Abstract
Aims
To examine how pharmaceutical products that were first marketed between 1950 and 1980 were promoted to physicians through advertisements and briefly review advertising regulations and accuracy of the advertisements in the light of modern knowledge.
Methods
We systematically reviewed advertisements promoting drugs for specific therapeutic areas, namely central nervous system disorders (anxiety and sleep disorders, depression, psychoses, and Parkinson's disease), respiratory disorders, cardiovascular disorders, and gastrointestinal disorders. We examined about 800 issues of the British Medical Journal (1950–1980) and about 150 issues of World Medicine (1965–1984).
Results
Advertising material was minimally regulated until the mid‐1970s. Many drugs were marketed with little preclinical or clinical knowledge and some with the expectation that prescribers would obtain further data. The peak of advertising occurred in parallel with the surge in the release of novel drugs during the 1960s, but declined markedly after the mid‐1970s. Advertisements generally contained little useful prescribing information. The period we investigated saw the release of many novel pharmaceuticals in the therapeutic areas we examined, and many (or their class successors) still play important therapeutic roles, including benzodiazepines, tricyclic antidepressants, phenothiazines, levodopa, selective and non‐selective β‐adrenoceptor antagonists, thiazide diuretics, β‐adrenoceptor agonists, and histamine H2 receptor antagonists.
Conclusions
Advertising pharmaceuticals in the BMJ and World Medicine in 1950–1980 was poorly regulated and often lacked rigour. However, advertisements were gradually modified in the light of increasing clinical pharmacological knowledge, and they reflect an exciting period for the introduction of many drugs that continue to be of benefit today.
Keywords: advertising; pharmaceutical products, cardiovascular disorders, CNS disorders, gastrointestinal disorders, respiratory disorders
Introduction
We have charted the rise of modern therapeutics as seen through advertisements for medicinal products that appeared in medical journals from 1950 to 1980. In doing so, we have generally used the names of medicines as used during that period, rather than their modern International Nonproprietary Names (e.g. ‘phenobarbitone’ rather than ‘phenobarbital’).
The word ‘advertise’ was first recorded in English in 1426, when it was used to mean ‘to call the attention of (a person) to something; to notify, warn, or inform, esp. in a formal or earnest manner’ 1. It was not until the start of the eighteenth century that the modern meaning of ‘advertise’ emerged: ‘to make generally known by means of an announcement in a public medium’.
Although this article deals with advertising to medical practitioners, advertising of medicines is far broader. Early in the history of pharmaceutical products, a distinction was drawn between the advertisement and sale of a concoction direct to the public by a pharmacist; the ingredients often being kept secret (proprietary or patent medicines), and the sale of ‘pure’ medicines (so‐called ethical or prescription medicines) where advertising was usually restricted to doctors. At the start of the twentieth century huge amounts were being spent advertising patent medicines in the United States; for example, up to US$1 million was spent annually promoting Scott's Emulsion (a cod liver oil preparation) 2. Claude Hopkins (1866–1932), an early pioneer of advertising, stated that ‘the greatest advertising men of my day were schooled in the medicine field’ 3. There is substantial evidence that early medicines were promoted in the UK and elsewhere, both to the general public and to physicians, in advertisements that made claims of efficacy that were at best questionable and sometimes, at least in the field of patent medicines, fraudulent. Harms were also little studied or discussed. For example, US adverts from the beginning of the twentieth century extolled the value of heroin cough drops, and cocaine tooth drops for children.
Until about 1950, there were few clinically efficacious pharmaceutical products. Drugs such as the sulphonamides, opiates, barbiturates, and phenytoin were readily available, but relatively little else, besides various over‐the‐counter medicines such as, for example, antacids to treat gastric ulcers. However, between 1950 and 1980 there was an explosion of novel drugs for a wide spectrum of illnesses, as can be seen in reviews of drug registrations in both the UK and the USA 4, 5, 6 and briefly illustrated in Figure 1. Many of these compounds were marketed with minimal preclinical investigation, let alone proper clinical evaluation, including double‐blind studies. This reflects the methods of drug development and regulation at that time, both of which were completely different from current practices.
Figure 1.
Number of FDA‐approved new molecular entities, 1945–1980; data taken from information supplied by M.S. Kinch and published in reference 4
The successful uptake of some drugs in clinical practice was due in some cases not merely to their efficacy, but also to very effective and sometimes extensive advertising to the medical profession. Quite often claims were made for indications and efficacy that, in retrospect, were unwarranted. As more evidence became available on the value of the drugs in specific clinical conditions, advertisements sometimes changed appropriately.
