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Case Study 1: Oralmat and Asthma
A double-blind placebo controlled study of Oralmat in adult asthma; evidence of improvement demonstrated
Study conducted by David M Cooper, Kerry M Rogers and John Falconer of John Hunter Children’s Hospital, Newcastle, Australia.
Asthma has profound effects on patients, their families and the community. Poorly controlled asthma can reduce patients’ well being, and interfere with their ability to exercise and to participate in sport and community activities.
Dr. David M. Cooper is a well-known Senior Pediatric Respiratory Physician at the John Hunter Hospital in Australia. He conducted a double-blinded, randomised investigation of the effects of Oralmat on asthma symptoms and respiratory function in mild to moderately asthmatic adults. The randomised, four week study, investigating changes in subjective and objective measures of asthma, among adult asthmatic patients taking Oralmat.
During this study, Dr. Cooper concluded that patients taking Oralmat reported improved well being, asthma symptoms and ability to exercise. Patients taking the placebo did not report equivalent improvements.
Below is the full case study
A double-blind placebo controlled study of a Rye based herbal extract (Oralmat™) in adult asthma; evidence of improvement demonstrated.
David M Cooper1
Kerry M Rogers2
John Falconer3
Senior Paediatric Respiratory Physician, John Hunter Children's Hospital, Newcastle, Australia.
Research Assistant, John Hunter Children's Hospital, Newcastle, Australia.
Hospital Scientist, John Hunter Children's Hospital, Newcastle, Australia.
Correspondence may be directed to David M. Cooper, John Hunter Children's Hospital, Locked Bag 1, Hunter Region Mail Centre, NSW, 2310.
E-mail: dcooper@mater.org.au
Financial support for this project was provided by Schumacher Pharmaceuticals, the manufacturers of OralmatTM. Schumacher Pharmaceuticals also provided the Oralmat used in this study. Schumacher Pharmacueticals was not involved in any other aspect of this study, Schumacher Pharmaceuticals had no influence on the decision to publish this paper.
We wish to acknowledge the roles of the following:
Financial support for this study was received from Schumacher Pharmaceuticals, who also provided the Oralmat used in this study.
Spirometric measurements and the collection of blood samples were performed by Majella Maher and Robyn Hankin, John Hunter Children's Hospital.
Word Counts.
Abstract: 130 words
Body of text:
ABSTRACT
OBJECTIVES: To investigate the effects of Oralmat on asthma symptoms and respiratory function in mildly to moderately asthmatic adults.
DESIGN AND SETTING: A double-blinded, randomised investigation of the effects of the commercially available rye-extract, OralmatTM, on asthma symptoms and spirometry measures.
MAJOR OUTCOME MEASURES: Changes in spirometry measures (FEV1, FEFmax, FEF25-75, FVC), surveyed subjective measures (including wellbeing, asthma symptoms and ability to exercise) and diary records (medication use, sleep disturbance, cough and breathlessness).
RESULTS: We found significant improvements in reported wellbeing, asthma symptoms and ability to exercise. There were no consistent, statistically significant changes in other surveyed subjective measures, spirometry measures or diary entries.
CONCLUSIONS: This study suggests that Oralmat may alleviate discomfort associated with asthma. Further research is needed to confirm the role of Oralmat in asthma treatment.
Keywords: Oralmat™, asthma, herbal medicine, complementary medicine (Check MeSH headings - see Index Medicus)
Introduction
Asthma has profound effects on patients, their families and the community. Poorly controlled asthma can reduce patients' wellbeing, and interfere with their ability to exercise and to participate in sport and community activities. Asthma can even result in loss of employment1. The 1989 cost of lost production due to asthma in NSW has been estimated to be $48 million2. Hence reducing the impact of asthma is an important health-care goal in both social and economic terms.
Many patients turn to complementary and alternative medicines as they strive to control their asthma. In a 1999 survey, 55% of children with asthma had used at least one alternative therapy3. Although only 4% of patients in this that survey and 8% of patients in a 1997 survey4 used herbal asthma treatments, 43% of adult asthmatics interviewed in a 1998 survey5 thought herbalism was useful to "a great" or “some" extent. That study also found that herbal therapy usage was greater among patients with very severe asthma (15%) than among patients with mild asthma (8%).
