The anticholinergic perennial rhinitis John W. Georgitis,
treatment
of allergic
MD Winston-Salem, N.C
Anticholinergic agents have been used for nonallergic rhinitis expressly to control rhinorrheu In allergic rhinitis, rhinorrhea can be extremely troublesome and unresponsive to traditional pharmacotherapeutic rhinitis treatments. Anticholinergic agents, through their specific ability to decrease nasal secretory response, should have benejkial effects for allergic rhinitis. In a recent trial ipratropium bromide at concentrations of 0.03% and 0.06% reduced rhinorrhea in allergic subjects without any demonstrable rebound effect. Therefore anticholinergic therapies may be TV useful adjunct in controlling the rhinorrhea associated with allergic rhinitis. (J tiLLERcrY Ci,:r,i.v IMMUNOL 1992;90:1071-6.) Key words: Rhinitis, allergic, perennial, ipratropium bromide
Allergic rhinitis is brought to the physician’s attention more often than rhinitis that develops from nonallergic conditions.’ This is reasonablebecauseinfectious rhinitis, such as that causedby a common cold, is commonly recognized as a self-limiting condition for which only moderatesymptomatic relief is available. Allergic rhinitis, however, is more often perceived as a recurrent or chronic condition that merits more definitive evaluation and treatment with a hope of successful therapeutic intervention. Because the common view of allergic rhinitis among practitioners and patientsalike is that “something can be done about it,” it is appropriateto investigate available treatments to characterizetheir potential benefits and risks with a view toward integrating them into routine practice. Symptomsof perennial allergic rhinitis include serous or seromucous hypersecretion, nasal blockage caused by swollen mucosa, and repetitive sneezing. The prominent hypersecretionis producedby the nasal submucous glands, which have parasympathetic innervation; thus this condition is associatedwith parasympathetic hyperactivity.2 Because anticholinergic agents such as ipratropium bromide are known to be effective parasympatholytic agents,’ it appearedlikely that anticholinergic agents would alleviate the hypersecretory rhinorrhea associatedwith perennial allergic rhinitis. From Bowman Gray School of Medicine. Reprint requests: John W. Georgitis, MD, Department of Pediatrics, Bowman Gray School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. 1 /O/42011
Abbreviation used
IB: Ipratropiumbromide
PH ALLEffiM:
kW?APY FOR Rf4wVmS
For years pharmacologic treatment of allergic rhinitis has been primarily based on the use of antihistamines and sympathomimetics.3-6These ageMscontrol the acute symptoms of rhinitis, especially the sneezing, itching, and nasal blockage. However, in perennial allergic rhinitis the acute symptomsquickly evolve into chronic sneezing, rhinorrhea. congestion, and itching. Antihistamines and sympathomimetics are still effective, but additional pharmacologicagents are neededby the patients. Corticosteroidseffectively block the late-phaseresponseand nasalinflammation. but allergic subjectscontinue to report nagging symptoms. Cromolyn sodium blocks the early and late response,but as with corticosteroids, rhinitis symptoms often remain. immunotherapy is an effective longterm therapy for allergic rhinitis even though its efficacy has been questioned. Short-term treatment of allergic rhinitis continues to be a mainstay goal of pharmacotherapyfor allergic rhinitis. Treatment aimed at single symptomsof rhinitis has merit but lacks extensive clinical investigations. Antihistamines are believed to be histamine receptor antagonists, but some noted antihistamines such as hydroxyzine have associative anticholinergic activity. Sympathomimeticsalso have a suspectedsin1071
J ALLERGY
1072 Georgitis
TABLE I. Demographic Regimen
Placebo 21 pg IB 42 pg IB Total
characteristics N
53 48 54
1.55
CLIN IMMUNOL DECEMBER 1992
of study participants Sex (M/F)
19134 19129 22132 60195
gular action by reducing the vascular congestion in the nasal mucosa. However, the phenomenon of rebound congestion from topical sympathomimetics limits the efficacy of these agents. Anticholinergic agents may have a use in controlling the excessive rhinorrhea of allergic rhinitis. This is predicated on the assumption that the nasal secretory response is primarily caused by cholinergic receptor stimulation. Clinical studies that use anticholinergic agents in large numbers of allergic subjects, however, have been lacking until recently. Cholinergic stimulation obviously occurs in allergic rhinitis, but the actual contribution to symptoms is difficult to ascertain in this condition. Studies of cholinergic activation and anticholinergic agents have primarily focused on nonallergic rhinitis. Despite the relative commonality of allergic rhinitis, use of anticholinergic medications in this disorder has been tested in small numbers of subjects with little variation in concentrations of the medications. Before anticholinergic agents are widely used to treat allergic rhinitis, demonstration of excessive cholinergic stimulation on the nasal allergic response is needed.
