Oral antihistamine-decongestant-analgesic combinations for the common cold

In Eccles 2014, the sum of nasal congestion differences over three days was significantly higher with the combination than with acetylsalicylic acid (P = 0.016).

“This was also the case when compared to acetylsalicylic acid (P = 0.016).”

• cites Eccles 2014 sourceDisputed

  In Results > Efficacy, Table 1 reports that the three-day sum of subjective nasal congestion intensity differences was not significant for the combination versus ASA (P = 0.969). The P = 0.016 result instead applies to total subjective nasal congestion relief over three days. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

First-generation antihistamines have a limited effect on rhinorrhoea and sneezing.

“There is a small amount of evidence that first‐generation antihistamines have a limited effect on rhinorrhoea and sneezing (De Sutter 2015).”

• cites De Sutter 2015 sourceSupported

In Bye 1980, no effect of active treatment on rhinorrhoea was noted.

“In Bye 1980, no effect of active treatment was noted.”

• cites Bye 1980 sourceSupported

In Berkowitz 1989 and Bye 1980, no significant difference in severity of cough was found between active treatment and control.

“Neither Berkowitz 1989 nor Bye 1980 found any significant difference in severity of cough between the active treatment group and the control group.”

• cites Berkowitz 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Bye 1980 sourceSupported

In Bye 1980, sneezing severity scores were significantly lower with active treatment on days two, three, and four.

“In Bye 1980, severity scores for sneezing were significantly lower with active treatment on days two, three, and four (no P values mentioned).”

• cites Bye 1980 sourcePartly supported

  The Results report significantly reduced sneezing scores on days 2, 3, and 4 for the pseudoephedrine–triprolidine combination versus placebo. The unqualified phrase “active treatment” is broader than that finding: pseudoephedrine alone was significant only on days 2 and 3, and triprolidine alone only on day 2. No page number is supplied for the passage. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In Eccles 2014, the sum of nasal congestion differences over three days was significantly higher with the combination therapy (pseudoephedrine + acetylsalicylic acid) than with placebo (P = 0.048).

“In Eccles 2014, the sum of nasal congestion differences over three days was significantly higher with the combination therapy (pseudoephedrine + acetylsalicylic acid) than with placebo (P = 0.048).”

• cites Eccles 2014 sourceSupported

In Eccles 2014, there was no significant difference between the combination and pseudoephedrine (P = 0.371).

“When compared to pseudoephedrine there was no significant difference (P = 0.371).”

• cites Eccles 2014 sourceSupported

Analgesics, decongestants, and antihistamines have some effect in monotherapy.

“Analgesics, decongestants, and antihistamines have some effect in monotherapy (Deckx 2016; De Sutter 2015; Eccles 2006b).”

• cites Deckx 2016 sourcePartly supported

  Deckx 2016 is relevant to the decongestant part of this multi-citation sentence, not the claims about analgesics or antihistamines. Its Authors’ conclusions say that multiple doses of nasal decongestants may have a small positive effect on subjective congestion in adults with the common cold, but the evidence is insufficient for firm conclusions; it cannot establish effectiveness for a single dose. The unqualified statement that decongestants 'have some effect' overstates that finding. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites De Sutter 2015 sourcePartly supported

  The sections on antihistamine monotherapy for adults and rhinorrhoea report small effects of sedating antihistamines on rhinorrhoea and sneezing. But the review finds no clinically significant overall benefit, and non-sedating antihistamines showed no effect on rhinorrhoea. Because this citation is one of three attached to the sentence, this verdict concerns its support for antihistamines, not the separately cited analgesics and decongestants. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Eccles 2006bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Barret 2007, a sufficiently important difference was about 25% for a cheap treatment without adverse effects.

“In a study on severity reduction in the common cold, Barret 2007 found that a sufficiently important difference meaning “the smallest amount of patient‐valued benefit that an intervention would require in order to justify associated costs, risk and other harms” was about 25% for a cheap treatment without adverse effects.”

• cites Barret 2007 sourceSupported

The review identified 30 studies (6304 participants) including 31 treatment comparisons.

“We identified 30 studies (6304 participants) including 31 treatment comparisons.”

• Also stated in: § Plain language summary · plain

  “We identified three new three new trials (1038 participants) in this 2021 update, bringing the total number of included trials to 30 (6304 participants).”

Seventeen trials documented their study protocol and reported on their prespecified outcomes.

“Seventeen trials documented their study protocol and reported on their prespecified outcomes.”

Antihistamine-decongestant odds ratio of treatment failure was 0.27 (95% CI 0.15 to 0.50).

“Antihistamine‐decongestant odds ratio (OR) of treatment failure was 0.27 (95% confidence interval (CI) 0.15 to 0.50).”

The decongestant-analgesic group experienced significantly more adverse effects than the control group (199/1122 versus 75/675; OR 1.62 95% CI 1.18 to 2.23; high certainty evidence; NNTH 17).

“the decongestant‐analgesic group experienced significantly more adverse effects than the control group (199/1122 versus 75/675; OR 1.62 95% CI 1.18 to 2.23; high certainty evidence; number needed to treat for an additional harmful outcome (NNTH 17).”

For antihistamine-analgesic-decongestant, the OR of treatment failure was 0.47 (95% CI 0.33 to 0.67; low certainty evidence).

“the OR of treatment failure was 0.47 (95% CI 0.33 to 0.67; low certainty evidence)”

Twelve trials were either funded by pharmaceutical companies or had authors employed by a pharmaceutical company with interests in the trial drug.

“It was noted that 12 of the trials were either funded by pharmaceutical companies or that the authors of the trial were employed by a pharmaceutical company with interests in the trial drug.”

Twenty-one trials compared active treatment with placebo.

“Twenty‐one trials compared active treatment with placebo.”

There was insufficient information regarding allocation concealment in almost all included trials.

“There was insufficient information regarding allocation concealment in almost all of the included trials, with either no description of the method of concealment or insufficient detail provided to permit a definitive judgement on how concealment was achieved.”

Antihistamine-decongestant: 14 trials (1298 participants).

“Antihistamine‐decongestant: 14 trials (1298 participants).”

For analgesic-decongestant, the OR of treatment failure was 0.28 (95% CI 0.15 to 0.52; moderate certainty evidence; NNTB 4.7).

“(OR of treatment failure 0.28, 95% CI 0.15 to 0.52; moderate certainty evidence; NNTB 4.7).”

In one analgesic-decongestant trial, 73% of participants in the analgesic-decongestant group reported a benefit compared with 52% in the control group (paracetamol).

“One trial reported on global effectiveness: 73% of participants in the analgesic‐decongestant group reported a benefit compared with 52% in the control group (paracetamol)”

Adverse effects were reported in only a small proportion of the trials.

“Adverse effects were reported in only a small proportion of the trials, some of which failed to clarify if the adverse reactions were seen in the placebo or treatment group(s).”