The use of dietary supplements, including herbal medicines, may be increasing. In an audit of 600 files from patients with atopy, Mullins6 found an increase in the use of dietary supplements from 7.5% in 1995 to 25% in 1997. Echinacea use was nil, 5% and 3% in 1995, 1996 and 1997, respectively.
Herbal remedies should not be dismissed without investigation. Disodium cromoglycate (Intal) was originally extracted as "khellin" from the root of the Egyptian plant ammivisnaga7.
The ill-considered use of herbal remedies may endanger patients. Herbal preparations may be intrinsically hazardous, or may become hazardous due to misidentification or substitution of plants, poor standardisation, preparation or labelling, adulteration or contamination8. Allergenicity is one intrinsic hazard of dietary supplements and herbal medicines, which should be of particular concern to asthmatic patients and their doctors. This hazard has been demonstrated by asthmatic and anaphylactic reactions to royal jelly9 and echinacea6.
Lane and Lane7 warned that alternative medicines might endanger asthmatic patients by impairing awareness of airway obstruction. This warning may explain the finding4 that patients who attempted self-treatment with herbal medicine were at greater risk of hospitalisation for asthma than were other patients. This increased risk may also have been caused by delays in medical treatment, incurred as patients sought relief using alternative remedies.
Given the potential for both benefit and harm from herbal remedies, clinicians need information, obtained from well-designed clinical trials, about herbal asthma remedies. A comprehensive survey10 found only two randomised trials investigating herbal asthma treatments.
In response to this paucity of evidence, Edvard Ernst called for randomised, clinical trials to enable clinicians to advise their patients about the risks and benefits of herbal treatments11.
We carried out a randomised, four-week study, investigating changes in subjective and objective measures of asthma, among adult asthmatic patients taking Oralmat, a commercially available rye-extract. During this study, patients taking Oralmat reported improved wellbeing, asthma symptoms and ability to exercise. Patients taking the placebo did not report equivalent improvements.
Methods
We used a randomised, placebo-controlled, double-blinded group design to investigate the effects of a commercially available rye-extract, OralmatTM, on subjective and objective measures of asthma.
Patient selection and allocation
Thirty-seven adult patients (19 male, 18 female) with mild, stable asthma were recruited into the study between May and December 1998. Patients were recruited through a newspaper advertisement, radio interviews and “word of mouth”. Mild stable asthma was defined by a previous diagnosis of asthma; at least a 20% fall in FEV1 in response to a hypertonic saline bronchial challenge(12), and no history of life-threatening asthma. Patients were excluded if, on testing or history, they were judged to have severe, unstable asthma, any other form of airway disease or other significant illness. Patients were informed of their right to withdraw from the study at any time.
After patients recruited to the study gave their informed consent to participation, each patient was assigned a number and subsequently randomised into either the Treatment (OralmatTM Drops Solution – Manufactured by Schumacher Pharmaceuticals Pty Ltd) or the Placebo group. To protect the privacy of patients and the integrity of the study, the manufacturers were never informed of patient identities. The investigators and patients remained blinded to patient allocation until all measurements and questionnaires had been completed.
Treatment
The manufacturers provided the Oralmat/placebo to the pharmacy at John Hunter Hospital, in vials already labelled with patient numbers. After each patient had completed an initial questionnaire and baseline spirometry, and these had been scrutinised for any reasons for exclusion, he or she was provided with the assigned vial.
Patients were asked to self-administer the Oralmat/placebo by placing three drops under the tongue, three times each day until the final (week 4) measurements were completed.
Measurements
Each patient completed an initial questionnaire, prior to the commencement of treatment, on his or her general medical history, his or her history of asthma, the current severity, treatment and triggers of the asthma, and other potentially relevant medical information. This questionnaire was scrutinised for reasons for exclusion, and was used both for characterisation of the patient sample and for comparisons of the pre-treatment health status of the treatment and placebo groups.