STUDIES OF ALLERGIC RHINITIS SUBJECTS Recent investigations have focused on the percentage and responsiveness of cholinergic responses in the nasal mucosa. Van Megan et al.’ compared allergic subjects with nonallergic subjects and healthy volunteers as controls. They found decreased receptor densities and dissociation constants in allergic mucosa compared with nonallergic and normal tissues. However, there was no difference in agonist binding between the tissues. Thus the nasal mucosa of a person who has allergic rhinitis appears to have lower numbers of cholinergic receptors, but the responsiveness of the receptors is the same in allergic, nonallergic, and normal nasal tissue. In nasal provocation studies of allergic rhinitis, cholinergic agents such as methacholine given topically induce nasal secretions without changing protein ratios. Meredith et al.’ in a study of 22 subjects found that methacholine nasal provocation increased total secretions of IgG, albumin, nonsecretory IgA, and
Mean age (yr)
33.1 33.8 32.5 33.1
Mean weight
(lb)
151.4 166.6 159.6 158.9
secretory IgA, whereas the proportions of these products to total protein did not alter. This demonstrated
that cholinergic stimulation increases nasal secretory response with little vascular contribution. Pretreatment with topical atropine decreased the secretion of these proteins by the nasal mucosa. Cholinergic stimulation also clearly affects nasal airflow, and anticholinergic agents may thus alter the nasal airflow changes that occur in allergic rhinitis. Devillier et al9 showed that methacholine in concentrations of 3 to 12 PmollL induced a dose-dependent increase in nasal airway resistance in both 17 allergic subjects and 14 healthy subjects similar to the dosedependent increase with substance P nasal provocation. The addition of 200 kg of oxytropium bromide blocked the dose-dependent increase in nasal airway resistance to methacholine but had little effect on the substance P increase in nasal airway resistance. Therefore anticholinergic agents may be beneficial in treating the symptom of nasal obstruction of allergic rhinitis.
OUR MULTICENTERED STUDY OF IB IN ALLERGIC RHINITIS Accordingly, in a recent study we compared the safety and efficacy of two dosages of IB nasal spray (21 and 42 pg per nostril three times a day) with placebo in patients who had perennial allergic rhinitis. The IB trial involved patients who had symptoms of allergic rhinitis of 6 to 9 months’ duration (Table I). Participants were between 18 and 75 years of age. Women had to either be of non-childbearing potential or use appropriate methods of contraception. Additional criteria included positive results of causally related allergic skin tests and normal radiographic appearance of the sinuses. Clinically significant symptoms of nasal hypersecretion had to occur for at least 1 hour daily during 4 of 7 days of the month preceding study entry and for 2 to 3 weeks per month during 6 months of the year. Symptoms had to be greater than mild. The distribution of symptoms among the participants before the study is shown in Figs. 1 and 2.
VOLUME NUMBER
30 6. PART 2
Anticholinergic
treatment
allergic
perennial
rlxnitis
1073
DtSTRiBUTtON OF RHtNORRHEA SEVERtTY Number of Patients
0.00 0.33 0.07 1.00 1.33 1.67 2.00 2.33 2.67 3.00 3.33 3.67 4.00 4.33 Severity Categofy FIG. 1. Prestudy
distribution
MSTRIBUTlON
of symptoms,
by severity,
among
study participants.