In the antihistamine-decongestant group, 128/419 (31%) versus 100/423 (13%) control participants suffered one or more adverse effects (OR 1.58, 95%CI 0.78 to 3.21; moderate certainty of evidence).

“the antihistamine‐decongestant group experienced more adverse effects than the control group: 128/419 (31%) versus 100/423 (13%) participants suffered one or more adverse effects (OR 1.58, 95%CI 0.78 to 3.21; moderate certainty of evidence).”

For antihistamine-analgesic-decongestant, global effect reported with active treatment (52%) and placebo (34%) was equivalent to a difference of less than one point on a four- or five-point scale.

“global effect reported with active treatment (52%) and placebo (34%) was equivalent to a difference of less than one point on a four‐ or five‐point scale”

For antihistamine-analgesic, NNTB was 6.67 (95% CI 4.76 to 12.5).

“NNTB 6.67 (95% CI 4.76 to 12.5).”

Overall, most combinations had a significant effect on general recovery in adults and older children.

“Overall, most combinations had a significant effect on general recovery in adults and older children.”

There was no difference between groups in side effects for the other combinations.

“however, there was no difference between groups in side effects for the other combinations.”

For antihistamine-decongestant, the number needed to treat for an additional beneficial outcome was 3.9 (95% CI 3.03 to 5.2).

“number needed to treat for an additional beneficial outcome (NNTB) 3.9 (95% CI 3.03 to 5.2).”

The included trials showed important differences in participants, interventions, outcomes, and study designs.

“The included trials showed important differences in participants, interventions, outcomes, and study designs.”

In the antihistamine-analgesic trial, 43% of participants in the control group and 70% in the active treatment group were cured after six days of treatment.

“Forty‐three per cent of participants in the control group and 70% in the active treatment group were cured after six days of treatment.”

For antihistamine-analgesic, there were not significantly more adverse effects in the active treatment group compared to placebo (drowsiness, hypersomnia, sleepiness 10/152 versus 4/120; OR 1.64 (95 % CI 0.48 to 5.59; low certainty evidence).

“there were not significantly more adverse effects in the active treatment group compared to placebo (drowsiness, hypersomnia, sleepiness 10/152 versus 4/120; OR 1.64 (95 % CI 0.48 to 5.59; low certainty evidence).”

Attrition and exclusion were adequately addressed across most trials.

“Attrition and exclusion were adequately addressed across most trials.”

The second antihistamine-analgesic trial also showed an effect in favour of the active treatment.

“The second trial also showed an effect in favour of the active treatment.”

In one antihistamine-analgesic-decongestant trial, 5/224 (2%) suffered adverse effects with the active treatment versus 9/208 (4%) with placebo.

“in one trial 5/224 (2%) suffered adverse effects with the active treatment versus 9/208 (4%) with placebo.”

For antihistamine-decongestant, the odds ratio of treatment failure was 0.31 (95% CI 0.20 to 0.48; moderate certainty evidence).

“The odds ratio (OR) of treatment failure was 0.31 (95% confidence interval (CI) 0.20 to 0.48; moderate certainty evidence)”

For antihistamine-analgesic-decongestant, NNTB was 5.6 (95% CI 3.8 to 10.2).

“NNTB 5.6 (95% CI 3.8 to 10.2).”

For antihistamine-analgesic, the OR of treatment failure was 0.33 (95% CI 0.23 to 0.46; moderate certainty evidence).

“The OR of treatment failure was 0.33 (95% CI 0.23 to 0.46; moderate certainty evidence)”

On the final evaluation day (follow-up 3 to 10 days), 55% of participants in the placebo group had a favourable response compared to 70% on active treatment.

“On the final evaluation day (follow‐up: 3 to 10 days), 55% of participants in the placebo group had a favourable response compared to 70% on active treatment.”

The combinations containing antihistamine-decongestant and analgesic-decongestant had significantly more adverse effects than placebo.

“The combinations containing antihistamine‐decongestant and analgesic‐decongestant had significantly more adverse effects than placebo.”

The combinations containing a decongestant had some effect on nasal obstruction.

“The combinations containing a decongestant also had some effect on nasal obstruction.”

In Weippl 1984, there was a significant effect on sneezing with active treatment compared with control at both evaluation times (P < 0.001).

“Weippl 1984 mentions a significant effect on sneezing with active treatment compared with control at both evaluation times (P < 0.001).”

• cites Weippl 1984Not checked — no full text of the source

In Virtanen 1983, sneezing severity scores were significantly lower with active treatment on days two to eight.

“In Virtanen 1983, severity scores for sneezing were significantly lower with active treatment on days two to eight (day two: exact P value not provided; day three: P < 0.001; day four P < 0.01; days six and seven: P < 0.01; and day eight: exact P value not provided).”

• cites Virtanen 1983 sourceNot checked — no full text of the source

In Berkowitz 1989, the difference in mean severity score for sneezing between groups is at most 0.3 severity point on a four-point scale.

“in Berkowitz 1989, the difference in mean severity score between groups is at most 0.3 severity point on a four‐point scale.”

• cites Berkowitz 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Berkowitz 1989, physicians found no significant differences between groups in severity of swelling and hyperaemia on days three and five.

“In Berkowitz 1989, physicians assessed severity of swelling and hyperaemia on days three and five of treatment, and found no significant differences between groups.”

• cites Berkowitz 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Hutton 1991, there was no difference between groups in the improvement of symptoms (P = 0.51).

“In Hutton 1991, there was no difference between groups in the improvement of symptoms (P = 0.51).”

• cites Hutton 1991 sourceNot checked — no full text of the source

In Berkowitz 1989, the difference in mean severity score for rhinorrhoea between groups is at most 0.3 severity point on a four-point scale.

“in Berkowitz 1989 the difference in mean severity score between groups is at most 0.3 severity point on a four‐point scale.”

• cites Berkowitz 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In five trials, 692 participants were evaluated for sedation: 26 of 345 (8%) in the active treatment group and 19 of 347 (5%) in the placebo group suffered from sedation (OR 1.38, 95% CI 0.63 to 3.00; low certainty evidence due to imprecision and inconsistency).

“In five trials, 692 participants were evaluated for sedation (drowsiness, hypersomnia, excessive sleepiness, asthenia): 345 in the active treatment group, of which 26 (8%) suffered from sedation, and 347 in the placebo group, of which 19 (5%) suffered from sedation (OR 1.38, 95% CI 0.63 to 3.00; 5 studies, 692 adults; Analysis 1.3; low certainty evidence due to imprecision and inconsistency) (Berk”

In Lebacq 1994, the combination of phenylpropanolamine + pheniramine maleate + mepyramine maleate was ineffective.

“The combination of phenylpropanolamine + pheniramine maleate + mepyramine maleate was ineffective.”

• cites Lebacq 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Rhinorrhoea and cough improved with antihistamine-decongestant-analgesic combinations.

“Rhinorrhoea and cough improved with antihistamine‐decongestant‐analgesic, whilst antihistamine‐decongestant combinations may have some effect on severity of sneezing, but not on the first day of treatment.”

