Clinical Pharmacology, 11e

Topics in drug therapy

Mike Schachter, Sir Peter Rubin

Synopsis

Drug therapy involves considerations beyond the strictly scientific pharmacological aspects of medicines. These include numerous issues relating to prescribers and to patients:

• Practical prescribing.

• The therapeutic situation.

• Treating patients with drugs.

• Iatrogenic disease.

• Benefits and risks.

• Public view of drugs and prescribers.

• Criticisms of modern drugs.

• Drug-induced injury.

• Complementary and alternative medicine.

• Placebo medicines.

• Guidelines, ‘essential’ drugs and prescribing.

• Compliance – patient and doctor.

• Pharmacoeconomics.

Practical prescribing

Sir Peter Rubin

First, on this topic, Professor Sir Peter Rubin, Chair of the General Medical Council, the body that regulates the practice of medicine by doctors in the UK, writes on the prescribing of medicines.

Prescribing is a task carried out many times each day and can seem mundane – a technical process that is far less stimulating and interesting than reaching a diagnosis. However, there is no such thing as a safe drug and prescribing has the potential to cause harm or death as well as good. This section includes some practical advice aimed at identifying common pitfalls and reducing risk.

The case histories are all real. The data given in the text and figures come from a study commissioned by the General Medical Council.1

Prescribing

Getting it right

Good prescribing starts with taking a good history:

• Does your patient have other medical conditions – some may be worsened by treatment you would normally give for their presenting complaint.

• What drugs is your patient taking now? What are they for? Are they all still needed? Could they be causing the symptoms or signs that have brought the patient to you? Could they interact with whatever you might think of prescribing?

• What drugs has your patient taken in the past? Why were they stopped? Did they cause side-effects?

• Is the patient allergic to any drugs?

• Are they taking any non-prescription (over-the-counter) drugs? If so, could they interact with whatever you might prescribe (for example, St John's wort is an enzyme-inducer)?

Good prescribing means:

• Making a diagnosis – or at least having a range of possibilities. Know what it is you are wishing to achieve and the evidence for the likely efficacy of the drug treatment you wish to give.

• Knowing your patient's kidney and liver function – most drugs are eliminated by these organs; and some drugs can damage them.

• Getting the dose right. For many drugs you will not know the dose, so do not pretend you do. Never, ever guess. Never be afraid to ask. Never be too busy to look up a dose – better to check now than make a trip to the Coroner's Court later.

• Explaining to your patient why you think this treatment will work, the likelihood of it working, the more common side-effects and what your plans are if it does not work.

• Being alert to the development of adverse drug reactions. If a patient develops new symptoms after starting a drug, it is probably the drug. If the adverse effect is in a fairly new drug – or is not already well known – you should report the event to the national body responsible for monitoring and recording adverse drug reactions.

• Being very clear about what it is you are prescribing.

• If using a hand-written prescription, write clearly.

• If working in a different hospital, remember that the prescription chart may not be the same as where you have just been.

• If using electronic prescribing, beware drop-down menus and drugs with similar looking names, e.g. carbimazole and carbamazepine.

Examples of when things went wrong

Focusing on the presenting complaint and forgetting other medical conditions

A 79-year-old man was admitted to a surgical ward. He told the admitting doctor that he had long-standing arthritis which had got worse since his doctor stopped diclofenac and he asked for it to be re-started. The doctor did so, but did not notice the patient's significant renal impairment. The patient went into renal failure and died. A drug which helps one condition may worsen another!

Forgetting that women get pregnant

A 40-year-old woman is found to be hypertensive. She has three children, the youngest being 15. Her GP commences ramipril. Neither the patient nor the doctor suspected that she was, in fact, in the second trimester of pregnancy. The baby died at birth from major renal and other abnormalities. Subsequent litigation was settled out of court in the patient's favour. Remember that pregnancy is always a possibility in women of child-bearing age!

Not knowing what you are prescribing

A 29-year-old woman came to the hospital with a urinary tract infection. The consultant told a young doctor looking after her to prescribe Penbritin®. She did so and the patient died from penicillin anaphylaxis despite having a bracelet warning of the allergy. Neither the young doctor nor the nurse who administered the drug had bothered to find out what they were giving, namely ampicillin. Know what you are prescribing!

Forgetting that a newly prescribed drug can interact with long-term drug treatment

A 64-year-old man had been taking warfarin for many years. He developed a chest infection and an out of hours doctor prescribed amoxicillin. Later that week he was admitted with a large, painful right knee haemarthrosis and an INR > 10 (see p. 489). New drugs may interact with those the patient has been taking for a long time!

Top ten prescribing errors in a UK hospital setting1

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Error

% of errors

Omission on admission

29.8

Wrong dose

19.6

No dose given

11.0

Wrong/no formulation

7.5

Omission on discharge

6.2

Wrong dosing intervals

6.1

Duplication

5.5

Wrong drug

3.1

No signature

1.7

Contraindication

1.1

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Why do mistakes happen?

Human error in one form or another – rather than a simple lack of knowledge – is responsible for most prescribing mistakes. Newly qualified doctors are no more likely than their older colleagues to prescribe incorrectly. Many factors associated with prescribing mistakes are common to mistakes in all walks of life and include the following:

• Rushing.

• Tired.

• Doing several things at once.

• Communication breakdown.

There are also factors specific to the medical environment, including:

• Not familiar with the drug chart (usually on moving to a new hospital).

• Unfamiliar patient – and not taking the time to become familiar with the full medical and drug history.

• Arithmetical errors in calculating dose.

• Omitting drugs for a newly admitted patient because of inadequate information.

When lack of knowledge does play a part, it is often the flawed application of knowledge in that particular patient – i.e. the right drug for the presenting condition, but the wrong drug for that patient because of coexisting medical or drug factors.

What all this adds up to is: prescribing is important, must be taken seriously and must be given the time and care that your patient deserves.

The General Medical Council expects that, by the time they graduate, medical students will be able to:2

• Prescribe drugs safely, effectively and economically.

• Establish an accurate drug history, covering both prescribed and other medication.

• Plan appropriate drug therapy for common indications, including pain and distress.

• Provide a safe and legal prescription.

• Calculate appropriate drug doses and record the outcome accurately.

• Provide patients with appropriate information about their medicines.

• Access reliable information about medicines.

• Detect and report adverse drug reactions.

• Demonstrate awareness that many patients use complementary and alternative therapies, and awareness of the existence and range of these therapies, why patients use them, and how this might affect other types of treatment that patients are receiving.

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‘The desire to take medicines is perhaps the greatest feature that distinguishes man from animals’ (Sir William Osler, 1849–1919).

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The therapeutic situation

Mike Schachter

Some background

Alleviating effects of disease and trauma has been a major concern of human beings from the earliest times. Records of the ancient civilisations of Mesopotamia (modern Iraq), India, China, Mexico and Egypt, from about 3000 BC, describe practices of diagnosis and treatment predicated on differing, often complex, concepts of disease: the supernatural, religious theories (sin, punishment of sin, uncleanness), omens, deities and rites. Among many modes of therapy, a reliance on diet and use of herbs figured prominently (the Mexicans knew of 1200 medicinal plants).

From about 500 BC, the Greek system of humoural medicine began to replace the supernatural with thinking that was rational, scientific and naturalistic. Its core concept was that health was an equilibrium, and disease a disequilibrium, of the four constituent fluids or ‘humours’ of the body (yellow bile, phlegm, blood and black bile). It followed that the condition was correctable by evacuation techniques to re-establish the balance, and hence came blooding, leeching, cathartics, sweating and emetics. Here, the focus was on the patient, as the degree of humoural imbalance was specific to that individual.

Remarkably, this system persisted among ‘learned and rational’ (i.e. university-trained) physicians until it was challenged in the 17th century. Thomas Sydenham3 (1624–1689) showed that during epidemics, many people could suffer the same disease, and different epidemics had distinct characteristics. Later, Giovanni Morgagni (1682–1771), by correlating clinical and autopsy findings, demonstrated that diseases related to particular organs. Now the study of disease, rather than the patient, became the centre of attention. Yet it was only in the 19th century that medicine developed as a science, when the microscope revealed the cell as the basic construction unit of the body and specific entities of pathology became recognisable, most notably in the case of infection with microorganisms (‘germ theory’).

The one major dimension of medicine that remained underdeveloped was therapeutics. An abundance of preparations in pharmacopoeias compared with a scarcity of genuinely effective therapies contributed to a state of ‘therapeutic nihilism’, expressed trenchantly by Oliver Wendell Holmes (1809–1894):

Throw out opium …; throw out a few specifics …; throw out wine, which is a food, and the vapours which produce the miracle of anaesthesia, and I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind, – and all the worse for the fishes…4

The writer was exaggerating to emphasise his point, but the position was to change throughout the 20th century as understanding of human physiology and pathophysiology deepened and agents that could be relied on to interfere with these processes became available. Modern physicians have at their disposal an array of medicines that empowers them to intervene beneficially in disease but also carries new responsibilities.

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Drug therapy involves a great deal more than matching the name of the drug to the name of a disease; it requires knowledge, judgement, skill and wisdom, but above all a sense of responsibility.

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Treating patients with drugs

A book can provide knowledge and contribute to the formation of judgement, but it can do little to impart skill and wisdom, which are the products of example of teachers and colleagues, of experience and of innate and acquired capacities. But: ‘It is evident that patients are not treated in a vacuum and that they respond to a variety of subtle forces around them in addition to the specific therapeutic agent.’5

When a patient receives a drug, the response can be the result of numerous factors:

• The pharmacodynamic effect of the drug and interactions with any other drugs the patient may be taking.

• The pharmacokinetics of the drug and its modification in the individual by genetic influences, disease, other drugs.

• The act of medication, including the route of administration and the presence or absence of the doctor.

• What the doctor has told the patient.

• The patient's past experience of doctors.

• The patient's estimate of what has been received and of what ought to happen as a result.

• The social environment, e.g. whether it is supportive or dispiriting.

The relative importance of these factors varies according to circumstances. An unconscious patient with meningococcal meningitis does not have a personal relationship with the doctor, but patients sleepless with anxiety because they cannot cope with their family responsibilities may respond as much to the interaction of their own personality with that of the doctor as to anxiolytics.

The physician may consciously use all of the factors listed above in therapeutic practice. But it is still not enough that patients get better: it is essential to know why they do so. This is because potent drugs should be given only if their pharmacodynamic effects are needed; many adverse reactions have been shown to be due to drugs that are not needed, including some severe enough to cause hospital admission.

Drugs can do good

Medically, this good may sometimes seem trivial, as in the avoidance of a sleepless night in a noisy hotel or of social embarrassment from a profusely running nose due to seasonal pollen allergy (hay fever). Such benefits are not necessarily trivial to recipients, concerned to be at their best in important matters, whether of business, pleasure or passion, i.e. with quality of life.

Or the good may be literally life-saving, as in serious acute infections (pneumonia, septicaemia) or in the prevention of life-devastating disability from severe asthma, from epilepsy or from blindness due to glaucoma.

Drugs can do harm

This harm may be relatively trivial, as in hangover from a hypnotic or transient headache from glyceryl trinitrate used for angina.

The harm may be life-destroying, as in the rare sudden death following an injection of penicillin, rightly regarded as one of the safest of antibiotics, or the destruction of the quality of life that occasionally attends the use of drugs that are effective in rheumatoid arthritis (adrenocortical steroids, penicillamine) and Parkinson's disease (levodopa).

There are risks in taking medicines, just as there are risks in food and transport. There are also risks in declining to take medicines when they are needed, just as there are risks in refusing food or transport when they are needed.

Efficacy and safety do not lie solely in the molecular structure of the drug. Doctors must choose which drugs to use and must apply them correctly in relation not only to their properties, but also to those of the patients and their disease. Then patients must use the prescribed medicine correctly (see Compliance p. 21).

Uses of drugs/medicines

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Drugs are used in three principal ways:

• To cure disease: primary and auxiliary.

• To suppress disease.

