The rhinorrhea associated with common colds is multifactorial and involves both transudation of plasma proteins and increased secretion by the submucosal glands of the nose [6]; secretion by the submucosal glands increases after the intranasal application of cholinergic agents [7] and through parasympathetic nervous system reflex mechanisms. The intranasal administration of anticholinergic agents, particularly ipratropium bromide and atropine methonitrate, has been associated with reduced nasal mucus production during experimentally induced rhinovirus colds [8-10]. In addition, methacholine-induced rhinorrhea can be prevented by the topical application of ipratropium [11] or atropine [12].

Initial clinical trials [13, 14] found that intranasal sprays of ipratropium bromide (84 µg per nostril three or four times daily) also reduced the rhinorrhea associated with naturally occurring colds. However, excessive drying related to the topical application of anticholinergic agents may worsen certain symptoms, such as nasal obstruction, without providing an overall clinical benefit. Consequently, we did this study to determine the efficacy and tolerability of intranasal ipratropium bromide for the treatment of common colds with regard to the effect of this therapy on the patient's overall perception of well-being and on subjective and objective measures of rhinorrhea.

Methods

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Study Design

This was a multicenter, double-blind, randomized, placebo-controlled trial. For the purposes of comparison, it incorporated a group of untreated patients that was monitored in the same way as the ipratropium and control groups. The trial involved 411 persons who had self-diagnosed common colds and were enrolled at one of three study centers. To avoid the autumn and spring allergy seasons, patients were enrolled between 1 November 1993 and 29 March 1994.

Study Participants

Patients were recruited by advertisement and were compensated for participation. Male and female patients 12 to 70 years of age who had had rhinorrhea associated with a common cold for no more than 36 hours were eligible. The rhinorrhea had to be scored as at least moderate in severity (a score of 5 or more on a visual analogue scale), and the severity had to be confirmed by the recovery of at least 1.5 g of nasal discharge over a 1-hour baseline observation period. For each participant, a medical history was taken and nasal and limited physical assessments, which included measurement of vital signs, were done at the time of study entry.

Persons with a history of asthma or chronic respiratory disease, allergic or perennial rhinitis, nasal polyps, seasonal allergic rhinitis with allergen in season, or frequent complications associated with upper respiratory infections (such as sinusitis or bronchitis) were excluded, as were pregnant and lactating women. Patients with a positive result on a streptococcal antigen screening test (Q-Test-Strep, Becton-Dickinson, Cockeysville, Maryland), signs of lower respiratory tract disease, or an oral temperature greater than 102 °F were also excluded from participation. Written informed consent was obtained from each patient in a form approved by the institutional review board of each study institution.

Treatment Administration

Patients who met the entrance criteria were randomly assigned by a computer-generated randomization sequence to one of three groups: that receiving ipratropium bromide nasal spray 0.06% in a buffered salt solution (two sprays per nostril, administered with a metered pump spray bottle designed to deliver a total dose of 84 µg per nostril); that receiving control nasal spray, which contained the same excipients as the ipratropium bromide spray but did not contain ipratropium bromide; or that receiving no treatment. The patients were instructed to clear their noses and administer two sprays in each nostril three times daily for 4 days at equally spaced intervals during waking hours. The protocol allowed patients to use their medication four times daily if rhinorrhea was not adequately controlled or fewer than three times daily if nasal dryness occurred.

The patients were consecutively enrolled at each study center, and randomization was done in blocks of six. The treatments were administered under double-blind conditions; the untreated group was not blinded. The ipratropium and control spray bottles were identical in appearance. To minimize unintentional bias in assigning patients to receive no treatment, empty bottles were used as place holders for these patients. The bottles were placed in sequence with the filled bottles and were labeled "Do Not Dispense to Patient."

Throughout the study, patients were instructed to take no other medications (such as antihistamines, decongestants, nasal decongestants or steroids, or saline nose drops) to relieve their nasal symptoms. Analgesics (including acetaminophen, aspirin, and ibuprofen) and antitussives (Robitussin or Robitussin-DM; A.H. Robbins Co., Richmond, Virginia) were allowed for the relief of disabling symptoms.