In Weippl 1984, there was a significant effect on rhinorrhoea with active treatment compared with control at both evaluation times (P < 0.001).

“Finally, in Weippl 1984, there was a significant effect on rhinorrhoea with active treatment compared with control at both evaluation times (P < 0.001).”

• cites Weippl 1984Not checked — no full text of the source

There is insufficient evidence for the effectiveness (global recovery) in young children.

“There is insufficient evidence for the effectiveness (global recovery) in young children.”

The number needed to treat for an additional beneficial outcome was 3.9.

“The pooled odds ratio of therapy failure at final evaluation was 0.31 (odds ratio (OR) 0.31, confidence interval (CI) 0.20 to 0.48; 6 trials, 565 adults; moderate certainty evidence; Analysis 1.1), and the number needed to treat for an additional beneficial outcome (NNTB) was 3.9.”

In Lebacq 1994, there was no difference in the aspect of the nasal mucosa between groups.

“in Lebacq 1994, the condition of the nasal mucosa was assessed at different time points using a four‐point scale (normal, red, violet, blue). There was no difference in the aspect of the nasal mucosa between groups (Table 7).”

• cites Lebacq 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Berkowitz 1989, sneezing severity scores were significantly lower with active treatment from day two until day five.

“In Berkowitz 1989, severity scores for sneezing were significantly lower with active treatment from day two until day five (exact P value not provided).”

• cites Berkowitz 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The pooled odds ratio of therapy failure at final evaluation for antihistamine-decongestant combinations was 0.31 (95% CI 0.20 to 0.48; 6 trials, 565 adults; moderate certainty evidence).

“The pooled odds ratio of therapy failure at final evaluation was 0.31 (odds ratio (OR) 0.31, confidence interval (CI) 0.20 to 0.48; 6 trials, 565 adults; moderate certainty evidence; Analysis 1.1), and the number needed to treat for an additional beneficial outcome (NNTB) was 3.9.”

Two trials evaluating rhinorrhoea objectively by counting or weighing used tissues found no difference between antihistamine-decongestant and control.

“Two trials evaluated rhinorrhoea objectively by counting used tissues, Debelic 1973, or by weighing the used tissues (Schrooten 1993). No difference between groups was found.”

• cites Debelic 1973Not checked — no full text of the source
• cites Schrooten 1993Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In four trials, 713 participants were evaluated for dry mouth: 63 of 358 (18%) in the active treatment group and 28 of 355 (8%) in the placebo group had dry mouth (OR 3.75, 95% CI 1.74 to 8.10; high certainty evidence).

“In four trials, 713 participants were evaluated for dry mouth: 358 in the active treatment group, of which 63 (18%) experienced dry mouth, and 355 in the placebo group, of which 28 (8%) had dry mouth (OR 3.75, 95% CI 1.74 to 8.10; 4 trials, 640 adults; Analysis 1.4; high certainty evidence) (Berkowitz 1989; Robert 2004; Schrooten 1993; Virtanen 1983).”

In Curley 1988, the mean severity score for cough was significantly less on days three, four, and five.

“In Curley 1988, the mean severity score for cough was significantly less on days three, four, and five (exact P value not provided).”

• cites Curley 1988 sourceNot checked — no full text of the source

In Middleton 1981, significantly more participants receiving active nighttime medication compared with paracetamol responded affirmatively to the question about whether the tablets helped: 73% versus 52% (OR 0.35, 95% CI 0.18 to 0.70; 191 adults; moderate certainty evidence).

“In Middleton 1981, overall subjective assessment was measured at the end of the study by asking “on the whole do you think the tablets have helped you?”. Significantly more participants receiving the active nighttime medication compared with the control group (paracetamol) responded affirmatively to the question: 73% versus 52% (OR 0.35, 95% CI 0.18 to 0.70; 191 adults; moderate certainty evidence”

• cites Middleton 1981 sourceNot checked — no full text of the source

In Hutton 1991, there was no difference between treatment groups in the number of parents reporting overall improvement (P = 0.74).

“In Hutton 1991, there was no difference between treatment groups in the number of parents reporting overall improvement (P = 0.74).”

Six trials reported adequate data to include in a meta-analysis of antihistamine-decongestant combinations.

“Six trials reported adequate data to include in a meta‐analysis (Bye 1980; Galvez 1985; Robert 2004; Scavino 1985; Schrooten 1993; Weippl 1984).”

Adverse effects were evaluated in eight trials including 1997 cold episodes.

“Adverse effects were evaluated in eight trials including 1997 cold episodes (Berkowitz 1989; Bye 1980; Debelic 1973; Galvez 1985; Robert 2004; Scavino 1985; Schrooten 1993; Virtanen 1983).”

In Robert 2004, no clear difference was seen between active treatment and placebo in peak nasal flow evaluated before and after three days of treatment.

“In Robert 2004, participants' peak nasal flow was evaluated before and after three days of treatment. No clear difference was seen between the active treatment and placebo.”

• cites Robert 2004 sourceNot checked — no full text of the source

The size of the effect on specific symptoms, when reported, was less than one severity point on a four- or five-point scale.

“The size of the effect on specific symptoms, when reported, was less than one severity point on a four‐ or five‐point scale.”

In Middleton 1981, drowsiness was mentioned by five participants receiving paracetamol and four receiving combination therapy (P = 0.68).

“In Middleton 1981, drowsiness was mentioned by five participants receiving paracetamol and four participants receiving the combination therapy (P = 0.68).”

• cites Middleton 1981 sourceNot checked — no full text of the source

In Martinez 1994, the active treatment significantly reduced the duration of nasal congestion.

“Conversely, in Martinez 1994, the active treatment significantly reduced the duration of nasal congestion.”

• cites Martinez 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The number needed to treat for an additional harmful outcome (NNTH) is 18 (95% CI 9 to 59).

“The number needed to treat for an additional harmful outcome (NNTH) is 18 (95% CI 9 to 59).”

In Sperber 1989, there was a difference in the sum of the day scores between the active treatment (4 +/- 3) and the placebo (7 +/- 2) for nasal congestion during five days of therapy on a four-point scale.

“There was a difference in the sum of the day scores between the active treatment (4 +/− 3) and the placebo (7 +/− 2; exact P value not provided).”

• cites Sperber 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Middleton 1981, the severity of nasal obstruction was not significantly different between treatment and placebo groups.

“In Middleton 1981, the severity of nasal obstruction was not significantly different between treatment and placebo groups.”

• cites Middleton 1981 sourceNot checked — no full text of the source

In Middleton 1981, 11 of 79 participants receiving paracetamol and 9 of 82 receiving active treatment mentioned adverse effects (P = 0.57).

“In Middleton 1981, both combinations (day and night) were evaluated together: 11 of 79 participants receiving paracetamol and nine of 82 participants receiving the active treatment mentioned adverse effects (P = 0.57).”

• cites Middleton 1981 sourceNot checked — no full text of the source

In Sperber 2000, two hours after the first dose there was a clear decrease (P = 0.002) in nasal congestion score in favour of active treatment.

