Assessment of Tachyphylaxis following Prolonged Therapy of Asthma with Inhaled Albuterol Aerosol

Assessment of Tachyphylaxis following Prolonged Therapy of Asthma with Inhaled Albuterol Aerosol* Lawrrmce H. Repsher, M.D., F.C.C.P.;]ohnA Anderson, M.D.; Hobert K. Bush, M.D.; Constantine J FaUiers, M.D.; lroing Kass, M.D., F.C.C.P.; james P. Kemp, M.D.; Charles Reed, M.D., F.C.C.P.; Sheldon Siegel, M.D .; and D. Hobert Webb, M.D. Controversy exists concerning possible tachyphylaxis of the acute bronc:bodilating effect of albuterol, especlally with regard to the duration of its acute bronchodilating action. We evaluated 140 patients with bronchial. asthma in a prospective double-blind controlled study of possible tachyphyluis to albuterol aerosol as compared to isoproterenol aerosol. We demonstrated statistically significant tachyphyluis with regard to duration of acute bronchodilating effect. We believe that this tachyphyluis is not dinicaUy significant because there was no tachyphyluis with regard to peak bronchodilating effect and because the duration of bron-

chodilating effect remains significantly greater, both quantitatively and statistically, when compared to isoproterenol aerosol. Moreover, it appeared that most of the tachyphylaxis was present at four weeks of therapy. There was a small increment of tachyphylaxis a&er eight weeks of therapy, but no further increase in tachyphylaxis was demonstrated after 13 weeks of inhaled albuterol therapy. We therefore feel that clinically significant tachyphylaxis to inhaled albuterol aerosol must be quite unusual and that chronic therapy with inhaled albuterol aerosol is probably both safe and efficacious for bronchospastic disorders.

known internationally as salbutamol, is a relatively beta. specific adrenergic amine. When administered topically by inhalation or systemically by oral and parenteral routes, it has been round to be an effective bronchodilator. u Because of albuterol's 3-rormyl group, it is resistant to degradation by both catecholamine-orthomethyl-transferase and hepatic gut suffiu:ase. Both prolonged effectiveness with oral administration and the absence of paradoxic bronchoconstriction have been noted. 3 Additionally, because of its enhanced beta. selectivity, cardiac and central nervous system stimulation have been shown to be minimal or absent, especially after inhalation. 4 However, controversy exists concerning the possible tachyphylaxis of the acute bronchodilating effect of albuterol, especially with regard to the duration of its acute bronchodilating action. 5 Duration of acute bronchodilating effect is commonly defined as that time period when the fOrced expiratory volume in the first second (FEVJ remains greater than 15 percent above baseline value. Studies demonstrating tachyphylaxis have been criticized fur not considering the frequently observed progressive improvement in baseline spirometry

values. 5 Results of studies showing little or no tachyphylaxis have been criticized fur not including a two-tofOur week washout period to allow fur a recovery of previously desensitized betas adrenergic receptors.5 Other studies have not evaluated adrenergic efficacy against a background of theophylline therapy, which is the generally accepted treatment fur a wide variety of bronchospastic disorders in the United States. While specifically looking fur evidence of tachyphylaxis after a 91-day period of therapy, the fOllowing double-blind study was simultaneously designed to obviate the preceding criticisms. We accordingly undertook to evaluate both the safety and the efficacy of inhaled albuterol as compared with inhaled isoproterenol.

~buterol,

*From Lutheran Medical Center; Wheat Ridge, Colorado; Henry Ford Hospital, Detroit; University of Wisconsin Clinical Sciences Center; Madison; National Jewish Hospital, Denver; University of Nebrulca, Omaha; University of Califumia at San Diego; Mayo Clinic, Rochester; Minnesota; University of Califumia at Los Angeles; and The Mason Clinic, Seattle. SupPo.:ted by a grant from the Schering-Plough Research Division, BIOOmfleld, New Jersey. Manuscript receiWd Aprill2, 1982; revision accepted July 18.

