on postoperative pain in pediatric inguinal herniorrhaphy.
Patients and Methods:
In this double-blinded, randomized controlled clinical trial, 90 children of American Society of Anesthesiologists (ASA) grade I-II, aged between 3 months and 7 years, and scheduled for elective unilateral inguinal herniorrhaphy under general anesthesia were assigned to three equal groups. Patients in the first group received 20 mg/kg of suppository acetaminophen. In the second group, 2 mg/kg of 0.5% bupivacaine was infiltrated in the incisional site, and in the third group, a caudal block was performed with 0.75 mL/kg of 0.25% bupivacaine. The Face, Legs, Activity, Cry, Consolability (FLACC) pain scale was applied 30 minutes after operation. Thereafter, the FLACC score was obtained every hour during the next 6 hours. If the FLACC score was 4 or over, we administered 0.5 mg/kg of intravenous meperidine. The data was transferred to SPSS-10 software and analyzed statistically with chi-square and analysis of variance tests. P < 0.05 was considered significant.
The mean analgesic duration in the acetaminophen, bupivacaine infiltration, and caudal block groups was 4.07, 5.40, and 5.37 hours, respectively. Significant differences were not observed between the bupivacaine infiltration and caudal block groups (P = 0.9), but the differences between the bupivacaine infiltration and acetaminophen groups (P = 0.034) and the caudal block and acetaminophen groups (P = 0.039) were significant. With regard to meperidine administration, significant differences were not observed between the bupivacaine infiltration and caudal block groups (P = 0.848), but significant differences were observed between these two groups and the acetaminophen group (P < 0.05).
Patients in the bupivacaine infiltration and caudal block groups had less postoperative pain than those in the acetaminophen group and received lower amount of meperidine. We concluded that in children, bupivacaine infiltration and caudal block with bupivacaine produce better analgesia than suppository acetaminophen. It seems that bupivacaine infiltration is better than caudal block because of its simplicity, lower incidence of complications, and failure rate.
PMCID: PMC4018710  PMID: 24904808
Bupivacaine; Anesthesia, Caudal; Pediatrics; Analgesia; Suppositories; Acetaminophen
19.  Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults 
Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine.
To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults.
Search methods
We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010.
Selection criteria
We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment.
Main results
Ten studies (2769 participants, 4062 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12, 5.2 and 5.0 for 2-hour pain-free and 1- and 2-hour headache relief, respectively, when medication was taken for moderate to severe pain. Nausea, photophobia and phonophobia were reduced more with paracetamol than with placebo at 2 hours (NNTs of 7 to 11); more individuals were free of any functional disability at 2 hours with paracetamol (NNT 10); and fewer participants needed rescue medication over 6 hours (NNT 6).
Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan 100 mg for 2-hour headache relief; there were no 2-hour pain-free data. There was no significant difference between the paracetamol plus metoclopramide combination and sumatriptan for relief of “light/noise sensitivity” at 2 hours, but slightly more individuals needed rescue medication over 24 hours with the combination therapy (NNT 17).
Adverse event rates were similar between paracetamol and placebo, and between paracetamol plus metoclopramide and sumatriptan. No serious adverse events occurred with paracetamol alone, but more “major” adverse events occurred with sumatriptan than with the combination therapy (NNH 32).
Authors’ conclusions
Paracetamol 1000 mg alone is an effective treatment for acute migraine headaches, and the addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg. Adverse events with paracetamol did not differ from placebo; “major” adverse events were slightly more common with sumatriptan than with paracetamol plus metoclopramide.
PMCID: PMC4161111  PMID: 21069700
Acetaminophen [adverse effects; * therapeutic use]; Analgesics, Non-Narcotic [adverse effects; * therapeutic use]; Antiemetics [adverse effects; * therapeutic use]; Drug Therapy, Combination; Hyperacusis [drug therapy]; Metoclopramide [adverse effects; therapeutic use]; Migraine Disorders [* drug therapy]; Photophobia [drug therapy]; Randomized Controlled Trials as Topic; Sumatriptan [adverse effects; therapeutic use]; Adult; Humans
20.  Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid 
Osteoporosis International  2010;22(8):2337-2345.
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.
PMCID: PMC3132314  PMID: 21116816
Cytokines; Fluvastatin; Inflammatory biomarkers; Osteoporosis; Post-dose symptoms; Zoledronic acid
21.  Comparing the Duration of the Analgesic Effects of Intravenous and Rectal Acetaminophen Following Tonsillectomy in Children 
Postoperative pain control (especially, after adenotonsillectomy) has a very important effect on recovery time, hospitalization duration, hemodynamic disorders, bleeding, nausea, vomiting and medical costs.
The aim of this study was to investigate and compare the effects of intravenous and rectal acetaminophen on controlling post-adenotonsillectomy pain in children, and duration of their analgesic effects.
Patients and Methods:
In this randomized double-blinded clinical trial, 96 children aged 4 - 10 years old with ASA physical status I or II who were candidates for adenotonsillectomy surgery in Amir-al-Momenin Hospital, Rasht, Iran were entered into the study and randomly divided into two equal groups. Anesthesia in both groups was induced injecting fentanyl-thiopental and at racurium; afterwards is of lurane was used to maintain anesthesia. After anesthesia induction, one group received intravenous and the other one, rectal acetaminophen, and were later compared based on CHIPPS criteria.