“Two hours after the first dose there was a clear decrease (P = 0.002) in favour of active treatment.”

• cites Sperber 2000 sourceNot checked — no full text of the source

In Loose 2004, the differences from baseline of nasal congestion scores and nasal relief scores were statistically larger for all active treatments and at all observation intervals compared to placebo.

“In Loose 2004, the differences from baseline of nasal congestion scores and nasal relief scores were statistically larger (exact P value not provided) for all active treatments and at all observation intervals compared to placebo.”

• cites Loose 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Eccles 2006a, global nasal congestion relief was greater with active treatment compared to paracetamol or placebo (P = 0.004).

“Global nasal congestion relief was also greater with active treatment compared to paracetamol or placebo (P = 0.004).”

• cites Eccles 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

After pooling, 7% of participants receiving combination therapy and 3% receiving placebo or paracetamol suffered from drowsiness (OR 1.64, 95% CI 0.48 to 5.59; 2 studies, 272 adults; low certainty evidence).

“After pooling, 7% of participants receiving the combination therapy and 3% of participants receiving placebo or paracetamol suffered from drowsiness (OR 1.64, 95% CI 0.48 to 5.59; 2 studies, 272 adults; low certainty evidence; Analysis 2.1).”

In Eccles 2006a, the combination was not different from pseudoephedrine monotherapy for global nasal congestion relief.

“This was not the case when the combination was compared to pseudoephedrine in monotherapy.”

• cites Eccles 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Sperber 2000, after the second administration the difference was still significant but smaller (P = 0.03).

“After the second administration the difference was still significant, but smaller (P = 0.03).”

• cites Sperber 2000 sourceNot checked — no full text of the source

In Gwaltney 2002, five of 61 participants receiving active treatment and 0 of 30 receiving placebo experienced drowsiness (P = 0.03).

“In Gwaltney 2002, five of 61 participants receiving the active treatment and 0 of 30 participants receiving placebo experienced drowsiness (P = 0.03).”

• cites Gwaltney 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In three trials, dry mouth occurred in 2.6% of participants in the active treatment group and 1.8% in the control group (OR 1.43, 95% CI 0.53 to 3.83; 3 studies, 764 adults; low certainty evidence).

“In three trials dry mouth was noted as an adverse effect (Eccles 2006a; Middleton 1981; Sperber 2000), occurring in 2.6% of participants in the active treatment group and 1.8% of participants in the control group (OR 1.43, 95% CI 0.53 to 3.83; 3 studies, 764 adults; low certainty evidence due to imprecision and inconsistency; Analysis 3.4).”

• cites Eccles 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Middleton 1981 sourceNot checked — no full text of the source
• cites Sperber 2000 sourceNot checked — no full text of the source

In Loose 2004, there was no clear difference between the different active combinations.

“There was no clear difference between the different active combinations.”

• cites Loose 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Montijo-Barrios 2011 found a significant difference in the proportion of children experiencing rhinorrhoea, noisy breathing, and mouth breathing between groups on days three, five, and seven.

“Montijo‐Barrios 2011 evaluated rhinorrhoea, noisy breathing, and mouth breathing on days three, five, and seven, and found a significant difference in the proportion of children experiencing these symptoms between groups (Table 10).”

• cites Montijo‐Barrios 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In five trials, 5.8% of participants suffered from some gastrointestinal upset in the active treatment group and 2.7% in the control group (OR 1.71, 95% CI 0.97 to 3.01; 5 trials, 1644 adults; high certainty evidence).

“In the same five trials, 5.8% of participants suffered from some gastrointestinal upset in the active treatment group and 2.7% in the control group (OR 1.71, 95% CI 0.97 to 3.01; 5 trials, 1644 adults; high certainty evidence; Analysis 3.5).”

In Sperber 1989, the difference in the sum of the severity scores over five days was three points on a four-point scale.

“in Sperber 1989, the difference in the sum of the severity scores over five days was three points on a four‐point scale”

• cites Sperber 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In five trials, 4.4% of participants suffered from sedation with active treatment and 3.2% with control (OR 1.34, 95% CI 0.76 to 2.37; 5 studies, 1644 adults; moderate certainty evidence).

“In the five trials, 4.4% of participants suffered from sedation with active treatment and 3.2% with control (OR 1.34, 95% CI 0.76 to 2.37; 5 studies, 1644 adults; moderate certainty evidence; Analysis 3.3).”

Montijo-Barrios 2011 did not find a difference between groups for sneezing.

“Montijo‐Barrios 2011 did not find a difference between groups for sneezing (Table 10).”

• cites Montijo‐Barrios 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Middleton 1981, significantly more participants receiving active daytime medication compared with paracetamol responded affirmatively to the question about whether the tablets helped: 73% versus 52% (OR 0.28, 95% CI 0.15 to 0.52; 181 participants; moderate certainty evidence).

“Significantly more participants receiving the active daytime medication compared with the control group (paracetamol) responded affirmatively to the question: 73% versus 52% (OR 0.28, 95% CI 0.15 to 0.52; 181 participants; moderate certainty evidence) (Analysis 3.1).”

• cites Middleton 1981 sourceNot checked — no full text of the source

In Sperber 2000, the difference was at most 1.06 severity points on a five-point scale.

“in the second trial of Sperber 2000, the difference was at most 1.06 severity points on a five‐point scale”

• cites Sperber 2000 sourceNot checked — no full text of the source

The antihistamine-decongestant-analgesic combination showed some effect on global effectiveness in two trials (Mizoguchi 2007; Thackray 1978).

“The combination showed some effect in two trials (Mizoguchi 2007; Thackray 1978).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source
• cites Thackray 1978 sourceNot checked — no full text of the source

None of the three trials assessing subjective severity of rhinorrhoea showed a favourable treatment effect.

“None of these trials showed a favourable treatment effect.”

• cites Middleton 1981 sourceNot checked — no full text of the source
• cites Sperber 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sperber 2000 sourceNot checked — no full text of the source

In Zhang 2018, there was no difference in total symptom score on any of the evaluation times, nor at the global evaluation point.

“Zhang 2018 found no difference in total symptom score on any of the evaluation times, nor at the global evaluation point.”

• cites Zhang 2018 sourceNot checked — no full text of the source

In Unuvar 2007, there was no meaningful difference in recovery rate.

“There was no meaningful difference in recovery rate.”

• cites Unuvar 2007 sourceNot checked — no full text of the source

In Eccles 2006a, the mean sum of nasal congestion differences over three days was 0.69 on a four-point scale.

“in Eccles 2006a, the mean sum of nasal congestion differences over three days was 0.69 (on a four‐point scale)”

• cites Eccles 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Zhang 2018 reported three participants with adverse effects in the control group and one participant with an adverse effect in the treatment group.

“Zhang 2018 reported three participants with adverse effects in the control group and one participant with an adverse effect in the treatment group.”