&printrequem: Dr. Replher, 8300Wut38thAoenue, Wheat Ridge, Colonulo 80033

34

METHODS

One hundred forty patients were evaluated at eight different centers. The number ofpatients evaluated at each center varied from 11 to 32. 1\venty-eight patients from one center were excluded from the final statistical analysis because the results obtained from this center were at such striking variance with the results obtained from the seven other centers. Even though it is statistically invalid to analyze the variant center's results along with the overall results, the inclusion of these results did not change the statistically significant findings of the seven other centers. Each patient signed an informed consent. The protocol was approved by the institutional review board at each center. Demographic characteristics and disease history are presented in Thble 1. No woman of childbearing potential was included in this study. All patients had a diagnosis of asthma for at least one year, with a mean of 14 years in the albuterol group and a mean of 15 years in the isoproterenol group. We controlled for the severity of asthma in the study patients by requiring the FEV,, prebronchodilator, to be between 30 percent and 70 percent of the mean predicted value. The reversibility of airways obstruction was documented by a required minimum increase of 20 percent in the maximum mid-expiratory '1lllchyphylald lollowtng Plolonged Therapy for Asthma (Repaheret el)

Table 1-Demograplaic Data and DUeaae Himny Albuterol

Isoproterenol

58

54

Total No. of

~ents analyzed mber of male patients Mean age Median age Age range Number Of female patients Mean age Median age

Co~n:Je in male and

female patients Mean age Median age Age range Disease History Status Stable Improving Duration (in years) Mean Median Range Severity Mild Moderate Severe Secondary pulmonary diagnosis None Chronic bronchitis Emphysema Asbestosis

44

P-Value

p>0.10

(13-65)

35 33 26

(14-64)

14 52

19 49 49 (31-64)

p>O. IO

37 40 (13-65)

38

p>O.IO

58 0

53

p>O. IO

17 14 (1-49)

21 15 (I-57)

p>O. lO

0

0 34 18

p>O.IO

49 2 2 1

p>O. IO

33 26

53 (36-64)

41 (14-64)

1

41 17

56

1 1 0

After fuur weeks of stabilization therapy, on each study day, the subject slowly and deeply inhaled two breaths from the study aerosol which was either albuterol, 85 mg of base per actuation, or isoproterenol, 75 mg of base per actuation. This provided equimolar doses of the study or control drug. Spirometric testing was pe"' furmed at baseline, 15, 30, 60, 90, 1.20, 180, 240, and 360 minutes fOllowing administration of the study aerosol. Heart rate and blood pressure were determined in the seated position both prior to spirometric testing and fur all of the post-medication time intervals. We perfOrmed a lead 2 electrocardiogram rhythm strip at baseline, at 60 minutes fOllowing inhalation of the test preparation, and additionally, whenever it was clinically indicated. The subjects were similarly observed after fuur, eight, and 13 weeks of continuous therapy with the study aerosols at a dose of two inhalations fuur times a day. The patients were also asked to compare their overall condition at two, fuur, and six hours to that of baseline. Chest auscultation was perfOrmed at baseline and two, fuur, and six hours after the use of the test preparation. These observations were rated on an eight-point scale. Additionally, the investigator also recorded his opinion of each subjects status at two, fuur, and six hours as compared to his opinion of their baseline condition. Serum theophylline levels were checked during the stabilization period at the second, sixth, and 16th week of the study period. Possible adverse reactions were monitored and recorded. The experimental design is indicated in 18ble 2. Data were analyzed by the analysis of covariance.

REsui.:I'S

Figures 1, 2, and 3, derived from :Tables 3 and 4, indicate that there is evidence of tachyphylaxis after inhaling two puffs of albuterol aerosol four times a day for 91 days. This is true, however, only with regard to the duration of significant bronchodilator response, but not with regard to peak bronchodilator effect, although there was an absolute drop of 0.139 L (16 percent) from 0.875 L at week zero to 0. 736 L at week 13. Quantitatively the amount of tachyphylaxis with respect to the duration of bronchodilator effect amounted to an absolute decrease of 72 minutes (30 percent) from 240 minutes at week zero to 168 minutes at week 13. There was no demonstrated tachyphylaxis with the inhaled isoproterenol aerosol, either with respect to magnitude or duration of bronchodilator effect. Nevertheless, the week 13 duration of bronchodilator effect for albuterol was statistically significantly greater than the week zero duration of bronchodilator effect for isoproterenol. Quantitatively this

