In this second part of a two-part article, the authors examine the efficacy and clinical effectiveness of, and evidence for, the use of herbal medicines
In a previous article (
PJ, 2012;289:161–2) we highlighted the important role of traditional herbal medicines throughout history. In this article we will examine the concepts of efficacy and meaning response, and how the scientific evidence base of herbal medicinal products is expanding and improving with modern analytical techniques.
Efficacy and clinical effectiveness
“Efficacy” has slightly differing definitions according to context. In healthcare it is generally considered as the capacity for a health intervention to produce a therapeutic effect. In pharmacology it has a precise meaning as the intrinsic activity of a drug, ie, the relative ability of a drug-receptor complex to produce a maximum functional response. To avoid confusion over the term “efficacy”, “clinical effectiveness” is often used in preference to refer to how well a medicine works in practice, because this term is inclusive of both pharmacological effects of bioactive compounds and non-medical effects that may either reinforce each other (placebo effect) or conversely, work against each other (“nocebo” effect).1
The non-therapeutic function of medicines is usually overlooked, yet it plays a significant role in eliciting the so-called “meaning response” — “the physiologic or psychological effects of meaning in the origins or treatment of illness”,1,2 such as the production of endogenous opiates.3 Observed placebo effects appear to be the result of the involvement of a number of different mechanisms and biological systems, including brain mechanisms involving expectation, anxiety and reward, in addition to various learning phenomena, including Pavlovian conditioning, and cognitive and social learning.4 With regard to traditional herbal medicines, the socio-cultural aspects are likely to elicit a physiological response, in addition to any intrinsic pharmacological activity of the plant, since they often exist within religious and mythical traditions, creating a vivid associated meaning.5
The use of herbal medicines and derived products should therefore be considered within the context of their use, as this undoubtedly will have an impact on their clinical effectiveness. For example, a traditional healer may also use chanting and prayers along with a crude plant extract, which may induce a meaning response, adding to the therapeutic effects of the plant extract. Similarly, the shape and colour of a tablet may have a subtle therapeutic effect, depending on cultural context.5 In the UK, it is likely that the increasingly scientific approach to, and even packaging of herbal medicinal products, will affect their clinical effectiveness — a topic that offers many opportunities for pharmacy practice-based research.
Evidence of clinical effectiveness is rated according to quality, with the highest levels of evidence ascribed to systematic reviews and meta-analyses of randomised-controlled trials. Key resources for such evidence are the Cochrane reviews, which are produced by an international collaboration of scientists. These reviews are internationally recognised as “the benchmark for high quality information about the effectiveness of healthcare” and are freely available at www.cochrane.org/.
A criticism commonly levelled at herbal medicinal products is that for many of them on the market there is a lack of clinical data from good quality randomised controlled trials, usually, it is stated, due to limited funding.6 However, although it is true there is a paucity of data for many herbal medicines, Cochrane reviews do exist for a few of them. For example, a Cochrane review of randomised, controlled trials on herbal medicine to treat low back pain, found that devil’s claw (Harpagophytum procumbens DC.), white willow bark (Salix alba L.) and cayenne pepper (Capsicum frutescens L.) seemed to reduce pain more than placebo in short-term trials, with the qualification that further trials were needed to clarify their equivalence against standard treatments in terms of efficacy, and that for long-term use there was no evidence that these substances are safe and useful.7 Another Cochrane review on St John’s wort (Hypericum perforatum L.), showed that it was equivalent, in treating patients with major depression, to selective serotonin uptake inhibitors.8
However, due to the nature of herbal medicines, ie, their variability in phytochemical make-up according to genotype, plant part used and environmental conditions, even well designed clinical trials may be flawed unless these factors are taken into consideration. A study of echinacea that showed no pharmacological effect beyond placebo for treating children’s common colds9 was criticised as it used non-standardised pressed plant juice from aerial parts only, rather than chemically characterised extracts from the entire plant.10,11 Recently the Medicines and Healthcare products Regulatory Agency issued a press release in which parents and carers are advised not to use oral herbal products containing echinacea for children under 12 years of age because of a lack of evidence regarding a potential risk of allergic reactions. The risk seems to be low.
Limited clinical evidence for herbal medicines is not always considered a serious problem by consumers or practitioners in the complementary and alternative medicine sector, since it is thought that traditional use over many generations without known negative effects, in addition to their being “natural”, implies that they are safe.
