CLINICAL PHARMACOLOGY 2003 (PART 2)

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PRESCRIBING, CONSUMPTION AND ECONOMICS Prescribing, consumption and economics The reasons for taking a drug history from patients are: • Drugs are a cause of disease. Withdrawal of drugs, if abrupt, can cause disease, e.g. benzodiazepines, antiepilepsy drugs. • Drugs can conceal disease, e.g. adrenal steroid. • Drugs can interact causing positive adverse effect, or negative adverse effect, i.e. therapeutic failure. • 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....

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PRESCRIBING, CONSUMPTION AND ECONOMICS I priority will [health payers] be able to achieve their Prescribing, consumption aim of ensuring that patients' clinical needs will be met (Report). and economics Prescribing that is inappropriate is the result of The reasons for taking a drug history from patients several factors: are: • Giving in to patient pressure to write unnecessary • Drugs are a cause of disease. Withdrawal of prescriptions. The extra time spent in careful drugs, if abrupt, can cause disease, e.g. explanation will, in the long run, be rewarded. benzodiazepines, antiepilepsy drugs. • Continuing patients, especially the elderly, on • Drugs can conceal disease, e.g. adrenal steroid. courses of medicinal treatment over many months • Drugs can interact causing positive adverse without proper review of their medication. effect, or negative adverse effect, i.e. therapeutic • Doctors 'frequently prescribe brand-name drugs failure. rather than cheaper generic equivalents, even • Drugs can give diagnostic clues, e.g. ampicillin where there is no conceivable therapeutic and amoxicillin causing rash in infectious advantage in so doing. The fact that the brand- mononucleosis — a diagnostic adverse effect, not name products often have shorter and more a diagnostic test. memorable names than their generic counterparts' • Drugs can cause false results in clinical contributes to this. (Report) (see also Ch. 6). chemistry tests, e.g. plasma cortisol, urinary • 'Insufficient training in clinical pharmacology. catecholamine, urinary glucose. Many of the drugs on the market may not have • Drug history can assist choice of drugs in the been available when a general practitioner was at future. medical school.35 The sheer quantity of new • Drugs can leave residual effects after products may lead to a practitioner becoming administration has ceased, e.g. chloroquine, over-reliant on drugs companies' promotional amiodarone. material, or sticking to "tried and tested" products • Drugs available for independent patient self- out of caution based on ignorance' (Report). medication are increasing in range and • Failure of doctors to keep up-to-date (see Doctor importance. compliance). (See also Appendix 2, The prescription.) Computerising prescribing addresses some of Prescribing should be appropriate.34 these issues, e.g. by prompting regular review of a patient's medication, by instantly providing generic Appropriate [prescribing is that] which bases the names from brand names, by giving ready access to choice of a drug on its effectiveness, safety and formularies and prescribing guidelines. convenience relative to other drugs or treatments (e.g. surgery or psychotherapy), and takes cost into account only when those criteria for choice have Cost-containment been satisfied. In some circumstances Cost-containment in prescription drug therapy appropriateness will require the use of more costly attracts increasing attention. It may involve two drugs. Only by giving appropriateness high particularly contentious activities: 34 35 The text on appropriate prescribing and some quotations This statement illustrates a common and serious (designated Report) are based on a UK Parliamentary Report misunderstanding of the role of medical schools. Their role is (The National Health Service Drugs Budget 1994 HMSO to teach the scientific basis of clinical pharmacology and safe London). Twelve Members of Parliament took evidence from drug therapy so that doctors can handle existing and future up to 100 organisations and individuals orally and/or in drugs intelligently, using current data sheets, formularies, writing. It is both a surprise and a pleasure to be able to etc. It is not to attempt to teach enormous numbers of continue to quote with approval from such a source. PNB, impossible-to-remember facts, the deadening effect of which MJB. on a thinking approach would be disastrous. 15
I TOPICS IN DRUG T H E R A P Y 1. Generic substitution, where a generic formulation tion frequency and cost per prescription are lower (p. 85) is substituted (by a pharmacist) for the for older than for younger doctors. There is no proprietary formulation prescribed by the reason to think that the patients of older doctors are doctor. worse off as a result. 2. Therapeutic substitution, where a drug of different chemical structure is substituted for Repeat prescriptions the drug prescribed by the doctor. The substitute is of the same chemical class and is About two-thirds of general (family) practice deemed to have similar pharmacological prescriptions are for repeat medication (half issued properties and to give similar therapeutic by the doctor at a consultation and half via the benefit. Therapeutic substitution is a receptionist without patient contact with the particularly controversial matter where it is doctor): 95% of patients' requests are acceded to done without consulting the prescriber, and without further discussion; 25% of patients who legal issues may be raised in the event of receive repeat prescriptions have had 40 or more adverse therapeutic outcome. repeats; 55% of patients aged over 75 years are on repeat medication (with periodic review). The following facts and opinions are worth think- Many patients taking the same drug for years are ing about: doing so for the best reason, i.e. firm diagnosis for • The UK National Health Service (NHS) spending which effective therapy is available, such as epilepsy, on drugs has been 9-11% per year (of the total diabetes, hypertension, but some are not. cost) over nearly 50 years. • 80% of the total cost of drugs is spent by general WARNINGS AND CONSENT practitioners, i.e. in primary care. • People over the age of 65 years receive on Doctors have a professional duty to inform and to average 13 prescriptions per year — twice as warn, so