Clinical Monitoring

After baseline monitoring and the administration of the first nasal spray treatment, patients remained at the study center for 6 hours. During this period, they provided hourly evaluations of the severity of their rhinorrhea and hourly collections of expelled nasal mucus. A visual analogue scale was used to evaluate symptom severity. This scale ranged from 0 to 10 and included five descriptions of severity: very mild (doubtful, trivial, or just noticeable), mild (present but not uncomfortable), moderate (present and somewhat uncomfortable or annoying), severe (present and definitely uncomfortable or annoying), and unbearable (necessitating additional treatment).

On study day 2, the patients returned to the study center before taking their first dose of medication or at least 4 hours after taking any dose. After receiving ipratropium, control spray, or no treatment, they evaluated the severity of their rhinorrhea and provided expelled nasal mucus every hour for 3 hours.

On the evenings of study days 1 through 4, all patients completed daily symptom record forms evaluating the overall severity of runny nose, nasal congestion, and sneezing for that day. On each of the 2 testing days, the patients were asked a single global question: "Compared to when you came into the clinic this morning, how was your cold over today's testing period?" One of four categorical responses (much better, better, no difference, or worse) was recorded. On study days 3 and 4, the patients continued their treatment on an outpatient basis and then returned to the study center on study day 5 for follow-up examination, collection of study records and spray devices, and completion of final global assessments. On study day 5, patients were asked, "Overall, how do you think being in this study helped your cold?" and "Overall, how was this treatment in the relief of your symptoms?"

Data Analysis

The data for all patients who were randomly assigned to treatment groups and who received at least one dose of their treatment were included in the analysis [410 of 411 patients]. The primary end point used to determine efficacy was the patient's global assessment of overall improvement obtained on study days 1, 2, and 5. Secondary measures of efficacy included 1) quantitation of nasal discharge weights and subjective assessments of rhinorrhea severity on the first 2 study days and 2) assessment of the severity of cold symptoms made using the visual analogue scale on the evening of each of the first 4 study days. The distribution of responses to each global question by study group was assessed. The stratified Wilcoxon test was the primary method of analysis used for the global assessments.

To assess rhinorrhea using the visual analogue scale, we subtracted the hourly scores after treatment from the baseline values and determined the hourly average change from baseline. The end points were the average change from baseline for each of the first two study days and the average change from baseline for the first 3 hours on each of these 2 days combined. These data were analyzed using an analysis of variance that incorporated the centers and treatment-by-center interactions as factors. Baseline nasal mucus weights were used as a covariate in the analysis of discharge weights. The daily visual analogue scale assessments of rhinorrhea, nasal congestion, and sneezing were analyzed in a similar way but without a baseline covariate.

Adverse events were recorded as they occurred, but we did not specifically ask about them. Staff members asked each patient how he or she had felt since the previous visit. Nasal examinations were done and vital signs were obtained on study day 1 and at the final study visit. The sample size for this trial was determined on the basis of global assessments that required the patients to choose one of four ordinal categories (much better, better, no difference, or worse) to describe the amelioration or lack of amelioration of their cold. By comparing the percentage of patients in the ipratropium group who chose either "much better" or "better" with the percentage of patients in the control group who chose these responses, we determined that a sample size of 130 patients per group would be sufficient to detect 20% differences in proportions ranging from 20% versus 40% to 70% versus 90% between the control and ipratropium groups, respectively, with a 90% power or greater ( equals 0.05). The same sample size had a similar power to detect 20% differences in the mean visual analog scale assessments of severity of rhinorrhea ( equals 0.05). Analyses were done using SAS, version 6 (SAS Institute, Cary, North Carolina) and StatXact (Cytel Corp., Cambridge, Massachusetts).

