Safety and complementary medicines

CHAPTER 7 SAFETY OF COMPLEMENTARY MEDICINES


Complementary medicines (CMs) are widely used by the public, who assume they are a safe, non-pharmaceutical option that can be used to prevent, treat and manage disease (MacLennan et al 2002). The perception that CMs are safe is largely based on the assumption that if something is ‘natural’ it is inherently safe, a view encouraged by many in the health food industry. Unfortunately the ‘natural’ argument is simplistic and not well thought out, because nature provides many examples of unsafe substances, such as the naturally occurring poisons hemlock, jimsonweed and oleander. There is also an assumption that possible side effects and toxicities will be listed on product labels and therefore, if the information is absent, the product must be well tolerated. In Australia, some warnings are required on labels; however, CMs are not accompanied by comprehensive consumer product information (CPI) in the same way as many pharmaceutical medicines; many CMs are self-selected without professional advice, which means that much-needed information is not delivered with the product (Jamison 2003, MacLennan et al 2002).


Importantly, people who use CMs tend to have poorer health than the general community (MacLennan et al 2006) and are not necessarily dissatisfied with their conventional care (Astin 1998), which raises the possibility of dual care by complementary and conventional medical practitioners. This situation is not necessarily dangerous and can produce significant benefits when well coordinated; however, if communication is poor, and complementary and conventional practitioners remain unaware of what the other has recommended, a potentially unsafe situation can arise. The prospect of interactions or adverse drug reactions leading to misdiagnosis, induction of withdrawal effects and misleading pathology test results are examples of unwanted outcomes when combined care is not coordinated.


In the real world, people are exposed to risk whenever they actively choose to undertake a treatment or choose to do without. Some risks are identifiable, while others are unknown. In practice, in order for patients to make an informed decision, these risks must be classified into those that are acceptable and those that are unacceptable, and then considered against the potential benefit, Over-the-counter (OTC) CMs offer a lower-risk and potentially more cost-effective option than other treatments for some indications and are generally considered safe when used appropriately under ‘normal’ circumstances; however, they are not entirely devoid of risk.



A BRIEF HISTORY OF MEDICATION SAFETY


The potential for medical care to cause harm has been appreciated throughout history. In ancient times, knowledge of medicine, pharmacology and the healing arts developed through trial and error, with many adverse outcomes and deaths along the way. Although both practitioners and patients were aware that health could be compromised by the ‘cures’ used to alleviate disease, it was in ancient Greece that patient safety was formally acknowledged as the highest priority. The maxim primum non nocere (First, do no harm) is attributed by some historians to Galen (AD 131–201) and is still a basic tenet of modern medical practice (Ilan & Fowler 2005).


As societies developed over the centuries, so too did their systems of medicine and healing — particularly the Vedic system of medicine, which originated more than 3000 years ago in India, and Chinese medicine, which has an appreciation of the importance of dosage. Persian medicine had a major influence on the development of medicine in the Middle East and Europe, most notably with The canon of medicine written by the Persian scientist Avicenna (AD 980–1037) in the 11th century. This major work documented 760 medicines, made comments about their use and effectiveness, and remained a standard medical text in western Europe for seven centuries. Avicenna recommended the testing of new medicines on animals and humans before general use, no doubt in recognition of their potential to have both beneficial and harmful effects.


In medieval Europe, there was a mixture of scientific and spiritual influences on the practice of medicine, so factors such as destiny, sin and astrology played a role in perceptions of health and disease. Two major trends appeared during this period, as the practice of medicine developed among both physicians of the upper classes and folk healers who lived in the villages. From the 14th to the 17th centuries, monasteries played a major role in the provision of medicine and developed great expertise in pharmacognosy. At the same time, the Christian church was instrumental in eliminating much of the practice of folk medicine through its witch-hunts, which many believe retarded the development of medicine.


In the 16th century, Paracelsus (1493–1541) was one of the first physicians to believe that chemicals could cure and cause certain illnesses. He determined that specific chemicals were responsible for the toxicity of a plant or animal poison, and documented the body’s responses to those chemicals. Paracelsus then concluded that the body’s response was influenced by the dose received. He further discovered that a small dose of a substance may be harmless, or even beneficial, whereas a larger dose can be toxic. In essence, he started expounding the concept of a dose–response relationship. Paracelsus made an enormous contribution to medicine when he stated plainly, ‘What is there that is not poison? All things are poison and nothing (is) without poison. Solely the dose determines that a thing is not a poison’ (Watson 2005). As a result, he is sometimes referred to as the ‘Father of Toxicology’.


