Description of the condition
The common cold is the most prevalent viral infection of the upper respiratory tract. Adults in the US experience two to four colds per year. It is estimated that USD 2.9 billion is spent annually on medications for patients with the common cold, yet the infection is self limiting (Fendrick 2003). There are at least 200 viral types and other infectious agents that can cause the common cold. The rhinoviruses are the most common and are responsible for 40% of cases: corona viruses causing 10%; respiratory syncytial virus, parainfluenza and influenza virus approximately 10% to 15%; and others 5% to 20% (Treanor 2000). The common cold usually occurs in early spring and autumn, with symptoms including sore throat, sneezing, nasal stuffiness and discharge, cough, mild fever, headache, hoarseness, lethargy and malaise, which resolve within seven to 10 days, although some symptoms persist for over three weeks. Despite the self limiting nature of the common cold, complications such as otitis media, bacterial sinusitis, and exacerbation of asthma and pneumonia can make it a significant and serious problem for part of the population. There is no effective therapy for the common cold and most medications are symptomatic (Heikkinen 2003).
Description of the intervention
As there is no cure for the common cold, current symptomatic treatments include antihistamines (De Sutter 2012), decongestants (De Sutter 2012), echinacea (Linde 2008), vitamin C (Hemilä 2013), zinc (Singh 2011b), heated humidified air (Singh 2011a), antivirals (Gwaltney 2002), antibiotics (Arroll 2010), Chinese medicinal herbs (Zhang 2009), non-steroidal anti-inflammatory agents (Kim 2009) and garlic (Lissiman 2012). However, none of these medications have been proven to be effective for the common cold due to a lack of strong evidence.
Acetaminophen (also known as paracetamol) is widely used as the major ingredient in combination medications for the common cold. As a non-steroidal anti-inflammatory drug (NSAID), acetaminophen has antipyretic and analgesic effects for mild to moderate pain or fever. However, the anti-inflammatory action or platelet-inhibiting properties are weak (Botting 2000). It is recommended as the first-line drug for relieving pain associated with osteoarthritis, rheumatism (Shen 2006) and lower back pain (Reece 2008). Many studies have shown that liver damage due to acetaminophen overdose is the most common cause of acute liver failure in the United States (Bower 2007). With the recommended therapeutic dosage, the side effects of acetaminophen are few, without the gastric toxicity of most NSAIDs. One study found that asthma morbidity and rhinitis may be caused by frequent use of acetaminophen (Shaheen 2000).
How the intervention might work
The mechanism of action of acetaminophen is still unclear despite it having been widely used for more than a century. Various studies have concluded that acetaminophen has a central analgesic effect which is generally explained by the following two mechanisms. The first mechanism is its selective reduction of prostaglandins, which are mediators of fever, pain and inflammation, by blocking the cyclooxygenase (COX) pathway in the central nervous system. However, this theory is not well supported and it is suggested that acetaminophen reduces the active oxidised form of COX to an inactive form, instead of binding to the active site of COX (Lucas 2005). The second mechanism is that the analgesic effect of acetaminophen involves stimulation of the descending serotonergic pathways; this is supported by the study finding that administration of a 5-hydroxytryptamine type 3 antagonist in humans blocks the analgesic action of acetaminophen (Pickering 2006).
Why it is important to do this review
Randomised controlled trials (RCTs) have found that acetaminophen is an effective (Burnett 2006; Mizoquchi 2007; Schachtel 1988) and safe (Graham 1990; Moore 2003) treatment for the common cold. A review article showed that acetaminophen in over-the-counter doses is safe and effective for colds and does not prolong the duration of colds or destroy the immune system (Eccles 2006b). Acetaminophen is used worldwide to treat the common cold despite there being little information about the effectiveness and safety of this treatment. We have performed a Cochrane systematic review of RCTs to determine the effectiveness and safety of acetaminophen for the common cold.
To determine the efficacy and safety of acetaminophen in the treatment of the common cold in adults.