• cites Zhang 2018 sourceNot checked — no full text of the source

In Mizoguchi 2007, the severity rating with active treatment was significantly lower than with placebo (P < 0.001).

“The severity rating with active treatment was significantly lower than with placebo (P < 0.001)”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

In Sperber 1989, recipients of active treatment showed improved nasal patency on rhinomanometry from pre-treatment baseline flow rates on days four (P = 0.08) and five (P = 0.06).

“In Sperber 1989, recipients of the active treatment showed improved nasal patency on rhinomanometry from the pre‐treatment baseline flow rates on days four (P = 0.08) and five (P = 0.06) of treatment.”

• cites Sperber 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Eccles 2006a, the difference in global nasal congestion relief was 0.7 on a five-point scale.

“and the difference in global nasal congestion relief was 0.7 (on a five‐point scale).”

• cites Eccles 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Sperber 1989, there was a reduction of 30% in nasal mucus weight with the active treatment compared with placebo (P = 0.04).

“However, in Sperber 1989 there was a reduction of 30% in nasal mucus weight with the active treatment compared with the placebo (P = 0.04).”

• cites Sperber 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Blanco 2000, no more participants felt sleepy with the active treatment than with the placebo.

“In Blanco 2000, no more participants felt sleepy with the active treatment than with the placebo.”

• cites Blanco 2000Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Thackray 1978, more participants receiving active treatment scored the active syrup as 'good' to 'excellent' compared with those receiving placebo syrup (exact P value not provided).

“More participants receiving the active treatment scored the active syrup as 'good' to 'excellent' compared with those receiving the placebo syrup (exact P value not provided).”

• cites Thackray 1978 sourceNot checked — no full text of the source

In Martinez 1994, the combination significantly reduced the duration of mucosal oedema on anterior rhinoscopia.

“In Martinez 1994, the combination significantly reduced the duration of mucosal oedema on anterior rhinoscopia.”

• cites Martinez 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Eccles 2006a, the combination treatment was more effective than placebo in increasing nasal airflow conductance (P < 0.001).

“In Eccles 2006a, the combination treatment was more effective than placebo in increasing nasal airflow conductance (P < 0.001).”

• cites Eccles 2006aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Thackray 1978, seven participants with the active treatment and four with the placebo felt giddy or drowsy.

“In Thackray 1978, seven participants with the active treatment and four with the placebo felt giddy or drowsy.”

• cites Thackray 1978 sourceNot checked — no full text of the source

In Mizoguchi 2007, more participants receiving active treatment rated their overall symptom relief during the night as 'good' or 'very good' on rising the following morning (50.2% versus 31.9%).

“more participants receiving the active treatment rated their overall symptom relief during the night as 'good' or 'very good' on rising the following morning (50.2% versus 31.9%).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

In Sperber 1989, overall and daily patency tended to be greater in recipients of pseudoephedrine + ibuprofen compared to placebo.

“The overall and daily patency tended to be greater in the recipients of pseudoephedrine + ibuprofen compared to placebo.”

• cites Sperber 1989Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Blanco 2000, no significant difference was found between groups in the general evolution of the common cold.

“In Blanco 2000, no significant difference was found between groups in the general evolution of the common cold.”

• cites Blanco 2000Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Mizoguchi 2007, two participants in the active treatment group and one participant in the placebo group experienced somnolence.

“In Mizoguchi 2007, two participants in the active treatment group and one participant in the placebo group experienced somnolence.”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

In pooled data from two trials, measured in the morning after an evening dose, significantly more participants evaluated the active evening dose treatment as beneficial (OR 0.47, 95% CI 0.33 to 0.67; 2 studies, 548 adults; low certainty evidence due to risk of bias and imprecision).

“Measured in the morning after an evening dose, significantly more participants evaluated the active evening dose treatment as beneficial (OR 0.47, 95% CI 0.33 to 0.67; 2 studies, 548 adults; low certainty evidence due to risk of bias and imprecision; Analysis 4.1).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source
• cites Thackray 1978 sourceNot checked — no full text of the source

There was no significant effect of an analgesic-decongestive combination on the subjective severity of sneezing.

“There was no significant effect.”

• cites Middleton 1981 sourceNot checked — no full text of the source
• cites Sperber 2000 sourceNot checked — no full text of the source

Zhang 2018 found no significant difference in decrease of severity of sneezing on a five-point severity score at any of the evaluation times.

“Zhang 2018 found no significant difference in decrease of severity of sneezing on a five‐point severity score at any of the evaluation times.”

• cites Zhang 2018 sourceNot checked — no full text of the source

In Mizoguchi 2007, the change in severity score for cough was at most 0.42 severity points on a five-point severity scale.

“change in severity score was at most 0.42 severity points on a five‐point severity scale.”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

In Mizoguchi 2007, severity scores of nasal congestion were significantly lower with active treatment at both evaluation times (P = 0.012 and P = 0.002).

“Severity scores were significantly lower with active treatment at both evaluation times (P = 0.012, and P = 0.002).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

On anterior rhinoscopy in Blanco 2000, a favourable effect on oedema of the nasal mucosa was seen on the third treatment day (P = 0.056).

“On anterior rhinoscopy in Blanco 2000, a favourable effect on oedema of the nasal mucosa was seen on the third treatment day (P = 0.056) (Table 14).”

• cites Blanco 2000Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In children there was no effect of the combination on cough.

“In children there was no effect.”

• cites Unuvar 2007 sourceNot checked — no full text of the source

The combination of antihistamine-analgesic was beneficial in the two trials.

“The combination of antihistamine‐analgesic was beneficial in the two trials”

In Thackray 1978, more participants with active treatment scored the active syrup as good to excellent than those with placebo syrup (exact P value not provided).

“More participants with active treatment scored the active syrup as good to excellent than those with the placebo syrup (exact P value not provided).”

• cites Thackray 1978 sourceNot checked — no full text of the source

Two trials showed some effect of an antihistamine-decongestant-analgesic combination on cough (Mizoguchi 2007; Thackray 1978).

“Two trials showed some effect (Mizoguchi 2007; Thackray 1978).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source
• cites Thackray 1978 sourceNot checked — no full text of the source

The combination of analgesic-decongestant was beneficial in the one trial providing data on this outcome.

“and the combination of analgesic‐decongestant was beneficial in the one trial providing data on this outcome.”

In Unuvar 2007, there were not significantly more children without rhinorrhoea on days three or five with the combination therapy in comparison with paracetamol.

“In contrast, in Unuvar 2007, there were not significantly more children without rhinorrhoea on days three or five with the combination therapy in comparison with paracetamol.”

• cites Unuvar 2007 sourceNot checked — no full text of the source

Blanco 2000 found a significantly greater reduction of rhinorrhoea compared with placebo on the third treatment day.

“Blanco 2000 found a significantly greater reduction of rhinorrhoea compared with placebo on the third treatment day.”

• cites Blanco 2000Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Mizoguchi 2007, the difference in severity score for nasal obstruction was at most 0.29 on a five-point severity scale.