• To prevent disease (prophylaxis): primary and secondary.

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Cure

implies primary therapy, as in bacterial and parasitic infections, that eliminates the disease and the drug is withdrawn; or auxiliary therapy, as with anaesthetics and with ergometrine and oxytocin in obstetrics.

Suppression

of diseases or symptoms is used continuously or intermittently to avoid the effects of disease without attaining cure (as in hypertension, diabetes mellitus, epilepsy, asthma), or to control symptoms (such as pain and cough) while awaiting recovery from the causative disease.

Prevention

(prophylaxis). In primary prevention, the person does not have the condition and avoids getting it. For malaria, vaccinations and contraception, the decision to treat healthy people is generally easy.

In secondary prevention, the patient has the disease and the objective is to reduce risk factors, so as to retard progression or avoid repetition of an event, e.g. aspirin and lipid-lowering drugs in atherosclerosis and after myocardial infarction, antihypertensives to prevent recurrence of stroke.

Taking account of the above, a doctor might ask the following questions before treating a patient with drugs:

1. Should I interfere with the patient at all?

2. If so, what alteration in the patient's condition do I hope to achieve?

3. Which drug is most likely to bring this about?

4. How can I administer the drug to attain the right concentration in the right place at the right time and for the right duration?

5. How will I know when I have achieved the objective?

6. What other effects might the drug produce, and are these harmful?

7. How will I decide to stop the drug?

8. Does the likelihood of benefit, and its importance, outweigh the likelihood of damage, and its importance, i.e. the benefit versus risk, or efficacy against safety?

Physician-induced (iatrogenic) disease

They used to have a more equitable contract in Egypt: for the first three days the doctor took on the patient at the patient's risk and peril: when the three days were up, the risks and perils were the doctor's.

But doctors are lucky: the sun shines on their successes and the earth hides their failures.6

It is a salutary thought that each year medical errors kill an estimated 44 000–98 000 Americans (more than die in motor vehicle accidents) and injure 1 000 000.7 Among inpatients in the USA and Australia, about half of the injuries caused by medical mismanagement result from surgery, but therapeutic mishaps and diagnostic errors are the next most common. In one survey of adverse drug events, 1% were fatal, 12% life-threatening, 30% serious and 57% significant.8 About half of the life-threatening and serious events were preventable. Errors of prescribing account for one-half and those of administering drugs for one-quarter of these. Inevitably, a proportion of lapses result in litigation, and in the UK 20–25% of complaints received by the medical defence organisations about general practitioners follow medication errors.

The most shameful act in therapeutics, apart from actually killing a patient, is to injure a patient who is but little disabled or who is suffering from a self-limiting disorder. Such iatrogenic disease,9 induced by misguided treatment, is far from rare.

Doctors who are temperamentally extremist will do less harm by therapeutic nihilism than by optimistically overwhelming patients with well-intentioned polypharmacy. If in doubt whether or not to give a drug to a person who will soon get better without it, don't.

In 1917 the famous pharmacologist Sollmann felt able to write:

Pharmacology comprises some broad conceptions and generalisations, and some detailed conclusions, of such great and practical importance that every student and practitioner should be absolutely familiar with them. It comprises also a large mass of minute details, which would constitute too great a tax on human memory, but which cannot safely be neglected.10

The doctor's aim must be not merely to give the patient what will do good, but to give only what will do good – or at least more good than harm. The information explosion of recent decades is now under better control such that prescribers can, from their desktop computer terminals, enter the facts about their patient (age, sex, weight, principal and secondary diagnoses) and receive suggestions for which drugs should be considered, with proposed doses and precautions.

Benefits and risks of medicines

Modern technological medicine has been criticised, justly, for following the tradition of centuries by waiting for disease to occur and then trying to cure it rather than seeking to prevent it in the first place. Although many diseases are partly or wholly preventable by economic, social and behavioural means, these are too seldom adopted and are slow to take effect. In the meantime, people continue to fall sick, and to need and deserve treatment.

We all have eventually to die from something and, even after excessive practising of all the advice on how to live a healthy life, the likelihood that the mode of death for most of us will be free from pain, anxiety, cough, diarrhoea, paralysis (the list is endless) seems so small that it can be disregarded. Drugs already provide immeasurable solace in these situations, and the development of better drugs should be encouraged.

Doctors know the sick are thankful for drugs, just as even the most dedicated pedestrians and environmentalists struck down by a passing car are thankful for a motor ambulance to take them to hospital. The reader will find reference to the benefits of drugs in individual diseases throughout this book and further expansion is unnecessary here. But a general discussion of risk of adverse events is appropriate.

Unavoidable risks

Consider, for the sake of argument, the features that a completely risk-free drug would exhibit:

• The physician would know exactly what action is required and use the drug correctly.

• The drug would deliver its desired action and nothing else, either by true biological selectivity or by selective targeted delivery.

• The drug would achieve exactly the right amount of action – neither too little, nor too much.

These criteria may be completely fulfilled, for example in a streptococcal infection sensitive to penicillin in patients whose genetic constitution does not render them liable to an allergic reaction to penicillin.

These criteria are partially fulfilled in insulin-deficient diabetes. But the natural modulation of insulin secretion in response to need (food, exercise) does not operate with injected insulin and even sophisticated technology cannot yet exactly mimic the normal physiological responses. The criteria are still further from realisation in, for example, some cancers and schizophrenia.

Some reasons why drugs fail to meet the criteria of being risk-free include the following:

• Drugs may be insufficiently selective. As the concentration rises, a drug that acts at only one site at low concentrations begins to affect other target sites (receptors, enzymes) and recruit new (unwanted) actions; or a disease process (cancer) is so close to normal cellular mechanisms that perfectly selective cell kill is impossible.

• Drugs may be highly selective for one pathway but the mechanism affected has widespread functions and interference with it cannot be limited to one site only, e.g. atenolol on the β-adrenoceptor, aspirin on cyclo-oxygenase.

• Prolonged modification of cellular mechanisms can lead to permanent change in structure and function, e.g. carcinogenicity.

• Insufficient knowledge of disease processes (some cardiac arrhythmias) and of drug action can lead to interventions that, although undertaken with the best intentions, are harmful.

• Patients are genetically heterogeneous to a high degree and may have unpredicted responses to drugs.

• Dosage adjustment according to need is often unavoidably imprecise, e.g. in depression.

• Prescribing ‘without due care and attention’.11

Reduction of risk

Strategies that can limit risk include those directed at achieving:

• Better knowledge of disease (research) – as much as 40% of useful medical advances derive from basic research that was not funded towards a specific practical outcome.

• Site-specific effect – by molecular manipulation.

• Site-specific delivery – drug targeting:

  image by topical (local) application

  image by target-selective carriers.

• Informed, careful and responsible prescribing.

Two broad categories of risk

1. First are those that we accept by deliberate choice. We do so even if we do not exactly know their magnitude, or we know but wish they were smaller, or, especially when the likelihood of harm is sufficiently remote though the consequences may be grave, we do not even think about the matter. Such risks include transport and sports, both of which are inescapably subject to potent physical laws such as gravity and momentum, and surgery to rectify disorders that we could tolerate or treat in other ways, as with much cosmetic surgery.

2. Second are those risks that cannot be significantly altered by individual action. We experience risks imposed by food additives (preservatives, colouring), air pollution and some environmental radioactivity. But there are also risks imposed by nature, such as skin cancer due to excess ultraviolet radiation in sunny climes, as well as some radioactivity.

It seems an obvious course to avoid unnecessary risks, but there is disagreement on what risks are truly unnecessary and, on looking closely at the matter, it is plain that many people habitually take risks in their daily and recreational life that it would be a misuse of words to describe as necessary. Furthermore, some risks, although known to exist, are, in practice, ignored other than by conforming to ordinary prudent conduct. These risks are negligible in the sense that they do not influence behaviour, i.e. they are neglected.12

Elements of risk

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Risk has two elements:

• The likelihood or probability of an adverse event.

• Its severity.

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In medical practice in general, concern ceases when risks fall below about 1 in 100 000 instances, when the procedure then is regarded as ‘safe’. In such cases, when disaster occurs, it can be difficult indeed for individuals to accept that they ‘deliberately’ accepted a risk; they feel ‘it should not have happened to me’ and in their distress they may seek to lay blame on others where there is no fault or negligence, only misfortune (see Warnings and consent).

The benefits of chemicals used to colour food verge on or even attain negligibility, although some cause allergy in humans. Our society permits their use.

There is general agreement that drugs prescribed for disease are themselves the cause of a significant amount of disease (adverse reactions), of death, of permanent disability, of recoverable illness and of minor inconvenience. In one major UK study the prevalence of adverse drug reactions as a cause of admission to hospital was 6.5% (see Chapter 9 for other examples).

Three major grades of risk

These are: unacceptable, acceptable and negligible. Where disease is life-threatening and there is reliable information on both the disease and the drug, then decisions, though they may be painful, present relatively obvious problems. But where the disease risk is remote, e.g. mild hypertension, or where drugs are to be used to increase comfort or to suppress symptoms that are, in fact, bearable, or for convenience rather than for need, then the issues of risk acceptance are less obvious.

Risks should not be weighed without reference to benefits any more than benefits should be weighed without reference to risks.

Risks are among the facts of life. In whatever we do and in whatever we refrain from doing, we are accepting risk. Some risks are obvious, some are unsuspected and some we conceal from ourselves. But risks are universally accepted, whether willingly or unwillingly, whether consciously or not.13

Whenever a drug is taken a risk is taken

The risk comprises the properties of the drug, the prescriber, the patient and the environment; it is often so small that second thoughts are hardly necessary, but sometimes it is substantial. The doctor must weigh the likelihood of gain for the patient against the likelihood of loss. There are often insufficient data for a rational decision to be reached, but a decision must yet be made, and this is one of the greatest difficulties of clinical practice. Its effect on the attitudes of doctors is often not appreciated by those who have never been in this situation. The patient's protection lies in the doctor's knowledge of the drug and of the disease, and experience of both, together with knowledge of the patient.

We continue to use drugs that are capable of killing or disabling patients at doses within the therapeutic range where the judgement of overall balance of benefit and risk is favourable. This can be very difficult for the patient who has suffered a rare severe adverse reaction to understand and to accept (see below).

In some chronic diseases that ultimately necessitate suppressive drugs, the patient may not experience benefit in the early stages. Patients with early Parkinson's disease may experience little inconvenience or hazard from the condition, and premature exposure to drugs can exact such a price in unwanted effects that they prefer the untreated state. What patients will tolerate depends on their personality, their attitude to disease, their occupation, mode of life and relationship with their doctor (see Compliance, p. 21).

Public view of drugs and prescribers

The current public view of modern medicines, ably fuelled by the mass media, is a compound of vague expectation of ‘miracle’ cures and ‘breakthroughs’ (often with the complicity of doctors) with outrage when anything goes wrong. It is also unreasonable to expect the public to trust the medical profession (in collaboration with the pharmaceutical industry) to the extent of leaving to them all drug matters, and of course this is not the case.

The public wants benefits without risks and without having to alter its unhealthy ways of living; a deeply irrational position, but then humans are not perfectly rational. It is easy to understand that a person who has taken into his body a chemical with intent to relieve suffering, whether or not it is self-induced, can feel profound anger when harm ensues.

Expectations have been raised and now, at the beginning of the 21st century, with the manifest achievements of technology all around us, the naive expectation that happiness can be a part of the technological package is increasingly seen to be unrealisable.

Patients are aware that there is justifiable criticism of the standards of medical prescribing – indeed doctors are in the forefront of this – as well as justifiable criticism of promotional practices of the profitably rich, aggressive, transnational pharmaceutical industry.

There are obvious areas where some remedial action is possible:

• Improvement of prescribing by doctors, including better communication with patients, i.e. doctors must learn to feel that introduction of foreign chemicals into their patients' bodies is a serious matter, which many or most do not seem to feel at present.14

• Introduction of no-fault compensation schemes for serious drug injury (some countries already have these).