RWEA
OF THE DURATION OF
Percent 30
treatment
of allergic
MD Winston-Salem, N.C
Anticholinergic agents have been used for nonallergic rhinitis expressly to control rhinorrheu In allergic rhinitis, rhinorrhea can be extremely troublesome and unresponsive to traditional pharmacotherapeutic rhinitis treatments. Anticholinergic agents, through their specific ability to decrease nasal secretory response, should have benejkial effects for allergic rhinitis. In a recent trial ipratropium bromide at concentrations of 0.03% and 0.06% reduced rhinorrhea in allergic subjects without any demonstrable rebound effect. Therefore anticholinergic therapies may be TV useful adjunct in controlling the rhinorrhea associated with allergic rhinitis. (J tiLLERcrY Ci,:r,i.v IMMUNOL 1992;90:1071-6.) Key words: Rhinitis, allergic, perennial, ipratropium bromide
Allergic rhinitis is brought to the physician’s attention more often than rhinitis that develops from nonallergic conditions.’ This is reasonablebecauseinfectious rhinitis, such as that causedby a common cold, is commonly recognized as a self-limiting condition for which only moderatesymptomatic relief is available. Allergic rhinitis, however, is more often perceived as a recurrent or chronic condition that merits more definitive evaluation and treatment with a hope of successful therapeutic intervention. Because the common view of allergic rhinitis among practitioners and patientsalike is that “something can be done about it,” it is appropriateto investigate available treatments to characterizetheir potential benefits and risks with a view toward integrating them into routine practice. Symptomsof perennial allergic rhinitis include serous or seromucous hypersecretion, nasal blockage caused by swollen mucosa, and repetitive sneezing. The prominent hypersecretionis producedby the nasal submucous glands, which have parasympathetic innervation; thus this condition is associatedwith parasympathetic hyperactivity.2 Because anticholinergic agents such as ipratropium bromide are known to be effective parasympatholytic agents,’ it appearedlikely that anticholinergic agents would alleviate the hypersecretory rhinorrhea associatedwith perennial allergic rhinitis. From Bowman Gray School of Medicine. Reprint requests: John W. Georgitis, MD, Department of Pediatrics, Bowman Gray School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. 1 /O/42011
Abbreviation used
IB: Ipratropiumbromide
PH ALLEffiM:
kW?APY FOR Rf4wVmS
For years pharmacologic treatment of allergic rhinitis has been primarily based on the use of antihistamines and sympathomimetics.3-6These ageMscontrol the acute symptoms of rhinitis, especially the sneezing, itching, and nasal blockage. However, in perennial allergic rhinitis the acute symptomsquickly evolve into chronic sneezing, rhinorrhea. congestion, and itching. Antihistamines and sympathomimetics are still effective, but additional pharmacologicagents are neededby the patients. Corticosteroidseffectively block the late-phaseresponseand nasalinflammation. but allergic subjectscontinue to report nagging symptoms. Cromolyn sodium blocks the early and late response,but as with corticosteroids, rhinitis symptoms often remain. immunotherapy is an effective longterm therapy for allergic rhinitis even though its efficacy has been questioned. Short-term treatment of allergic rhinitis continues to be a mainstay goal of pharmacotherapyfor allergic rhinitis. Treatment aimed at single symptomsof rhinitis has merit but lacks extensive clinical investigations. Antihistamines are believed to be histamine receptor antagonists, but some noted antihistamines such as hydroxyzine have associative anticholinergic activity. Sympathomimeticsalso have a suspectedsin1071
J ALLERGY
1072 Georgitis
TABLE I. Demographic Regimen
Placebo 21 pg IB 42 pg IB Total
characteristics N
53 48 54
1.55
CLIN IMMUNOL DECEMBER 1992
of study participants Sex (M/F)
19134 19129 22132 60195
gular action by reducing the vascular congestion in the nasal mucosa. However, the phenomenon of rebound congestion from topical sympathomimetics limits the efficacy of these agents. Anticholinergic agents may have a use in controlling the excessive rhinorrhea of allergic rhinitis. This is predicated on the assumption that the nasal secretory response is primarily caused by cholinergic receptor stimulation. Clinical studies that use anticholinergic agents in large numbers of allergic subjects, however, have been lacking until recently. Cholinergic stimulation obviously occurs in allergic rhinitis, but the actual contribution to symptoms is difficult to ascertain in this condition. Studies of cholinergic activation and anticholinergic agents have primarily focused on nonallergic rhinitis. Despite the relative commonality of allergic rhinitis, use of anticholinergic medications in this disorder has been tested in small numbers of subjects with little variation in concentrations of the medications. Before anticholinergic agents are widely used to treat allergic rhinitis, demonstration of excessive cholinergic stimulation on the nasal allergic response is needed.