Criteria for considering studies for this review
Types of studies
RCTs which evaluated acetaminophen in the treatment of the common cold in adults. We included studies using acetaminophen as one ingredient of a combination therapy. We excluded studies if they did not compare acetaminophen with placebo but used active comparators in the control group. We also excluded studies in which the participants had complications such as otitis media, bacterial sinusitis and exacerbation of asthma or pneumonia.
Types of participants
Participants with the common cold, aged 12 years or older, of either gender.
Types of interventions
Acetaminophen at various doses or in combination with other ingredients versus placebo or no treatment for the common cold.
Types of outcome measures
- Subjective symptom score. Total scores are calculated by summing up all symptom scores. Each symptom score was graded on a severity visual analogue scale (VAS) of 0 to 3, 0 to 4, or 0 to 10 cm.
- Duration of common cold symptoms.
- Overall well being.
- Adverse events.
- Financial costs.
Search methods for identification of studies
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, part of The Cochrane Library, www.thecochranelibrary.com (accessed 13 February 2013), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to February 2013), EMBASE (1980 to February 2013), CINAHL (1982 to February 2013) and LILACS (1985 to February 2013).
We used the following search strategy to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). The search strategy was adapted to search EMBASE (see Appendix 1), CINAHL (see Appendix 2) and LILACS (see Appendix 3). There were no language or publication restrictions.
1 Common Cold/
2 common cold*.tw.
3 (upper adj5 respiratory infection*).tw.
4 upper respiratory tract infection*.tw.
5 (coryza or acute rhinit* or rhinosinusit* or nasosinusit*).tw.
8 Coronavirus Infections/
9 respiratory syncytial viruses/ or respiratory syncytial virus, human/
10 Respiratory Syncytial Virus Infections/
11 parainfluenza virus 1, human/ or parainfluenza virus 3, human/
12 parainfluenza virus 2, human/ or parainfluenza virus 4, human/
13 exp influenzavirus a/ or exp influenzavirus b/
15 (infection* adj5 (rhinovirus* or coronavirus* or adenovir* or rsv or respiratory syncytial virus* or parainfluenza* or influenza*)).tw.
18 (acetaminophen or acetominophen or panadol or paracetamol or tylenol).tw.
19 17 or 18
20 16 and 19
Searching other resources
The review authors contacted the pharmaceutical manufacturers for details of unpublished and ongoing trials. We also searched and identified the relevant trials or reviews in reference lists. There were no language or publication restrictions.
Data collection and analysis
Selection of studies
Two review authors (LS, YJ) independently scanned the title, abstract and keywords of every record retrieved to determine which studies required further assessment.
Data extraction and management
Two review authors (LS, YJ) independently extracted data regarding details of study population, intervention and outcomes using a standard data extraction form specifically adapted for this review. The data extraction form included the following items.
- General information: published/unpublished, title, authors, country of study, contact address, year of study, language of publication, year of publication, sponsor/funding organisation, setting.
- Methodological details: including criteria for 'Risk of bias' assessment (below).
- Intervention: descriptions of acetaminophen (dose, route, timing), descriptions of co-medication(s) (dose, route, timing).
- Participants: inclusion and exclusion criteria, total number and number in comparison groups, sex, age, baseline characteristics, withdrawals/losses to follow-up (reasons/description), subgroups.
- Outcomes: subjective symptom score, days from the onset to resolution of symptoms, overall well being, adverse events, costs.
Assessment of risk of bias in included studies
Two review authors (LS, YJ) independently assessed each included study using The Cochrane Collaboration's tool for assessing 'Risk of bias' (Higgins 2011). This tool addresses six specific domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (for example, extreme baseline imbalance) (Appendix 4). We assessed blinding and completeness of outcome data for each outcome separately. We completed a 'Risk of bias' table for each eligible study. We resolved disagreements by discussion to reach a consensus and a third review author (DBR) adjudicated any persisting differences.
We used a 'Risk of bias' summary figure to present all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.
Measures of treatment effect
We described the treatment effect according to the included studies.