Our aim has been to investigate how some of the substantial number of novel pharmaceutical compounds released on to the market from 1950 to 1980 were advertised to the medical profession in the UK. We have examined the claims made in such advertisements in the light of modern experimental and clinical pharmacology and therapeutics knowledge and, where possible, how such adverts changed as knowledge accrued. We have examined several major therapeutic areas that experienced extensive advertising and also reflected important examples of drug discovery and development, and have presented results chronologically.
Methods
We performed a systematic review of advertisements that appeared in UK medical journals (1950–1980). Our primary source was the British Medical Journal (BMJ), the major UK journal for general practitioners during the 1950s and beyond. All advertising material in the BMJ has been scanned and is available online 7. We examined advertisements for drugs for specific therapeutic areas, namely central nervous system disorders (anxiety and sleep disorders, depression, psychosis, and Parkinson's disease), respiratory disorders, cardiovascular disorders, and gastrointestinal disorders. We examined online approximately every other issue from 1950 to 1980, some 800 issues in total. We also reviewed about 150 issues of World Medicine, a magazine that was sent free to all physicians between 1965 and 1984 and relied on pharmaceutical advertising for its income; we did this primarily to seek adverts that did not appear in BMJ. Adverts in World Medicine were also often in full colour, rather than the black‐and‐white advertisements in the BMJ. We also examined several other major UK‐based journals in the therapeutic areas we investigated (Journal of Mental Science/British Journal of Psychiatry; Journal of Neurology, Neurosurgery, and Psychiatry; British Heart Journal; British Journal of Diseases of the Chest; Gut), but found that they contained few if any advertisements until the late 1970s. We used the archives of the Bodleian Library (Oxford) to source the journals.
All drug trade names and any phrases or sentences in the advertisements we quote have been italicized.
A brief review of UK drug advertising regulation in 1950s and beyond
It is beyond our scope to examine in detail changes in drug regulation regarding the quality, safety and efficacy of medicines during this period. Detailed reviews of drug regulation in the UK and US and the formation and role of organizations such as the UK Committee on Safety of Medicines (CSM) can be found elsewhere 8, 9, 10.
The establishment of the Committee on Drugs (1963) 9 marked the start of effective regulation of new medicines in the UK. Regulation of the marketing and advertising of drugs did not occur until many years later with the result that many advertisements identified in this review are quite shocking to the modern eye. For example, in 1964 an advert for Physeptone cough mixture stated that the preparation contained 2 mg of methadone per fluid drachm, with the misleading comment that ‘the risk of addiction is negligible’, continuing with the statement that information on dosing could be found in the Wellcome Medical Diary (BMJ, 08‐02‐64).
Guidance for advertising to medical practitioners in the UK was first provided in the Association of British Pharmaceutical Industry (ABPI) Code of Sales Promotion Practice for Medical Specialities in the United Kingdom, published in October 1958. This was only two pages long and, covered the behaviour of representatives, hospitality, gifts, and provision of samples, but said little about what an advertisement could state. Updates of the Code became gradually longer, and by 1974 provided guidelines that resulted in the type of advertisement that is now the norm. For example, the ABPI decreed that the word ‘safe’ could not be used without qualification, that active ingredients had to be listed, that approved or nonproprietary names and recommended dosages should be included, together with the route of administration, and that adverse effects, precautions, and contraindications should be listed, as well as information on how further information could be obtained. However, our investigations have shown that these guidelines were often being ignored two to three years later. The current code was published in 2016 and is 68 pages long 11. Since 1993 the Code has been regulated by the Prescription Medicines Code of Practice Authority (PMCPA), which acts independently of the ABPI.
The key rules regarding adverts are:
advertisements should comply with the particulars listed in the summary of product characteristics (SmPC);
the product should be presented objectively, without exaggerating its properties, and rational use of the product should be encouraged;
the advertisement should not be misleading;
it should not state or imply that the product is ‘safe’.
Since adverts in the 1950s up to the mid‐1970s, were not strictly regulated, few if any of the current rules had any place in marketing executives' thinking, as will be seen from many of the examples we give. In mitigation, it should be emphasized that hyperbole, and a certain lack of honesty, was prevalent in all advertising during this period 12; pharmaceutical companies were probably neither better nor worse than other companies at the time. However, pharmaceutical advertising, an area where total probity should be mandatory, still remains far from perfect, according to a fairly recent survey 13.