• Informed public discussion of the issues between the medical profession, industrial drug developers, politicians and other ‘opinion-formers’ in society, and patients (the public).

• Restraint in promotion by the pharmaceutical industry including self-control by both industry and doctors in their necessarily close relationship, which the public is inclined to regard as a conspiracy, especially when the gifts and payments made to doctors get into the news. (This is much less prevalent than it was in the 1990s.)

If restraint by both parties is not forthcoming, and it may not be, then both doctor and industry can expect even more control to be exercised over them by politicians responding to public demand. If doctors do not want their prescribing to be restricted, they should prescribe better.

Criticisms of modern drugs

Extremist critics have attracted public attention for their view that modern drug therapy, indeed modern medicine in general, does more harm than good; others, while admitting some benefits from drugs, insist that this is medically marginal. These opinions rest on the undisputed fact that favourable trends in many diseases preceded the introduction of modern drugs and were due to economic and environmental changes, sanitation, nutrition and housing. They also rest on the claim that drugs have not changed expectation of life or mortality (as measured by national mortality statistics), or at least it is very difficult to show that they have, and that drugs indisputably can cause illness (adverse reactions).

If something is to be measured then the correct criteria must be chosen. Overall mortality figures are an extremely crude and often an irrelevant measure of the effects of drugs whose major benefits are so often on quality of life rather than on its quantity.

Two examples of inappropriate measurements will suffice:

1. In the case of many infections it is not disputed that environmental changes have had a greater beneficial effect on health than the subsequently introduced antimicrobials. But this does not mean that environmental improvements alone are sufficient in the fight against infections. When comparisons of illnesses in the pre- and post-antimicrobial eras are made, like is not compared with like. Environmental changes achieved their results when mortality from infections was high and antimicrobials were not available; antimicrobials were introduced later against a background of low mortality as well as of environmental change; decades separate the two parts of the comparison, and observers, diagnostic criteria and data recording changed during this long period. It is evident that determining the value of antimicrobials is not simply a matter of looking at mortality rates.

2. About 1% of the UK population has diabetes mellitus, a figure which is increasing rapidly, and about 1% of death certificates mention diabetes. This is no surprise because all must die and insulin is no cure15 for this lifelong disease. A standard medical textbook of 1907 stated that juvenile-onset ‘diabetes is in all cases a grave disease, and the subjects are regarded by all assurance companies as uninsurable lives: life seems to hang by a thread, a thread often cut by a very trifling accident’. Most, if not all, life insurance companies now accept young people with diabetes with no or only modest financial penalty, the premium of a person 5–10 years older. Before insulin replacement therapy was available few survived beyond 3 years16 after diagnosis; they died for lack of insulin. It is unjustified to assert that a treatment is worthless just because its mention on death certificates (whether as a prime or as a contributory cause) has not declined. The relevant criteria for juvenile-onset diabetes are change in the age at which the subjects die and the quality of life between diagnosis and death, and both of these have changed enormously.

Drug-induced injury17 (see also Ch. 9)

Responsibility for drug-induced injury raises important issues affecting medical practice and development of needed new drugs, as well as of law and of social justice.

Negligence and strict and no-fault liability

All civilised legal systems provide for compensation to be paid to a person injured as a result of using a product of any kind that is defective due to negligence (fault: failure to exercise reasonable care).18 But there is a growing opinion that special compensation for serious personal injury, beyond the modest sums that general social security systems provide, should be automatic and not dependent on fault and proof of fault of the producer, i.e. there should be ‘liability irrespective of fault’, ‘no-fault liability’ or ‘strict liability’.19 After all, victims need assistance (compensation) regardless of the cause of injury and whether or not the producer and, in the case of drugs, the prescriber deserves censure. The question why a person who has suffered injury due to the biological accident of disease should have to depend on social security payments while an identical injury due to a drug (in the absence of fault) should attract special added compensation receives no persuasive answer except that this is what society seems to want.

Many countries are now revising their laws on liability for personal injury due to manufactured products and are legislating Consumer Protection Acts (Statutes) which include medicines, for ‘drugs represent the class of product in respect of which there has been the greatest pressure for surer compensation in cases of injury’.20

Issues that are central to the debate include:

• Capacity to cause harm is inherent in drugs in a way that sets them apart from other manufactured products; and harm often occurs in the absence of fault.

• Safety, i.e. the degree of safety that a person is entitled to expect, and adverse effects that should be accepted without complaint, must often be a matter of opinion and will vary with the disease being treated, e.g. cancer or insomnia.

• Causation, i.e. proof that the drug in fact caused the injury, is often impossible, particularly where it increases the incidence of a disease that occurs naturally.

• Contributory negligence. Should compensation be reduced in smokers and drinkers where there is evidence that these pleasure drugs increase liability to adverse reactions to therapeutic drugs?

• The concept of defect, i.e. whether the drug or the prescriber or indeed the patient can be said to be ‘defective’ so as to attract liability, is a highly complex matter and indeed is a curious concept as applied to medicine.

Nowhere has a scheme that meets all the major difficulties yet been implemented. This is not because there has been too little thought, it is because the subject is so difficult. Nevertheless, no-fault schemes operate in New Zealand, Scandinavia and France.21 The following principles might form the basis of a workable compensation scheme for injury due to drugs:

• New unlicensed drugs undergoing clinical trial in small numbers of subjects (healthy or patient volunteers): the developer should be strictly liable for all adverse effects.

• New unlicensed drugs undergoing extensive trials in patients who may reasonably expect benefit: the producer should be strictly liable for any serious effect.

• New drugs after licensing by an official body: the manufacturer and the community should share liability for serious injury, as new drugs provide general benefit. An option might be to institute a defined period of formal prospective drug surveillance monitoring, in which both doctors and patients agree to participate.

• Standard drugs in day-to-day therapeutics: there should be a no-fault scheme, operated by or with the assent of government that has authority, through tribunals, to decide cases quickly and to make awards. This body would have authority to reimburse itself from others – manufacturer, supplier, prescriber – wherever that was appropriate. An award must not have to wait on the outcome of prolonged, vexatious, adversarial, expensive court proceedings. Patients would be compensated where:

  image causation was proven on ‘balance of probability’22

  image the injury was serious

  image the event was rare and remote and not reasonably taken into account in making the decision to treat.

Complementary, alternative and traditional medicine

Practitioners of complementary and alternative medicine (CAM)23 are severely critical of modern drugs, and use practices according to their own special beliefs. It is appropriate, therefore, to discuss such medical systems here.

The term ‘complementary and alternative medicine’ covers a broad range of heterogeneous systems of therapy (from acupuncture to herbalism to yoga), and diagnosis (from bioresonance to pulse and tongue diagnosis). The present discussion relates largely to CAM but recognises that traditional or indigenous medicinal therapeutics has developed since before history in all societies. This comprises a mass of practices varying from the worthless to highly effective remedies, such as digitalis (England), quinine (South America), reserpine (India), atropine (various countries). It is the task of science to find the gems and to discard the dross,24 and at the same time to leave intact socially valuable supportive aspects of traditional medicine.

There is no doubt that the domain of CAM has grown in popularity in recent years; a survey estimated that about 20% of the UK population had consulted a CAM practitioner in the previous year.25 In Germany, the figure exceeds 60%, with $2.06 billion in over-the-counter sales in 2003.26 Usage rises sharply among those with chronic, relapsing conditions such as cancer, multiple sclerosis, human immunodeficiency virus (HIV) infection, psoriasis and rheumatological diseases. It is difficult to resist the conclusion that when scientific medicine neither guarantees happiness nor wholly eliminates the disabilities of degenerative diseases in long-lived populations, and when drugs used in modern medicine cause serious harm, public disappointment naturally leads to a revival of interest in alternatives that alluringly promise efficacy with complete safety. These range from a revival of traditional medicine to adoption of the more modern cults.27

Features common to medical cults are: absence of scientific thinking, naive acceptance of hypotheses, uncritical acceptance of causation, e.g. reliance on anecdote or opinion (as opposed to evidence), assumption that if recovery follows treatment it is due to the treatment, and close attention to the patient's personal feelings. Lack of understanding of how therapeutic effects may be measured is also a prominent feature. An extensive analysis of recommendations of CAM therapies for specific medical conditions from seven textbook sources revealed numerous treatments recommended for the same condition – for example: addictions (120 treatments recommended), arthritis (121), asthma (119) and cancer (133) – but there was lack of agreement between these authors as to the preferred therapies for specified conditions.28 The question must arise that if numerous and heterogeneous treatments are effective for the same condition, could they not have some common feature, such as the ability of the practitioner to inspire confidence in the patient?

A proposition belongs to science if we can say what kind of event we would accept as refutation (and this is easy in therapeutics). A proposition (or theory) that cannot clash with any possible or even conceivable event (evidence) is outside science, and this in general applies to cults where everything is interpreted in terms of the theory of the cult; the possibility that the basis of the cult is false is not entertained. This appears to be the case with medical cults, which join freudianism, and indeed religions, as outside science (after Karl Popper). Willingness to follow where the evidence leads is a distinctive feature of conventional scientific medicine.

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A scientific approach does not mean treating a patient as a mere biochemical machine. It does not mean the exclusion of spiritual, psychological and social dimensions of human beings. But it does mean treating these in a rational manner.

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Some common false beliefs of CAM practitioners are that synthetic modern drugs are toxic, but products obtained in nature are not.29 Scientific medicine is held to accept evidence that remedies are effective only where the mechanism is understood, that it depends on adherence to rigid and unalterable dogmas, and recognises no form of evaluation other than the strict randomised controlled trial. Traditional (pre-scientific) medicine is deemed to have special virtue, and the collection and formal analysis of data on therapeutic outcomes, failures as well as successes, is deemed inessential. There is also a tenet that if the patient gets better when treated in accordance with certain beliefs, this provides evidence for the truth of these beliefs (the post hoc ergo propter hoc30 fallacy).

Exponents of CAM often state that comparative controlled trials of their medicines against conventional medicines are impracticable because the classic double-blind randomised controlled designs are inappropriate and in particular do not allow for the individual approach characteristic of complementary medicine. But modern therapeutic trial designs can cope with this. There remain extremists who contend that they understand scientific method, and reject it as invalid for what they do and believe, i.e. their beliefs are not, in principle, refutable. This is the position taken up by magic and religion where subordination of reason to faith is a virtue.

CAM particularly charges that conventional medicine seriously neglects patients as whole integrated human beings (body, mind, spirit) and treats them too much as machines. Conventional practitioners may well feel uneasily that there has been and still is truth in this, that with the development of specialisation some doctors have been seduced by the enormous successes of medical science and technology and have become liable to look too narrowly at their patients where a much broader (holistic) approach is required. It is evident that such an approach is likely to give particular satisfaction in psychological and psychosomatic conditions for which conventional doctors in a hurry have been all too ready to think that a prescription meets all the patients' needs.

CAM does not compete with the successful mainstream of scientific medicine. Users of CAM commonly have chronic conditions and have tried conventional medicine but found that it has not offered a satisfactory solution, or has caused adverse effects. The problems, when they occur, are often at the interface between CAM and mainstream medicine. A doctor prescribing a conventional medicine may be unaware that a patient is taking herbal medicine, and there is ample scope for unwanted herb–drug interaction by a variety of mechanisms.31 These include the following:

• CYP450 enzyme induction – St John's wort (by reducing the plasma concentration or therapeutic efficacy of warfarin, ciclosporin, simvastatin, oral contraceptives).

• CYP450 enzyme inhibition – piperine (by increasing plasma concentrations of propranolol and theophylline).

• Additive action – St John's wort on serotonin-specific reuptake inhibitors (by increasing their unwanted effects).

More troubling is the issue of conflicting advice between CAM and mainstream drugs, as witnessed by the advice to travellers from some homoeopathic pharmacies to use their products for malaria prophylaxis in place of conventional drugs (an action that drew criticism from the Society of Homoeopaths). Regulations being introduced by European Union Directive (and voluntarily in the UK) will move towards formal registration of practitioners of some forms of CAM (notably herbal medicines), according to agreed standards of qualification.