Unit of analysis issues
All included studies were RCTs. The unit of analysis was the individual participant and the individual participants were randomised.
Dealing with missing data
If data are available in the future to pool, we will analyse data according to the intention-to-treat (ITT) principle; that is, we will analyse all participants included in the study at the point of randomisation according to their assigned treatment group, regardless of whether or not the treatment was completed.
Assessment of heterogeneity
We described the heterogeneity amongst the included studies. In the future, if the number and characteristics of studies suggest that meta-analysis may be feasible, we will measure heterogeneity using the Chi
Assessment of reporting biases
We did not assess publication bias as we only included four trials. Ten studies is a minimum to create a funnel plot (Higgins 2011). In future updates, if we identify more studies, we will conduct a funnel plot analysis to check for publication bias.
Two review authors (LS, YJ) independently entered data into RevMan 2012. We summarised findings of individual studies in a narrative format. We did not pool data because of heterogeneity in study design, outcomes and time points. In the future, if there is sufficient homogeneity in populations, study design and outcome measures, we will pool results following the assessment for statistical heterogeneity as described above.
We did not perform a subgroup analysis in this review. In the future, if we identify suitable studies, we will consider subgroup analysis depending on numbers and characteristics of studies. A priori subgroups will include the following.
- Baseline symptom severity.
- Time from symptom onset to enrolment in the study.
We did not conduct a sensitivity analysis. If a sufficient number of trials are found in future updates, we will carry out a sensitivity analysis to assess the robustness of the results as follows.
- Exclusion of studies with inadequate allocation concealment.
- Exclusion of studies in which the outcome evaluation was unblinded.
Description of studies
The search retrieved 39 records from MEDLINE (Ovid), 59 records from CENTRAL, 243 records from Embase.com, 15 records from CINAHL and one record from LILACS. With duplicates removed this left a total of 269 search results. See the Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
Our primary search generated 269 results. After screening, we considered 10 trials to be potentially eligible and reviewed the full text. Seven trials met our inclusion criteria. The full texts of three trials have not been retrieved, so we listed them in the section Characteristics of studies awaiting classification. We excluded three trials due to lack of placebo control.
All included trials were randomised, double-blind, placebo-controlled, parallel-group trials. Two studies were conducted in the US (Ryan 1987; Sperber 2000), one study in Ukraine and Russia (Bachert 2005) and one study in Australia (Graham 1990). Two studies took place in an out-patient setting, one in a Medical University, and one did not specify the setting. One trial consisted of five treatment arms: two arms for different doses of acetaminophen, two arms for different doses of aspirin and one arm for placebo (Bachert 2005). One trial had four treatment arms: one arm for acetaminophen, one arm for aspirin, one arm for ibuprofen and one arm for placebo (Graham 1990). One trial had three treatment arms: one arm for acetaminophen, one arm for fenoprofen and one arm for placebo (Ryan 1987). One trial had two arms: 60 mg of pseudoephedrine plus 1000 mg of acetaminophen or placebo (Sperber 2000). Among these four studies, only one included participants with an experimental infection by rhinovirus type 2 (Graham 1990).
The ages of participants ranged from 17 to 65 years. The entry criteria in the trials were similar.
For the intervention group, acetaminophen was used in various doses. In two studies (Bachert 2005; Ryan 1987) participants took only a single dose because the study period was four or six hours. One study (Bachert 2005) used a dose of 500 mg (one tablet) and 1000 mg (two tablets); the other study (Ryan 1987) used 650 mg. The dose in another study (Sperber 2000) was 1000 mg (one tablet containing pseudoephedrine 60 mg and acetaminophen 1000 mg) every six hours. The dose in another study was 1000 mg (two capsules) every six hours (Graham 1990).
A number of different tools were used for determining subjective symptom scores in the included studies, which included ordinal scales from 0 to 3, 0 to 4, or 0 to 10. Most trials reported subjective symptom scores but each cold symptom included in the studies was different.