“the difference in severity score was at most 0.29 on a five‐point severity scale (Mizoguchi 2007).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

Thackray 1978 showed no beneficial effect of an antihistamine-decongestive-analgesic combination on the subjective severity of sneezing compared with placebo (P = 0.14).

“The trial showed no beneficial effect compared with placebo (P = 0.14).”

• cites Thackray 1978 sourceNot checked — no full text of the source

In Thackray 1978, there was a clear difference between the number of participants rating the formulation as 'good, very good or excellent' on the morning after the dose received the night before (P < 0.01).

“In Thackray 1978, there was a clear difference between the number of participants rating the formulation as 'good, very good or excellent' on the morning after the dose received the night before (P < 0.01).”

• cites Thackray 1978 sourceNot checked — no full text of the source

In Mizoguchi 2007, at both evaluation times, severity scores for cough were significantly lower with the active treatment (P = 0.0004 and P < 0.001).

“In Mizoguchi 2007, at both evaluation times, severity scores were significantly lower with the active treatment (P = 0.0004 and P < 0.001).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

In Blanco 2000, some decrease in nasal congestion was observed on the third day of treatment (P = 0.041).

“In participants who received active treatment, some decrease in nasal congestion was observed on the third day of treatment (P = 0.041).”

• cites Blanco 2000Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Sachsenroder 1972, significantly more participants receiving the active treatment rated the effect on rhinorrhoea as 'good' compared with placebo treatment (P < 0.001) on each of the three treatment days.

“In Sachsenroder 1972, significantly more participants receiving the active treatment rated the effect on rhinorrhoea as 'good' compared with placebo treatment (P < 0.001) on each of the three treatment days.”

• cites Sachsenroder 1972Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Zhang 2018 found no significant difference between groups in decrease of severity of nasal obstruction on a five-point severity score at any of the evaluation times.

“Zhang 2018 found no significant difference between groups in decrease of severity of nasal obstruction on a five‐point severity score at any of the evaluation times.”

• cites Zhang 2018 sourceNot checked — no full text of the source

Zhang 2018 found no significant difference in the decrease of severity of rhinorrhoea on a five-point severity score at any of the evaluation times.

“Zhang 2018 found no significant difference in the decrease of severity of rhinorrhoea on a five‐point severity score at any of the evaluation times.”

• cites Zhang 2018 sourceNot checked — no full text of the source

Where pooling of results was possible, the review found an NNTB of four for the combination of antihistamine-decongestant.

“Where pooling of results was possible, we found an NNTB of four for the combination of antihistamine‐decongestant.”

In Mizoguchi 2007, the difference in severity score for rhinorrhoea was at most 0.33 severity points on a five-point severity scale.

“the difference in severity score was at most 0.33 severity points on a five‐point severity scale.”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

Zhang 2018 found no significant difference in decrease of severity of cough on a four-point severity score at any of the evaluation times, despite the presence of dextromethorphan in the active treatment.

“Zhang 2018 found no significant difference in decrease of severity of cough on a four‐point severity score at any of the evaluation times, despite the presence of dextromethorphan in the active treatment.”

• cites Zhang 2018 sourceNot checked — no full text of the source

In Mizoguchi 2007, severity of runny nose was significantly lower with active treatment at both evaluation times (P = 0.017 and P = 0.001).

“At both evaluation times, severity scores were significantly lower with active treatment (P = 0.017 and P = 0.001).”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

In Thackray 1978, more participants evaluated the active syrup as beneficial for rhinorrhoea compared with placebo (exact P value not provided).

“In Thackray 1978, more participants evaluated the active syrup as beneficial for rhinorrhoea compared with placebo (exact P value not provided).”

• cites Thackray 1978 sourceNot checked — no full text of the source

The paediatric trial by Unuvar 2007 failed to show any effect on cough.

“In contrast, the paediatric trial by Unuvar 2007 failed to show any effect on cough.”

• cites Unuvar 2007 sourceNot checked — no full text of the source

The results of the older studies were in line with the more recent, higher-quality studies.

“However, the results of these older studies were in line with the more recent, higher‐quality studies”

The review found evidence to support the effectiveness of combinations with antihistamines, analgesics, and decongestants compared to placebo.

“We found evidence to support the effectiveness of combinations with antihistamines, analgesics, and decongestants compared to placebo.”

For analgesics with decongestants, there were six trials in adults and one trial in children (2525 participants).

“For analgesics with decongestants, we found six trials in adults and one trial in children (2525 participants)”

The certainty of evidence was mostly moderate to low due to imprecision or risk of bias.

“The certainty of evidence was mostly moderate to low due to imprecision or risk of bias.”

Dizziness was more frequent with analgesic-decongestant combinations.

“and dizziness was more frequent with analgesic‐decongestant combinations.”

The review's findings show that combinations with decongestants decrease nasal obstruction.

“This is in accordance with our findings that combinations with decongestants decrease nasal obstruction.”

Evidence of the effectiveness of these combinations in young children is lacking.

“given that evidence of their effectiveness is lacking”

Based on the available data, adverse effects were usually more frequent with the active treatment than with control.

“but based on the available data we found that adverse effects were usually more frequent with the active treatment than with control.”

For the combination of antihistamines with analgesics and decongestants, there were five trials in adults and one trial in children (1014 participants).

“and for the combination of antihistamines with analgesics and decongestants, we found five trials in adults and one trial in children (1014 participants).”

The review's findings show that most combinations showed some general benefit.

“which confirms our findings that most combinations showed some general benefit.”

In the trial using cold episodes as unit of analysis, 199 participants had 1 cold, 36 had 2 colds, and 7 had 3 colds.

“199 participants had 1 cold, 36 had 2 colds, and 7 had 3 colds”

Dry mouth and insomnia were more frequent with antihistamine-decongestant combinations.

“Dry mouth and insomnia were more frequent with antihistamine‐decongestant”

In most trials it was unclear how participants were recruited, i.e., it is not clear if the included participants were actively seeking care for their symptoms of the common cold.

“In most trials it was unclear how the participants were recruited, that is it is not clear if the included participants were actively seeking care for their symptoms of the common cold.”

Despite the large number of combination products and formulations on the market and the vast amounts sold, there are only a limited number of studies evaluating their effectiveness, especially in young children.

“The most striking finding is that despite the large number of combination products and formulations on the market, and the vast amounts sold, there are only a limited number of studies evaluating their effectiveness, especially in young children.”

The least studied combination was antihistamines with analgesics, with three trials in adults (1508 participants) and one trial in young children (100 participants).

“The least studied combination was antihistamines with analgesics (three trials in adults (1508 participants) and one trial in young children (100 participants)).”

The most studied combination was antihistamines combined with decongestants, with eight trials in adults (1091 participants), two trials in young children (113 participants), and four trials including older children (214 participants).

“The most studied combination was antihistamines combined with decongestants (eight trials in adults (1091 participants), two trials in young children (113 participants), and four trials including older children (214 participants)).”