Changes in the volume of advertising 1950–1980
In the early 1950s the BMJ carried few pharmaceutical advertisements, sometimes as few as one or two pages in 1950. By the late 1950s adverts occupied 30–40 pages per issue. This growth reflected the development of new compounds during the decade (Figure 1).
Advertising volume in the BMJ remained substantial during the 1960s (30–40 pages per issue), but by the later 1970s the volume decreased markedly, and by the early 1980s adverts often covered only two or three pages. When World Medicine ceased publication in December 1984, the Editor stated that it was closing as a result of reductions in allowable promotional spending imposed on pharmaceutical companies by the then Department of Health and Social Security (DHSS) and the consequent loss of advertising revenue. One suspects that more targeted advertising through company representatives, selective mailing, and company presence at both small and large scientific meetings had been found to be more cost effective, as advertising remained modest not only in the BMJ but also in the specialist journals we examined, and it seems unlikely that this decrease was in any way related to the more rigorous regulation of pharmaceutical advertising that occurred in the late 1970s.
Advertising pharmaceutical products in the BMJ in the 1950s
It would be invidious to criticize some of the social attitudes captured within the advertising images or texts directed at doctors from nearly 70 years ago because of what is now considered unacceptable; examples include sexism and a paternalistic approach to patients. Nevertheless, some general points can be made. Advertisement illustrations during the 1950s and 1960s were mostly pencil‐like sketches, and patients were generally good‐looking professional people. The place of the woman was clearly in the home. For example, an advert for Drinamyl (dexamphetamine, Menley & James) shows a woman, needing treatment for anxiety, having to deal with cooking, sewing, and washing clothes by hand in a large tub, with a mangle nearby (BMJ, 12‐04‐52).
Doctors in illustrations were invariably men of mature years and, if general practitioners (GPs), wearing expensive‐looking suits and seated at their desks or, if hospital‐based, white‐coated and standing by the bedside, usually accompanied by an attractive young female nurse. If the doctor was talking to the patient, his spectacles would often be held in one hand, presumably suggesting that this was a personal and intimate conversation. More than 20 years later, advertisements still gave the impression that being a physician was a male preserve.
Advertisements for proprietary or over‐the‐counter (OTC) medications appeared regularly, as well as those for food supplements and products that might be suggested to patients as being of value, such as Clarks Shoes for children. Adverts for medical equipment can be found, as well as publishers' announcements of recent medical books. Products that might be of value to the doctor's lifestyle also appeared, including good quality cars and cigarettes.
Equally redolent of another age were advertisements for therapeutic agents. Did Lembar really act as an efficient antacid, given that it contained only lemon juice, sucrose, and liquid glucose (BMJ, 14‐01‐50)? The Boots Company headlined their advert for Epitone with ‘It depends what you mean by tonic’, going on to state ‘Some say that strychnine is the only true tonic’. Boots clearly saw the value of this highly toxic alkaloid, as they praised the value of Epitone, which contained not only strychnine but also caffeine, ferrous iron, and vitamin B complex, emphasizing its value to the well‐being of the convalescent patient (BMJ, 12‐04‐52). What is disturbing is that even in 1966 strychnine was still being suggested to have therapeutic properties; Parke Davis, for example, claimed that Metatone, a solution of vitamin B1, mineral glycerophosphates, and strychnine, ‘promoted full recovery after influenza and other debilitating illnesses’ (BMJ, 19‐03‐66).
Dosages were often given in milligrams, but in some cases the old apothecaries' weight system of grains (gr) was used, a grain being 64.8 mg. Parke Davis reported that their product Carbital contained 1½ gr of pentobarbitone sodium and 4 gr of carbromal per capsule (BMJ, 24‐02‐51). Abbott, when advertising their combined Nembutal plus Belladonna formulation, quoted doses in milligrams, with the weight in grains in parentheses, but then spoilt their use of metric measures by stating that the capsule was equivalent to about 7 minims of tincture belladonna. A minim is also an apothecary measure, 7 minims being about 0.4 ml, but that was not stated (BMJ, 24‐02‐51). Even in the 1960s occasional advertisements can be found with this archaic measurement; for example, a 1964 advert for Calcidrine syrup (Abbott) gave the doses of both pentobarbitone and codeine in grains (BMJ, 08‐02‐64).