Risk of bias in included studies
|Figure 1. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 2. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.|
Ryan 1987 states that computer-generated randomisation was used and Bachert 2005 states that patients were allocated by permuted block randomisation (block size of five). The method of randomisation was not discussed in the other two studies (Graham 1990; Sperber 2000). The method of allocation concealment was unclear in the four studies.
All four studies were blinded using identically appearing tablets or capsules.
Incomplete outcome data
One study had no missing data (Ryan 1987). The other three studies had incomplete data and ITT analyses were performed.
For all studies, no information was available for participants who were not enrolled.
Other potential sources of bias
Effects of interventions
1. Subjective symptom score
Different scales were used to report the primary outcomes. Therefore, we did not pool data.
Ryan 1987 estimated the intensity of pain on a four-point scale ('none' = 0, 'mild' = 1, 'moderate' = 2, 'severe' = 3). There were 32 participants in both the acetaminophen group and the placebo group. The baseline mean for the pain scores was 2.34 for the acetaminophen group and 2.25 for the placebo group. The authors calculated the pain intensity difference (PID) by subtracting the pain intensity score at one, two, three and four hours from the scores at zero hour. There was a decrease in mean pain intensity score of 0.87 in the acetaminophen group and 0.66 in the placebo group. The difference in pain intensity scores between the two groups was not statistically significant.
Bachert 2005 used an ordinal scale (from 0 = none to 10 = severe) to rate the common cold symptoms. The symptoms were rated at baseline and again at two, four and six hours after treatment. The baseline intensity of the common cold symptoms was comparable between groups. Each symptom score was reported in Table III of their study. A significant decrease was seen in the mean intensity score for headache, achiness and feverish discomfort in the acetaminophen group at most time points (P < 0.001) compared to the placebo group. However, the study did not show a significant difference in sore throat between the two groups at ant time point.
Sperber 2000 assessed common cold symptoms using a zero to four-point scale which represented "absent, mild, moderate, moderately severe, or severe". Symptoms were scored before and at two hours after the first and second doses. The mean scores for headache, nasal obstruction and rhinorrhoea were significantly decreased after the first or second dose in the pseudoephedrine and the acetaminophen group. There was no statistical difference in scores for sneezing, sore throat, cough and malaise between the acetaminophen group and the placebo group. The score values were reported in Table 2 of their study.
Graham 1990 used the same scale described in Ryan 1987. These scores were recorded daily for day 0 to 14. Scores for each cold symptom were totalled by adding scores from days one to 14 and subtracting the baseline score. Nasal obstruction was significantly increased in the acetaminophen group compare to the placebo group (P < 0.05). No significant differences were seen for headache, malaise and achiness between the acetaminophen group and the placebo group.
2. Duration of common cold symptoms
None of the included studies reported the duration of common cold symptoms.
1. Overall well being
None of the included studies reported overall well being.
2. Adverse events
Two studies reported different side effects of acetaminophen. Sperber 2000 reported adverse events such as nervousness, nausea, dizziness, dry mouth and somnolence in the pseudoephedrine and the acetaminophen group. Bachert 2005 reported the two most frequently cited adverse events which were increased sweating and gastrointestinal disturbances.
3. Financial costs
None of the included studies reported financial costs.
Summary of main results
The findings of four studies identified by this review were inconsistent. Two studies showed that acetaminophen was effective for relieving headache (Bachert 2005; Sperber 2000), but one study with a small number of participants found no significant change in headache intensity in either the intervention or placebo group (Graham 1990). Effectiveness of acetaminophen in improving nasal obstruction was found in the acetaminophen group in one of the two included studies and this was statistically significant (Sperber 2000). On the other hand, Graham 1990 showed an increased number of participants with nasal obstruction in the acetaminophen group compared to the placebo group. No correlation was found between subjective changes in achiness in three studies (Graham 1990; Ryan 1987; Sperber 2000). However, outcomes from another study were found to favour acetaminophen in improving achiness (Bachert 2005). Sore throat was shown to be similar in both the acetaminophen and placebo group, with no significant change.