The following will suffice to give the flavour of homoeopathy, the principal complementary medicine system involving medicines, and the kind of criticism with which it has to contend.

Homoeopathy

Homoeopathy32 is a system of medicine founded by Samuel Hahnemann (German physician, 1755–1843) and expounded by him in the Organon of the Rational Art of Healing.33 Hahnemann described his position:

After I had discovered the weakness and errors of my teachers and books I sank into a state of sorrowful indignation, which had nearly disgusted me with the study of medicine. I was on the point of concluding that the whole art was vain and incapable of improvement. I gave myself up to solitary reflection, and resolved not to terminate my train of thought until I had arrived at a definite conclusion on the subject.34

By understandable revulsion at the medicine of his time, by experimentation on himself (a large dose of quinine made him feel as though he had a malarial attack) and by search of records he ‘discovered’ a ‘law’ that is central to homoeopathy35, and from which the name is derived:

Similar symptoms in the remedy remove similar symptoms in the disease. The eternal, universal law of Nature, that every disease is destroyed and cured through the similar artificial disease which the appropriate remedy has the tendency to excite, rests on the following proposition: that only one disease can exist in the body at any one time.

In addition to the above, Hahnemann ‘discovered’ that dilution potentiates the effect of drugs, but not of trace impurities (provided the dilution is shaken correctly, i.e. by ‘succussion’), even to the extent that an effective dose may not contain a single molecule of the drug. It has been pointed out36 that the ‘thirtieth potency’ (1 in 1030), recommended by Hahnemann, provided a solution in which there would be one molecule of drug in a volume of a sphere of literally astronomical circumference.

The therapeutic efficacy of a dilution at which no drug is present (including sodium chloride prepared in this way) is explained by the belief that a spiritual energy diffused throughout the medicine by the particular way in which the dilutions are shaken (succussion) during preparation, or that the active molecules leave behind some sort of ‘imprint’ on solvent or excipient.37 The absence of potentiation of the inevitable contaminating impurities is attributed to the fact that they are not incorporated by serial dilution. Thus, writes a critic: ‘We are asked to put aside the whole edifice of evidence concerning the physical nature of materials and the normal concentration–response relationships of biologically active substances in order to accommodate homoeopathic potency’.38 But no hard evidence that tests the hypothesis is supplied to justify this, and we are invited, for instance, to accept that sodium chloride merely diluted is no remedy, but that ‘it raises itself to the most wonderful power through a well prepared dynamisation process’ and stimulates the defensive powers of the body against the disease.

Pharmacologists have felt, in the absence of conclusive evidence from empirical studies that homoeopathic medicines can reproducibly be shown to differ from placebo, that there is no point in discussing its hypotheses.39 But empirical studies can be made without accepting any particular theory of causation; nor should the results of good studies be disregarded just because the proposed theory of action seems incredible or is unknown.

A meta-analysis of 186 double-blind and/or randomised placebo-controlled trials of homoeopathic remedies found that 89 had adequate data for analysis. The authors concluded that their results ‘were not compatible with the hypothesis that the clinical effects are completely due to placebo’, but also found ‘insufficient evidence from these studies that homoeopathy is clearly efficacious for any single clinical condition’.40 A subsequent analysis of 110 homoeopathic and 110 conventional medicine trials found that there was ‘weak evidence for a specific effect of homeopathic remedies, but strong evidence for a specific effect of conventional interventions’. The authors concluded: ‘This finding is compatible with the notion that the clinical effects of homeopathy are placebo effects’.41 These studies evoked strong reactions from practitioners of homoeopathy and others, but they raise the possibility that patients' reactions to homoeopathy, and indeed some other forms of CAM, may rest within an understanding of the complex nature of the placebo response and, in particular, its biology (see below).

Conclusion

There is a single fundamental issue between conventional scientific medicine and traditional, complementary and alternative medicine (although it is often obscured by detailed debates on individual practices); the issue is: what constitutes acceptable evidence, i.e. what is the nature, quality and interpretation of evidence that can justify general adoption of modes of treatment and acceptance of hypotheses? When there is agreement that a CAM treatment works, it becomes conventional and, in respect of that treatment, there is no difference between CAM and orthodox scientific medicine.

In the meantime, we depend on the accumulation of evidence from empirical studies to justify the allocation of resources for future research.

Placebo medicines

A placebo42 is any component of therapy that is without specific biological activity for the condition being treated.

Placebo medicines are used for two purposes:

• As a control in scientific evaluation of drugs (see Therapeutic trials, p. 45).

• To benefit or please a patient, not by any pharmacological actions, but for psychological reasons.

All treatments have a psychological component, whether to please (placebo effect) or, occasionally, to vex (negative placebo or nocebo43 effect).

A placebo medicine is a vehicle for ‘cure’ by suggestion, and is surprisingly often successful, if only temporarily.44 All treatments carry a placebo effect – physiotherapy, psychotherapy, surgery, entering a patient into a therapeutic trial, even the personality and style of the doctor – but the effect is most easily investigated with drugs, for the active and the inert can often be made to appear identical to allow comparisons.

The deliberate use of drugs as placebos is a confession of therapeutic failure by the doctor. Failures, however, are sometimes inevitable and an absolute condemnation of the use of placebos on all occasions would be unrealistic.

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A placebo-reactor is an individual who reports changes of physical or mental state after taking a pharmacologically inert substance.

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Placebo-reactors are suggestible people who are likely to respond favourably to any treatment. They have misled doctors into making false therapeutic claims.

Negative reactors, who develop adverse effects when given a placebo, exist but, fortunately, are fewer.

Some 30–80% of patients with chronic stable angina pectoris and 30–50% with depression respond to placebos. Placebo reaction is an inconstant attribute: a person may respond at one time in one situation and not at another time under different conditions. In one study on medical students, psychological tests revealed that those who reacted to a placebo tended to be extroverted, sociable, less dominant, less self-confident, more appreciative of their teaching, more aware of their autonomic functions and more neurotic than their colleagues who did not react to a placebo under the particular conditions of the experiment.

Modern brain-scanning techniques provide evidence that the placebo effect has a physiological basis. Positron emission tomography showed that both opioid and placebo analgesia were associated with increased activity in the same cortical area of the brain, the greatest responses occurring in high placebo responders.45 Functional magnetic resonance imaging demonstrated that strong cortical activation correlated with greater placebo-induced pain relief.46

It is important that all who administer drugs should be aware that their attitudes to the treatment may greatly influence the outcome. Undue scepticism may prevent a drug from achieving its effect, and enthusiasm or confidence may potentiate the actions of drugs.

Tonics are placebos, often expensive multivitamin supplements. They may be defined as substances that aspire to strengthen and increase the appetite of those so weakened by disease, misery, overindulgence in play or work, or by physical or mental inadequacy, that they cannot face the stresses of life. The essential feature of this weakness is the absence of any definite recognisable defect for which there is a known remedy. As tonics are placebos, they must be harmless.47

Guidelines, ‘essential’ drugs and prescribing

Increasingly, doctors recognise that they need guidance through the bountiful menu (thousands of medicines) so seductively served to them by the pharmaceutical industry. Principal sources of guidance are the pharmaceutical industry (‘prescribe my drug’) and governments (‘spend less’), and also the developing (profit-making) managed care/insurance bodies (‘spend less’) and the proliferating drug bulletins offering independent, and supposedly unbiased advice (‘prescribe appropriately’).

Even the pharmaceutical industry, in its more sober moments, recognises that their ideal world in which doctors, advised and informed by industry alone, were free to prescribe whatever they pleased,48 to whomsoever they pleased, for as long as they pleased with someone other than the patient paying, is an unrealisable dream of a ‘never-never land’.

The industry knows that it has to learn to live with restrictions of some kinds and one of the means of restriction is the formulary, a list of formulations of medicines with varying amounts of added information. A formulary may list all nationally licensed medicines prescribable by health professionals, or list only preferred drugs.

It may be restricted to what a third-party payer will reimburse, or to the range of formulations stocked in a hospital (and chosen by a local drugs and therapeutics committee, which all hospitals or groups of hospitals should have), or the range agreed by a partnership of general practitioners or primary care health centre.

All restricted formularies are heavily motivated to keep costs down without impairing appropriate prescribing. They should make provision for prescribing outside their range in cases of special need with an ‘escape clause’.

Thus, restricted formularies are in effect guidelines for prescribing. There is a profusion of these from national sources, hospitals, group practices and specialty organisations (epilepsy, diabetes mellitus).

‘Essential’ drugs

Economically disadvantaged countries may seek help to construct formularies. Technical help comes from the World Health Organization (WHO) with its ‘Model List of Essential Medicines’,49 i.e. drugs (or representatives of classes of drugs) ‘that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in the appropriate dosage forms’. Countries seeking such advice can use the list as a basis for their own choices (the WHO also publishes model prescribing information).50 The list, updated regularly, contains about 300 items.

The pharmaceutical industry dislikes the concept of drugs classed as essential, as others, by implication, are therefore judged inessential. But the WHO programme has attracted much interest and approval (see WHO Technical Report series: ‘The use of essential drugs’: current edition).

Cost-containment

Cost-containment in prescription drug therapy attracts increasing attention. It may involve two particularly contentious activities:

1. Generic substitution, where a generic formulation (see Chap. 7) is substituted (by a pharmacist) for the proprietary formulation prescribed by the doctor.

2. Therapeutic substitution, where a drug of different chemical structure is substituted for the drug prescribed by the doctor. The substitute is of the same chemical class and is deemed to have similar pharmacological properties and to give similar therapeutic benefit. Therapeutic substitution is a particularly controversial matter where it is done without consulting the prescriber, and legal issues may be raised in the event of adverse therapeutic outcome.

The following facts and opinions are worth some thought:

• UK National Health Service (NHS) spending on drugs has been 9–11% per year (of the total cost) for nearly 50 years.

• General practitioners (i.e. primary care) spend some 80% of the total cost of drugs.

• In the past 25 years, the number of NHS prescriptions has risen from 5.5 to over 13 per person.

• The average cost per head of medicines supplied to people aged over 75 years is nearly five times that of medicines supplied to those below pensionable age (in the UK: women 62 years, men 65 years, but under revision).

• Under-prescribing can be just as harmful to the health of patients as over-prescribing.

It is crucially important that incentives and sanctions address quality of prescribing as well as quantity: ‘it would be wrong if too great a preoccupation with the cost issue in isolation were to encourage under-prescribing or have an adverse effect on patient care’ (Report).

Reasons for under-prescribing include: lack of information or lack of the will to use available information (in economically privileged countries there is, if anything, a surplus of information); fear of being blamed for adverse reactions (affecting doctors who lack the confidence that a knowledge of pharmacological principles confers); fear of sanctions against over-costly prescribing. Prescription frequency and cost per prescription are lower for older than for younger doctors. There is no evidence that the patients of older doctors are worse off as a result.

Taking a drug history

The reasons for taking a drug history from patients are:

• Drugs are a cause of disease. Withdrawal of drugs, if abrupt, can also cause disease, e.g. benzodiazepines, antiepilepsy drugs.

• Drugs can conceal disease, e.g. adrenal steroid.

• Drugs can interact, producing a positive adverse effect or a negative adverse effect, i.e. therapeutic failure. This is an increasing problem with polypharmacy, especially in the elderly.

• Drugs can give diagnostic clues, e.g. ampicillin and amoxicillin causing rash in infectious mononucleosis – a diagnostic adverse effect, not a diagnostic test.

• Drugs can cause false results in clinical chemistry tests, e.g. plasma cortisol, urinary catecholamine, urinary glucose, serum renin and aldosterone.

• Drug history can assist choice of drugs in the future.

• Drugs can leave residual effects after administration has ceased, e.g. chloroquine, amiodarone.

• Drugs available for independent patient self-medication are increasing in range and importance.

(See also Appendix: the prescription.)