In practice, this refers to the biological effect of chemicals that can be either beneficial or deleterious. Which of these effects occurs depends on the amount of active material present at the site of action (internal dose), and the concentration of the amount present relates to the amount of substance administered (external dose).


During the 18th and 19th centuries deliberate clinical testing of medicines began, and the study of dose–response relationships led to the safer use of medicines. From the 19th century onwards, developments in pharmacology, physiology and chemistry meant that drugs could be artificially synthesised and be produced by large-scale manufacturing. During this time, animal- and plant-based medicines began to be replaced in clinical use by mass-produced pharmaceutical medicines that were being newly created in laboratories or synthesised from traditional medicines (e.g. morphine from Papaver somniferum).


Up to this point, Western herbalism had been intrinsically linked to the practice of medicine, and herbal products were an important source of treatment. Empirical knowledge accumulated and formed a body of evidence now referred to as ‘traditional evidence’, a knowledge base built on the basic tenets of good clinical practice (i.e. careful observation of the patient, the environment and the diseases). This huge and diverse store of learning includes not only prescriptions for health, but also safety information. The traditional evidence base is still expanding and becoming more accessible as researchers investigate and document various healing practices worldwide. Although traditional evidence provides a valuable starting point, it has many limitations, especially with regard to issues of safety. Careful patient observation is likely to detect immediate or serious adverse effects, but is less likely to identify slow-onset responses or mild to moderate side effects that could be considered symptoms of a new disease. Additionally, many medicinal preparations contained multiple ingredients, making it difficult to identify which one might be responsible for inducing an adverse reaction.


More recently, the traditional evidence base has been joined by a scientific evidence base, which provides additional information about pharmacological actions, clinical effects and safety; however, much still remains unknown.



Clinical note — History of poisons


The history of poisons dates back to the earliest times, when humans observed toxic effects in nature, most likely by chance. By 1500 BC, written records indicate that the poisons hemlock, opium and certain metals were used in warfare and in facilitating executions. Over time, poisons were used with greater sophistication; notable poisoning victims include Socrates, Cleopatra and Claudius. Today, the ‘science of poisons’ is known as toxicology. This field of learning investigates the chemical and physical properties of poisons and their physiological or behavioural effects on living organisms, and uses qualitative and quantitative methods for analysis and for the development of procedures to treat poisoning (Langman & Kapur 2006). The 20th century was marked by an advanced understanding of toxicology; DNA and various biochemicals that maintain cellular functions were discovered, so that today we are discovering the toxic effects on organs and cells at the molecular level.


This is particularly true regarding the safety of CMs in children and in women who are pregnant or lactating, and concerning drug interactions, which is a relatively new phenomenon. Just as Galen pronounced hundreds of years ago, ‘First, do no harm’ should remain the practitioner’s guide.



WHAT IS SAFETY?


Safety is a complex issue that is determined by considering the interaction between ‘likelihood’ and ‘consequence’. These two variables will differ for each medicine and individual. The likelihood can be graded from ‘near impossible’ to ‘certainly likely’, and the severity of consequence can be graded from ‘negligible’ to ‘serious and life-threatening’, with many outcomes lying somewhere between these extremes (Fig 7.1).


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FIGURE 7.1 Interaction between the two variables of ‘likelihood’ and ‘severity of consequence’ with regard to medication safety


With regard to medication safety, avoidance of an adverse drug reaction (ADR) is paramount. Several factors are associated with an increased likelihood of developing an ADR, such as advanced age and polypharmacy, but most ADRs occur in people who are prescribed treatment within the limits of accepted clinical practice (Burgess et al 2005).



BENEFITS, RISK AND HARM


Many different sources of risk are associated with therapeutic products:


• The product itself — side effects and toxicity of ingredients, administration form, potential harm through excessive dosage and length of time used.

• Manufacturing factors — poor manufacturing process, which introduces contaminants, uses unsafe excipients or incorrect ingredients etc.