that patients, who are increasingly many as the population in general. informed and educated, may make meaningful • 'The average cost per head of medicines personal choices, which it is their right to do (unless supplied to people aged over 75 is nearly five they opt to leave the choice to the doctor, which it is times that of medicines supplied to those below also their right to do). pensionable age (currently in UK women 60 years; men 65)' (Report). • 'Underprescribing can be just as harmful to the • Warnings that will affect the patient's choice to accept health of patients as overprescribing.' or reject the treatment • Warnings that will affect the safety of the treatment It is crucially important that incentives and once it has begun, e.g. risk of stopping treatment, sanctions address quality of prescribing as well as occurrence of drug toxicity. quantity: 'it would be wrong if too great a pre- occupation with the cost issue in isolation were to encourage underprescribing or have an adverse Just as engineers say that the only safe aeroplane effect on patient care' (Report). is the one that stays on the ground in still air on a disused airfield or in a locked hangar, so the only Reasons for underprescribing include: lack of safe drug is one that stays in its original package. If information or lack of the will to use available drugs are not safe then plainly patients are entitled information (in economically privileged countries to be warned of their hazards, which should be there is, if anything, a surplus of information); fear explained to them, i.e. probability, nature and of being blamed for adverse reactions (affecting severity. doctors who lack the confidence that a knowledge There is no formal legal or ethical obligation on of pharmacological principles confers); fear of doctors to warn all patients of all possible adverse sanctions against over-costly prescribing. Prescrip- consequences of treatment. It is their duty to adapt 16
PRESCRIBING, CONSUMPTION AND ECONOMICS I the information they give (not too little, and not so doctor discharges the obligation he owes to a much as to cause confusion) so that the best interest patient to take reasonable care in all aspects of his of each patient is served. If there is a 'real' (say 1-2%) treatment of that patient. The provision of risk inherent in a procedure of some misfortune information is a corollary of the patient's right to occurring, then doctors should warn patients of the self-determination which is a right recognised by possibility that the injury may occur, however well law. Failure to provide appropriate information the treatment is performed. Doctors should take will usually be a breach of duty and if that breach into account the personality of the patient, the leads to the patient suffering injury then the basis likelihood of any misfortune arising and what for a claim for compensation exists.37 warning was necessary for each particular patient's The keeping of appropriate medical records, welfare.36 written at the time of consultation (and which is so Doctors should consider what their particular frequently neglected) is not only good medical individual patients would wish to know (i.e. would practice, it is the best way of ensuring that there is an be likely to attach significance to) and not only what answer to unjustified allegations, made later, when they think (paternalistically) that the patients ought memory has faded;38 for example, allegations by to know. It is part of the professionalism of doctors patients that they would have declined a treatment to tell what is appropriate to the individual patient's that has done harm if the doctor had given a proper interest. If things go wrong doctors must be prepared warning. 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 FORMULARIES, GUIDELINES AND critically at doctors who seek to justify under- 'ESSENTIAL' DRUGS information by saying that they feared to confuse or Increasingly, doctors recognise that they need frighten the patient (or that they left it to the patient to guidance through the bountiful menu (thousands of ask, as one doctor did). The increasing availability of medicines) so seductively served to them by the phar- patient information leaflets (PILs) prepared by the maceutical industry. Principal sources of guidance manufacturer indicates the increasing trend to give more information. Doctors should know what their 37 patients have read (or not read, as is so often the Ian Dodds-Smith. 38 case) when patients express dissatisfaction. A professor of clinical pharmacology who has made special studies of prescribing and patient information writes: Evidence that extensive information on risks 'What should a prescriber record in the notes?' causes 'unnecessary' anxiety or frightens patients Given the existing format of general practitioner notes and suggests that this is only a marginal issue and it the limited time available for each consultation, it seems does not justify a general policy of withholding of unlikely that detailed information will be recorded in the information. notes. A compromise is therefore inevitable. My suggestion is that doctors should make a point of recording the fact that they have warned patients about treatments which are Legal hazards for prescribers potentially hazardous. Specific examples include the description of dietary precautions to be taken if a Doctors would be less than human if, as well as monoamine oxidase inhibitor has been prescribed and the trying to help their patients, they were not also issue of steroid treatment cards to patients given prednisolone. Similarly, it would be wise to record that a concerned to protect themselves from allegations of young woman given a retinoid for acne is taking adequate malpractice (negligence) (see Regret avoidance). The contraceptive precautions, or that a patient taking legal position regarding a doctor's duty has been carbimazole for thyrotoxicosis had been warned to report to pungently put by a lawyer specialising in the field: the surgery in the event of a severe sore throat. 'Despite all of these uncertainties, the good news is that The provision of information to patients is treated patients who receive leaflets are more satisfied than those by (English) law as but one part of the way a who do not. Satisfied patients are less likely to complain, and are therefore presumably less likely to take legal action against prescribers' (George C F 1994 Prescribers' Journal 34: 36 Legal correspondent 1980 British Medical Journal 280:575. 7-11). 17