Results

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Patients

Four hundred eleven patients with common colds were enrolled in this trial (123 to 144 patients per center). Only 1 patient was excluded from the intention-to-treat analysis; this was an untreated patient who was disqualified because of a history of frequent complications during upper respiratory infections. The demographic characteristics and illness features of the study groups were similar at the time of enrollment (Table 1). Most participants (87%) were between 14 and 24 years of age, and only 5 (1%) were older than 50 years of age.

The only difference between the study groups at the time of enrollment was that the nasal discharge weight over the 1-hour observation period was slightly lower in the controls than in the untreated patients (P = 0.05). Most patients in the ipratropium and control groups (82%) received their study medication as specified by the protocol. The mean duration of treatment was 4 days (range, 2 to 7 days), and no differences in duration were found between the two groups (data not shown). Two ipratropium recipients were lost to follow-up (one on study day 2 and one on study day 5), but all patients completed the first 2 days of the trial and were included in the analysis.

Concomitant medications for cold-related symptoms were used often (Table 1). Analgesics (used by 12% to 22% of patients) or antitussives (used by 4% to 10% of patients) were the drugs most commonly used for symptom relief in all three study groups. Two patients began receiving antibiotic therapy after study enrollment. One patient in the ipratropium group started receiving amoxicillin on study day 4 because of an ear infection, and penicillin was prescribed for another ipratropium recipient on study day 2 because of a non-group A streptococcal pharyngeal infection.

Nasal Symptoms and Rhinorrhea

Over the 6-hour observation period on study day 1, nasal discharge weights in all three groups were reduced from the values obtained during the baseline 1-hour observation period. However, the ipratropium group consistently showed the greatest reduction (Figure 1). On study day 2, ipratropium was better than either no treatment (P 0.0004) or the control spray (P < equals 0.0112) at each hourly observation during the 3 hours after dosing. The mean hourly discharge weights for the first 3 hours of observation on study days 1 and 2 combined were 1.24 g/h for ipratropium recipients, 1.67 g/h for controls, and 1.87 g/h for untreated patients (P = 0.0024 for ipratropium compared with control spray; P < 0.001 for ipratropium compared with no treatment) (Table 2). This indicated an overall reduction in nasal mucus discharge weight of 26% for ipratropium compared with the control spray and of 34% for ipratropium compared with no treatment. When individual study days were analyzed, treatment with ipratropium resulted in hourly mean nasal discharge weights that were 20% to 38% lower than those seen with the control spray (P = 0.0393 on study day 1; P < 0.001 on study day 2) and 32% to 44% lower than those seen with no treatment (P < 0.001 for both study days). In contrast, nasal discharge weights did not differ between the controls and the untreated patients on study day 1 (P = 0.082), study day 2 (P > 0.2), or the combined study days (P = 0.142).

View larger version (16K): [in this window] [in a new window]   Figure 1. Nasal discharge weights (mean ± SE) after intranasal sprays of ipratropium bromide 0.06%, buffered salt solution (control spray), or no treatment in persons with common colds. The hourly mucus discharge weight for the ipratropium recipients was lower than that for the control spray recipients at hour 6 on study day 1 (P = 0.04) and at all three hourly observations on study day 2 (P < 0.001). Ipratropium was also better than no treatment at all hourly observations on study days 1 (P < 0.001) and 2 (P < 0.001).

The subjective assessments of the severity of rhinorrhea also favored ipratropium on study day 1 and study day 2 (Figure 2). Ipratropium was better than either the control spray (P 0.0203) or no treatment (P < 0.001) beginning 1 hour after dose administration and continuing at all remaining evaluation points on study days 1 and 2. The hourly improvement in rhinorrhea severity, determined on the basis of visual analogue scale scores for the first 3 hours of treatment on study days 1 and 2 combined, averaged 3.13 for ipratropium, 2.36 for the control spray, and 1.76 for no treatment (P < 0.001 for ipratropium compared with the control spray and for ipratropium compared with no treatment). Overall, ipratropium was associated with improvement in the rhinorrhea severity score that was 33% better than the improvement seen in the control group and 78% greater than the improvement seen in the untreated group on study days 1 and 2. When individual study days were analyzed, treatment with ipratropium resulted in rhinorrhea scores that were 31% lower than those seen with the control spray (P < 0.001 for both days) and 66% to 79% lower than no treatment (P < 0.001 for both days).