• Prescribing faults — incorrect product prescribed, based on insufficient information about it, the patient or the disease, or simply negligence.

• Patient factors — incorrect use of a product when information for appropriate use is poorly understood, or insufficient or inappropriate self-diagnosis and treatment.

Whenever a treatment is chosen, it is done so in the belief that its potential benefit will outweigh its potential to cause harm. Practice guidelines and traditions provide guidance when making risk–benefit evaluations and are based on common treatment decisions made many times before by many clinicians, together with the available evidence. The safety information tends to come from a variety of sources, such as post-marketing surveillance and spontaneous reporting schemes, laboratory and animal studies, anecdotal reports, theoretical reasoning and, increasingly, formal studies.


The amount of safety literature published on pharmaceutical medicines is overwhelming. It has been estimated that 30% of the primary published literature about ADR appears in anecdotal reports and 35% as formal studies or randomised controlled trials (Aronson et al 2002). As regards the safety of complementary medicines, traditional evidence and theoretical reasoning are heavily relied upon to provide guidance because relatively little reliable information has been published in the peer-reviewed literature. This poses a challenge for practitioners when making a rational decision about the relative risks of treatment and is one of the great difficulties of CAM practice. For the public who are interested in using OTC products, it is just as difficult to find reliable and understandable information about their safety and efficacy.



ADVERSE DRUG REACTIONS (ADRs)


The World Health Organization defines an ADR as a ‘response to a medicine which is noxious and unintended that occurs at doses normally used in humans’. When two medicines interact in a way that produces an unwanted effect, this is also referred to as an ADR. Adverse reactions have been classified into different types depending on severity and likelihood or onset of reaction, and do not always result in serious outcomes; however, an ADR is considered serious when it is suspected of causing death, danger to life, admission to hospital, prolongation of hospital stay, absence from productive activity, increased investigational or treatment costs, or birth defects.


Adverse reactions can arise from either an intrinsic or an extrinsic effect. An intrinsic effect refers to the active ingredient itself, such as the herbal medicine present within a product, whereas an extrinsic effect relates to product characteristics resulting from poor manufacturing processes or quality control, such as contamination and adulteration. Intrinsic adverse effects can be categorised in a similar way to pharmaceutical medicines and are mainly type A or type B reactions.



Type A reactions


Type A reactions are the most common form and are typically dose-related, predictable from the known pharmacology of the medicine, associated with high morbidity but low mortality, and potentially avoidable (Routledge et al 2004). People most at risk of a type


TABLE 7.1 Potential Risks Associated With the Use of Complementary Medicines
























Type of harm Circumstances
Delay in diagnosis
When a patient has avoided or delayed seeking medical advice because they are self-treating with CMs.

When a complementary medicine practitioner has not referred a patient to a medical practitioner for early diagnosis.
Adverse effects
Increased risk of adverse reactions with inappropriate use of CM products or when patients self-select CM products without professional advice.

Increased risk if products used are not manufactured to pharmaceutical grade quality.
Drug interactions Increased risk of drug interactions when patients: (a) self-select CM products without professional advice; (b) do not disclose use of CM products to their pharmacist or medical physician; (c) do not disclose use of pharmaceutical drugs to their CM practitioner.
Financial cost If an expensive medicine or therapy is not providing benefits and a patient continues to use it, this presents an unnecessary financial burden.
Lost opportunity to treat Failure to undertake a different treatment with proven benefits, when the current treatment is ineffective but is being used to the exclusion of others.
False hope of a cure When cure is unlikely, the use of any medicine or therapy that is associated with false hope may delay important considerations, such as attending to ‘unfinished business’.