I TOPICS IN DRUG T H E R A P Y are the pharmaceutical industry ('prescribe my drug') 'Essential' drugs. Economically disadvantaged and governments ('spend less'); also the developing countries may need help to construct formularies. (profit-making) managed care/insurance bodies Technical help has been forthcoming since 1977 ('spend less'); and the proliferating drug bulletins from the World Health Organization (WHO) with offering independent, and supposedly unbiased its Model List of Essential Drugs, i.e. drugs (or advice ('prescribe appropriately'). representatives of classes of drugs) 'that satisfy the Even the pharmaceutical industry, in its more health care needs of the majority of the population; sober moments, recognises that their ideal world in they should therefore be available at all times in which doctors, advised and informed by industry adequate amounts and in the appropriate dosage alone, were free to prescribe whatever they pleased,39 forms'. Countries needing such advice can use the to whomsoever they pleased, for as long as they list as a basis for their own choices (WHO also pleased with someone other than the patient paying, publishes model prescribing information).40 The list is an unrealisable dream of a 'never-never land'. is updated every few years and contains about The industry knows that it has to learn to live 300 items. The current list is provided as Appendix 1 with restrictions of some kinds and one of the means to this chapter. of restriction is the formulary, a list of formulations of The pharmaceutical industry dislikes the concept medicines with varying amounts of added infor- that some drugs may be classed as essential and mation. A formulary may list all nationally licensed therefore others, by implication, are deemed inessen- medicines prescribable by health professionals, or list tial. But the WHO programme has attracted much only preferred drugs. interest and approval (see WHO Technical Report It may be restricted to what a third party payer Series: The use of essential drugs: current edition). 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 Compliance partnership of general practitioners or primary care health centre. Successful therapy, especially if it is long-term, All restricted formularies are heavily motivated comprises a great deal more than choosing a standard to keep costs down without impairing appropriate medicine. It involves patient and doctor compliance.41 prescribing (p. 15). They should make provision for The latter is liable to be overlooked (by doctors), for prescribing outside their range in cases of special doctors prefer to dwell on the deficiencies of their need with an 'escape clause'. patients rather than of themselves. Thus restricted formularies are in effect guidelines for prescribing. There is a profusion of these from PATIENT COMPLIANCE national sources, hospitals, group practices and specialty organisations (epilepsy, diabetes mellitus). Patient compliance is the extent to which the actual behaviour of the patient coincides with medical advice and instructions: it may be complete, partial, 39 It is difficult for us now to appreciate the naive fervour and 40 trust in doctors that allowed them almost unlimited rights to There is an agency for WHO publications in all UN prescribe (in the early years of the UK National Health countries. 41 Service: founded in 1948). Beer was a prescription item in The term compliance has been objected to as having hospitals until, decades later, an audit revealed that only 1 in overtones of obsolete, authoritarian attitudes, implying 10 bottles reached a patient. More recently (1992): There 'obedience' to doctors' 'orders'. The world concordance has could be fewer Christmas puddings consumed this year. The been suggested as an alternative which expresses the duality puddings were recently struck off a bizarre list of items that of drug prescribing (by the doctor) and taking (by the doctors were able to prescribe for their patients. They were patient). We retain compliance, pointing out that it applies removed by Health Department officials without complaint equally to those doctors who neither keep up-to-date, nor from the medics, on the grounds they had "no therapeutic or follow prescribing instructions, and to patients who fail, for clinical value".' (Lancet 1992 340: 1531). whatever reason, to keep to a drug regimen. 18
COMPLIANCE I erratic, nil, or there may be overcompliance. To Prime factors for poor patient compliance are: make a diagnosis and to prescribe evidence-based • Frequency and complexity of drug regimen. Many effective treatment is a satisfying experience for studies attest to compliance being inhibited by doctors, but too many assume that patients will polypharmacy, i.e. more than three drugs to be gratefully or accurately do what they are told, i.e. taken concurrently or more than three drug- obtain the medicine and consume it as instructed. taking occasions in the day (the ideal of one This assumption is wrong. occasion only is often unattainable). The rate of nonpresentation (or redemption) of • Unintentional noncompliance, or forgetfulness,45 prescriptions42 (UK) is around 5% but up to 20% or may be addressed by associating drug-taking even more in the elderly (who pay no prescription with cues in daily life (breakfast, bedtime), by charge). Where lack of money to pay for the special packaging (e.g. calendar packs) and by medicine is not the cause, this is due to lack of enlisting the aid of others (e.g. carers, teachers). motivation. • 'Intelligent' or wilful noncompliance.46 Patients Having obtained the medicine, some 25-50% (sometimes even more) of patients either fail to 44 Cautionary tales: follow the instruction to a significant extent (taking — A 62-year-old man requiring a metered-dose inhaler (for 50-90% of the prescribed dose), or they do not take the first time) was told to 'spray the medicine to the throat'. it at all. He was found to have been conscientiously aiming and firing the aerosol to his anterior neck around the thyroid Patient noncompliance is identified as a major cartilage, four times a day for two weeks (Chiang A A, Lee J C 1994 New England Journal of Medicine 330:1690). factor in therapeutic failure in both routine practice — A patient thought that 'sublingual' meant able to speak and in scientific therapeutic trials; but, sad to say, two languages; another that tablets cleared obstructed blood doctors, are too often noncompliant about remedying vessels by exploding inside them (E A Kay) — reference, no this. All patients are potential noncompliers;43 good doubt, to colloquial use of the term 'clot-busting drugs' (for compliance cannot be reliably predicted on clinical thrombolytics). — These are extreme examples, most are more subtle and criteria, but noncompliance often can be. less detectable. Doctors may smile at the ignorant naivety of In addition to therapeutic failure, undetected patients, but the smile should be replaced by a blush of noncompliance may lead to the best drug being shame at their own deficiencies as communicators. 