Data analysis indicated a significant relationship between reduction of postoperative pain and the use of intravenous or rectal acetaminophen (P = 0.0001); in group receiving IV acetaminophen, only 10.4% of patients had no pain whereas in group receiving rectal acetaminophen, this number reached 43.8%. Also, on 4 and 6 hour time intervals, pain in rectal acetaminophen receiving group was less than that in IV acetaminophen receiving group (P < 0.05). Demand for additional analgesic medication in rectal acetaminophen receiving group was less than that in IV group (P = 0.0001).
Post-operative pain in rectal acetaminophen group was less than that in intravenous acetaminophen group, and rectal acetaminophen group demanded their first additional analgesic medication later.
PMCID: PMC3961018  PMID: 24660154
Acetaminophen; Pain, Postoperative; Child, Hospitalized
22.  A Randomized Placebo-Controlled Trial of Acetaminophen for Prevention of Post-Vaccination Fever in Infants 
PLoS ONE  2011;6(6):e20102.
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.
Trial registration NCT00325819
PMCID: PMC3117800  PMID: 21698100
23.  Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults 
This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly.
Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events.
Search methods
We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update.
Selection criteria
Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults.
Data collection and analysis
Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected.
Main results
Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo.
Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups.
Authors’ conclusions
This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
PMCID: PMC4171965  PMID: 19160199
Acetaminophen [*administration & dosage; adverse effects]; Administration, Oral; Analgesics, Non-Narcotic [*administration & dosage; adverse effects]; Analgesics, Opioid [*administration & dosage; adverse effects]; Codeine [*administration & dosage]; Drug Therapy, Combination; Pain, Postoperative [*drug therapy]; Adult; Humans
24.  Can Clinical Trials Requiring Frequent Participant Contact Be Conducted Over the Internet? Results From an Online Randomized Controlled Trial Evaluating a Topical Ointment for Herpes Labialis 
The Internet has tremendous appeal for conducting randomized clinical trials and may be especially applicable to trials requiring frequent participant contact. Trials of cold sore remedies, for example, often require daily clinic visits during outbreaks, imposing substantial burden on participants. An Internet-based randomized clinical trial design may reduce this burden, permitting frequent symptom reports with considerably less effort.
To evaluate the feasibility of a Web-based randomized clinical trial requiring frequent participant interaction, using a 6-month, double-blind, randomized, placebo-controlled pilot trial of a topical ointment containing dioctyl sodium sulfosuccinate (DSS) (Zilex; Meditech Pharmaceuticals, Inc, Scottsdale, Arizona, USA) intended for treatment of recurrent herpes labialis. A secondary objective was to obtain preliminary data on effectiveness outcomes, to assist in planning a fully-powered trial of DSS.
Adults with physician-confirmed herpes labialis were recruited to apply to the trial. Eligible applicants were randomized to DSS or placebo, mailed to them upon enrolment with instructions to apply topically every 2 hours for the duration of every cold sore outbreak. Participants were instructed to complete online questionnaires at 2-week intervals and, at the initiation of a cold sore, daily "outbreak questionnaires" until outbreak termination. Feasibility outcome measures included trial participant characteristics, frequency of cold sores, participant retention and adherence (to study medication), and data completeness. Treatment effectiveness outcome measures included outbreak duration, days to crust formation, and pain.
Of the 292 individuals applying, 182 screened eligible; 32 participants with confirmed herpes labialis enrolled in the trial. 16 were randomized into the verum group and 16 into the placebo group. 29 (91%) participants completed the trial. During the trial, 34 outbreaks were reported among 23 (72%) participants, resulting in a cold sore incidence rate of 19.8 per 100 person-months of observation. Online data were available for 32 outbreaks; the absence of a resolution date made it impossible to accurately calculate the duration of 12 (38%) outbreaks. Although the DSS treatment group had a shorter mean outbreak duration (6.6 vs 7.7 days, P= .2) and fewer mean days to crust formation (3.5 vs 4.9, P= .1), these differences did not reach statistical significance. The DSS group has statistically significant lower mean pain scores (3.1 vs 7.6, P= .04), but participants in this group also consumed more acetaminophen tablets than the placebo group (1.1 versus 0.5, P=.55). Adherence to medication was similar in both groups: 7 (50%) of the verum group reported using the cream as directed compared to 6 (46.2%) in the placebo group; ( P= .8).
We efficiently recruited participants and achieved high overall retention rates. However, participant adherence to the daily outbreak visit schedules was low and only 7 (50%) participants used the cream as directed. These limitations could be addressed in future Internet-based studies by using Personal Digital Assistants (PDAs), using reminder devices, and providing incentives. By enhancing participant adherence, clinical trials requiring frequent participant contact may be feasible over the Internet.
PMCID: PMC1550589  PMID: 15111272
Internet; randomized controlled trial; clinical trial; herpes labialis; dioctyl sodium sulfosuccinate
25.  The effects of indomethacin, diclofenac, and acetaminophen suppository on pain and opioids consumption after cesarean section 
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.
PMCID: PMC3700328  PMID: 23833739
Acetaminophen; cesarean section; diclofenac; indomethacin; opioid

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