STUDIES OF ALLERGIC RHINITIS SUBJECTS Recent investigations have focused on the percentage and responsiveness of cholinergic responses in the nasal mucosa. Van Megan et al.’ compared allergic subjects with nonallergic subjects and healthy volunteers as controls. They found decreased receptor densities and dissociation constants in allergic mucosa compared with nonallergic and normal tissues. However, there was no difference in agonist binding between the tissues. Thus the nasal mucosa of a person who has allergic rhinitis appears to have lower numbers of cholinergic receptors, but the responsiveness of the receptors is the same in allergic, nonallergic, and normal nasal tissue. In nasal provocation studies of allergic rhinitis, cholinergic agents such as methacholine given topically induce nasal secretions without changing protein ratios. Meredith et al.’ in a study of 22 subjects found that methacholine nasal provocation increased total secretions of IgG, albumin, nonsecretory IgA, and
Mean age (yr)
33.1 33.8 32.5 33.1
Mean weight
(lb)
151.4 166.6 159.6 158.9
secretory IgA, whereas the proportions of these products to total protein did not alter. This demonstrated
that cholinergic stimulation increases nasal secretory response with little vascular contribution. Pretreatment with topical atropine decreased the secretion of these proteins by the nasal mucosa. Cholinergic stimulation also clearly affects nasal airflow, and anticholinergic agents may thus alter the nasal airflow changes that occur in allergic rhinitis. Devillier et al9 showed that methacholine in concentrations of 3 to 12 PmollL induced a dose-dependent increase in nasal airway resistance in both 17 allergic subjects and 14 healthy subjects similar to the dosedependent increase with substance P nasal provocation. The addition of 200 kg of oxytropium bromide blocked the dose-dependent increase in nasal airway resistance to methacholine but had little effect on the substance P increase in nasal airway resistance. Therefore anticholinergic agents may be beneficial in treating the symptom of nasal obstruction of allergic rhinitis.
OUR MULTICENTERED STUDY OF IB IN ALLERGIC RHINITIS Accordingly, in a recent study we compared the safety and efficacy of two dosages of IB nasal spray (21 and 42 pg per nostril three times a day) with placebo in patients who had perennial allergic rhinitis. The IB trial involved patients who had symptoms of allergic rhinitis of 6 to 9 months’ duration (Table I). Participants were between 18 and 75 years of age. Women had to either be of non-childbearing potential or use appropriate methods of contraception. Additional criteria included positive results of causally related allergic skin tests and normal radiographic appearance of the sinuses. Clinically significant symptoms of nasal hypersecretion had to occur for at least 1 hour daily during 4 of 7 days of the month preceding study entry and for 2 to 3 weeks per month during 6 months of the year. Symptoms had to be greater than mild. The distribution of symptoms among the participants before the study is shown in Figs. 1 and 2.
VOLUME NUMBER
30 6. PART 2
Anticholinergic
treatment
allergic
perennial
rlxnitis
1073
DtSTRiBUTtON OF RHtNORRHEA SEVERtTY Number of Patients
0.00 0.33 0.07 1.00 1.33 1.67 2.00 2.33 2.67 3.00 3.33 3.67 4.00 4.33 Severity Categofy FIG. 1. Prestudy
distribution
MSTRIBUTlON
of symptoms,
by severity,
among
study participants.
RWEA
OF THE DURATION OF
Percent 30