45 deemed ineffective when it is not, leading to Where noncompliance, whether intentional or substitution by second-rank drugs. unintentional, is medically serious it becomes necessary to bypass self-administration (unsupervised) and to resort to Noncompliance may occur because: directly observed (i.e. supervised) oral administration or to • the patient has not understood the instructions, injection (e.g. in schizophrenia). 46 Of the many causes of failure of patient compliance the so cannot comply,44 or following case must be unique: • understands the instructions, but fails to carry On a transatlantic flight the father of an asthmatic boy was them out. 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 42 Many factors are associated with prescription had a lengthy conversation with one of the doctors, who nonredemption. Perhaps the cameo of a person least likely to gave his name. As a consequence, on arrival, he faxed his redeem a prescription is a middle-aged woman, not exempt wife at home to stop the treatment of their son immediately. from prescription charges (in UK National Health Service) She did so, and two days later the well-controlled patient who has a symptomatic condition requiring an 'acute' had a brisk relapse that responded to urgent treatment by the prescription that is issued by a trainee general practitioner family doctor (who had been conscientiously following on a Sunday (Beardon P H G et al 1994 British Medical guidelines recently published in an authoritative journal). Journal 307: 846). The family doctor later ascertained that the doctor in the 43 Even where the grave consequences of noncompliance are plane was a member of the editorial team of the journal that understood (glaucoma: blindness) (renal transplant: organ had so recently published the guidelines that were rejection), significant noncompliance has been reported in as favourable to inhaled corticosteroid (Cox S 1994 Is many as 20% of patients; psychologists will be able to eavesdropping bad for your health? British Medical Journal suggest explanations for this. 309: 718). 19
I TOPICS IN DRUG T H E R A P Y decide they do not need the drug or they do not the patient's lifestyle. Use fixed-dose like the drug, or take 2-3-day drug holidays. combinations or sustained-release (or injectable • Lack of information. Oral instructions alone are not depot), as appropriate; arrange direct enough; one-third of patients have been found observation of each dose in exceptional cases unable to recount instructions immediately on • Provide oral and written information adapted to leaving the consulting room. Lucid and legible the patient's understanding and medical and labelling of containers is essential, as well as cultural needs patient-friendly information leaflets, which are • Use patient-friendly packaging, e.g. calendar increasingly available via doctors and packs, where appropriate; or monitored-dose pharmacists and as package inserts. (In systems, e.g. boxes compartmented and labelled hospitals, pharmacists have been known to • See the patient regularly and not so infrequently throw away patient package inserts because they that the patient feels the doctor has lost interest present problems for their administrative • Use computer-generated reminders for repeat routine.) prescriptions. • Poor patient-doctor relationship and lack of motivation to take medicines as instructed offer a Directly observed therapy (DOT) (where a reliable major challenge to the prescriber whose person supervises each dose). In addition to the areas diagnosis and prescription may be perfect, but where it is obviously in the interest of patients that yet loses efficacy by patient noncompliance. they be supervised, e.g. children, DOT is employed Unpleasant disease symptoms, particularly (even imposed) where free-living uncooperative where these are recurrent and known by patients may be a menace to the community, e.g. previous experience to be quickly relieved, multiple-drug-resistant tuberculosis. provide the highest motivation, i.e. self- motivation, to comply. But particularly where the patient does not feel ill, adverse effects are • An account of the disease and the reason for immediate, and benefits are perceived to be prescribing remote, e.g. in hypertension, where they may be • The name of the medicine many years away in the future, then doctors • The objective — to treat the disease and/or must consciously address themselves to — to relieve symptoms, i.e. how important the motivating compliance. The best way to medicine is, whether the patient can judge its motivate patients compliance is to cultivate the efficacy and when benefit can be expected to patient-doctor relationship. Doctors cannot be occur expected actually to like all their patients, but it • How and when to take the medicine is a great help (where liking does not come • Whether it matters if a dose is missed and what, if naturally) if they make a positive effort to anything, to do about it (see p. 23) • How long the medicine is likely to be needed understand how individual patients must be • How to recognise adverse effects and any action that feeling about their illnesses and their treatments, should be taken, including effects on car driving i.e. to empathise with their patients. This is not • Any interaction with alcohol or other medicines. always easy, but its achievement is the action of the true professional, and indeed is part of their professional duty of care. A remarkable instance of noncompliance, with hoarding, was that of a 71-year-old man who Suggestions to doctors to enhance patient com- attempted suicide and was found to have in his home pliance are: 46 bottles containing 10 685 tablets. Analysis of his • Form a nonjudgemental alliance or partnership prescriptions showed that over a period of 17 months with the patient, giving the patient an he had been expected to take 27 tablets of several opportunity to ask questions different kinds daily.48 • Plan a regimen with the minimum number of From time to time there are campaigns to collect drugs and drug-taking occasions, adjusted to fit all unwanted drugs from homes in an area. Usually 20