In some older trials, data required to judge methodological rigour were not reported, mostly information related to the randomisation process.

“In some of the (often older) trials, data required to judge the methodological rigour were not reported, that is mostly information related to the randomisation process.”

The active treatment in the Mizoguchi 2007 trial also contained dextromethorphan.

“However, the active treatment in this trial also contained dextromethorphan.”

• cites Mizoguchi 2007 sourceNot checked — no full text of the source

For antihistamine-decongestant, adverse effects: dry mouth (4 studies, 640 participants) showed an odds ratio of 3.75 (95% CI 1.74 to 8.10).

“1.4 Adverse effects: dry mouth 4 640 Odds Ratio (M‐H, Random, 95% CI) 3.75 [1.74, 8.10]”

For analgesic-decongestant, adverse effects: gastrointestinal (5 studies, 1644 participants) showed a risk ratio of 1.71 (95% CI 0.97 to 3.01).

“3.5 Adverse effects: gastrointestinal 5 1644 Risk Ratio (M‐H, Random, 95% CI) 1.71 [0.97, 3.01]”

For analgesic-decongestant, adverse effects: dizziness, lightheadedness (4 studies, 1287 participants) showed an odds ratio of 2.86 (95% CI 1.02 to 8.01).

“3.6 Adverse effects: dizziness, lightheadedness 4 1287 Odds Ratio (M‐H, Random, 95% CI) 2.86 [1.02, 8.01]”

For analgesic-decongestant, adverse effects: dry mouth (3 studies, 764 participants) showed an odds ratio of 1.43 (95% CI 0.53 to 3.83).

“3.4 Adverse effects: dry mouth 3 764 Odds Ratio (M‐H, Random, 95% CI) 1.43 [0.53, 3.83]”

For antihistamine-decongestant, adverse effects: insomnia (2 studies, 344 participants) showed an odds ratio of 2.89 (95% CI 0.88 to 9.56).

“1.5 Adverse effects: insomnia 2 344 Odds Ratio (M‐H, Random, 95% CI) 2.89 [0.88, 9.56]”

For antihistamine-analgesic-decongestant, global evaluation after 5 days of treatment (1 study, 83 participants) showed an odds ratio of 1.17 (95% CI 0.49 to 2.77).

“4.3 Global evaluation: after 5 days of treatment 1 83 Odds Ratio (M‐H, Random, 95% CI) 1.17 [0.49, 2.77]”

For antihistamine-decongestant, adverse effects: drowsiness, hypersomnia, and excessive sleepiness (5 studies, 692 participants) showed an odds ratio of 1.38 (95% CI 0.63 to 3.00).

“1.3 Adverse effects: drowsiness, hypersomnia, and excessive sleepiness 5 692 Odds Ratio (M‐H, Random, 95% CI) 1.38 [0.63, 3.00]”

For antihistamine-analgesic-decongestant, global evaluation after 3 days of treatment (1 study, 109 participants) showed an odds ratio of 0.34 (95% CI 0.09 to 1.31).

“4.2 Global evaluation: after 3 days of treatment 1 109 Odds Ratio (M‐H, Random, 95% CI) 0.34 [0.09, 1.31]”

For antihistamine-decongestant, adverse effects: all (7 studies, 842 participants) showed an odds ratio of 1.58 (95% CI 0.78 to 3.21).

“1.2 Adverse effects: all 7 842 Odds Ratio (M‐H, Random, 95% CI) 1.58 [0.78, 3.21]”

For analgesic-decongestant, adverse effects: all (6 studies, 1797 participants) showed an odds ratio of 1.62 (95% CI 1.18 to 2.23).

“3.2 Adverse effects: all 6 1797 Odds Ratio (M‐H, Random, 95% CI) 1.62 [1.18, 2.23]”

For antihistamine-decongestant, adverse effects: gastrointestinal upset (2 studies, 296 participants) showed an odds ratio of 2.81 (95% CI 0.64 to 12.33).

“1.6 Adverse effects: gastrointestinal upset 2 296 Odds Ratio (M‐H, Random, 95% CI) 2.81 [0.64, 12.33]”

For antihistamine-decongestant, global evaluation (6 studies, 565 participants) showed a risk difference of -0.26 (95% CI -0.33 to -0.19).

“1.1 Global evaluation 6 565 Risk Difference (M‐H, Random, 95% CI) ‐0.26 [‐0.33, ‐0.19]”

For antihistamine-analgesic-decongestant, global evaluation on the morning after evening dosing (2 studies, 548 participants) showed an odds ratio of 0.47 (95% CI 0.33 to 0.67).

“4.1 Global evaluation: on the morning after evening dosing 2 548 Odds Ratio (M‐H, Random, 95% CI) 0.47 [0.33, 0.67]”

For analgesic-decongestant, global evaluation (1 study, 181 participants) showed an odds ratio of 0.28 (95% CI 0.15 to 0.52).

“3.1 Global evaluation 1 181 Odds Ratio (M‐H, Random, 95% CI) 0.28 [0.15, 0.52]”

For antihistamine-analgesic, adverse effects: drowsiness, hypersomnia, and excessive sleepiness (2 studies, 272 participants) showed an odds ratio of 1.64 (95% CI 0.48 to 5.59).

“2.1 Adverse effects: drowsiness, hypersomnia, and excessive sleepiness 2 272 Odds Ratio (M‐H, Random, 95% CI) 1.64 [0.48, 5.59]”

For analgesic-decongestant, adverse effects: drowsiness, hypersomnia, lethargy, excessive sleepiness and other central nervous system adverse effects (5 studies, 1644 participants) showed an odds ratio of 1.34 (95% CI 0.76 to 2.37).

“3.3 Adverse effects: drowsiness, hypersomnia, lethargy, excessive sleepiness and other central nervous system adverse effects 5 1644 Odds Ratio (M‐H, Random, 95% CI) 1.34 [0.76, 2.37]”

There were large differences in study design, participants, interventions, and outcomes among included trials.

“and there were large differences in study design, participants, interventions, and outcomes.”

There was frequently not enough information in the trials to judge the certainty of the evidence.

“There was frequently not enough information in the trials to judge the certainty of the evidence.”

The 30 included studies differed in the way they were conducted, the included participants, the treatments used, and in the way the effect was measured.

“The 30 included studies differed in the way they were conducted, the included participants, the treatments used, and in the way the effect was measured.”

There is no evidence of effectiveness in young children.

“There is no evidence of effectiveness in young children.”

The current evidence suggests that antihistamine-analgesic-decongestant combinations have some general benefit in adults and older children.

“The current evidence suggests that antihistamine‐analgesic‐decongestant combinations have some general benefit in adults and older children.”

There was no effect in younger children.

“There was no effect in younger children.”

The evidence suggests that all combinations have some beneficial effect on overall symptoms of the common cold in adults and older children.

“The evidence suggests that all combinations have some beneficial effect on overall symptoms of the common cold in adults and older children.”

Based on scarce data, the effect on individual symptoms is probably too small to be clinically relevant.