Patients were asked to keep a daily record (diary) of symptoms and medication during the study, and to complete follow-up questionnaires after one and four weeks of treatment. These latter questionnaires investigated the patients’ perceptions of symptomatic changes on a scale of –3 (worse) through 0 (same) to 3 (better), as well as any changes in medication use during the trial.
At week 0, week 1 and week 4 of the study, lung function was measured using a Medical Graphics PF/Dx 1085 Spirometry System, according to recommended techniques. Patients were asked not to use bronchodilators less than two hours before spirometry. Following the initial spirometry, 2 ml of salbutamol (2.5mg/ml), combined with 2 ml of normal saline, was administered by nebuliser. Ten minutes subsequently, spirometry was repeated. This spirometry provided measurements of FVC, FEV1, FEFMax and FEF25-75%, before and after bronchodilator use.
A blood sample was collected from each patient at week 0, week 1 and week 4 of the study. These samples were analysed for relevant haematological and immunological and biochemical characteristics.
Each patient’s sitting blood pressure was measured during each visit.
Analyses
Data were analysed using Microsoft Excel ’97 and SPSS for Windows.
The medical profile of the patient group was expressed in terms of pre-treatment spirometry and the patients’ responses to the initial questionnaire. Pre-treatment differences between the treatment and placebo groups were assessed using Chi-squared analyses of patient responses to the initial questionnaire and Students’ t-tests performed on pre-treatment spirometry measurements.
Between-treatments differences in patients’ responses to the follow-up questionnaire were assessed using the Mann-Whitney test of two medians.
Changes in week 1 spirometric measures, expressed as percentages of predicted values, were calculated as the difference between the week 1 and week 0 values, expressed as a percentage of the week 0 values. The same calculation was performed for the week 4 spirometric measures. Between treatments, differences in mean scores for these values were assessed using MANOVA and Student’s t-test.
Between-treatments differences in mean scores for the haematological, immunological and biochemical measures (expressed as percentages of predicted values, where appropriate) were assessed using Student’s t-test.
Diary records were summed separately for each patient and each question, for days 1 to 5 (Sum 1) and for days 24 to 28 (Sum 2). The differences between Sum 1 and Sum 2 were calculated and a Mann-Whitney test was use to compare these differences between the Oralmat and placebo groups.
Some patients ceased taking preventative medications during the experiment. To determine the effects of these changes on the results, the above calculations were repeated with the omission of these patients.
Results
Pre-treatment Characteristics
We found no significant pre-treatment differences between the treatment and placebo groups in any of the measured or surveyed parameters.
In the pre-treatment questionnaire, 60% of patients reported experiencing an asthma exacerbation in the previous year, with 27.8% reporting an exacerbation in the previous month. Eight percent reported a hospital admission due to asthma in the previous year. Slightly over half (52.8%) of the patients said they coughed regularly, while 88.9% reported wheezing in the previous year. Two-thirds of patients reported night or early morning awakening due to asthma.
Pre-treatment mean values for all spirometry measures fell below the population mean (100%), with the lowest mean measure being 66.4%, for pre-bronchodilator FEF25-75%, and the highest mean measure being 97.2%, for post-bronchodilator FVC (Table 3).
|
3: Mean spirometry measures (all patients) prior to treatment
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||||||||
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MEASUREMENT
PRE/POST BRONCH0DIL.
|
FEV1
PRE
|
FEV1
POST
|
FVC
PRE
|
FVC
POST
|
FEFMAX
PRE
|
FEFMAX
POST
|
FEF25-75%
PRE
|
FEF25-75%
POST
|
|
MEAN
STANDARD DEVIATION
|
87.1
24.4
|
91.2
23.8
|
95.7
19.4
|
97.2
18.4
|
96.9
25.9
|
92.8
23.1
|
66.4
35.3
|
76.9
38.5
|
Questionnaires
Patients taking Oralmat reported significantly greater improvements in wellbeing (p<0.01) and asthma symptoms (p<0.01) during week 1 of the study, and in wellbeing (p<0.01) and ability to exercise (p<0.05) during week 4 of the study, than did patients taking the placebo (Figures 1 to 6; Table 4).