View larger version (16K): [in this window] [in a new window]   Figure 2. Rhinorrhea severity scores (mean ± SE) after intranasal sprays of ipratropium bromide 0.06%, buffered salt solution (control spray), or no treatment in persons with common colds. Ipratropium was more effective than the control spray at all hourly observations on study days 1 (P < 0.02) and 2 (P < 0.001). Ipratropium was also better than no treatment at all time points on study days 1 and 2 (P < 0.001).

Rhinorrhea, nasal congestion, and sneezing were assessed in the evening on study days 1 through 4. As shown in Figure 3, these assessments indicated that ipratropium ameliorated rhinorrhea better than did either the control spray (P 0.002) or no treatment (P < 0.001) for each of the four study days. Sneezing severity scores were also reduced more rapidly in the ipratropium group than in the other groups, and they were reduced more than in the control group on study days 2 (20% reduction, P = 0.03) and 4 (30% reduction, P = 0.02). In contrast, resolution of nasal congestion did not differ in the ipratropium and the control groups (P > 0.2). Both ipratropium and the control spray were superior to no treatment in reducing the severity of nasal congestion and sneezing on each study day.

View larger version (18K): [in this window] [in a new window]   Figure 3. Daily scores for rhinorrhea, nasal congestion, and sneezing. Rhinorrhea differed in the ipratropium group and the control group for each of study days 1 through 4; the ipratropium recipients also had lower scores for sneezing on study days 2 and 4. Both the ipratropium and the control spray differed from no treatment for rhinorrhea, nasal congestion, and sneezing on most study days. * P < 0.01; P < 0.05.

Global Assessments

To determine the patients' overall assessments of treatment benefit, we asked each patient how the day's participation had made them feel on study days 1 and 2. As shown in Table 3, the ipratropium recipients gave consistently higher ratings on both days than did the other two groups. On study day 1, 87% of ipratropium recipients, 73% of controls, and 57% of the untreated patients rated their condition as much better or better (P = 0.004 for ipratropium compared with control spray; P < 0.001 for ipratropium compared with no treatment [Mantel-Haenszel test]). Differences were also noted on study day 2, at which time 74% of ipratropium recipients, 61% of controls, and 58% of untreated patients indicated that their condition was much better or better (P = 0.015 for ipratropium compared with control spray; P = 0.004 for ipratropium compared with no treatment).

During the last global assessment, on study day 5, patients were asked how participating in the study had helped their colds. Eighty-one percent of ipratropium recipients, 65% of controls, and 18% of untreated patients indicated that they felt much better or better (P = 0.003 for ipratropium compared with control spray; P < 0.001 for ipratropium compared with no treatment). When they were asked to evaluate their treatment for relief of symptoms on the final study day, 88% of ipratropium recipients compared with 74% of controls indicated that their treatment had been very useful or useful (P = 0.002).

Tolerance

Ipratropium was generally well tolerated and was associated with no serious adverse events. However, more patients receiving ipratropium than patients receiving control spray or no treatment reported adverse events, primarily local nasal symptoms. Blood-tinged mucus was reported by 16.8% of ipratropium recipients, 3.6% of controls, and 2.2% of untreated patients (P = 0.0005 for ipratropium compared with control spray; P = 0.0004 for ipratropium compared with no treatment). Nasal dryness was reported by 11.7% of ipratropium recipients, 3.6% of controls, and 0% of untreated patients (P = 0.012 for ipratropium compared with control spray; P = 0.0002 for ipratropium compared with no treatment). Three ipratropium recipients required dose reductions because of local intolerance with nasal irritation. Other local adverse effects (nasal irritation, epistaxis) occurred in fewer than 3% of patients in any group. Headache was reported by 8.8% of ipratropium recipients, 1.5% of controls, and 2.2% of untreated patients (P = 0.011 for ipratropium compared with control spray; P = 0.030 for ipratropium compared with no treatment). No clinically important differences were seen among the groups in nasal examination findings at follow-up (data not shown).