COMPLIANCE I the public are asked to deliver the drugs to their Requiring patients to produce containers when local pharmacies. In one UK city (600 000 population) they attend the doctor, who counts the tablets, seems 500 000 'solid dose units' (tablets, capsules, etc.) were to do little more than show the patient that the doctor handed in (see Opportunity cost); such quantities cares about the matter (which is useful); and a tablet have even caused local problems for safe waste absent from a container has not necessarily entered disposal. the patient's body. On the other hand, although Factors that are insignificant for compliance are: patients are known to practise deliberate deception, age49 (except at extremes), gender, intelligence (except to maintain effective deception successfully over at extreme deficiency) and education level (probably). long periods requires more effort than most patients are likely to make. The same applies to the use of Overcompliance. Patients (up to 20%) may take monitored-dosage systems (e.g. compartmented more drug than is prescribed, even increasing the boxes) as memory aids and to electronic containers dose by 50%. In diseases where precise compliance that record times of opening. with frequent or complex regimens is important, Some pharmacodynamic effects, e.g. heart rate e.g. in glaucoma where sight is at risk, there have with beta-adrenoceptor blocker, provide a physio- been instances of obsessional patients responding logical marker as an indication of the presence of to their doctors' overemphatic instructions by drug in the body. clock-watching in a state of anxiety to avoid the slightest deviance from timed administration of the Compliance in new drug development correct dose, to the extent that their daily (and nightly) life becomes dominated by this single Noncompliance, discovered or undiscovered, can purpose. invalidate therapeutic trials (in which it should always be monitored). In new drug development Evaluation of patient compliance. Merely asking trials the diluting effect of undetected noncompliance patients whether they have taken the drug as directed (prescribed doses are increased) can result in unduly is not likely to provide reliable evidence;50 and it can high doses being initially recommended (licensed) be assumed that anything that can happen to impair (with toxicity in good compliers after marketing), so compliance, will happen sometimes. Estimations of that the standard dose has soon to be urgently compliance are based on studies using a variety of reduced (this has probably occurred with some new measures. nonsteroidal anti-inflammatory drugs). 47 After Drug and Therapeutics Bulletin 1981 19: 73. DOCTOR COMPLIANCE Patient information leaflets. In economically privileged countries original or patient-pack dispensing is becoming the Doctor compliance is the extent to which the norm, i.e. patients receive an unopened pack just as it left the behaviour of doctors fulfils their professional duty: manufacturer. The pack contains a Patient Information Leaflet (PIL) (which is therefore supplied with each repeat • not to be ignorant prescription). Its content is increasingly determined by • to adopt new advances when they are regulatory authority. The requirements to be comprehensive sufficiently proved (which doctors are often slow and, in this litigous age, to protect both manufacturer and regulatory authority, to some extent impair the patient- to do) friendliness of PILs. But studies have shown that patients • to prescribe accurately51 who receive leaflets are more satisfied than those who do • to tell patients what they need to know not. Doctors need to have copies of these leaflets so that they can discuss with their patients what they are (or are not) 50 reading. Hippocrates (5th cent. BC) noted that patients are liars 48 Smith S E et al 1974 Lancet 1: 937. regarding compliance. The way the patient is questioned 49 But the elderly are commonly taking several drugs — a may be all-important, e.g. 'Were you able to take the tablets?' major factor in noncompliance — and monitoring may get a truthful reply where, 'Did you take the tablets?' compliance in this age group becomes particularly may not, because the latter question may be understood by important. The over-60s (UK) are, on average, each receiving the patient as implying personal criticism (Pearson R M 1982 two or three medications. British Medical Journal 285: 757). 21
I TOPICS IN DRUG T H E R A P Y • to warn, i.e. to recognise the importance of the act of prescribing. Underdosing In one study in a university hospital, where standards might be expected to be high, there was Use of suboptimal doses of drugs in serious disease, an error of drug use (dose, frequency, route) in 3% sacrificing efficacy for avoidance of serious adverse of prescriptions and an error of prescription writing effects, has been documented. It particularly affects (in relation to standard hospital instructions) in drugs of low therapeutic index (see Index), i.e. 30%. Many errors were trivial, but many could have where the effective and toxic dose ranges are close, resulted in overdose, serious interaction or under- or even overlap, e.g. heparin, anticancer drugs, treatment. aminoglycoside antimicrobials. In these cases In other hospital studies error rates in drug dose adjustment to obtain maximum benefit with administration of 15-25% have been found, rates minimum risk requires both knowledge and rising rapidly where four or more drugs are being attentiveness. given concurrently, as is often the case; studies on hospital inpatients show that each receives about The clinical importance of missed dose(s) six drugs, and up to 20 during a stay is not rare. Merely providing information (on antimicrobials) Even the most conscientious of patients will miss a did not influence prescribing, but gently asking dose or doses occasionally. Patients should therefore physicians to justify