flow rate (MMEF), and minimum increase ofl5 percent in the FEV1 fOllowing two inhalations of isoproterenol aerosol sulfate pressurized aerosol (75 j.l.g base per actuation). Up to 25 percent of the patients in each group were taking a stable corticosteroid dose of either oral prednisone or inhaled beclomethasone dipropionate. No patients who were receiving cromolyn sodium were included in the study. Patients who had been receiving immunotherapy continued to receive this therapy during the course of the study. In order to allow fur washout of previous inhaled beta adrenergic amine therapy, this study included a fuu!'-week stabilization period, during which time all subjects received no inhaled or systemic adrenergic agonists. All subjects did receive anhydrous theophylline therapy (Slo-Phyllin). Theophylline dosage was prescribed so that the patient demonstrated serum theophylline levels ofS-20 f.Lg/ml fuur hours after the last dose of Slo-Phyllin. Spirometric measurements, including FEV1, furced vital capacity (FVC), and MMEF were perfOrmed on a Collins wate!'-sealed computerized spirometer. Predicted normal ranges were taken from Morris et al.1

Table 2-E~ Daign Stabilization period (No adrenergic bronchodilatOrs, onl~ oral theop ylline) Weeks Chest X-ray, SMA-12, CBC, urinalysis Auscultation, ECG, subjective assessment Patient~ Heart rate, lood pressure, pulmonary function PLisma theophylline Serial spirometry

-4 -3 -2 -1

0

1

2

Double-blind comparison 3

4

5

6

7

8

X

9

10

11

Follow-up 12

13

14

X

X

X X

X X

X X

X

X X

X X X

X X

X X

X

X

X

X

X

X X

X

X

X

EXI)erimental design of randomized double-blind study of albuterol and isoproterenol aerosols in adults with bronchial asthma; x represents stuay week that prOcedure was perfOrmed. Week 0 value was after initial, single dose of aerosol. CHEST I 85 I 1 I JANUARY, 1984

35

... ....

~ ~' I"--

....

...,

.... •

- 1\

I

IJ

J

I

~ ~-· """ ~ ~

"" '\\

'\ ~~-·~,

~ ~

uf!

"\ ~--~

-

~. ~

II 10

'- ·-----· .

..

• • ,

...

.__,

FIGURE 1. Absolute values of mean FEV1 after inhaling albuterol aerosol at study weeks 0, 4, 8 and 13. There is no significant difference in peak bronchodilation, but there is a significant difference in duration of bronchodilatation between week 0 and weeks 8 and 13.

~

21110

.... ..., .... .... ....

1~ [\

I I

.... FIGURE 2. Absolute values of mean FEV1 after inhaling isoproterenol aerosol at study weeks 0, 4, 8 and 13. There is no significant difference in either peak or duration ofbronchodilatation between any of the study weeks.

...

-

v Iv....._r-,·_ . Ill

2

.... fff!~\

II

2

....

Vf

v

'

I

'

I ! .. ..

"

•

~

""'

.

'

!

.. I

,

~ ~"-. ~~

11

30

to

•

120

...

- -

- --

'\

"" '\

'\ r-..

~

"f\~ ~

~

....,.,........ Wll. 0

I

\ ~~

- ----

~-"*'•

~;

~

II 'W

........,.. •. 0

I

I

\

-I

"-<

~

~ ;

r--....

~

,.,l

I

I

...l

~

-~

- I

FIGURE 3. Absolute values of mean FEV1 after inhaling either albuterol or isoproterenol aerosol, comparing study weeks 0 and 13. Duration of bronchodilatation from inhalation of albuterol at study week 13 exceeds that of isoproterenol both at week 0 and 13.

I

Table 3-Mean FEV1-Ab1olute Valuea 15

30

60

120

90

180

240

360

WeekO

Min

Min

Min

Min

Min

Min

Min

Min

Albuterol N Isoprotemol N p Value Week4 Albuterol N Isoprotemol N p Value WeekS Albuterol N Isoprotemol N p Value Week 13 Albuterol N Isoprotemol N p Value