After omission of the responses of patients who had changed their medication regimen, patients taking Oralmat reported significantly greater improvements in wellbeing (p<0.01), asthma symptoms (p<0.01) and ability to exercise (p<0.05) during week 1 of the study, and in wellbeing (p<0.05) and ability to exercise (p<0.01) during week 4 of the study, than did patients taking the placebo.
We found no significant differences in other questionnaire responses between patients taking Oralmat and those taking the placebo.
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4: Responses to follow-up surveys on patients’ perceptions of health changes
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WEEK 1
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||||||
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|
ORALMAT
|
PLACEBO
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||||
|
|
better
|
same
|
worse
|
better
|
same
|
worse
|
|
General wellbeing
|
10
|
7
|
1
|
2
|
14
|
2
|
|
Asthma symptoms
|
10
|
6
|
2
|
0
|
13
|
5
|
|
Ability to exercise
|
8
|
8
|
2
|
4
|
13
|
1
|
|
|
||||||
|
WEEK 4
|
||||||
|
|
ORALMAT
|
PLACEBO
|
||||
|
|
better
|
same
|
worse
|
better
|
same
|
worse
|
|
General wellbeing
|
10
|
4
|
1
|
5
|
8
|
3
|
|
Asthma symptoms
|
9
|
6
|
0
|
6
|
9
|
1
|
|
Ability to exercise
|
10
|
5
|
0
|
4
|
10
|
2
|
Figure 1: Perceived changes in wellbeing among patients taking Oralmat or a placebo (Patients who continued taking preventative medicine)
Figure 2:Perceived changes in asthma symptoms among patients taking Oralmat or a placebo (Patients who continued taking preventative medicine)
Figure 3: Perceived changes in ability to exercise among patients taking Oralmat or a placebo (Patients who continued taking preventative medicine)
We found no significant differences between the Oralmat and placebo groups in blood pressure, in haematological, biochemical or immunological measures, or in symptomatic changes reported in patient diaries.
Discussion.
Patients taking Oralmat reported greater improvements in wellbeing, asthma symptoms and ability to exercise than did patients taking the placebo. These differences were statistically significant, and continued to be significant once patients who had ceased taking preventative medications were omitted from the analyses.
Why were significant differences between the Oralmat and placebo groups found for these variables, but not for other surveyed variables or for variables reported in the patient diaries? Although all patients reported some asthma symptoms, and these symptoms were likely to affect both patients’ wellbeing and ability to exercise, the nature of patients’ symptoms varied. Only 19 patients reported coughing more than once a week, and eight patients reported regularly coughing up sputum. Similarly, in the patient diaries, only 11 patients reported any sleep disturbance during the first 5 days of the study. TwentyAlso in this diary, twenty-two patients reported coughing and 20 patients reported breathlessness during the first 5 days of the study. The smaller number of patients reporting these specific symptoms reduced the chance that we would find any statistically significant improvements in these symptoms.
In view of the absence of objectively measured changes, such as changes in spirometric measures, how much weight should we give to changes in subjective measures? Subjective measures of asthma can be deceptive, as patients may underestimate their level of airway obstruction13. However, spirometric measures do not always reflect disease processes such as hyperinflation and airways plugging13. The reversal of hyperinflation, as asthma treatment reduces bronchial inflammation, may vitiate improvements in forced expiratory volume15. Conversely, significant symptomatic improvements may be noted during treatment, as decreasing residual volume improves lung compliance15.
In consequence, patients may report changes in asthma symptoms without parallel changes in spirometry measures. In a study by Juniper et al.16, patients reported improvements in their asthma and reduced bronchodilator use during twelve months of treatment with budesonide, despite the absence of any improvement in FEV1. Patients taking the placebo did not report any significant improvement in symptoms or in bronchodilator use. A pioneering study of Intal17 found significant, even “striking”, symptomatic improvements, but noted that “reliance on simple spirometry alone would have led to a failure to recognise the therapeutic value of FPL670 [Intal] in six of the ten patients.”