their prescriptions caused a be told whether this matters and what they should marked fall in inappropriate prescribing. do about it, if anything. On a harsher note, of recent years, doctors who have given drugs, of the use of which they have later admitted ignorance (e.g. route of administration and/ • loss of efficacy (acute disease) or dose), have been charged with manslaughter52 and • resurgence (chronic disease) have been convicted. Shocked by this, fellow doctors • rebound or withdrawal syndrome. have written to the medical press offering under- standing sympathy to these, sometimes junior, colleagues; 'There, but for the grace of God, go I'.53 But the public response is not sympathetic. Doctors Loss of efficacy relates to the pharmacokinetic put themselves forward as trained professionals who properties of the drugs. With some short t1/2, drugs offer a service of responsible, competent provision of there is a simple issue of a transient drop in plasma drugs which they have the legal right to prescribe. concentration below a defined therapeutic level. But The public is increasingly inclined to hold them to with others there may be complex issues such as that claim, and, where they seriously fail, to exact recovery of negative feedback homoeostatic mech- retribution.54 anisms, e.g. adrenocortical steroids. Therapeutic effect If you don't know about a drug, find out before may not decline in parallel with plasma concen- you act, or take the personal consequences, which, tration. With some drugs a single missed dose increasingly, may be very serious indeed. may be important, e.g. oral contraceptives, with others (long t1/2) several doses may be omitted before there is any serious decline in efficacy, e.g. 51 Accuracy includes legibility: a doctor wrote Intal (sodium thyroxine (levothyroxine). cromoglycate) for an asthmatic patient: the pharmacist read it as Inderal (propranolol): the patient died. See also, Names 54 of drugs. A doctor wrote a prescription for isosorbide ninitrate 52 Unlawful killing in circumstances that do not amount to 20 mg 6-hourly but because of the illegibility of the murder (which requires an intention to kill), e.g. causing handwriting the pharmacist dispensed felodipine in the death by negligence that is much more serious than mere same dose (maximum daily dose 10 mg). The patient died carelessness; reckless, breach of the legal duty of care. and a court ordered the doctor and pharmacist to pay 53 Attributed to John Bradford, an English preacher and compensation of $450 000 to the family. Charatan F 1999 martyr (16th cent), on seeing a convicted criminal pass by. British Medical Journal 319: 1456. 22
PLACEBO MEDICINES I These pharmacokinetic considerations are com- A placebo-reactor is an individual who reports changes of plex and important, and are, or should be, taken into physical or mental state after taking a pharmacologically account by drug manufacturers in devising dosage inert substance. schedules and informative Data Sheets. Manu- facturers should aim at one or two doses per day (not more), and this is generally best achieved with Placebo-reactors are suggestible people and drugs having relatively long biological effect tl/2, or likely to respond favourably to any treatment. They where the biological effect il/2 is short, by using have misled doctors into making false therapeutic sustained-release formulations. claims. Negative reactors, who develop adverse effects Discontinuation syndrome (recurrence of disease, when given a placebo, exist but, fortunately, are rebound, or withdrawal syndrome) may occur due fewer. to a variety of mechanisms (see Index). Some 35% of the physically ill and 40% or more of the mentally ill respond to placebos. Placebo reaction is an inconstant attribute; a person may respond at one time in one situation and not at Placebo medicines another time under different conditions. There is some consistency in the type of person who tends to react to any therapeutic intervention. In one study A placebo55 is any component of therapy that is without on medical students, psychological tests revealed specific biological activity for the condition being treated. that those who reacted to a placebo tended to be extraverted, sociable, less dominant, less self- Placebo medicines are used for two purposes: confident, more appreciative of their teaching, more aware of their autonomic functions and more • As a control in scientific evaluation of drugs (see neurotic than their colleagues who did not react to a Therapeutic trials) (see p. 60) placebo under the particular conditions of the • To benefit or please a patient, not by any experiment. pharmacological actions, but by psychological It is of great importance that all who administer means. drugs should be aware that their attitudes to the All treatments have a psychological component, treatment may greatly influence the result. Undue whether to please (placebo effect) or, occasionally, scepticism may prevent a drug from achieving its to vex (negative placebo or nocebo56 effect). effect and enthusiasm or confidence may potentiate A placebo medicine is a vehicle for 'cure' by the actions of drugs. suggestion, and is surprisingly often successful, if only temporarily.57 All treatments carry placebo effect: 57 physiotherapy, psychotherapy surgery, entering a As the following account by a mountain rescue guide illustrates: The incident involved a 15-year-old boy who patient into a therapeutic trial, even the personality sustained head injuries and a very badly broken leg. and style of the doctor; but the effect is most easily Helicopter assistance was unavailable and therefore we had investigated with drugs, for the active and the inert to carry him by stretcher to the nearest landrover (several can often be made to appear identical so that miles away) and then on to a waiting ambulance. comparisons can be made. During this long evacuation the boy was in considerable distress and we administered Entonox (a mixture of nitrous The deliberate use of drugs as placebos is a oxide and oxygen, 50% each) sparingly as we only had one confession of failure by the doctor. Failures however small cylinder. He repeatedly remarked how much better he are sometimes inevitable and an absolute condem- felt after each intake of Entonox (approximately every nation of the use of placebos on all occasions would 20 minutes) and after 7 hours or so we eventually got him be unrealistic. 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 55 Latin: placebo, I shall be pleasing or acceptable. faulty. There was no doubt that the boy felt considerable pain 56 Latin: nocebo, I shall injure; the term is little used. relief as a result of thinking he was receiving Entonox/ 23