For most studies, all acetaminophen-related adverse effects were mild or moderate except for two cases of severe nausea reported in one study (Sperber 2000).
Overall completeness and applicability of evidence
The time periods of the included studies were short. Three studies estimated the effect of acetaminophen in four to six hours. It is not known whether a prolonged study duration would alter the applicability of the results. Among the four included studies, one study compared a combination of acetaminophen and pseudoephedrine to placebo, so it is difficult to tell from which ingredient the effect and adverse events resulted.
Quality of the evidence
The method of allocation concealment was unclear in all the included studies. Two studies were supported by pharmaceutical companies. The study period was short for most studies. There were serious methodological limitations. Confidence intervals were not reported in all of the studies so it is difficult to evaluate the accuracy of the results. However, we found two studies including small numbers of participants which may affect the accuracy of the results. We did not perform a funnel plot analysis and so could not evaluate publication bias. Overall we consider the quality of the evidence to be low to moderate.
Potential biases in the review process
We undertook a complete, systematic search of the literature to identify all studies meeting the inclusion criteria for this review. However, the full texts of three trials have not been retrieved. We contacted the trial authors by e-mail but did not receive any replies so we cannot confirm whether these three studies will meet the inclusion criteria.
In one included study (Graham 1990), 60 healthy volunteers were challenged with rhinovirus and randomised to one of four treatment arms: aspirin, acetaminophen, ibuprofen or placebo. Fourteen out of 15 volunteers were successfully infected in both the acetaminophen and placebo treatment arms. However, among those infected participants, only nine of the acetaminophen group experienced an upper respiratory illness, compared to 11 in the placebo group, so this could overestimate the effect in the acetaminophen group.
Agreements and disagreements with other studies or reviews
The results of this review are in agreement with Eccles' systematic review (Eccles 2006b). This review included one randomised controlled trial (Bachert 2005) and one placebo-controlled study. The authors concluded that there was relatively little information on the use of acetaminophen in treating colds.
Implications for practice
The data in this review do not provide sufficient evidence to inform practice regarding the use of acetaminophen for the common cold in adults.
Implications for research
A large randomised controlled trial is needed to determine whether acetaminophen is effective when compared with placebo in treating the common cold. Randomised controlled trials should consider the following:
We thank Elizabeth Dooley, Managing Editor of the Cochrane Acute Respiratory Infections Group. We thank the Chinese Cochrane Centre for help in completing the protocol. We also wish to thank the following people for commenting on the draft protocol: Chanpen Choprapawon, Ann Fonfa, Nicholas Moore, Andrew Pothecary, Mark Griffin and Hans van der Wouden; and we thank the following people for commenting on the draft review: Noha Usama, Nicholas Moore, Andrew Pothecary, Robert Ware and Hans van der Wouden.
Data and analyses
This review has no analyses.
