Herbal medicines for the treatment of COPD: a systematic review

Chronic obstructive pulmonary disease (COPD) is a group of conditions characterised by airflow obstruction 1. Chronic bronchitis (CB) and emphysema are two major conditions within this group. COPD is a public health concern worldwide, and the prevalence of this disease is increasing. According to the World Health Organization report in 1998, COPD was the sixth leading cause of death and the twelfth most common cause of morbidity worldwide. Both the direct and indirect economic costs of COPD to the society are substantial. In the USA, 16 million people have symptomatic COPD incurring estimated total economic costs for COPD-related morbidity and mortality of US$23.9 billion 2. In the UK, about 1.5 million patients suffer from COPD with a total annual cost to the National Health Service of ∼£491 million for direct costs only and £982 million including indirect costs 1.

There is no cure for COPD 3. Current conventional treatment is aimed at relieving symptoms, preventing recurrent exacerbations, preserving optimal lung function and enhancing the quality of life 4. Smoking cessation is the only therapeutic intervention shown to reduce disease progression 5. Although the conventional management of COPD has been improved since the 1990s, the progress is slow 6. Unsatisfactory treatment outcomes from conventional drugs, and adverse effects associated with several classes of drugs, such as steroids and theophylline, contribute substantially to the increasing popularity of complementary and alternative medicine (CAM) and, in particular, herbal medicine 7.

There is a long history of using herbal remedies to treat COPD, particularly in China, India and other Asian countries. Herbal expectorants, based on extracts from Hedera helix (ivy) or Thymus vulgaris (thyme) also enjoy considerable popularity in many European countries 8. Despite the popularity of herbal medicine, there has been no comprehensive systematic review of herbal medicines for treating COPD. The objective of the current review, therefore, was to systematically review the existing evidence on the effectiveness of herbal medicines for the treatment of COPD.

METHODS

All methods detailed below were according to a pre-defined, unpublished protocol.

RESULTS

The current authors located a total of 529 potentially relevant titles and abstracts. Of these, 48 articles were obtained for detailed evaluation and 19 RCTs 9, 12–30 were subsequently identified for further analysis. No unpublished RCTs were located. Of the 19 RCTs identified for further analysis, five were excluded because they did not report clinically relevant outcomes 26, 27, did not test a herbal remedy 29, did not use a systemic route of administration 28, or included asthmatic patients 30. Figure 1⇓ provides a flowchart of all included and excluded trials.

Fourteen RCTs 9, 12–24 met all inclusion criteria and were assessed. The main characteristics of these studies are summarised in table 2⇓. They originate from four countries (China, n = 10; Germany, n = 2; Switzerland, n = 1; and Italy, n = 1) and were published between 1991 and 2004 in three languages (Chinese, n = 8; English, n = 4; and German, n = 2). A total of 1,359 subjects were randomised and 1,314 were analysed by the original investigators. Most of the trials studied herbal mixtures whereas four trials tested herbal monopreparations. Eleven studies included only adult subjects (three trials specified their subjects as senile), two included both children and adults, and one included children only. Patients were diagnosed as having COPD in five RCTs and CB in nine RCTs. In one RCT, patients were specified as being in remission whereas three other RCTs included patients in acute exacerbation.

The methodological quality of the trials was generally low with a median Jadad score of 2, ranging from 1 to 5 (tables 2⇓ and 3⇓). Of the 14 included RCTs, only three 9, 16, 24 described the methods for randomisation and five 9, 15, 17, 21, 22 mentioned double blinding, of which only one 9 described the method of blinding appropriately. Details of dropouts and withdrawals were described in only five trials 9, 15, 17, 21, 24. Only two trials 9, 15 were placebo controlled.

The 14 RCTs were categorised into three groups according to the type of control interventions. Detailed results are summarised in table 1⇓ and described below. Information on the preparations, such as manufactures and compositions, can be found in the Appendix.