Prescribing should be appropriate:51

Appropriate [prescribing is that] which bases the choice of a drug on its effectiveness, safety and convenience relative to other drugs or treatments (e.g. surgery or psychotherapy), and considers cost only when those criteria for choice have been satisfied. In some circumstances appropriateness will require the use of more costly drugs. Only by giving appropriateness high priority will [health providers] be able to achieve their aim of ensuring that patients' clinical needs will be met. (Report)

Prescribing that is inappropriate is the result of several factors:

• Giving in to patient pressure to write unnecessary prescriptions. The extra time spent in careful explanation will, in the long run, be rewarded.

• Continuing patients, especially the elderly, on courses of medicinal treatment over many months without proper review of their medication.

• Doctors may ‘prescribe brand-name drugs rather than cheaper generic equivalents, even where there is no conceivable therapeutic advantage in so doing. The fact that the brand-name products often have shorter and more memorable names than their generic counterparts’ contributes to this (Report). (See also Ch. 7.)

• ‘Insufficient training in clinical pharmacology. Many of the drugs on the market may not have been available when a general practitioner was at medical school. The sheer quantity of new products may lead to a practitioner becoming over-reliant on drugs companies' promotional material, or sticking to “tried and tested” products out of caution based on ignorance’ (Report).

• Failure of doctors to keep up to date (see below, Doctor compliance). Computerising prescribing addresses some of these issues, for example by prompting regular review of a patient's medication, by instantly providing generic names from brand names, by giving ready access to formularies and prescribing guidelines.

Repeat prescriptions

About two-thirds of general (family) practice prescriptions are for repeat medication (half issued by the doctor at a consultation and half via the practice nurse or receptionist without patient contact with the doctor). Some 95% of patients' requests are acceded to without further discussion; 25% of patients who receive repeat prescriptions have had 40 or more repeats; and 55% of patients aged over 75 years are on repeat medication (with periodic review).

Many patients taking the same drug for years are doing so for the best reason, i.e. firm diagnosis for which effective therapy is available, such as epilepsy, diabetes, hypertension, but some are not.

Warnings and consent

Doctors have a professional duty to inform and to warn, so that patients, who are increasingly informed and educated, may make meaningful personal choices, which it is their right to do (unless they opt to leave the choice to the doctor, which it is also their right). Patients now have access to a potentially confusing quantity of detail about the unwanted effects of drugs (information sheet, the internet, the media) but without the balancing influence of data on their frequency of occurrence. It would be prudent for doctors to draw attention at least to adverse effects that are common, serious (even if uncommon), or avoidable or mitigated if recognised.

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Warnings to patients are of two kinds:

• Warnings that will affect the patient's choice to accept or reject the treatment.

• Warnings that will affect the safety of the treatment once it has begun, e.g. risk of stopping treatment, occurrence of drug toxicity.

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Just as engineers say that the only safe aeroplane is the one that stays on the ground in still air on a disused airfield or in a locked hangar, so the only safe drug is one that stays in its original package. If drugs are not safe then plainly patients are entitled to be warned of their hazards, which should be explained to them, as to probability, nature and severity.

There is no formal legal or ethical obligation on doctors to warn all patients of all possible adverse consequences of treatment. It is their duty to adapt the information they give (not too little, and not so much as to cause confusion) so that the best interest of each patient is served. If there is a ‘real’ (say 1–2%) risk inherent in a procedure of some misfortune occurring, then doctors should warn patients of the possibility that the injury may occur, however well the treatment is performed. Doctors should take into account the personality of the patient, the likelihood of any misfortune arising and what warning was necessary for each particular patient's welfare.52

Doctors should consider what their particular individual patients would wish to know (i.e. would be likely to attach significance to) and not only what they think (paternalistically) the patients ought to know. It is part of the professionalism of doctors to tell what is appropriate to the individual patient's interest. If things go wrong doctors must be prepared to defend what they did or, more important in the case of warnings, what they did not do, as being in their patient's best interest. Courts of law will look critically at doctors who seek to justify under-information by saying that they feared to confuse or frighten the patient (or that they left it to the patient to ask, as one doctor did). The increasing availability of patient information leaflets (PILs) prepared by the manufacturer indicates the increasing trend to give more information. Doctors should know what their patients have read (or not read, as is so often the case) when patients express dissatisfaction.

Evidence that extensive information on risks causes ‘unnecessary’ anxiety or frightens patients suggests that this is only a marginal issue and it does not justify a general policy of withholding of information.

Legal hazards for prescribers

Doctors would be less than human if, as well as trying to help their patients, they were not also concerned to protect themselves from allegations of malpractice (negligence). A lawyer specialising in the field put the legal position regarding a doctor's duty pungently:

The provision of information to patients is treated by (English) law as but one part of the way a doctor discharges the obligation he owes to a patient to take reasonable care in all aspects of his treatment of that patient. The provision of information is a corollary of the patient's right to self-determination which is a right recognised by law. Failure to provide appropriate information will usually be a breach of duty and if that breach leads to the patient suffering injury then the basis for a claim for compensation exists.53

The keeping of appropriate medical records, written at the time of consultation (and which is so frequently neglected), is not only good medical practice, it is the best way of ensuring that there is an answer to unjustified allegations, made later, when memory has faded. At the very least, these should include records of warning about treatments that are potentially hazardous.

Compliance

Successful therapy, especially if it is long term, comprises a great deal more than choosing a standard medicine. It involves patient and doctor compliance.54 The latter is liable to be overlooked (by doctors), for doctors prefer to dwell on the deficiencies of their patients rather than of themselves.

Patient compliance

Patient compliance is the extent to which the actual behaviour of the patient coincides with medical advice and instructions; it may be complete, partial, erratic, nil, or there may be over-compliance. To make a diagnosis and to prescribe evidence-based effective treatment is a satisfying experience for doctors, but too many assume that patients will gratefully or accurately do what they are told, i.e. obtain the medicine and consume it as instructed. This assumption is wrong.

The rate of non-presentation (or redemption) of prescriptions in the UK is around 5%, but is up to 20% or even more in the elderly (who pay no prescription charge). Where lack of money to pay for the medicine is not the cause, this is due to lack of motivation or apprehension about drugs.

Having obtained the medicine, some 25–50% (sometimes even more) of patients either fail to follow the instruction to a significant extent (taking 50–90% of the prescribed dose), or they do not take it at all.

Patient non-compliance or non-adherence is identified as a major factor in therapeutic failure in both routine practice and in scientific therapeutic trials; but, sad to say, doctors are too often non-compliant about remedying this. All patients are potential non-compliers;55 clinical criteria cannot reliably predict good compliance, but non-compliance often can be predicted.

In addition to therapeutic failure, undetected non-compliance may lead to rejection of the best drug when it is effective, leading to substitution by second-rank medicines.

Non-compliance may occur because:

• the patient has not understood the instructions, so cannot comply,56 or

• the patient understands the instructions, but fails to carry them out.

Prime factors for poor patient compliance are:

• Frequency and complexity of the drug regimen. Many studies attest to polypharmacy as an inhibitor of compliance, i.e. more than three drugs taken concurrently or more than three drug-taking occasions in the day (the ideal of one occasion only is often unattainable).

• Unintentional non-compliance, or forgetfulness,57 may be addressed by associating drug-taking with cues in daily life (breakfast, bedtime), by special packaging (e.g. calendar packs) and by enlisting the aid of others (e.g. carers, teachers).

• ‘Intelligent’ or wilful non-compliance.58 Patients decide they do not need the drug (asymptomatic disease) or they do not like the drug (unwanted effects), or take 2–3-day ‘drug holidays’.

• Illness. This includes cognitive impairment and psychological problems, with depression being a particular problem.

• Lack of information. Oral instructions alone are not enough; one-third of patients are unable to recount instructions immediately on leaving the consulting room. Lucid and legible labelling of containers is essential, as well as patient-friendly information leaflets, which are increasingly available via doctors and pharmacists, and as package inserts.

• Poor patient–doctor relationship and lack of motivation to take medicines as instructed offer a major challenge to the prescriber whose diagnosis and prescription may be perfect, yet loses efficacy by patient non-compliance. Unpleasant disease symptoms, particularly where these are recurrent and known by previous experience to be quickly relieved, provide the highest motivation (i.e. self-motivation) to comply. But particularly where the patient does not feel ill, adverse effects are immediate, and benefits are perceived to be remote, e.g. in hypertension, where they may be many years away in the future, doctors must consciously address themselves to motivating compliance. The best way to achieve compliance is to cultivate the patient–doctor relationship. Doctors cannot be expected actually to like all their patients, but it is a great help (where liking does not come naturally) if they make a positive effort to understand how individual patients must feel about their illnesses and their treatments, i.e. to empathise with their patients. This is not always easy, but its achievement is the action of the true professional, and indeed is part of their professional duty of care.

Suggestions for doctors to enhance patient compliance/adherence

• Form a non-judgemental alliance or partnership with the patient, giving the patient an opportunity to ask questions.

• Plan a regimen with the minimum number of drugs and drug-taking occasions, adjusted to fit the patient's lifestyle. Use fixed-dose combinations, sustained-release (or injectable depot) formulations, or long t½ drugs as appropriate; arrange direct observation of each dose in exceptional cases.

• Provide clear oral and written information adapted to the patient's understanding and medical and cultural needs.

• Use patient-friendly packaging, e.g. calendar packs, where appropriate; or monitored-dose systems, e.g. boxes compartmented and labelled (Dosette boxes).

• See the patient regularly and not so infrequently that the patient feels the doctor has lost interest.

• Enlist the help of family members, carers, friends.

• Use computer-generated reminders for repeat prescriptions.

Directly observed therapy

(DOT) (where a reliable person supervises each dose). In addition to the areas where supervision is obviously in the interest of patients, e.g. a child, DOT is employed (even imposed) among free-living uncooperative patients who may be a menace to the community, such as those with multiple drug-resistant tuberculosis.

What every patient needs to know59

• An account of the disease and the reason for prescribing.

• The name of the medicine.

• The objective:

  image to treat the disease and/or

  image to relieve symptoms, i.e. how important the medicine is, whether the patient can judge its efficacy and when benefit can be expected to occur.

• How and when to take the medicine.

• Whether it matters if a dose is missed and what, if anything, to do about it (see p. 24).

• For how long the medicine is likely to be needed.

• How to recognise adverse effects and any action that should be taken, including effects on car driving.

• Any interaction with alcohol or other medicines.

A remarkable instance of non-compliance, with hoarding, was that of a 71-year-old man who attempted suicide and was found to have in his home 46 bottles containing 10 685 tablets. Analysis of his prescriptions showed that over a period of 17 months he had been expected to take 27 tablets of several different kinds daily.60

From time to time there are campaigns to collect all unwanted drugs from homes in an area. Usually the public are asked to deliver the drugs to their local pharmacies. In one UK city (population 600 000), 500 000 ‘solid dose units’ (tablets, capsules, etc.) were handed in (see below, Opportunity cost); such quantities have even caused local problems for safe waste disposal.

Factors that are insignificant for compliance are: age61 (except at extremes), sex, intelligence (except at extreme deficiency) and educational level (probably).

Over-compliance

Patients (up to 20%) may take more drug than is prescribed, even increasing the dose by 50%. In diseases where precise compliance with frequent or complex regimens is important, for example in glaucoma where sight is at risk, there have been instances of obsessional patients responding to their doctors' overemphatic instructions by clock-watching in a state of anxiety to avoid the slightest deviance from timed administration of the correct dose, to the extent that their daily (and nightly) life becomes dominated by this single purpose.

Evaluation of patient compliance

Merely asking patients whether they have taken the drug as directed is not likely to provide reliable evidence.62 It is safest to assume that any event that can impair compliance will sometimes happen.

Estimations of compliance come from a variety of measures. DOT (above) is the most accurate, and identification of the drug or metabolites in plasma (or an artificial biological marker in the case of a clinical trial) is persuasive at least of recent compliance.

