Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Intranasal ipratropium bromide reduced rhinorrhea and improved cold symptoms

ACP J Club. 1996 Nov-Dec;125:73. doi:10.7326/ACPJC-1996-125-3-073


Source Citation

Hayden FG, Diamond L, Wood PB, Korts DC, Wecker MT. Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1996 Jul 15;125:89-97.


Abstract

Objective

To determine whether intranasal ipratropium bromide is effective and safe for reducing common cold symptoms.

Design

6-day, randomized, double-blind, placebo-controlled trial.

Setting

3 U.S. university health services.

Patients

411 adults (mean age 22 y, 91% white) with at least moderate rhinorrhea and documented nasal discharge (for < 36 hours) associated with a cold. Exclusion criteria included asthma, chronic respiratory disease, allergic rhinitis, fever, or probable bacterial infection.

Intervention

Patients were allocated to nasal spray with ipratropium bromide, 0.06% in a buffered salt solution (2 sprays/nostril [84 µg] 3 times/d for 4 d) (n = 137), the same nasal spray without ipratropium (n = 137), or no medication (n = 137). No cold medications other than analgesics and antitussives were allowed.

Main outcome measures

The main outcome measure was a global assessment of overall improvement (report by patients of being better or much better). Rhinorrhea was monitored in the clinic hourly for the first 6 hours on day 1 and hourly for 3 hours on day 2. Symptoms were monitored for 4 days.

Main results

Analysis was by intention to treat. Ipratropium reduced rhinorrhea (P ≤ 0.01), weight of nasal discharge (P < 0.001), and sneezing (P < 0.05) but not nasal congestion. Overall improvement was reported at day 1 in 87% of the ipratropium group, 73% of the placebo group, and 57% of the untreated group. At day 5, 81% of the ipratropium group, 65% of the placebo group, and 18% of the untreated group reported overall improvement (P = 0.003). {This 17% absolute difference in improvement between the ipratropium and placebo groups means that 6 patients (95% CI, 4 to 16) would need to be treated with ipratropium (rather than placebo) for 4 days to result in improvement for 1 additional patient; the relative risk improvement was 26%, CI 9% to 47%* }. Rates of nasal dryness (12% vs 4%), blood-tinged mucus (17% vs 4%), and headache (9% vs 2%) were greater in the ipratropium group than in the placebo group.

Conclusion

Patients who used nasal sprays that contained ipratropium bromide reported improved cold symptoms and less rhinorrhea but had more adverse effects than did patients who received placebo or no treatment.

Source of funding: Boehringer Ingelheim Pharmaceutical, Inc.

For article reprint: Dr. F.G. Hayden, Box 473, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.

*Numbers calculated from data in article.


Commentary

Zinc lozenges reduced the duration of common cold symptoms

A cure for the common cold is not yet at hand, but these 2 randomized controlled trials indicate that some relief is available. Mossad and colleagues showed that, if started within 24 hours of onset, zinc gluconate lozenges can shorten the duration of cold symptoms, whereas Hayden and colleagues found that ipratropium nasal spray can reduce rhinorrhea. The patients enrolled in each of these studies were similar to patients with viral upper respiratory tract infections commonly seen in medical practice. The ipratropium study excluded patients with fever (body temperature > 39 °C), allergies, asthma, or bronchitis; the zinc study excluded only patients who were pregnant or had known immune deficiency. Each study used a placebo group, and the ipratropium study used a "no treatment" group as well. The metallic taste of zinc could have made blinding difficult. However, Mossad and colleagues showed that only about half the patients correctly guessed whether they were taking zinc lozenges or placebo, and the participants in the zinc group did not stop treatment prematurely because of side effects. Hayden and colleagues also used objective measures of rhinorrhea (weight of nasal discharge). In each study, the patients who received active treatment had baseline characteristics that were similar to those of the patients who received placebo, compliance was good, follow-up was nearly complete, and patients were appropriately analyzed in the group to which they were assigned (i.e., intention-to-treat analysis). Thus, the studies rate high marks for basic research methods.

In the ipratropium study, patients had cold symptoms and at least moderate rhinorrhea for ≤ 36 hours; therefore, the conclusions of the study are applicable to patients in the rhinorrheal stage of a cold. Ipratropium nasal spray reduced rhinorrhea and sneezing but not nasal congestion. It would have been helpful if Hayden and colleagues had specifically asked the patients about other common cold symptoms, such as malaise, sore throat, and coughing. Because malaise and sore throat usually precede rhinorrhea, the global improvement that Hayden and colleagues described probably refers primarily to reduced rhinorrhea.

The adverse effects of anticholinergic medications are well known, and Hayden and colleagues were remiss for not asking study participants about the specific expected side effects of ipratropium nasal spray. It is likely that they underestimated the prevalence of the adverse effects of ipratropium because they simply recorded them as they were spontaneously reported. On the other hand, Mossad and colleagues used both an open-ended question and categorical responses to identify the specific side effects of the zinc lozenges. Not surprisingly, patients reported more side effects when asked specifically about adverse effects of the zinc lozenges than when asked to respond to an open-ended question.

Compared with the placebo group, patients using this particular zinc gluconate-glycine complex had fewer days with cough, headaches, hoarseness, throat symptoms, nasal congestion, and nasal drainage. Previous clinical trials of zinc lozenges in the treatment of the common cold have shown conflicting results, which may be partly attributable to the different formulations and doses used in the various studies. One other study (1) that used the same formulation showed similar results, but it would be more convincing to see the results replicated in other settings.

The benefits of zinc lozenges and ipratropium nasal spray are clinically important but are tempered by their adverse effects (unpleasant taste and nausea with zinc lozenges and nasal drying with ipratropium nasal spray). We do not know what the economic and epidemiologic effects of these treatments will be. Will they reduce work and school absenteeism or complications of colds? Will they affect transmission of cold viruses?

Ipratropium nasal inhalers for treating cold symptoms are now available by prescription at local pharmacies in the United States. 1 of 2 local health-food stores that I called stocked the zinc gluconate lozenges.

What do we tell our patients? If asked, I will tell mine that one particular formulation of zinc lozenges (but perhaps not other preparations) reduced the duration of colds by nearly half when they were started within 24 hours of the onset of symptoms; 5 lozenges should be dissolved in the mouth daily until symptoms resolve. To reduce the sneezing and rhinorrhea associated with the common cold, ipratropium nasal spray can be used, but patients should be told to titrate the number of sprays to prevent excessive nasal drying.

Peter S. Millard, MD, PhD
Eastern Maine Medical CenterBangor, Maine, USA


Reference

1. Godfrey J, Conant Sloane B, Smith DS, et al. Zinc gluconate and the common cold: a controlled clinical study. J Intern Med Res. 1992;20:234-46.