Oral antihistamine-decongestant-analgesic combinations for the common cold

Review question

Are combination formulas containing antihistamines (AH), decongestants (DC), and/or analgesics (AN), sold over-the-counter, effective in treating the symptoms of the common cold?


On average, young children have six to eight colds per year, and adults have two to four. The common cold is caused by viruses, and symptoms include sore throat, nasal stuffiness and discharge, sneezing, and cough. The common cold usually resolves by itself within one to two weeks; however, it has a large impact on time off work or school.

As there is no cure for the common cold, only symptomatic treatment is available. Several treatments are needed to tackle the variety of symptoms, therefore different products are combined in one pill: antihistamines against sneezing, cough, and nasal discharge; decongestants against nasal stuffiness; and analgesics against sore throat.

Search date

The evidence is current to 10 June 2021.

Study characteristics

Study participants were adults or children with the common cold. The effects of four combinations (AH + DC; AH + AN; AN + DC; AH + AN + DC) were compared to those of placebo (dummy treatment) (24 trials) or an active substance (6 trials). A beneficial effect was defined as a decrease in severity or duration of overall symptoms or of specific symptoms such as stuffy nose, runny nose, cough, or sneezing. We also investigated whether side effects were more common with the combination treatments than with placebo.

Study funding sources

Only three studies reported independent financing.

Key results

We identified three new three new trials (1038 participants) in this 2021 update, bringing the total number of included trials to 30 (6304 participants). The evidence suggests that all combinations have some beneficial effect on overall symptoms of the common cold in adults and older children. There was no effect in younger children. The AH + DC and DC + AN combinations result in more side effects than placebo; however, there was no difference between groups in side effects for the other combinations. In 2005, the US Food and Drug Administration issued a warning about adverse effects associated with the use of over-the-counter nasal preparations containing phenylpropanolamine.

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

Authors' conclusions: 

We found a lack of data on the effectiveness of antihistamine-analgesic-decongestant combinations for the common cold. Based on these scarce data, the effect on individual symptoms is probably too small to be clinically relevant. The current evidence suggests that antihistamine-analgesic-decongestant combinations have some general benefit in adults and older children. These benefits must be weighed against the risk of adverse effects. There is no evidence of effectiveness in young children. In 2005, the US Food and Drug Administration issued a warning about adverse effects associated with the use of over-the-counter nasal preparations containing phenylpropanolamine.

Read the full abstract...

Although combination formulas containing antihistamines, decongestants, and/or analgesics are sold over-the-counter in large quantities for the common cold, the evidence for their effectiveness is limited. This is an update of a review first published in 2012.


To assess the effectiveness of antihistamine-decongestant-analgesic combinations compared with placebo or other active controls (excluding antibiotics) in reducing the duration of symptoms and alleviating symptoms (general feeling of illness, nasal congestion, rhinorrhoea, sneezing, and cough) in children and adults with the common cold.

Search strategy: 

We searched CENTRAL, MEDLINE via EBSCOhost, Embase, CINAHL via EBSCOhost, LILACS, and Web of Science to 10 June 2021. We searched the WHO ICTRP and ClinicalTrials.gov on 10 June 2021.

Selection criteria: 

Randomised controlled trials investigating the effectiveness of antihistamine-decongestant-analgesic combinations compared with placebo, other active treatment (excluding antibiotics), or no treatment in children and adults with the common cold.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. We categorised the included trials according to the active ingredients.

Main results: 

We identified 30 studies (6304 participants) including 31 treatment comparisons. The control intervention was placebo in 26 trials and an active substance (paracetamol, chlorphenindione + phenylpropanolamine + belladonna, diphenhydramine) in six trials (two trials had placebo as well as active treatment arms). Reporting of methods was generally poor, and there were large differences in study design, participants, interventions, and outcomes. Most of the included trials involved adult participants. Children were included in nine trials. Three trials included very young children (from six months to five years), and five trials included children aged 2 to 16. One trial included adults and children aged 12 years or older. The trials took place in different settings: university clinics, paediatric departments, family medicine departments, and general practice surgeries. 

Antihistamine-decongestant: 14 trials (1298 participants). Eight trials reported on global effectiveness, of which six studies were pooled (281 participants on active treatment and 284 participants on placebo). The odds ratio (OR) of treatment failure was 0.31 (95% confidence interval (CI) 0.20 to 0.48; moderate certainty evidence); number needed to treat for an additional beneficial outcome (NNTB) 3.9 (95% CI 3.03 to 5.2). 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. Of the two trials not pooled, one showed some global effect, whilst the other showed no effect.

Adverse effects: 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).

Antihistamine-analgesic: four trials (1608 participants). Two trials reported on global effectiveness; data from one trial were presented (290 participants on active treatment and 292 participants on ascorbic acid). The OR of treatment failure was 0.33 (95% CI 0.23 to 0.46; moderate certainty evidence); NNTB 6.67 (95% CI 4.76 to 12.5). Forty-three per cent of participants in the control group and 70% in the active treatment group were cured after six days of treatment. The second trial also showed an effect in favour of the active treatment.

Adverse effects: 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).

Analgesic-decongestant: seven trials (2575 participants). 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) (OR of treatment failure 0.28, 95% CI 0.15 to 0.52; moderate certainty evidence; NNTB 4.7).

Adverse effects: 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). 

Antihistamine-analgesic-decongestant: six trials (1014 participants). Five trials reported on global effectiveness, of which two studies in adults could be pooled: 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; the OR of treatment failure was 0.47 (95% CI 0.33 to 0.67; low certainty evidence); NNTB 5.6 (95% CI 3.8 to 10.2). One trial in children aged 2 to 12 years, and two trials in adults found no beneficial effect.

Adverse effects: in one trial 5/224 (2%) suffered adverse effects with the active treatment versus 9/208 (4%) with placebo. Two other trials reported no differences between treatment groups.