Appendix 1. Embase.com search strategy
Appendix 2. CINAHL (Ebsco) search strategy
S33 S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32
S32 (MH "Quantitative Studies")
S31 TI placebo* or AB placebo*
S30 (MH "Placebos")
S29 TI random* or AB random*
S28 (MH "Random Assignment")
S27 TI (singl* blind* or singl* mask* or doubl* blind* or doubl* mask* or trebl* blind* or trebl* mask* or tripl* blind* or tripl* mask*) or AB (singl* blind* or singl* mask* or doubl* blind* or doubl* mask* or trebl* blind* or trebl* mask* or tripl* blind* or tripl* mask* )
S26 TI clinic* N1 trial* or AB clinic* N1 trial*
S25 PT clinical trial
S24 (MH "Clinical Trials+")
S23 S19 and S22
S22 S20 or S21
S21 TI (acetaminophen or acetominophen or panadol or paracetamol or tylenol) or AB (acetaminophen or acetominophen or panadol or paracetamol or tylenol)
S20 (MH "Acetaminophen")
S19 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18
S18 TI infection* N5 respiratory syncytial virus* or AB infection* N5 respiratory syncytial virus*
S17 TI respiratory syncytial virus infection* or AB respiratory syncytial virus infection*
S16 TI infection* N5 rsv or AB infection* N5 rsv
S15 TI infection* N5 influenza* or AB infection* N5 influenza*
S14 TI infection* N5 parainfluenza* or AB infection* N5 parainfluenza*
S13 TI infection* N5 adenovir* or AB infection* N5 adenovir*
S12 TI infection* N5 coronavir* or AB infection* N5 coronavir*
S11 TI infection* N5 rhinovir* or AB infection* N5 rhinovir*
S10 (MH "Influenzavirus A+") OR (MH "Influenzavirus B+") OR (MH "Influenzavirus C")
S9 (MH "Respiratory Syncytial Virus Infections")
S8 (MH "Respiratory Syncytial Viruses")
S7 (MH "Coronavirus Infections")
S6 (MH "Coronavirus")
S5 TI (coryza or acute rhinit* or rhinosinusit* or nasosinusit*) or AB (coryza or acute rhinit* or rhinosinusit* or nasosinusit*)
S4 TI upper respiratory infection* or AB upper respiratory infection*
S3 TI upper respiratory tract infection* or AB upper respiratory tract infection*
S2 TI common cold* or AB common cold*
S1 (MH "Common Cold")
Appendix 3. LILACS search strategy
(mh:"Common Cold" OR "common cold" OR "common colds" OR "Resfriado Común" OR "Resfriado Comum" OR coryza OR "Coriza Aguda" OR "upper respiratory tract infection" OR "upper respiratory tract infections" OR "upper respiratory infection" OR "upper respiratory infections" OR "Infecciones del Tracto Respiratorio Superior" OR "Infecciones de las Vías Respiratorias Superiores" OR "Infecções do Trato Respiratório Superior" OR "Infecções das Vias Respiratórias Superiores" OR "Infecções das Vias Aéreas Superiores" OR "Infecções do Sistema Respiratório Superior" OR "acute rhinitis" OR rhinosinusitis OR nasosinusitis OR rinit* OR mh:rhinovirus OR rhinovir* OR mh:coronavirus OR coronavir* OR mh:"Coronavirus Infections" OR mh:"Respiratory Syncytial Viruses" OR "respiratory syncytial virus" OR "respiratory syncytial viruses" OR rsv OR "Virus Sincitiales Respiratorios" OR "Vírus Sinciciais Respiratórios" OR mh:"Respiratory Syncytial Virus, Human" OR mh:"Respiratory Syncytial Virus Infections" OR mh:"Parainfluenza Virus 1, Human" OR mh:"Parainfluenza Virus 3, Human" OR mh:"Parainfluenza Virus 2, Human" OR mh:"parainfluenza virus 4, human" OR parainfluenza* OR mh:"Influenzavirus A" OR mh:b04.820.545.405* OR mh:b04.909.777.545.405* OR mh:"Influenzavirus B" OR mh:b04.820.545.407* OR mh:b04.909.777.545.407* OR influenza* OR mh:adenoviridae OR adenovir*) AND (mh:acetaminophen OR acetaminophen OR acetominophen OR acetaminofén OR acetaminofen OR acetamidophenol OR acetaminofeno OR acetamidofenol OR panadol OR paracetamol OR tylenol) AND db:("LILACS")
Appendix 4. Assessment of risk of bias
Criteria for a judgement of 'yes' for the sources of bias
1. Was the allocation sequence randomly generated?
Yes, low risk of bias
A random (unpredictable) assignment sequence.
Examples of adequate methods of sequence generation are computer-generated random sequence, pre-ordered sealed envelopes, telephone call to a central office, coin toss (for studies with two groups), rolling a dice (for studies with two or more groups), drawing of balls of different colours.
No, high risk of bias
- Quasi-randomised approach: examples of inadequate methods are: alternation, birth date, social insurance/security number, date in which invited to participate in the study and hospital registration number.
