Repeated Methacholine Challenge Produces Tolerance in Normal but Not in Asthmatic Subjects* William S. Beckett, M.D.;t Marjorie E. Marenberg, M.RH.;+ and lbtricia E. lbce§ Repeated methacholine challenge in DOrmai nonasthmatic subjects (who require higher doses of methacholine than do asthmatic subjects to produce a 10 percent decrease in FEV1) can produce progressively diminishing methacholine respoosiveness (or tolerance) with serial challenges. To determine whether tolerance to methacholine occurs in asthmatic subject$ as it does in oonasthmatic subjects, we studied eight young (mean age, 14 years) mild asthmatic patients (occasiooal but DOt regular use of bronchodilator medications, pc. methacholine range 0.1 to 7.0 mglml) who underwent 6ve sequential methacholine challenges at 1.5-h intervals. Serially increasing concentrations of methacholine were given until FEV1 feU by !O percent. Results were compared with those in seven nonastbmatic control
subjects who underwent an identical protocol. As seen in previous studies, the normal subjects demonstrated signi6cant tolerance to methacholine when each of 8ve challenges was compared to the &rst. By contrast, in the asthmatic group, the mean cumulative dose of methacholine producing a 20 percent fall in FEV1 in the 6£tb challenge was not signi6cantly different from the dose required in the 8rst challenge. These results indicate that inarked tolerance to methacholine does not occur in mild asthmatic patients with multiple repeated challenges over 6 h. The lower cumulative dose of methacholine required by asthmatic patients may be insufficient to produce tolerance. (Chat 1992; 102:775-79)
Two applications of methacholine challenge testing have frequently been utilized. In the first, aiIway responsiveness of patients suspected of having asthma is measured to confirm the diagnosis, drawing upon the high degree ofcorrelation between higher responsiveness (greater potency of the drug in producing a response) and the clinical condition asthma. In the second, serial measurements are made to detect changes in aiIway responsiveness induced by external agents such as antigens (ragweed pollen), 1 irritant gases (such as ozone and sulfur dioxide),2 or antiasthmatic drugs. In normal subjects without aiIway disease, use of serial measurements of methacholine responsiveness may be affected by short-term tolerance when more than one measurement is made within a 24-h period. Administration of methacholine in serially increasing doses sufficient to 'produce a 20 percent fall in the FEV. results in a progressive decrease in the response to methacholine on subsequent challenges performed at intervals of 1 or 4 h. With multiple challenges at
high doses of methacholine, a mean eightfold increase in the cumulative administered dose of methacholine required to produce the same 20 percent fall in FEV. was demonstrated in a group of normal subjects. 3 This tolerance is a true drug effect and not due to diurnal variation in aiIway responsiveness, since the magnitude of the tolerance is proportional to the number of challenges performed within a fixed time interval. The tolerance may be physiologically and clinically significant, and ~t is spontaneously reversible within a period of several hours. The occurrence of tolerance may be important to those who use repeated methacholine challenge to assess the effects ofenvironmental exposures on aiIway responsiveness, since it may affect the outcome of s~ch studies. In addition, it may add to the understanding of the control of airway responsiveness. In the present study, we investigated whether adaptation to methacholine occurs in mild asthmatic subjects under circumstances in which tolerance can be demonstrated in nonasthmatic subjects.
*From the De~ents of Internal Medicine and Epidemiology and Public Health, Occupati
subjects who underwent an identical protocol. As seen in previous studies, the normal subjects demonstrated signi6cant tolerance to methacholine when each of 8ve challenges was compared to the &rst. By contrast, in the asthmatic group, the mean cumulative dose of methacholine producing a 20 percent fall in FEV1 in the 6£tb challenge was not signi6cantly different from the dose required in the 8rst challenge. These results indicate that inarked tolerance to methacholine does not occur in mild asthmatic patients with multiple repeated challenges over 6 h. The lower cumulative dose of methacholine required by asthmatic patients may be insufficient to produce tolerance. (Chat 1992; 102:775-79)
Two applications of methacholine challenge testing have frequently been utilized. In the first, aiIway responsiveness of patients suspected of having asthma is measured to confirm the diagnosis, drawing upon the high degree ofcorrelation between higher responsiveness (greater potency of the drug in producing a response) and the clinical condition asthma. In the second, serial measurements are made to detect changes in aiIway responsiveness induced by external agents such as antigens (ragweed pollen), 1 irritant gases (such as ozone and sulfur dioxide),2 or antiasthmatic drugs. In normal subjects without aiIway disease, use of serial measurements of methacholine responsiveness may be affected by short-term tolerance when more than one measurement is made within a 24-h period. Administration of methacholine in serially increasing doses sufficient to 'produce a 20 percent fall in the FEV. results in a progressive decrease in the response to methacholine on subsequent challenges performed at intervals of 1 or 4 h. With multiple challenges at
high doses of methacholine, a mean eightfold increase in the cumulative administered dose of methacholine required to produce the same 20 percent fall in FEV. was demonstrated in a group of normal subjects. 3 This tolerance is a true drug effect and not due to diurnal variation in aiIway responsiveness, since the magnitude of the tolerance is proportional to the number of challenges performed within a fixed time interval. The tolerance may be physiologically and clinically significant, and ~t is spontaneously reversible within a period of several hours. The occurrence of tolerance may be important to those who use repeated methacholine challenge to assess the effects ofenvironmental exposures on aiIway responsiveness, since it may affect the outcome of s~ch studies. In addition, it may add to the understanding of the control of airway responsiveness. In the present study, we investigated whether adaptation to methacholine occurs in mild asthmatic subjects under circumstances in which tolerance can be demonstrated in nonasthmatic subjects.
*From the De~ents of Internal Medicine and Epidemiology and Public Health, Occupati