Most adverts gave the brand name of the medicinal product and often also the chemical formula of newer compounds. This must have meant nothing to most readers when presented with a long chemical name, such as that given in very small print below the trade name of the Burroughs Wellcome drug Kemadrin: dl‐1‐cyclohexyl‐1‐phenyl‐3‐pyrrolidinopropan‐1‐ol hydrochloride, now known by its International Nonproprietary Name (INN) procyclidine. Generic or non‐proprietary drug names were seldom used in adverts, even though the INN scheme had been developed by the World Health Organization in the early 1950s, and a similar scheme, the British Approved Name (BAN), was also in use in the British Pharmacopoeia after 1953.
ICI Pharmaceuticals clearly felt that any useful clinical trial information might well confuse the physician. Consequently, an advert for Sulphamethazine included a small drawing of a doctor in his white coat sitting at a desk containing pamphlets, chewing the end of his spectacle arm, and looking mystified, with text suggesting that he probably would not understand scientific results (Figure 2).
Figure 2.
An ICI advert for sulphonamides (BMJ, 18‐04‐53)
Claims for efficacy of a drug over a wide range of conditions were not unusual. Menley & James suggested that Benzedrine (racemic amphetamine sulphate) was indicated in depressive states, behavioural disorders of children, enuresis, post‐encephalitic Parkinsonism, psychopathic states, narcolepsy and alcoholism. The justification was that the ‘wide range of indications, though apparently dissimilar, require stimulation of the central nervous system as an essential therapeutic measure’ (BMJ, 12‐01‐52). A couple of months later the same company was advertising Drinamyl (the dextro‐rotatory isomer of amphetamine) as having particular value in patients suffering from ‘emotional imbalance’, a vague term encompassing many psychiatric disorders (BMJ, 12‐04‐52).
Euvalerol (Allen and Hanburys) was an interesting combination of a synthetic chemical, a hormone, and a natural extract, containing, as it did, phenobarbitone, diethylstilboestrol and valerian extract, again with the contents bizarrely listed in respectively milligrams, grains, and drachms (1 drachm being roughly 3.5 ml). This mixture was proposed to be of particular value in treating the menopause (BMJ, 07‐04‐51). Quite a few products contained mixtures of several drugs, usually with claims about the merits of the individual drugs and the consequent benefits therefore of the mixture. For example, Bellergal contained belladonna, ergotamine and phenobarbitone, and was suggested by Sandoz to be of value in treating ‘the problem patient’ by restoring ‘autonomic balance’, a claim that would have been difficult to support scientifically (BMJ, 09‐04‐66). This product was still being advertised 3 years later, with the suggestion that it would help alleviate menopausal problems.
A striking example of the lack of any requirement to demonstrate clear efficacy before releasing a drug on to the market is seen in a 1952 example, Roche's full‐page advertisement for Rimifon (isoniazid) for the treatment of tuberculosis (Figure 3; BMJ, 12‐04‐52). Note the statement that it was being made available so that clinical trials could be conducted (and by that they merely meant that individual physicians could observe whether it was apparently efficacious in their individual patients). The same journal issue had another full‐page advert for the same drug from Herts Pharmaceuticals, but with the brand name Pycazide, also stating that they were making it available immediately (Figure 3). The journal contained yet another full‐page advert for isoniazid from Squibb, who used the trade name Nydrazid. Squibb were more circumspect, stating that they would make the drug available ‘when early therapeutic expectations of the trial have been confirmed’.
Figure 3.
Two of three adverts launching the anti‐tuberculosis drug isoniazid (BMJ, 12‐04‐52)
In the following sections we examine the development and marketing between 1950 and 1980 of key compounds introduced to treat central nervous system (CNS) disorders, respiratory drugs, cardiovascular drugs and gastrointestinal drugs.
Drugs for CNS disorders
Introduction
Dividing this section into appropriate sub‐sections proved troublesome, as the use of many drugs changed over time, and claims for efficacy in several therapeutic areas were rife and sometimes unjustified. We have therefore classified products by the indications for which they were initially advertised.
Hypnotics and anxiolytics
We grouped these two categories of therapeutic drugs because the same, or similar, chemical classes of drug were, and still are, often used.
The barbiturates were foremost in treating both anxiety and sleep disorders in the 1950s. Phenobarbitone was discovered by Bayer chemists and first marketed in Germany in 1912 under the brand name Luminal, used thereafter as both a sedative and anxiolytic, and subsequently widely prescribed in the UK. The related drug pentobarbitone (Nembutal) was more generally used as an anaesthetic, because of its short half‐life. Nevertheless, in 1951 Parke Davis combined pentobarbitone with another sedative/hypnotic carbromal (also discovered by Bayer in 1909) as Carbrital (BMJ, 24‐02‐51), which they claimed combined the ‘rapid, but relatively brief hypnotic action of pentobarbitone, with the prolonged sedative effect of carbromal’ and ‘produced slumber simulating natural undisturbed sleep of adequate depth and duration, and patients awaken refreshed and alert’.