Requiring patients to produce containers when they attend the doctor, who counts the tablets, seems to do little more than show the patient that the doctor cares about the matter (which is useful); a tablet absent from a container has not necessarily entered the patient's body. On the other hand, although patients are known to practise deliberate deception, to maintain effective deception successfully over long periods requires more effort than most patients are likely to make. Memory aids, such as drug diaries, monitored-dosage systems (e.g. compartmented boxes) and electronic containers that record times of opening are helpful.

Some pharmacodynamic effects, such as heart rate with a β-adrenoceptor blocker, provide a physiological marker as an indicator of the presence of drug in the body. Monitoring plasma drug concentrations is possible but to do so without informing the patient raises ethical issues.

Doctor compliance

Doctor compliance is the extent to which the behaviour of doctors fulfils their professional duty:

• not to be ignorant

• to adopt new advances when they are sufficiently proved (which doctors are often slow to do)

• to prescribe accurately63

• to tell patients what they need to know

• to warn, i.e. to recognise the importance of the act of prescribing (see also p. 6).

In one study in a university hospital, where standards might be expected to be high, there was an error of drug use (dose, frequency, route) in 3% of prescriptions and an error of prescription writing (in relation to standard hospital instructions) in 30%. Many errors were trivial, but many could have resulted in overdose, serious interaction or under-treatment.

In other hospital studies, error rates in drug administration of 15–25% have been found, with rates rising rapidly where four or more drugs are being given concurrently, as is often the case; studies of hospital inpatients show that each receives about six drugs, and up to 20 during a stay is not rare. Merely providing information (on antimicrobials) did not influence prescribing, but gently asking physicians to justify their prescriptions caused a marked fall in inappropriate prescribing.

On a harsher note, in recent years doctors who gave drugs about which they later admitted ignorance (e.g. route of administration and/or dose) stood charged with manslaughter64 and were convicted. Shocked by this, fellow doctors have written to the medical press offering understanding sympathy to these, sometimes junior, colleagues, in effect saying ‘There, but for the grace of God, go I ’.65 The public response, however, is not sympathetic. Doctors put themselves forward as trained professionals who offer a service of responsible, competent provision of drugs that they have the legal right to prescribe. The public is increasingly inclined to hold them to that claim, and, where doctors seriously fail, to exact retribution.66

If you do not know about a drug, find out before you act, or take the personal consequences, which, increasingly, may be very serious indeed.

Underdosing

Use of suboptimal doses of drugs in serious disease occurs, sacrificing therapeutic efficacy to avoid serious adverse effects. Instances are commonest with drugs of low therapeutic index (see Index), i.e. where the effective and toxic dose ranges are close, or even overlap, e.g. heparin, anticancer drugs, aminoglycoside antimicrobials. In these cases dose adjustment to obtain maximum benefit with minimum risk requires both knowledge and attentiveness.

The clinical importance of missed dose(s)

Even the most conscientious of patients will miss a dose or doses occasionally. Patients should therefore be told whether this matters and what they should do about it, if anything.

image

Missed dose(s) may lead to:

• Loss of therapeutic efficacy (acute disease).

• Resurgence (chronic disease).

• Rebound or withdrawal syndrome.

image

Loss of therapeutic efficacy involves the pharmacokinetic properties of drugs. With some drugs of short t½, the issue is simply a transient drop in plasma concentration below a defined therapeutic concentration. The issues are more complex where therapeutic effect may not decline in parallel with plasma concentration, as with recovery of negative feedback homoeostatic mechanisms (adrenocortical steroids).

A single missed dose may be important with some drugs, e.g. oral contraceptives, but with others (long t½), omission of several doses is tolerated without any serious decline in efficacy, e.g. levothyroxine.

These pharmacokinetic considerations are complex and important, and are, or should be, taken into account by drug manufacturers in devising dosage schedules and informative data sheets. Manufacturers should aim at one or two doses per day (not more), and this is generally best achieved with drugs with relatively long biological effect t½ or, where the biological effect t½ is short, by using sustained-release formulations.

Discontinuation syndrome (recurrence of disease, rebound, or withdrawal syndrome) may occur due to a variety of mechanisms (see Index).

Pharmacoeconomics (see also Ch. 5)

Even the richest societies cannot satisfy the appetite of their citizens for health care based on their real needs, on their wants and on their (often unrealistic) expectations.

Health-care resources are rationed67 in one way or another, whether according to national social policies or to individual wealth. The debate on supply is not about whether there should be rationing, but about what form rationing should take; whether it should be explicit or concealed (from the public).

Doctors prescribe, patients consume and, increasingly throughout the world, third (purchasing) parties (government, insurance companies) pay the bill with money they have obtained from increasingly reluctant healthy members of the public.

The purchasers of health care are now engaged in serious exercises to contain drug costs in the short term without impairing the quality of medical care, or damaging the development of useful new drugs (which is an enormously expensive and long-term process). This can be achieved successfully only if reliable data are available on costs and benefits, both absolute and relative. The difficulties of generating such data, not only during development, but later under conditions of actual use, are enormous and are addressed by a special breed of professionals: the health economists.

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Economics is the science of the distribution of wealth and resources. Prescribing doctors, who have a duty to the community as well as to individual patients, cannot escape involvement with economics.

image

The economists' objective

The objective is to define needs, thereby enabling the deployment of resources according to priorities set by society, which has an interest in fairness between its members.

Resources can be distributed by the outcome of an unregulated power struggle between professionals and associations of patients and public pressure groups – all, no doubt, warm-hearted towards deserving cases of one kind or another, but none able to view the whole scene. Alternatively, distribution can occur by a planned evaluation that allows division of the resources based on some visible attempt at fairness.

A health economist68 writes:

The economist's approach to evaluating drug therapies is to look at a group of patients with a particular disorder and the various drugs that could be used to treat them. The costs of the various treatments and some costs associated with their use (together with the costs of giving no treatment) are then considered in terms of impact on health status (survival and quality of life) and impact on other health care costs (e.g. admissions to hospital, need for other drugs, use of other procedures).

Economists are often portrayed as people who want to focus on cost, whereas in reality they see everything in terms of a balance between costs and benefits.

Four economic concepts have particular importance to the thinking of every doctor who makes a decision to prescribe, i.e. to distribute resources:

• Opportunity cost means that which has to be sacrificed in order to carry out a certain course of action, i.e. costs are benefits foregone elsewhere. Money spent on prescribing is not available for another purpose; wasteful prescribing is as an affront to those who are in serious need, e.g. institutionalised mentally handicapped citizens who everywhere would benefit from increased resources, or patients requiring hip replacement.

• Costeffectiveness analysis is concerned with how to attain a given objective at minimal financial cost, e.g. prevention of post-surgical venous thromboembolism by heparins, warfarin, aspirin, external pneumatic compression. Analysis includes the cost of materials, adverse effects, any tests, nursing and doctor time, duration of stay in hospital (which may greatly exceed the cost of the drug).

• Cost–benefit analysis is concerned with issues of whether (and to what extent) to pursue objectives and policies; it is thus a broader activity than cost–effectiveness analysis and puts monetary values on the quality as well as on the quantity (duration) of life.

• Cost–utility analysis is concerned with comparisons between programmes, such as an antenatal drug treatment which saves a young life, or a hip replacement operation which improves mobility in a man of 60 years. Such differing issues are also the basis for comparison by computing quality-adjusted life years (see below).

An allied measure is the cost–minimisation analysis, which finds the least costly programme among those shown or assumed to be of equal benefit. Economic analysis requires that both quantity and quality of life be measured. The former is easy, the latter is hard to determine.

In the UK the National Institute for Health and Clinical Excellence (NICE) appraises the clinical effectiveness and cost-effectiveness of drugs, devices and diagnostic tools, and advises health-care professionals in the NHS on their use. The NHS is legally obliged to make resources available to implement NICE guidance, so avoiding differential treatment according to a patient's area of residence – so-called ‘postcode prescribing’.

Quality of life

Everyone is familiar with the measurement of the benefit of treatment in saving or extending life, i.e. life expectancy: the measure is the quantity of life (in years). But it is evident that life may be extended and yet have a low quality, even to the point that it is not worth having at all. It is therefore useful to have a unit of health measurement that combines the quantity of life with its quality, to place individual and social decision-making on a sounder basis than mere intuition. Economists met this need by developing the quality-adjusted life year (QALY) whereby estimations of years of life expectancy are modified according to estimations of quality of life.

Quality of life has four principal dimensions:69

1. Physical mobility.

2. Freedom from pain and distress.

3. Capacity for self-care.

4. Ability to engage in normal work and social interactions.

The approach for determining quality of life is by questionnaire, to measure what the subject perceives as personal health. The assessments are refined to provide improved assessment of the benefits and risks of medicines to the individual and to society. The challenge is to ensure that these are sufficiently robust to make resource allocation decisions between, for example, the rich and the poor, the educated and the uneducated, the old and the young, as well as between groups of patients with very different diseases. Plainly, quality of life is a major aspect of what is called outcomes research.

Guide to further reading

Blake D.R. Alternative prescribing and negligence. Br. Med. J.. 2003;326:455.

Buetow S., Elwyn G. Patient safety and patient error. Lancet. 2007;369:158–161.

De Smet P.A.G.M. Health risks of herbal remedies. Clin. Pharmacol. Ther.. 2004;76(1):1–17.

Ernst E. A historical perspective on placebo. Clin. Med. (Northfield Il). 2008;8(1):9–10.

Kandela P. Sketches from The Lancet: doctors' handwriting. Lancet. 1999;353:1109.

Ker K., Edwards P., Roberts I. Misadventures to patients during surgical and medical care in England and Wales: an analysis of deaths and hospital episodes. J. R. Soc. Med.. 2011;104:292–298.

Loudon I. A brief history of homeopathy. J. R. Soc. Med.. 2006;99:607–610.

Mason S., Tovey P., Long A.F. Evaluating complementary medicine: methodological challenges of randomised controlled trials. Br. Med. J.. 2002;325:832–834.

McGuffin M. Should herbal medicines be regulated as drugs? Clin. Pharmacol. Ther.. 2008;83(3):393–395.

Meltzer M.I. Introduction to health economics for physicians. Lancet. 2001;358:993–998. (and subsequent papers in this quintet)

Neale G., Chapman E.J., Hoare J., Olsen S. Recognising adverse events and critical incidents in medical practice in a district general hospital. Clin. Med. (Northfield Il). 2006;6(4):157–162.

Osterberg L., Blaschke T. Adherence to medication. N. Engl. J. Med.. 2005;353(5):487–497.

Panesar S.S., Cleary K., Sheikh A. Reflections on the National Patient Safety Agency's database of medical errors. J. R. Soc. Med.. 2009;102:256–258.

Rawlins M.D. NICE work – providing guidance to the British National Health Service. N. Engl. J. Med.. 2004;351(3):1381–1385.

Robertson J., Hill S.R. The Essential Medicines List for a global patient population. Clin. Pharmacol. Ther.. 2007;82(5):498–500.

Simpson S.H., Eurich D.T., Majumdar S.R., et al. A meta-analysis of the association between adherence to drug therapy and mortality. Br. Med. J.. 2006;333:15.

Appendix: the prescription

The prescription is the means by which patients receive medicines that are considered unsafe for sale directly to the public. Its format is officially regulated to ensure precision in the interests of safety and efficacy, and to prevent fraudulent misuse; full details appear in national formularies, and prescribers have a responsibility to comply with these.

Prescriptions of pure drugs or of formulations from the British National Formulary (BNF)70 are satisfactory for almost all purposes. The composition of many of the preparations in the BNF is laid down in official pharmacopoeias, e.g. British Pharmacopoeia (BP). There are also many national and international pharmacopoeias.