2631+52 54 2421+55 48 .007

2702+55 54 2400+57 48 .0002

2716+59 54 2296+62 48 .0001

2710+65 54 2205+68 47 .0001

2697+64 54 2198+67 48 .0001

2674+74 54 2085+77 48 .0001

2491+66 54 2015+70 47 .0001

2183+68 53 1943+74 44 .0197

2550+52 55 2470+55 48 .3

2591+50 55 2378+53 48

.0045

2620+48 55 2213+51 48 .0001

2617+54 55 2199+58 48 .0001

2615+54 55 2112+57 48 .0001

2467+56 55 2018+59 48 .0001

2302+55 55 1984+58 48 .0002

2088+54 52 1950+57 47

2542+52

2578+54

2629+59

2594+56

2468+58 47 .17

2333+63 47 .001

2240+60 47 .0001

2415+66 55 2161+70 47 .0106

2165+66

2456+56 47 .26

2523+61 55 2209+65 47 .0007

1941+66 52 1994+70 47 .58

2505+47 55 2471+50 47 .63

2562+48 55 2368+50 47 .006

2536+48 55 2243+50 47 .0001

2516+60

2509+63

2335+63

2171+63 47 .0002

2102+66 47 .0001

2090+66 47 .0001

55

55

55

55

amounted to a mean difference of 78 minutes, which favored the albuterol aerosol. There were no treatment failures in the albuterol group, but there were five treatment failures (p <.02) in the isoproterenol group. Figure 1 indicates that most of the tachyphylaxis secondary to inhaled albuterol aerosol occurs by fuur weeks and increases only slightly by eight weeks of bronchodilator therapy. There was no apparent increase in tachyphylaxis after an additional five weeks of therapy, although it did persist throughout the study. There were no significant changes (p >.05) in the baseline spirometry values fur either albuterol or isoproterenol aerosols throughout the entire 13-week study period. Table 5 shows that the incidence of cardiac and respiratory side effects was much lower with albuterol aerosol than with isoproterenol aerosol. Central and peripheral nervous system side effects tended to have a lower incidence in the albuterol group. These differences, however, were not statistically significant. The Table 4-Bt.ueline FEV1 and Mtuimum FEV1 Doer Weeks 0, 4, 8 andl3 Week 0 Albuterol Baseline FEV1 Maximum FEV1 Difference Isoprotemol Baseline FEV1 Maximum FEV1 Difference

Week 4

Week 8

Week 13

Mean 2104 + 103 2026 + 102 2104 + 104 2138 + 105 N 57 58 56 55 Mean 2979+ 112 2829+ 112 2844+ 114 2874+ 116 N 58 58 56 55 875 803 740 736 Mean 1994+ 107 1911 + 107 1952+ 110 1982+ 110 N 52 52 49 48 Mean 2536+ 117 2510+ 117 2524+ 121 2523+ 122 N 52 52 49 48 542 599 572 541

55

55

55

55

2058+71 47 .27 2135+63 54 2045+66 47

.08

1943+61 52 1988+64 46

.32

.60

study aerosol was preferred by the patients receiving albuterol when compared with the patients receiving isoproterenol. Indeed, three patients in the isoproterenol group dropped out initially because of lack of efficacy and because of unpleasant side effects. Two additional subjects in the isoproterenol group dropped out because they developed serious paradoxic bronchospasm. DISCUSSION

It has been accepted practice in the United States to use long-duration betas specific adrenergic aerosols, specifically isoetherine and metaproterenol, as therapy fur a variety of bronchospastic pulmonary disorTable 5-Number cf Patienta Reporting Side E.ffecta During Su-Hour Temng Perioda (All VuiU Combined)

No. patients enrolled No. patients with side effects Cardiovascular system Palpitations 'Thchycardia Increased heart rate Atrial flutter Increased blood pressure Central and peripheral nervous system 'Iremor Nervousness Insomnia Dizziness Other Respiratory system Cough induction Bronchospasm Other

Albuterol

Isoproterenol

60

58 37 15t

33 8*

6

2 1

0 2 14t

6

7

1

3 0 1

1

0 11

-g

6

1

1 3

17t

6

8 1 2 3 7

"'! 2

14

*Number of patients; some patients reported more than one side ell'ect in a category. tlncludes 6 patients whose data were not analyzed for efficacy since they did not complete the study. CHEST I 85 I 1 I JANUARV,1884