A reaction are frail, older patients who are also likely to be receiving a combination of medicines and those with altered hepatic or renal function. There is now mounting evidence to indicate that some type A adverse reactions are due to genetic polymorphisms, which affect an individual’s drug clearance rate and therefore toxicological response. This may explain why certain individuals taking medicines in the recommended doses experience adverse reactions, whereas the majority of the population does not. Examples related to pharmaceutical medicine are bleeding with anticoagulants and hypoglycaemia with the use of insulin. An example for herbal medicine is licorice-associated hypertension, which is thought to be caused by increased renal sodium retention. The glycyrrhetinic acid in licorice inhibits renal 11-beta-hydroxysteroid dehydrogenase type 2 and, by that mechanism, increases the access of cortisol to the mineralocorticoid receptor that causes renal sodium retention and potassium loss. If continued for sufficient time, clinically significant changes in blood pressure and potassium status develop, which can be avoided by recommending that high-dose licorice herbal products not be used for longer than 2 weeks (Heilmann et al 1999). In recognition of this adverse effect, some manufacturers produce licorice products that do not contain glycyrrhetinic acid, so that they can be used more safely in the long term.


Table 7.2 gives some examples of known or suspected type A adverse reactions to herbs and natural supplements. For many herbal and natural medicines, there is insufficient reliable information about possible adverse reactions; where available, evidence from clinical trials, case reports and post-marketing surveillance systems are the main sources of information used in this book.


TABLE 7.2 Examples of Known or Suspected Type A Adverse Reactions to Herbs and Natural Supplements




































Herb or natural supplement Adverse effect/s
Andrographis paniculata Vomiting, anorexia and gastrointestinal discomfort
Creatine Nausea, vomiting, cramping, dehydration, fluid retention
Trigonella foenum (fenugreek) Diarrhoea, flatulence
Fish oils Gastrointestinal discomfort, diarrhoea
Allium sativum (garlic) Breath and body odour, nausea, dyspepsia, flatulence, diarrhoea, increased bleeding
Zingiber officinale (ginger) Gastric irritation, dyspepsia
Camellia sinensis (green or black tea) CNS stimulation
Gymnema sylvestre Hypoglycaemia
Paullinia cupana (guarana) CNS stimulation
Selenium Nausea, vomiting, irritability, fatigue, nail changes


Type B reactions


Type B reactions are idiosyncratic and uncommon, difficult to predict and not dose related. They tend to have higher morbidity and mortality than type A reactions and are often immunologically mediated (Myers & Cheras 2004). Other factors contributing to type B reactions are receptor or drug metabolism abnormalities and the unmasking of a biological deficiency (e.g. glucose-6-phosphate dehydrogenase deficiency) (Bryant et al 2003). They do not appear to relate to genetic polymorphisms.


An example of a type B reaction to a pharmaceutical drug is interstitial nephritis with the use of NSAIDs. With regard to CMs, Asteracaea dermatitis provides a good example of a type B hypersensitivity reaction — specifically, an allergic contact dermatitis caused by exposure to allergens from the Asteraceae family or the daisy group of plants and plant extracts. Some examples of common plants that belong to this family are arnica (Arnica montana), chamomile (Chamomilla recucita), marigold (Calendula officinalis), echinacea (Echinacea spp), tansy (Tanacetum vulgare), feverfew (Tanacetum parthenium) and yarrow (Achillea millefolium). The most important allergens in the Asteraceae family are the sesquiterpene lactones, which are present in the oleoresin fraction of the leaves, stems, flowers and possibly pollen (Gordon 1999). The condition is most frequently seen in middle-aged and elderly people; it typically starts in summer and disappears in the autumn or winter. The dermatitis manifests as eczema and can develop from exposure to airborne particles, direct topical application (such as cosmetics, perfumes, essential oils) or oral ingestion of allergenic components. The diagnosis of allergy can be difficult to establish, because there are few completely reliable laboratory tests and sometimes symptoms can mimic infectious disease symptoms. Table 7.3 gives examples of known or suspected type B adverse reactions.


TABLE 7.3 Examples of Known or Suspected Type B Adverse Reactions to Herbs and Natural Supplements



























Herb or natural supplement Adverse effect/s
Andrographis paniculata Urticaria
Aloe vera Hypersensitivity and contact dermatitis
Chamomilla recutita Asteraceae dermatitis
Echinacea spp Asteraceae dermatitis and anaphylaxis
Tanacetum parthenium (feverfew) Asteraceae dermatitis — lip swelling, mouth ulceration and soreness when the leaves are chewed
Zingiber officinale (ginger) Contact dermatitis with topical use
Thymus vulgaris (thyme) Contact dermatitis with topical use of the oil
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Jul 18, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Safety and complementary medicines

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