“Based on these scarce data, the effect on individual symptoms is probably too small to be clinically relevant.”

The review found a lack of data on the effectiveness of antihistamine-analgesic-decongestant combinations for the common cold.

“We found a lack of data on the effectiveness of antihistamine‐analgesic‐decongestant combinations for the common cold.”

We downgraded the certainty of the evidence one level to moderate due to a serious risk of bias.

“We downgraded the certainty of the evidence one level to moderate due to a serious risk of bias.”

We concluded that antihistamine-decongestant combinations have some effect on general recovery compared to placebo.

“We therefore concluded that antihistamine‐decongestant combinations have some effect on general recovery compared to placebo.”

A combination of antihistamines and analgesic probably has no effect on nasal symptoms or cough in adults.

“Based on these results we can conclude that a combination of antihistamines and analgesic probably has no effect on nasal symptoms or cough in adults.”

The review could not pool the results of the trials of nasal obstruction because of differences in outcome measures or lack of adequate data.

“We could not pool the results of these trials because of differences in outcome measures or lack of adequate data.”

The combination of antihistamine with analgesics is generally well tolerated.

“We can conclude that the combination of antihistamine with analgesics is generally well tolerated.”

Antihistamine-analgesic combinations may have a positive effect on subjective general recovery.

“As both trials had a favourable result, we can conclude that antihistamine‐analgesic combinations may have a positive effect on subjective general recovery.”

Decongestant-analgesic combinations are probably effective in alleviating nasal obstruction.

“We can conclude that decongestant‐analgesic combinations are probably effective in alleviating nasal obstruction.”

Adverse effects are overall more frequent with a decongestant + analgesic combination than with control treatment.

“In conclusion, adverse effects are overall more frequent with a decongestant + analgesic combination than with control treatment.”

Dizziness is more frequent with a decongestant + analgesic combination than with control treatment.

“Specifically, dizziness is more frequent.”

There is very weak evidence that there is some effect on nasal symptoms in small children.

“We have very weak evidence that there is some effect on nasal symptoms in small children.”

A combination containing decongestant-antihistamine-analgesic may have some favourable effect on rhinorrhoea in adults.

“We can conclude that a combination containing decongestant‐antihistamine‐analgesic may have some favourable effect on rhinorrhoea in adults.”

All four combinations of over-the-counter treatments for the common cold showed a general benefit in adults and children aged over six years.

“All four combinations showed a general benefit in adults and children aged over six years.”

A combination of decongestant-antihistamine-analgesic may have some favourable effect on nasal obstruction.

“We can conclude that a combination of decongestant‐antihistamine‐analgesic may have some favourable effect on nasal obstruction.”

The results for rhinorrhoea in children were equivocal.

“However, the results in children were equivocal.”

It was not possible to draw any conclusions on the effectiveness of an antihistamine-decongestant-analgesic combination for cough in adults because in both trials where some effect was seen, it may have been due to the presence of dextromethorphan.

“It was not possible to draw any conclusions on the effectiveness of a combination of antihistamine‐decongestant‐analgesic for cough in adults since in both trials where some effect was seen, it may have been due to the presence of dextromethorphan.”

The limited short-term beneficial effect of antihistamines may explain some of the effect found in combinations with antihistamines.

“which may explain some of the effect we found in the combinations with antihistamines.”

The unclear recruitment in most trials may jeopardise the generalisability of the findings.

“This may jeopardise the generalisability of the findings.”

Using cold episodes as the unit of analysis in that trial does not introduce meaningful bias.

“we do not think that this introduces meaningful bias.”

• AssumptionRests on an assumption: The common cold is a short, acute, benign condition.

The effect found on severity of specific symptoms is much lower than the 25% threshold for a sufficiently important difference.

“The effect found on severity of specific symptoms is much lower than this.”

These combinations have potentially associated dangers in young children.

“and their potentially associated dangers.”

• AssumptionRests on an assumption: The common cold is a short, acute, benign condition.

The effect of these combinations on individual symptoms is probably too small to be clinically relevant.

“The effect on individual symptoms is probably too small to be clinically relevant.”

• AssumptionRests on an assumption: The common cold is a short, acute, benign condition.

Most combinations containing decongestants reduced nasal obstruction.

“Most combinations containing decongestants reduced nasal obstruction”

A review by the FDA identified 123 deaths related to the use of cough or cold products in children under six years of age over the past few decades.

“and a review by the FDA identified 123 deaths related to the use of such products in children under six years of age over the past few decades (Sharfstein 2007).”

• cites Sharfstein 2007 sourceNot checked — no full text of the source

The lack of reported methodological rigour data in older trials does not pose a threat to the validity of the meta-analysis.

“therefore we believe this does not pose a threat to the validity of the meta‐analysis.”

In 2005 the US Food and Drug Administration issued a warning for OTC nasal preparations containing phenylpropanolamine because of the increased risk of intracranial bleeding.

“in 2005 the US Food and Drug Administration (FDA) issued a warning for OTC nasal preparations containing phenylpropanolamine because of the increased risk of intracranial bleeding (FDA 2005).”

• cites FDA 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

There may be some effect of the combinations on rhinorrhoea.

“and there may be some effect on rhinorrhoea.”

The results of this systematic review seem generalisable.

“The results of this systematic review therefore seem generalisable.”

It is unclear whether the treatment benefits justify the cost of adverse effects.

“It is unclear whether the treatment benefits justify this cost of adverse effects.”

It is unclear whether antihistamine-analgesic-decongestant combinations have some additional effect on cough, since in the trials with some effect, the active treatment also contained an antitussive.

“It is unclear whether antihistamine‐analgesic‐decongestant combinations have some additional effect on cough, since in the trials with some effect, the active treatment also contained an antitussive.”

When the size of the effect was reported, it was invariably small (less than one point on a four- or five-point severity scale).

“However, when the size of the effect was reported (which was rarely the case), it was invariably small (less that one point on a four‐ or five‐point severity scale).”

In Koytchev 2003, the risk of bias for blinding was high.

“Blinding (performance bias and detection bias) All outcomes High risk”

For Middleton 1981, selective reporting was judged at high risk of reporting bias because not all prespecified outcomes in the trial protocol were reported.

“Selective reporting (reporting bias) High risk Not all prespecified outcomes in trial protocol were reported (reporting bias). “No side effects were reported””

Blinding in the included study was at low risk of bias because active and placebo tablets were packaged in the same manner and were identical in appearance and taste.

“Active and placebo tablets were packaged in the same manner and were identical in appearance and taste.”

Incomplete outcome data in the included study was at low risk of bias because follow-up was for 52 of 53 included participants.

“Follow‐up for 52 of 53 included participants”

Random sequence generation in the included study was at low risk of bias because participants were assigned randomisation numbers in ascending numerical order, with treatment assignment based on a randomisation schedule provided by the study sponsor.

“Enrolled participants were assigned randomisation numbers in ascending numerical order, with treatment assignment based on a randomisation schedule provided by the study sponsor.”