Considered alone, reported improvements in subjective measures would be insignificant but, in the context of a randomised double-blinded clinical trial, they cannot be dismissed. If the improvements in subjective measures reported by patients taking Oralmat occurred in response to other factors (increased contact with medical and nursing staff, for example) we would expect patients taking the placebo to report equivalent improvements. Although there was a slight trend to improvement in the placebo group during week 4, this was significantly less than that in the Oralmat group. There was no trend toward improvement in the placebo group during week 1.
What caused the reported improvements in asthma symptoms among patients taking Oralmat? We found no improvements in lung function, as measured by spirometry. However, limitations in the size of this study meant that only very large differences in spirometric values would have been detected. We cannot conclude, from these results, that Oralmat does not cause objectively measurable changes in lung function.
Reported improvements in asthma symptoms and ability to exercise are not necessarily due to improved lung function. An increased ability to exercise was reported after acupuncture18. This change was explained as a consequence of a decreased perception of breathlessness in patients whose lung function remained unaltered. Diazepam19 and dihydrocodeine20 have also been shown to reduce perceptions of breathlessness. Like these treatments, Oralmat may alter perceptions, so that patients are less distressed by their asthma. Such effects should not be disregarded. Treatments that reduce distress due to asthma may be clinically useful, . provided that theyHowever, care should be taken to ensure that these treatments do not abolish awareness of severe airway obstruction7.
Further studies are needed to verify the effects of Oralmat. Ideally, these studies should use a crossover design, involving sufficient patients to facilitate identification of clinically significant spirometric effects.
If further clinical trials support the finding that Oralmat has a beneficial effect on asthma symptoms, researchers will need to investigate potential sources of improvement. Analyses of Oralmat should be performed, concurrently with these clinical trials, to identify ingredients of the extract, and to determine which ingredients are present in potentially bioeffective quantities.
In view of this report, clinicians may choose to give qualified support to the use of Oralmat by patients who are seeking complementary asthma treatment. It is important to stress to patients that this remedy should not replace conventional treatments, but should only be used as a supplement, at least until further evidence is available.
References
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- Mellis CM, Peat JK, Bauman AE, Woolcock AJ. The cost of asthma in New South Wales. Med J Aust 1991;155:522-8
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- Blanc PD, Kuschner WG, Yelin EH. Use of herbal products, coffee or black tea, and over-the-counter medications in self-treatments among adults with asthma. J Allergy Clin Immunol 1997;100:789-91
- Ernst E. Complementary therapies for asthma: what patients use. J. Asthma 1998;35:667-
- Mullins RJ. Echinacea-associated anaphylaxis Med J Aust 1998; 168:170-1
- Lane DJ, Lane TV. Alternative and complementary treatment for asthma. Thorax 1991;46:787-97
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- Leung R, Thien, FCK, Czarny, D. Royal jelly-induced asthma and anaphylaxis. . J Allergy Clin Immunol 1995, 96(6) 1004-7
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- Ernst E. Complementary/Alternative medicine for asthma: We do not know what we need to know. Chest 1999;115:1-2
- Chai H, Farr RS, Froelich LA, Mathison DA, McLean JA, Rosenthal RR, et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975;56:323-27
- Teeter JG, Bleeker ER. Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Chest 1998;113:272-7
- Jones PW. Quality of life measurement in asthma. Eur Resp J 1995;8:885-887
- Woolcock AJ, Read, J. Improvement in bronchial asthma not reflected in forced expiratory volume. Lancet 1965; 2:1323-25.
- Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O’Byrne PM, Hargeave FE. Effect of long term treatment with an inhaled corticosteroid (Budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832-6.
- Howell JBL, Altounyan REC. A double blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet 1967;(2):539-42
- Jobst K, Chen JH, McPherson K, Arrowsmith J, Brown V, Efthrimiou J, et al. Controlled trial of acupuncture for disabling breathlessness. Lancet 1986;11:1416-8
- Mitchell-Heggs P, Murphy K, Minty K, Guz A, Patterson SC, Minty PSB, et al. Diazepam in the treatment of dyspnoea in the "pink puffer" syndrome. Q J Med 1980;40:9-20
- Stark RO, O'Neill PA. Dihydrocodeine for breathlessness in "pink puffers". Br Med J 1983;286:1280-1