I TOPICS IN DRUG T H E R A P Y Tonics are placebos. They may be defined as Economics is the science of the distribution of wealth substances with which it is hoped to strengthen and and resources. Prescribing doctors, who have a duty to increase the appetite of those so weakened by the community as well as to individual patients, cannot disease, misery, overindulgence in play or work, or escape involvement with economics. 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 The economists' objective defect for which there is a known remedy. Since The objective is to enable needs to be defined so that tonics are placebos, they must be harmless.58 available resources may be deployed according to priorities set by society, which has an interest in fairness between its members. The question is whether resources are to be distributed in accordance Pharmacoeconomics with and unregulated power struggle between professionals and associations of patients and public Even the richest societies cannot satisfy the appetite pressure groups — all, no doubt, warm-hearted of their citizens for health care based on their real towards deserving cases of one kind or another, but needs, on their wants and on their (often unrealistic) none able to view the whole scene; or whether there expectations. is to be a planned evaluation that allows division of Health care resources are rationed59 in one way or the resources on the basis of some visible attempt at another, whether according to national social policies fairness. or to individual wealth. The debate on supply is not A health economist60 writes: about whether there should be rationing, but about what form rationing should take; whether it should The economist's approach to evaluating drug be explicit or concealed (from the public). therapies is to look at a group of patients with a Doctors prescribe, patients consume and, increas- particular disorder and the various drugs that ingly throughout the world, third (purchasing) could be used to treat them. The costs of the parties (government, insurance companies) pay the various treatments and some costs associated with bill with money they have obtained from increasingly their use (together with the costs of giving no reluctant healthy members of the public. treatment) are then considered in terms of impact The purchasers of health care are now engaged on health status (survival and quality of life) and in serious exercises to contain drug costs in the short impact on other health care costs (e.g. admissions term without, it is hoped, impairing the quality of to hospital, need for other drugs, use of other medical care, or damaging the development of useful procedures). new drugs (which is an enormously expensive and Economists are often portrayed as people who long-term process). This can be achieved successfully want to focus on cost, whereas in reality they see only if reliable data are available on costs and everything in terms of a balance between costs and benefits, both absolute and relative. The difficulties benefits. of generating such data, not only during develop- Four economic concepts have particular impor- ment, but later under actual-use conditions, are tance to the thinking of every doctor who takes up a enormous and are addressed by a special breed of pen to prescribe, i.e. to distribute resources. professionals: the health economists. • Opportunity cost means that which has to be sacrificed in order to carry out a certain course of 58 Tonics (licensed) available in the UK include: Gentian action, i.e. costs are benefits foregone elsewhere. Mixture, acid (or alkaline) (gentian, a natural plant bitter If money is spent on prescribing, that money is substance, and dilute HC1 or sodium bicarbonate): Labiton not available for another purpose; wasteful (thiamine, caffeine, alcohol, all in low dose). 59 prescribing can be seen as an affront to those The term rationing is used here to embrace the allocation of priorities as well as the actual withholding of resources (in 60 this case, drugs). Prof Michael Drummond. 24
SE LF-MEDIC ATION I who are in serious need, e.g. institutionalised Quality of life has four principal dimensions:61 mentally handicapped citizens who everywhere 1. physical mobility would benefit from increased resources. 2. freedom from pain and distress • Cost-effectiveness analysis is concerned with how 3. capacity for self-care to attain a given objective at minimum financial 4. ability to engage in normal work and social cost, e.g. prevention of postsurgical venous interactions. thromboembolism by heparins, warfarin, aspirin, external pneumatic compression. The approach to measure quality of life has been developed by questionnaire to measure what the Analysis includes cost of: materials, adverse subject perceives as personal health. The assessments effects, any tests, nursing and doctor time, are being refined to provide improved assessment of duration of stay in hospital (which may greatly the benefits and risks of medicines to the individual exceed the cost of the drug). and to society. The challenge is to ensure that these • Cost-benefit analysis is concerned with issues of are sufficiently robust to make resource allocation whether (and to what extent) to pursue decisions between, for example: the rich and the objectives and policies; it is thus a broader poor, the educated and the uneducated, the old and activity than cost-effectiveness analysis and puts the young, as well as between groups of patients monetary values on the quality as well as on the quantity (duration) of life. having very different diseases. Plainly, quality of life is a major aspect of what is called outcomes • Cost-utility analysis is concerned with research. comparisons between programmes, e.g. 