37

ders. However, previously published reports about tachyphylaxis with adrenergic agonists have raised reasonable concern about this therapy, particularly when the use of adrenergic aerosol inhalers has been abused. Fortunately, there have been no reports of "epidemics" of asthmatic deaths as there were with Isoproterenol-Forte in the late 1960'5;8 nevertheless, some concern still remains about individual morbidity and mortality should there be a clinically-significant loss of efficacy as a result of tachyphylaxis of an important therapeutic modality. The present study included a four-week washout period to allow for resensitization of the be~ receptors. It also included a background of therapeutic theophylline levels and no statistically significant baseline spirometry changes. The inhaled albuterol aerosol showed no statistically-significant tachyphylaxis with respect to peak bronchodilator effect. On the other hand, there was statistically significant tachyphylaxis with respect to the duration of the bronchodilator effect. However, tachyphylaxis was not demonstrated with inhaled isoproterenol aerosol, either with respect to the magnitude or the duration of the bronchodilator effect. Despite this, the week 13 duration of bronchodilator effect of albuterol was statistically significantly greater than either the week zero or week 13 duration of bronchodilator effect of isoproterenol. Because of this and in view of the fact that none of the patients receiving albuterol elected to discontinue the study, either because of side effects or because of lack of efficacy, we concluded that the tachyphylaxis demonstrated with the duration of the albuterol bronchodilating effect was not clinically significant. There also had been some concern about tachyphylaxis to the "protective" effect of inhaled albuterol, that is, the loss of protection against histamine-induced bronchospasm. To the contrary, a fOur-week study of the inhaled albuterol aerosol showed no loss of protection against histamine-induced bronchospasm.9 A previously published study has shown loss of protection against exercise-induced asthma after prolonged oral albuterol therapy;10 nevertheless, there was no similar loss of protection after prolonged therapy with inhaled albuterol. 10 One might still be concerned about further tachyphylaxis developing after more than 13 weeks of therapy. Fortunately, bronchial bet~ adrenergic tachyphylaxis generally develops early in the course of therapy and tends to be stable. 11 This study support this finding in that most of the tachyphylaxis was

•

evident at fOur weeks of therapy and that virtually all of the tachyphylaxis was present at eight weeks of therapy with further tachyphylaxis demonstrated after an additionalfive weeks of inhaled albuterol aerosol therapy. A similar pattern of tachyphylaxis has been demonstrated by in vitro granulocyte responses to isoproterenol, histamine, and prostaglandin E 1 during treatment of asthmatic patients. 12 This study, therefOre, supports the previous clinical impression that severe tachyphylaxis due to inhaled albuterol aerosol in normally prescribed doses must be quite unusual. Furthermore, this study confirms that treatment with this specific, long-acting be~ adrenergic aerosol combined with theophylline in usual therapeutic doses is probably both safe and efficacious therapy for chronic bronchospastic disorders. ACKNOWLEDGMENT: The authors thank Miss Nicolette Cav-

allaro fur her editorial assistance in the preparation of this manuscript.

REFERENCES 1 Palmer KNV. Diament ML. Effect of salbutamol on spirometry and blood-gas tensions in bronchial asthma. Br Med J 1969; 1:31-2 2 'Thttersfield AE, McNichol MS. Salbutamol and isoproterenol, a double-blind trial to compare bronchodilator and cardiovascular activity. N Engl J Med 1969; 281:1323-26 3 Reed CE. Physiology and pharmacology of belllt adrenergic agents. Chest 1978; 73:949-57 4 Paterson JW, Courtney-Evans RW, Prime FJ. Selectivity of bronchodilator action of salbutamol in asthmatic patients. Br J Dis Chest 1971; 65:21-38 5 Plummer AL. The development of drug tolerance to belllt adrenergic agents. Chest 1978; 73:949-56 6 Morris HG, Koski A, Johnson LC. Spirometric standards fur healthy non-smoking adults. Am Rev Respir Dis 1971; 103:57-67 7 Chervinsky P, Bellinkolf S. Comparison of metaproterenol and isoproterenol aerosols: Spirometric evaluation after two months of therapy. Ann Allergy 1969; 27:611 8 Conolly ME, Davies DS, Dollery CI: George CF. Resistance to beta-adrenoreceptor stimulants. Br J Pharmac 1971; 43:389 9 Peele E'I; Gibson GJ. Effects of long term inhaled salbutamol therapy and the provocation of asthma by histamine. Am Rev Respir Dis 1980; 121:978 10 Gibson GJ, Greenacre JK, Konig P, Connolly ME, Pride NB. Use of exercise challenge to investigate possible tolerance to belllt adrenoceptor stimulation in asthma. Br J Dis Chest 1978; 72:199-206 11 Nelson HS, Raine D, Doner HC, Posey WC. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am Rev Respir Dis 1977; 116:871-78 12 Busse WW. Granulocyte response in vitro with isoproterenol, histamine, and prostaglandin E 1 during treatment with beta adrenergic aerosols in asthma. Am Rev Respir Dis 1979; 120:377-84

Tachyphylaxl8lollowtng Prolonged Therapy lor Asthma (Repaher et Ill)