Traditional extemporaneous prescription-writing art, defining drug, base, adjuvant, corrective, flavouring and vehicle, is obsolete, as is the use of the Latin language. Certain convenient Latin abbreviations do survive for lack of convenient English substitutes. They appear below, without approval or disapproval.

image

The elementary requirements of a prescription [now usually viewed on screen by a computer programme] are that it should state what is to be given to whom and by whom prescribed, and give instructions on how much should be taken, how often, by what route and for how long, or the total quantity to be supplied, as below.

image

1. Date.

2. Address of doctor.

3. Name and address of patient: date of birth is also desirable for safety reasons; in the UK it is a legal requirement for children aged under 12 years.

4. image. This is a traditional esoteric symbol71 for the word ‘Recipe’ – ‘take thou’, which is addressed to the pharmacist. It is pointless; but as many doctors gain a harmless pleasure from writing it with a flourish before the name of a proprietary preparation of whose exact nature they may be ignorant, it is likely to survive as a sentimental link with the past.

5. Name and dose of the medicine.

  Abbreviations. Only abbreviate where there is an official abbreviation. Never use unofficial abbreviations or invent your own; it is not safe to do so.

  Quantities (after BNF):

    – 1 gram or more: write 1 g, etc.

    – less than 1 g: write as milligrams: 500 mg, not 0.5 g

    – less than 1 mg: write as micrograms, e.g. 100 micrograms, not 0.1 mg

    – for decimals, a zero should precede the decimal point where there is no other figure, e.g. 0.5 mL, not .5 mL; for a range, 0.5–1 g

    – do not abbreviate microgram, nanogram or unit

    – use millilitre (mL or ml), not cubic centimetre (cc)

    – for home/domestic measures, see below. State dose and dose frequency; for ‘as required’, specify minimum dose interval or maximum dose per day.

6. Directions to the pharmacist, if any: ‘mix’, ‘make a solution’. Write the total quantity to be dispensed (if this is not stated in 5 above); or duration of supply.

7. Instruction for the patient, to be written on container by the pharmacist. Here brevity, clarity and accuracy are especially important. It is dangerous to rely on the patient remembering oral instructions. The BNF provides a list of recommended ‘cautionary and advisory labels for dispensed medicines’, representing a balance between ‘the unintelligibly short and the inconveniently long’, for example: ‘Do not stop taking this medicine except on your doctor's advice’.

Pharmacists nowadays use their own initiative in giving advice to patients.

8. Signature of doctor.

Example of a prescription

for a patient with an annoying unproductive cough:

1., 2., 3., as above

4. image

5. Codeine Linctus, BNF, 5 mL

6. Send 60 mL

7. Label: Codeine Linctus (or NP). Take 5 mL twice a day and on retiring

8. Signature of doctor.

Computer-issued prescriptions must conform to recommendations of professional bodies. Computer-generated facsimile signatures do not meet the legal requirement.

If altered by hand (undesirable), the alteration must be signed.

Medicine containers

Reclosable child-resistant containers and blister packs are now standard, as is dispensing in manufacturers' original sealed packs containing a patient information leaflet. These add to immediate cost but may save money in the end (increased efficiency of use, and safety).

Unwanted medicines

Patients should be encouraged to return these to the original supplier for disposal.

Drugs liable to cause dependence

or be the subject of misuse. Doctors have a particular responsibility to ensure that: (1) they do not create dependence, (2) the patient does not increase the dose and create dependence, (3) they do not become an unwitting source of supply to addicts. To many such drugs, special prescribing regulations apply (see BNF).

Abbreviations

(see also Weights and measures, below)

image

b.d.: bis in die

twice a day (b.i.d. is also used)

BNF

British National Formulary

BP

British Pharmacopoeia

BPC

British Pharmaceutical Codex

i.m.: intramuscular

by intramuscular injection

IU

International Unit

i.v.: intravenous

by intravenous injection

NP: nomen proprium

proper name

o.d.: omni die

every day

o.m.: omni mane

every morning

o.n.: omni nocte

every night

p.o.: per os

by mouth

p.r.: per rectum

by the anal/rectal route

p.r.n.: pro re nata

as required. It is best to add the maximum frequency of repetition, e.g. aspirin and codeine tablets, 1 or 2 p.r.n., 4-hourly

p.v.: per vaginam

by the vaginal route

q.d.s.: quater die sumendus

four times a day (q.i.d. is also used)

rep.: repetatur

let it be repeated, as in rep. mist(ura), repeat the mixture

s.c.: subcutaneous

by subcutaneous injection

stat: statim

immediately

t.d.s.: ter (in) die sumendus

three times a day (t.i.d. is also used)

image

Weights and measures

In this book doses are given in the metric system, or in international units (IU) when metric doses are impracticable.

Equivalents:

1 litre (L or l) = 1.76 pints

1 kilogram (kg) = 2.2 pounds (lb).

Abbreviations:

1 gram (g)

1 milligram (mg) (1 × 10− 3 g)

1 microgram72 (1 × 10− 6 g)

1 nanogram72 (1 × 10− 9 g)

1 decilitre (dL) (1 × 10− 1 L)

1 millilitre (mL) (1 × 10− 3 L).

Home/domestic measures

A standard 5 mL spoon and a graduated oral syringe are available. Otherwise the following approximations will serve:

1 tablespoonful = 14 mL (or ml)

1 dessertspoonful = 7 mL (or ml)

1 teaspoonful = 5 mL (or ml).

Percentages, proportions, weight in volume

Some solutions of drugs (e.g. local anaesthetics, adrenaline/epinephrine) for parenteral use are labelled in a variety of ways: percentage, proportion, or weight in volume (e.g. 0.1%, 1: 1000, 1 mg/mL). In addition, dilutions may have to be made by doctors at the time of use. Such drugs are commonly dangerous in overdose and great precision is required, especially as any errors are liable to be by a factor of 10 and can be fatal. Doctors who do not feel confident with such calculations (because they do not do them frequently) should feel no embarrassment,73 but should recognise that they have a responsibility to check their results with a competent colleague or pharmacist before proceeding.

1 http://www.gmc-uk.org/about/research/research_commissioned_4.asp (accessed 4 October 2011).

2 http://www.gmc-uk.org/education/undergraduate/tomorrows_doctors_2009.asp (accessed 4 October 2011).

3 His work had such a profound influence on medicine that he was called the ‘English Hippocrates’.

4 Medical Essays (1891). American physician and poet, and Dean of Harvard Medical School; he introduced the term anaesthesia instead of ‘suspended animation’ or ‘etherisation’. Address delivered before the Massachusetts Medical Society, 30 May 1860 (Oliver Wendell Holmes, Medical Essays. Kessinger Publishing, p. 140).

5 Sherman L J 1959 The significant variables in psychopharmaceutic research. American Journal of Psychiatry 116:208–214.

6 Michel de Montaigne (1533–1592). French essayist.

7 Kohn L, Corrigan J, Donaldson M (eds) for the Committee on Quality of Health Care in America, Institute of Medicine 2000 To Err is Human: Building a Safer Health System. National Academy Press, Washington, DC.

8 Bates D W, Cullen D J, Laird N et al 1995 Incidence of adverse drug events and potential adverse drug events. Journal of the American Medical Association 274:29–34.

9 Iatrogenic means ‘physician-caused’, i.e. disease consequent on following medical advice or intervention (from the Greek iatros, physician).

10 Sollman T A 1917 Manual of Pharmacology. Saunders, Philadelphia.

11 This phrase is commonly used in the context of motor vehicle accidents, but applies equally well to the prescribing of drugs.

12 Sometimes the term minimal risk is used to mean risk about equal to going about our ordinary daily lives; it includes travel on public transport, but not motor bicycling on a motorway.

13 Pochin E E 1975 The acceptance of risk. British Medical Bulletin 31:184–190.

14 Doctors who seek to exculpate themselves from serious, even fatal, prescribing errors by appealing to undoubted difficulties presented by the information explosion of modern times, allied to pressures of work, are unlikely to get sympathy, and increasingly are more likely to be told, ‘If you can't stand the heat, get out of the kitchen’ (a dictum attributed to Harry S Truman, US President 1948–52, though he assigns it to US Army General Harry Vaughn). Pharmacists and nurses stand ready and willing to relieve doctors of the burden of prescribing.

15 A cure eliminates a disease and may be withdrawn when this is achieved.

16 Even if given the best treatment. ‘Opium alone stands the test of experience as a remedy capable of limiting the progress of the disease’, wrote the great Sir William Osler, successively Professor of Medicine in Pennsylvania, McGill, Johns Hopkins and Oxford universities, in 1918, only 3 years before the discovery of insulin.

17 This discussion is about drugs that have been properly manufactured and meet proper standards, e.g. of purity, stability, as laid down by regulatory bodies or pharmacopoeias. A manufacturing defect would be dealt with in a way no different from manufacturing errors in other products.

18 A plaintiff (person who believes he/she has been injured) seeking to obtain compensation from a defendant (via the law of negligence) must prove three things: (1) that the defendant owed a duty of care to the plaintiff; (2) that the defendant failed to exercise reasonable care; and (3) that the plaintiff has a suffered actual injury as a result.

19 The following distinction is made in some discussions of product liability. Strict liability: compensation is provided by the producer/manufacturer. No-fault liability or scheme: compensation is provided by a central fund.

20 Royal Commission on Civil Liability and Compensation for Personal Injury 1978 HMSO, London: Cmnd. 7054. Although the Commission considered compensation for death and personal injury suffered by any person through manufacture, supply or use of products, i.e. all goods whether natural or manufactured, and included drugs and even human blood and organs, it made no mention of tobacco and alcohol.

21 Gaine W J 2003 No-fault compensation schemes. British Medical Journal 326:997–998.

22 This is the criterion for (UK) civil law, rather than ‘beyond reasonable doubt’, which is the criterion of criminal law.

23 The definition adopted by the Cochrane Collaboration is as follows: ‘Complementary and alternative medicine (CAM) is a broad domain of healing resources that accompanies all health systems, modalities, and practices and their accompanying theories and beliefs, other than those intrinsic to the politically dominant health system of a particular society or culture in a given historical period. CAM includes all such practices and ideas self-defined by their users as preventing or treating illness or promoting health and well-being. Boundaries within CAM and between the CAM domain and that of the dominant system are not always sharp or fixed.’

24 Traditional medicine is fostered particularly in countries where scientific medicine is not accessible to large populations for economic reasons, and destruction of traditional medicine would leave unhappy and sick people with nothing. For this reason, governments are supporting traditional medicine and at the same time initiating scientific clinical evaluations of the numerous plants and other items employed, many of which contain biologically active substances. The World Health Organization is supportive of these programmes.

25 Ernst E 2000 The role of complementary and alternative medicine. British Medical Journal 32:1133–1135.

26 De Smet P A G M 2005 Herbal medicine in Europe – relaxing regulatory standards. New England Journal of Medicine 352:1176–1178.

27 A cult is a practice that follows a dogma, tenet or principle based on theories or beliefs of its promulgator to the exclusion of demonstrable scientific experience (definition of the American Medical Association). Scientific medicine changes in accord with evidence obtained by scientific enquiry applied with such intellectual rigour as is humanly possible. But this is not the case with cults, the claims for which are characterised by absence of rigorous intellectual evaluation and unchangeability of beliefs. The profusion of medical cults prompts the question why, if each cult has the efficacy claimed by its exponents, conventional medicine and indeed the other cults are not swept away. Some practitioners use conventional medicine and, where it fails, turn to cult practices. Where such complementary practices give comfort they are not to be despised, but their role and validity should be clearly defined. No community can afford to take these cults at their own valuation; they must be tested, and tested with at least the rigour required to justify a therapeutic claim for a new drug. It is sometimes urged in extenuation that traditional and cult practices do no harm to patients, unlike synthetic drugs. But, even if that were true (which it is not), investment of scarce resources in delivering what may be ineffective, though sometimes pleasing, experiences, e.g. dance therapy, exaltation of flowers or the admittedly inexpensive urine therapy, means that resources are not available for other desirable social objectives, e.g. housing, art subsidies, medicine. We do not apologise for this diversion to consider medical cults and practices, for the world cannot afford unreason, and the antidote to unreason is reason and the rigorous pursuit of knowledge, i.e. evidence-based medicine.