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 outcomes can be placed on the same Self-medication basis for comparison by computing quality- To feel unwell is common, though the frequency adjusted life years (see below). varies with social and cultural circumstances. An allied measure is the cost-minimisation analysis People commonly experience symptoms or which finds the least costly programme among complaints and commonly want to take remedial those shown or assumed to be of equal benefit. action. In one study of adults randomly selected Economic analysis requires that both quantity and from a large population, 9 out of 10 had one or more quality of life be measured. The former is easy, the complaints in the 2 weeks before interview; in latter is hard. another of premenopausal women a symptom occurred as often as 1 day in 3; in both studies a medicine was taken for more than half these Quality of life occurrences. 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 Increasingly, educated and confident consumers are aware (in years). But it is evident that life may be extended of five consumer rights (United Nations charter): • access (to a wide range of products) and yet have a low quality, even to the point that it • choice (self-determination) is not worth having at all. It is therefore useful to • information (on which to base choice) have a unit of health measurement that combines the • redress (when things go wrong) quality of life with its quality to allow individual and • safety (appropriate to the use of the product). social decisions to be made on a sounder basis than mere intuition. To meet this need economists have developed the quality-adjusted-life-year (QALY); estimations of years of life expectancy are modified 61 Williams A1983. In: Smith G T (ed) Measuring the social according to estimations of quality of life. benefits of medicine. Office of Health Economics, London. 25
I TOPICS IN DRUG T H E R A P Y Modern consumers (patients) wish to take a Information — available with all purchases greater role in the maintenance of their own health (printed) and rigorously reviewed (by panels of and are often competent to manage (uncomplicated) potential users) for user-friendliness and chronic and recurrent illnesses (not merely short-term adequacy for a wide range of education and symptoms) after proper medical diagnosis and with intellectual capacity only occasional professional advice, e.g. use of Patient compliance. histamine H2-receptor blocker, topical corticosteroid and antifungal, and oral contraceptive. They are Doctors must recognise the increasing importance of understandably unwilling to submit to the incon- questioning about self-medication when taking a drug venience of visiting a doctor for what they rightly history. feel they can manage for themselves, given adequate information. Increased consumer autonomy leads to satisfied: • consumers (above) GUIDE TO FURTHER READING • governments (lower drug bill) Barach P, Small S D 2000 Reporting and preventing • industry (profits) medical mishaps: lessons from non-medical near • doctors (reduced work load). miss reporting systems. British Medical Journal 320: 759-763. The pharmaceutical industry enthusiastically de Craen A et al 1996 Effect of colour of drugs: estimates that extending the use of self-medication systematic review of perceived effect of drugs and to all potentially self-treatable illnesses could save their effectiveness. British Medical Journal 313: 100-150 million general practitioner consultations 1624-1626 per year (in the UK: population 57 million). But Editorial 1988 When to believe the unbelievable. there will also be added costs as pharmacists extend Nature 333: 787 A report of an investigation into their responsibilities for supply and information. experiments with antibodies in solutions that Regulatory authorities are increasingly receptive contained no antibody molecules (as in some to switching hitherto prescription-only medicines homoeopathic medicines). The editor of Nature (POM) for self-medication (over-the-counter, OTC, took a three-person team (one of whom was a sale) via pharmacies (P) or via any retail outlet professional magician, included to detect any (general sale). The operation is known as POM-OTC trickery) on a week-long visit to the laboratory that or POM-P 'switch'. It requires particularly exacting claimed positive results. Despite the scientific standards of safety. seriousness of the operation it developed comical aspects (codes of the contents of test tubes were taped to the laboratory ceiling); the Nature team, • short-term relief of symptoms where accurate having reached an unfavourable view of the diagnosis is unnecessary experiments 'sped past the [laboratory] common- • uncomplicated cases of some chronic and recurrent room filled with champagne bottles destined now disease (a medical diagnosis having been made and advice given). 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 Safety in self-medication (an overriding require- for entertainment. See also Nature 1994 370: 322 ment) depends on four items: Ernst E, Thompson J 2001 Heavy metals in traditional • The drug — its inherent properties, dose and Chinese medicines: a systematic review. Clinical duration of use, including its power to induce Pharmacology and Therapeutics 70: 497-504 dependence Ferner R E 2000 Medication errors that have led to • The formulation — devised with unsupervised manslaughter charges. British Medical Journal 321: use in mind, e.g. low dose 1212-1216 26
SE L F - M E D I CAT I O N I Kleijnen J et al 1994 Placebo effect in double-blind systems. Clinical Pharmacology and Therapeutics clinical trials. Lancet 344:1347-1349 67: 331-334 Mead T (ed) 1998 Science-based complementary Vickers A 2000 Complementary medicine. British medicine. Royal College of Physicians of London; Medical Journal 321: 683-686 London Vickers A, Zollman C 1999 Homeoepathy. British Meltzer M 12001 Introduction to health economics for Medical Journal 319:1115-1118 physicians. Lancet 358: 993-998 (and subsequent Volmink J, Matchaba P, Garner P 2000 Directly papers in this quintet). observed therapy and treatment adherence. Lancet Moynihan R et al 2000 Coverage by the news media of 355:1345-1350 the benefits and risks of medications. New England Weingart S N et al 2000 Epidemiology of medical Journal of Medicine 342:1645-1650 error. British Medical Journal 320: 774-777 Reason J 2000 Human error: models and management. Zollman C, Vickers A1999 What is complementary British Medical Journal 320: 768-770 medicine? British Medical Journal 319: 693-696 Thomas K B 1994 The placebo in general practice. (and other articles in this series). Lancet 344:1066 Urquhart J 2000 Erratic patient compliance with prescribed drug regimens: target for drug delivery 27