However, some effects may not be immediate and thus correlated with the use of a particular plant. A well known example is Aristolochia spp. This is a genus of plants that has been used for perhaps thousands of years in traditional medical systems throughout the world. Its toxicity has only been known since the 1990s.12 More recently, butterbur (Petasites hybridus [L.] G. Gaertn, B. Mey & Scherb), used traditionally for migraine, asthma and hay fever, has been linked with 40 cases of liver toxicity, including two cases of liver failure requiring transplantation.
Although this plant is known to contain the hepatotoxic pyrrolizidine alkaloids, what is of concern is that these cases involved the use of butterbur-containing products where the pyrrolizidine alkaloids had been removed, indicating that other constituents (possibly sesquiterpenes) were responsible for the toxicity. Butterbur is not found in any herbal medicinal product registered in the UK under the Traditional Herbal Medicines Registration Scheme,13 but is an ingredient in a number of herbal products sold as food supplements. This highlights the importance of the THMRS and why community pharmacists should advise members of the public to use only licensed products, which have safety and quality assurance, unlike unlicensed products that pose potential risks to consumers.
Understanding the mechanisms responsible for the clinical effects of herbal products is complex due to the presence of multiple constituents within one herbal ingredient, and thus pharmacokinetic/pharmacodynamic data for these products are often unavailable. In both Ayurvedic and traditional Chinese medicine, complexity is compounded by the fact that each preparation usually contains multiple herbal (and sometimes non-herbal) ingredients, with each ingredient possibly containing a number of (as yet unknown) bioactive constituents. This added level of complexity creates difficulties in establishing standards and, due to the unknown toxicity of constituents, safety may be compromised, which in part explains why to date no Ayurvedic or Chinese herbal products have been registered under the THMRS. Other obstacles to acceptance of these treatments by mainstream western healthcare providers include the unstable nature of therapeutic efficacy of different preparations of the same traditional Chinese medicine, and lack of standardised Western clinical trials.14,15 At the same time, the increasing popularity in the complementary and alternative medicine market dictates that new insights into these medicines, such as understanding modes of action, are required.15
The emerging “omics” technologies (eg, genomics and proteomics) may provide the solution. They could revolutionise our understanding of the clinical effects of herbal products and validate the traditional medicinal uses beyond a simple placebo effect. They also have centuries of anecdotal evidence.
The “omics”, in combination with bioinformatics, provide the tools for analysing complex modes of action and, in the case of metabonomics, make it possible to understand the metabolic changes within complex biological systems following an intervention. For example, it has been shown that herbal medicines interact with gut flora, either by being processed by gut bacteria which convert constituents into active compounds, or through increasing the proportion of beneficial bacteria, which helps modulate the immune system. Traditional Chinese medicines have been shown to be effective in the treatment of some chronic diseases and metabolic syndromes (eg, eczema and the control of glucose and lipid metabolism), and probably on multiple pharmacological targets. “Omics” offer opportunities to understand such complex preparations better.16
These analytical techniques may be useful for establishing chemical and pharmacological standardisation and toxicological potential of plant extracts. They may also be able to indicate which phytopharmaceuticals will prove useful for co-administration to reduce adverse reactions from synthetic drugs, or even increase efficacy through synergistic effects,17 such as the medicinal plant extracts shown to potentiate antibiotic activity.18
Within the next few years, the evidence base of many herbal medicinal products is likely to increase significantly with the application of the “omic” technologies, enabling a more holistic understanding of how all the constituents in a herbal medicine work together and act on biological systems. For the time being, although evidence on efficacy or mode of action may be limited, community pharmacists can rely on licensed or registered herbal medicinal products meeting the levels of quality and safety that consumers require. However, even with these products, there is the potential for as yet unknown interactions if they are taken concomitantly with other medicines, which is why their inclusion within the Yellow Card Scheme (the MHRA’s reporting system for monitoring the safety of medicines) is important, with community pharmacists able to contribute significantly to the overall pharmacovigilance of these products.
Acknowledgements Our research on this topic has been made possible thanks to two charitable donations under the UK’s matched funding scheme. We are grateful to Fa Bionorica and Fa Schwabe for their support. The sponsors are not responsible for any of the content in this article, which was written without their input.
Sarah Edwards is research fellow, InÃªs Da-Costa-Rocha is research fellow and Michael Heinrich is head and professor at the Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, London.
M. Jayne Lawrence is chief science adviser and Colin Cable is pharmaceutical sciences information adviser at the Royal Pharmaceutical Society
Correspondence to: Professor Heinrich (email email@example.com)
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