28 Ernst E (ed) 2001 The Desktop Guide to Complementary and Alternative Medicine. Harcourt, Edinburgh.

29 Black cohosh (Cimicifuga racemosa), taken for hot flushes and other menopausal symptoms (but no better than placebo in clinical trial), can cause serious liver disorder. Herbal teas containing pyrrolizidine alkaloids (Senecio, Crotalaria, Heliotropium) cause serious hepatic veno-occlusive disease. Comfrey (Symphytum) is similar but also causes hepatocellular tumours and haemangiomas. Sassafras (carminative, antirheumatic) is hepatotoxic. Mistletoe (Viscum) contains cytotoxic alkaloids. Ginseng contains oestrogenic substances that have caused gynaecomastia; long-term users may show ‘ginseng abuse syndrome’ comprising central nervous system excitation; arterial hypertension can occur. Liquorice (Glycyrrhiza) has mineralocorticoid action. An amateur ‘health food enthusiast’ made himself a tea from ‘an unfamiliar [ to him ] plant’ in his garden; unfortunately this was the familiar foxglove (Digitalis purpurea) and as a result he became very ill, but happily recovered. Other toxic natural remedies include lily of the valley (Convallaria) and horse chestnut (Aesculus). ‘The medical herbalist is at fault for clinging to outworn historical authority and for not assessing his drugs in terms of today's knowledge, and the orthodox physician is at fault for a cynical scepticism with regard to any healing discipline other than his own’ (Penn R G 1983 Adverse reactions to herbal medicines. Adverse Drug Reaction Bulletin 102:376–379). The Medicines and Healthcare products Regulatory Agency provides advice at: http://www.mhra.gov.uk.

30 Latin: after this; therefore on account of this.

31 Hu Z, Yang X, Ho P C L et al 2005 Herb–drug interactions: a literature review. Drugs 65:1239–1281.

32 Greek: homos = same; patheia = suffering.

33 1810: trans. Wheeler C E 1913 (Organon of the Rational Art of Healing.) Dent, London.

34 Hahnemann S 1805 Aesculapius in the Balance. Leipzig.

35 By contrast, allopathy was a system of medicine based on the principle that induction of a new disease would drive out an existing disease. It was practised by measures that included purging, bleeding and sweating. Use of the word to distinguish homoeopathy from conventional scientific medicine is clearly incorrect.

36 Clark A J 1937 General pharmacology. In: Hefter's Handbuch. Springer, Berlin.

37 Homoeopathic practitioners repeatedly express their irritation that critics give so much attention to dilution. They should not be surprised, considering the enormous implications of their claim.

38 Cuthbert A W 1982 Pharmaceutical Journal (15 May):547.

39 Editorial 1988 When to believe the unbelievable. Nature 333:787. A report of an investigation into experiments with antibodies in solutions that contained no antibody molecules (as in some homoeopathic medicines). The editor of Nature took a three-person team (one of whom was a professional magician, included to detect any trickery) on a week-long visit to the laboratory that claimed positive results. Despite the scientific seriousness of the operation, it developed comical aspects (codes of the contents of test tubes were taped to the laboratory ceiling); the Nature team, having reached an unfavourable view of the experiments, ‘sped past the (laboratory) common-room filled with champagne bottles destined now not to be opened’. Full reports in this issue of Nature (28 July 1988), including an acrimonious response by the original scientist, are highly recommended reading, both for scientific logic and for entertainment. See also Nature (1994) 370:322.

40 Linde K, Clausius N, Melchart D et al 1997 Are the clinical effects of homoeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 350:834–843.

41 Shang A, Huwiler-Müntener K, Nartey L et al 2005 Are the clinical effects of homeopathy placebo effects? Comparative study of placebo-controlled trias of homeopathy and allopathy. Lancet 366:726–732.

42 Latin: placebo = shall be pleasing or acceptable. For a comment on its historical use, see Edwards M 2005 Lancet 365:1023.

43 Latin: nocebo = shall injure; the term is little used.

44 As the following account by a mountain rescue guide illustrates: ‘The incident involved a 15-year-old boy who sustained head injuries and a very badly broken leg. Helicopter assistance was unavailable and therefore we had to carry him by stretcher to the nearest landrover (several miles away) and then on to a waiting ambulance. During this long evacuation the boy was in considerable distress and we administered Entonox (a mixture of nitrous oxide and oxygen, 50% each) sparingly as we only had one small cylinder. He repeatedly remarked how much better he felt after each intake of Entonox (approximately every 20 minutes) and after 7 hours or so, we eventually got him safely into the ambulance and on his way to hospital. On going to replace the Extonox we discovered the cylinder was still full of gas due to the equipment being faulty. There was no doubt that the boy felt considerable pain relief because he thought he was receiving Entonox.’

45 Petrovic P, Kalso E, Petersson K et al 2002 Placebo and opioid analgesia – imaging a shared neuronal network. Science 295:1737–1740.

46 Wager T D, Rilling J K, Smith E S et al 2004 Placebo induced changes in fMRI in anticipation and experience of pain. Science 303:1162–1167.

47 Tonics (licensed) available in the UK include: Gentian Mixture, acid (or alkaline) (gentian, a natural plant bitter substance, and dilute hydrochloric acid or sodium bicarbonate); Labiton (thiamine, caffeine, alcohol, all in low dose).

48 It is difficult for us now to appreciate the naive fervour and trust in doctors that allowed them almost unlimited rights to prescribe in the early years of the UK National Health Service (founded in 1948). Beer was a prescription item in hospitals until, decades later, an audit revealed that only 1 in 10 bottles reached a patient. More recently (1992): ‘There could be fewer Christmas puddings consumed this year. The puddings were recently struck off a bizarre list of items that doctors were able to prescribe for their patients. They were removed by Health Department officials without complaint from the medics, on the grounds they had “no therapeutic or clinical value”.’ (Lancet (1992) 340:1531).

49 Available on the WHO website: http://www.who.org.

50 There is an agency for WHO publications in all UN countries.

51 The text on appropriate prescribing and some quotations (designated ‘Report’) are based on a UK Parliamentary Report (The National Health Service Drugs Budget 1994 HMSO, London). Twelve members of Parliament took evidence from up to 100 organisations and individuals orally and/or in writing.

52 Legal correspondent 1980 British Medical Journal 280:575.

53 Ian Dodds-Smith.

54 The term ‘compliance’ meets objection as having undertones of obsolete, authoritarian attitudes, implying ‘obedience’ to doctors' ‘orders’. The words adherence or concordance are preferred by some, the latter because it expresses the duality of drug prescribing (by the doctor) and taking (by the patient), i.e. a therapeutic alliance. We retain compliance, pointing out that it applies equally to those doctors who neither keep up to date, nor follow prescribing instructions, and to patients who fail, for whatever reason, to keep to a drug regimen.

55 Even where the grave consequences of non-compliance are understood (glaucoma: blindness) (renal transplant: organ rejection), significant non-compliance has been reported in as many as 20% of patients; psychologists will be able to suggest explanations for this.

56 Cautionary tales. (1) A 62-year-old man requiring a metered-dose inhaler (for the first time) was told to ‘spray the medicine to the throat’. He was found to have been conscientiously aiming and firing the aerosol to his anterior neck around the thyroid cartilage, four times a day for 2 weeks (Chiang A A, Lee J C 1994 New England Journal of Medicine 330:1690). (2) A patient thought that ‘sublingual’ meant able to speak two languages; (3) another that tablets cleared obstructed blood vessels by exploding inside them (E A Kay) – reference, no doubt, to colloquial use of the term ‘clot-busting drugs’ (for thrombolytics). These are extreme examples; most are more subtle and less detectable. Doctors may smile at the ignorant naivety of patients, but the smile should give way to a blush of shame at their own deficiencies as communicators.

57 Where non-compliance, whether intentional or unintentional, is medically serious it becomes necessary to bypass self-administration (unsupervised) and to resort to directly observed (supervised) oral administration or to injection (e.g. in schizophrenia).

58 Of the many causes of failure of patient compliance, the following case must be unique. On a transatlantic flight the father of an asthmatic boy was seated in the row behind two doctors. He overheard one of the doctors expressing doubt about the long-term safety in children of inhaled corticosteroids. He interrupted the conversation, explaining that his son took this treatment; he had a lengthy conversation with one of the doctors, who gave his name. Consequently, on arrival, he faxed his wife at home to stop the treatment of their son immediately. She did so, and 2 days later the well controlled patient had a brisk relapse that responded to urgent treatment by the family doctor (who had been conscientiously following guidelines recently published in an authoritative journal). The family doctor later ascertained that the doctor in the plane was a member of the editorial team of the journal that had so recently published the guidelines that were favourable to inhaled corticosteroid (Cox S 1994 Is eavesdropping bad for your health? British Medical Journal 309:718).

59 After: Drug and Therapeutics Bulletin 1981; 19:73. Patient information leaflets. In economically privileged countries, original or patient-pack dispensing is becoming the norm, i.e. patients receive an unopened pack just as it left the manufacturer. The pack contains a patient information leaflet (PIL) (which therefore accompanies each repeat prescription). Regulatory authorities increasingly determine its content. In this litigious age, requirements to be comprehensive and, to protect both manufacturer and regulatory authority, impair the patient-friendliness of PILs. But studies have shown that patients who receive leaflets are more satisfied than those who do not. Doctors need to have copies of these leaflets so that they can discuss with their patients what they are (or are not) reading.

60 Smith S E, Stead K C 1974 Non-compliance or mis-prescribing? Lancet i:937 [letter].

61 But the elderly are commonly taking several drugs – a major factor in non-compliance – and monitoring compliance in this age group becomes particularly important. The over-60s in the UK are, on average, each receiving two or three medications.

62 Hippocrates (460–377 BC) noted that patients are liars regarding compliance. The way the patient is questioned may be all important, e.g. ‘Were you able to take the tablets?’ may get a truthful reply, whereas ‘Did you take the tablets?’ may not, because the latter question may be understood by the patient as implying personal criticism (Pearson R M 1982 Who is taking their tablets? British Medical Journal 285:757).

63 Accuracy includes legibility: a doctor wrote Intal (sodium cromoglicate) for an asthmatic patient; the pharmacist read it as Inderal (propranolol) – the patient died. See also, Names of drugs (Ch. 7).

64 Unlawful killing in circumstances that do not amount to murder (which requires an intention to kill), e.g. causing death by negligence that is much more serious than mere carelessness; reckless breach of the legal duty of care.

65 Attributed to John Bradford, an English preacher and martyr (16th century), on seeing a convicted criminal pass by.

66 A doctor wrote a prescription for isosorbide dinitrate 20 mg 6-hourly, but because of the illegibility of the handwriting the pharmacist dispensed felodipine in the same dose (maximum daily dose 10 mg). The patient died and a court ordered the doctor and pharmacist to pay compensation of $450 000 to the family. Charatan F 1999 Family compensated for death after illegible prescription. British Medical Journal 319:1456.

67 The term ‘rationing’ is used here to embrace the allocation of priorities as well as the actual withholding of resources (in this case, drugs).

68 Professor Michael Drummond.

69 Williams A 1983 In: Smith G T (ed) Measuring the Social Benefits of Medicine. Office of Health Economics, London.

70 Supplied free to all doctors practising in the UK National Health Service.

71 Derived from the eye of Horus, Ancient Egyptian sun god.

72 Spell out in full in prescriptions.

73 Called to an emergency tension pneumothorax on an intercontinental flight, two surgeons, who chanced to be passengers, were provided with lidocaine 100 mg in 10 mL (in the aircraft medical kit). They were accustomed to thinking in percentages for this drug and ‘in the heat of the moment’ neither was able to make the conversion. Chest surgery was conducted successfully with an adapted wire coat-hanger as a trocar (‘sterilised’ in brandy), using a urinary catheter. The patient survived the flight and recovered in hospital. Wallace W A 1995 Managing in-flight emergencies: a personal account. British Medical Journal 311:374.



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