Four patients (three receiving ipratropium and one receiving control spray) reported adverse events that could be considered anticholinergic in nature (dry eyes, dry mouth). There were no other reports of potential systemic anticholinergic effects, such as tachycardia, constipation, urinary retention, or blurred vision, and no treatment-related changes in vital signs were evident when the groups were compared (data not shown).

Discussion

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We found that intranasal ipratropium provided subjective and objective relief of the rhinorrhea associated with common colds and had greater overall clinical effectiveness than either a buffered saline control or no treatment. The reductions in rhinorrhea as judged according to subjective and objective measures, which correlate with each other [15], averaged approximately 30% compared with the control spray over the first 2 days of treatment. In addition, consistent differences in global assessments of overall clinical benefit were found between the group receiving ipratropium and the groups receiving control spray or no treatment. However, the differences between the ipratropium group and the control group, although statistically significant, were relatively modest. As did Dockhorn and colleagues in a previous trial of ipratropium for the treatment of common colds [13], we found that a high proportion of patients receiving the control spray reported subjective improvement in cold symptoms after treatment. This improvement may have been due to several factors, including a beneficial effect of saline nasal spray on the symptoms of the common cold; the well-recognized placebo effect associated with the treatment of colds [1]; and the natural history of common colds, which involves the resolution of symptoms over time. However, it is important to note that the apparent benefit of the control spray that was seen in subjective assessments Figure 3 was not evident in the objective measure of nasal discharge weight.

Our finding that intranasal ipratropium has a beneficial effect in patients with rhinorrhea is consistent with the findings reported in earlier published studies of experimental [9] and natural colds [13, 14, 16]. Recent studies of natural colds found that ipratropium, 84 µg per nostril, was associated with reductions in nasal discharge weights of 23% to 27% compared with the control spray and of 47% compared with no treatment [13, 14]. In our study, amelioration of the severity of rhinorrhea extended over the 4-day study period, as shown by the daily symptom assessments. These findings support the conclusion that cholinergic responses are important in the pathogenesis of rhinorrhea during colds.

It is interesting to note that our ipratropium recipients had significant reductions in sneezing severity compared with our patients receiving the control spray on 2 study days (Figure 3). Although we did not count sneezes, which would have provided an objective measure of sneeze frequency, our results are consistent with the observation that parasympathetic pathways are involved in sneeze production [17]. In this regard, first-generation, sedating antihistamines that possess anticholinergic activity also relieve cold-associated sneezing [18, 19]. In contrast, second-generation, highly selective histamine 1-antihistamines do not provide consistent relief of cold-associated sneezing [20, 21]. These observations support the conclusion that cholinergic mechanisms are partly responsible for sneezing during colds.

In contrast, nasal congestion did not differ between ipratropium recipients and controls. This finding confirms those of previous studies [13, 14] and indicates that the pathogenetic mechanisms responsible for nasal congestion probably differ from those mechanisms that cause rhinorrhea. Our findings also indicate that intranasal ipratropium did not adversely affect nasal congestion.

Previous investigators found that single intranasal doses of ipratropium as great as 400 µg were not associated with any systemic cholinergic signs or symptoms [22]. In one study [14], ipratropium given at a dose twice that used in our study was associated with an increased incidence of anticholinergic symptoms, specifically dry mouth. Ipratropium 0.06%, however, did not cause excess systemic cholinergic effects in either the earlier study [14] or our study, although excessive local drying caused nasal irritation in some recipients. The rates of blood-tinged nasal mucus (17%) and of dryness (12%) were higher in our trial than in two previous studies [13, 14] that reported blood-tinged nasal mucus in 6% to 9% and nasal dryness in 4% to 5% of persons with colds who were treated with ipratropium 0.06%. In our study, headaches tended to be more frequent in ipratropium recipients for unknown reasons. Previous studies of ipratropium [13, 14, 22], including studies of the short-term use of this drug during colds and of the prolonged use of this drug to treat vasomotor and perennial rhinitis, have not found excess rates of headache in ipratropium recipients compared with controls [13, 14, 22]. In addition, headache is a frequent cold-associated symptom; it is present in approximately 70% of patients with natural rhinovirus colds [23]. The low frequency of headache recorded in our study may reflect our passive method of collecting tolerance data. It is also possible that the ipratropium group had more severe illness overall, which would account for the greater incidence of headache seen in that group. In any event, the apparent difference in frequency of headache was not reflected in the global assessments of overall effectiveness.