DISCUSSION

The present study has identified several herbal remedies with the potential to improve pulmonary function, to relieve symptoms or to reduce exacerbation severity and frequency in the treatment of COPD. Studies on herbal products containing P. ginseng, H. helix, S. miltiorrhiza and some TCHM decoctions generated encouraging results. However, interpretation and extrapolation of these results are difficult for a number of reasons.

First, insufficient data are currently available for any specific herbal remedy. Only one trial was identified for each of the tested herbal interventions and most of these trials were of small sample size and none reported formal sample size or power calculations.

Secondly, the overall methodological quality of the studies is low (table 3⇓). Blinding and randomisation are two essential features for minimising bias 31. However, in this review, only five out of 14 RCTs were double blinded. Part of the reason for the lack of blinding may be the difficulty in finding a credible placebo that is indistinguishable in colour, taste and smell, and also pharmacologically inert in the conditions under investigation. This may be particularly problematic for herbal decoctions. Similarly, four trials compared herbal medicines against “no treatment”, which does not account for placebo effects and is a source of bias. The method for randomisation was rarely described. In two RCTs 19, 20, there was a substantial difference between the numbers of patients in test and control groups. This could suggest that inappropriate methods of randomisation were used. These weaknesses, and the lack of descriptions of dropouts and withdrawals, contribute to the often low scores on the Jadad scale. The validity of some RCTs was further limited by failings to report the concealment of treatment allocation and details of statistical analysis, or inappropriate analyses.

Thirdly, seven RCTs compared a herbal medicine with another herbal medicine. Despite some positive results shown in these trials, interpretation is difficult due to the unknown effect of the control intervention.

Furthermore, quality control of the herbal extracts is important to ensure the reproducibility of the study. Of the 12 herbal preparations (excluding herbal decoctions) listed in the Appendix, data on extract standardisation are only available for one preparation. Details on the extract solvent were also only reported for one preparation.

Finally, the European Agency for the Evaluation of Medicinal Products recommended using both FEV₁ and a measure of symptomatic benefit as a combined primary outcome, and states that the end-point for symptomatic benefit should be justified by referencing published data that support its validity 32. However, only one trial 14 used a referenced symptomatic benefit measure, in spite of the availability of a number of validated, well accepted and widely applied instruments, such as the St George's Respiratory Questionnaire 33 and Chronic Respiratory Questionnaire 34.

The increasing popularity and, particularly, the easy access to herbal remedies raises safety issues. The common assumption among consumers that herbal medicines are safe is dangerous. Herbal medicines might be linked to serious AE and herb–drug interaction may have serious clinical consequences 35. Several relevant herbs, such as Salvia milhiorrhiza, Glycyrrhiza uralensis, P. ginseng and Angelica sinensis were reported to interact with a range of conventional medicines 36–38. Unfortunately, in most of the included RCTs, AE were not monitored and herb–drug interactions were considered in none of the reports. The included studies involved a large number of individual herbs in various combinations (see Appendix). The AE and herb–drug interactions of most of these herbs and preparations are not well documented. Therefore, further studies on the safety of these remedies are required.

Limitations of the current review and, indeed, systematic reviews in general pertain to the potential incompleteness of the reviewed evidence. The distorting effects arising from publication bias and location bias are well documented 39–43. In the current review, 10 out of 14 included RCTs were published in China, a country which has been previously shown to produce large numbers of positive CAM studies 44. For the current study, databases were searched with a focus on the American and European literature and those which specialise in complementary medicine, and included hand-searches. There were no restrictions in terms of publication language. The current authors are, therefore, confident that their search strategy has located most of the published trials on the subject. However, whether all unpublished trials were identified remains uncertain. A further limitation of this review is (as pointed out previously) the paucity and limited quality of the primary data.

APPENDIX: COMPOSITION AND CHARACTERISTICS OF MEDICINAL HERBAL PREPARATIONS USED IN THE INCLUDED RANDOMISED CLINICAL TRIALS