- Non-random approaches: allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Insufficient information about the sequence generation process to permit judgement.
2. Was the treatment allocation adequately concealed?
Yes, low risk of bias
Assignment must be generated independently by a person not responsible for determining the eligibility of the participants. This person has no information about the persons included in the trial and has no influence on the assignment sequence or on the decision about whether the person is eligible to enter the trial. Examples of adequate methods of allocation concealment are: central allocation, including telephone, web-based and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes.
No, high risk of bias
Examples of inadequate methods of allocation concealment are: alternate medical record numbers; unsealed envelopes; date of birth; case record number; alternation or rotation; an open list of random numbers; or any information in the study that indicated that investigators or participants could influence the intervention group.
Randomisation stated but no information on method of allocation used is available.
3. Blinding - was knowledge of the allocated interventions adequately prevented during the study?
(a) Was the participant blinded to the intervention?
Yes, low risk of bias
The treatment and control groups are indistinguishable for the participants or if the participant was described as blinded and the method of blinding was described.
No, high risk of bias
Blinding of study participants attempted, but likely that the blinding could have been broken; participants were not blinded, and the non-blinding of others is likely to introduce bias.
(b) Was the care provider blinded to the intervention?
Yes, low risk of bias
The treatment and control groups are indistinguishable for the care/treatment providers or if the care provider was described as blinded and the method of blinding was described.
No, high risk of bias
Blinding of care/treatment providers attempted, but likely that the blinding could have been broken; care/treatment providers were not blinded, and the non-blinding of others is likely to introduce bias.
(c) Was the outcome assessor blinded to the intervention?
Yes, low risk of bias
Adequacy of blinding should be assessed for the primary outcomes. The outcome assessor was described as blinded and the method of blinding was described.
No, high risk of bias
No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding
4. Were incomplete outcome data adequately addressed?
(a) Was the drop-out rate described and acceptable?
The number of participants who were included in the study but did not complete the observation period or were not included in the analysis must be described and reasons given.
Yes, low risk of bias
If the percentage of withdrawals and drop-outs does not exceed 20% for short-term follow-up and 30% for long-term follow-up and does not lead to substantial bias. (N.B. these percentages are arbitrary, not supported by literature.)
No missing outcome data
Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).
Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.
Missing data have been imputed using appropriate methods.
No, high risk of bias
Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.
(b) Were all randomised participants analysed in the group to which they were allocated? (intention-to-treat (ITT) analysis)
Yes, low risk of bias
Specifically reported by authors that ITT analysis was undertaken and this was confirmed on study assessment, or not stated but evident from study assessment that all randomised participants are reported/analysed in the group to which they were allocated for the most important time point of outcome measurement (minus missing values), irrespective of non-compliance and co-interventions.
No, high risk of bias
Lack of ITT analysis confirmed on study assessment (patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation) regardless of whether ITT reported or not.
'As-treated' analysis done with substantial departure from the intervention received compared to that assigned at randomisation; potentially inappropriate application of simple imputation.
Described as ITT analysis, but unable to confirm on study assessment, or not reported and unable to confirm by study assessment.
Plain language summary title, 16 August 2013
I was wondering why the plain language summary uses Aceteminophen in the title instead of paracetemol.
I agree with the conflict of interest statement below:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback
Cochrane Collaboration, Training Coordinator.
The plain language summary title has been amended accordingly. Thank you for your comment.
Last assessed as up-to-date: 13 February 2013.
Contributions of authors
Siyuan Li (SL), Jirong Yue (JY), Bi Rong Dong (BD), Xiufang Lin (FL), Taixiang Wu (TW) and Ming Yang (MY) were all involved in developing the protocol.
SL, JY, BD, MY were involved in selection of studies, extracting data and writing up findings.
TW provided statistical expertise.
Declarations of interest
Sources of support
- Chinese Cochrane Centre, China.
- No sources of support supplied
Medical Subject Headings (MeSH)
MeSH check words