It is important to consider the limitations of our study. First, most of our patients were young and had no concomitant health problems. We were therefore unable to draw conclusions about the efficacy and safety of intranasal ipratropium in older populations or in populations of persons with underlying illness. However, inhaled forms of ipratropium are being used to treat bronchospastic lung disease. Second, we enrolled patients with colds of undefined viral cause outside of the autumn and spring months, which are periods during which the prevalence of rhinovirus activity is high. Consequently, the illness of our patients was probably due to various viral pathogens, and our findings do not pertain specifically or exclusively to colds caused by rhinoviral infection. Third, the use of concomitant medications, specifically nonsteroidal anti-inflammatory agents and antitussives, tended to be greater in the ipratropium group than in the other two groups. However, the active agents (guaifenesin, dextromethorphan, acetaminophen, ibuprofen, and aspirin) are very unlikely to have influenced our primary end points, rhinorrhea and sneezing, which are targeted by anticholinergic agents. Indeed, at least one study [24] has suggested that acetaminophen or aspirin may actually worsen nasal symptoms during experimental rhinovirus colds, although a subsequent study found that the nonsteroidal drug naproxen alleviated constitutional symptoms and cough without affecting nasal symptoms [25]. Consequently, we do not feel that the use of concomitant medication was an important variable in our trial.

We observed rapid reductions in nasal mucus production Figure 1 and symptom scores Figure 2 after study enrollment in all three study groups. The reasons for these reductions are unknown but may relate to a reduction in cholinergic stimulation indoors; to diurnal variations in cold symptoms, which have been noted in previous studies of cloistered patients [18, 19]; and to the natural history of the common cold. Dosing frequency is another issue. We did not determine how many patients took their study medication three times daily or four times daily. The protocol allowed for flexibility in dosing if treatment did not adequately control symptoms or if excess dryness developed. This dosing regimen is consistent with the currently approved package insert for intranasal ipratropium.

The magnitude of the effects seen in our trial needs to be considered in the context of previous studies of treatment regimens for common colds [1, 26]. Previous trials [27, 28] have found that treatment with pseudoephedrine either alone or in combination with an antihistamine has been associated with significantly higher rates of overall improvement compared with an oral placebo. However, first-generation antihistamines, such as chlorpheniramine, which substantially reduce sneezing and have modest antisecretory effects in common colds, do not provide a significant benefit on global measures of improvement in adults with common colds [18, 19]. Furthermore, first-generation antihistamines are associated with excess sedation [29], and the nonsedating second-generation antihistamines, such as terfenadine, have not consistently ameliorated symptoms in persons with common colds [20, 21]. To our knowledge, the antisecretory effects of intranasal ipratropium and oral antihistamines have not been directly compared, and no information is available to indicate whether treatment of cold symptoms with ipratropium or other agents might reduce the frequency of cold-associated complications, such as sinusitis or otitis.

In summary, our results indicate that the intranasal application of the anticholinergic agent ipratropium bromide can provide specific relief of cold-associated rhinorrhea and sneezing.

Dr. Diamond: University of Colorado School of Pharmacy, Campus Box C-238, 4200 East 9th Avenue, Denver, CO 80262.

Dr. Wood: University of Rhode Island Health Services, Potter Building, Butterfield Road, Kingston, RI 02881.

Drs. Korts and Wecker: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877.