Concerns about both the addiction potential of barbiturates, and the dangers inherent in overdose (including lack of an effective antidote) led to a search for safer alternatives. Riker marketed an extract of Rauwolfia serpentina as Serpiloid, as an anxiolytic, giving no details of the chemical content, other than saying that it was an accurately standardized extract of the whole root (BMJ, 26‐03‐55).
Several years later Boots began advertising Melsedin (methaqualone) as a drug chemically unrelated to barbiturates, claiming it to be the ‘ideal hypnotic free from the potential hazards of barbiturate therapy’ (BMJ, 19‐03‐60). Methaqualone subsequently achieved notoriety as a popular recreational drug with the street name of ‘Ludes’ (US brand name Quaaludes) and became regulated under the Misuse of Drugs Act in 1971. Roussel combined methaqualone with the antihistamine diphenhydramine hydrochloride, to increase the sedative effect, and marketed it as Mandrax in 1965; by the 1970s tablets of Mandrax acquired the street name ‘Mandies’. Another sedative combination marketed in 1960 was Nebrinal (Wander; BMJ, 19‐03‐60), a particularly dangerous combination of two central depressant drugs, pentobarbitone and mephenesin.
The recognized harms associated with barbiturates allowed companies to emphasize the fact that their sedative/hypnotic drugs were not barbiturates. Smith & Nephew specifically stated this when advertising Welldorm (dichloralphenazone; BMJ, 10‐06‐61), as did Wyeth when promoting Indorm (propriomazine), a histamine H1 receptor antagonist (BMJ, 15‐07‐61).
In 1960 British Drug Houses issued an advert that highlighted the safety of their new product, a drug that would subsequently become infamous – Distaval. In time, everyone would know it by its generic name thalidomide (BMJ, 06‐02‐60). It was announced that the drug ‘is welcome for its potent hypnotic effect combined with outstanding safety’. The text continued: ‘having no demonstrable toxicity and minimal side‐effects, this hypnotic can safely be given to infants and elderly’. Interestingly, this is an early advert with detailed dosage requirements, giving dosages for adults and infants, both as a bedtime hypnotic and a daytime sedative. A subsequent advert emphasized safety in children following accidental overdose (BMJ, 24‐06‐61; Figure 4); the text stated that ‘barbiturates claim a mounting toll of childhood victims’ pointing out that ‘Distaval is outstandingly safe’. References to papers in clinical journals were given. The safety claims followed studies by manufacturers, Chemie Grünenthal, that had found it to be almost impossible to obtain a value for the LD50 (lethal dose in 50% of an experimental animal cohort).
Figure 4.
One of several adverts extolling the safety of Distaval (thalidomide) in the BMJ (24‐06‐61)
Thalidomide was first marketed in Germany in 1957 and although there was an increase in births of disabled children in Germany and elsewhere, no link with the drug was made until 1961, and the drug was only withdrawn after an Australian physician wrote a very short letter to The Lancet, suggesting an association between use in pregnancy and the appearance of phocomelia in a child 14. This letter appeared only a couple of weeks after a full‐page advert had been published in the BMJ (25‐11‐61), promoting the drug's benefits, including its low toxicity. More than 10 000 children were born with thalidomide‐related disabilities worldwide, and this disaster led, in part, to changes in the law regarding drug registration.
An advert for another novel drug also made its first appearance in the BMJ (05‐11‐60) although, in contrast to the Distaval advert, it gave absolutely no pharmacological or clinical information. This was the Roche compound Librium (the benzodiazepine chlordiazepoxide, although only the full chemical name was given). It was claimed to be ‘the successor to the tranquillizers’. Even one year later, subsequent adverts provided no further clinical information, other than the comment that ‘the era of tranquillizers that preceded Librium therapy saw a succession of drugs – thirty‐five by the last count. And yet today Librium has attained a clinical stature which may well establish it as the successor to this entire group’. For the contemporary clinician the advert was valueless. It did not even suggest that further information could be obtained by writing to the company. Two years later, adverts for Librium were no more informative; indeed, in one case (BMJ, 23‐05‐64) there was no information about its therapeutic use, just a picture of a bottle and someone seated in a boat, peacefully fishing (Figure 5).
Figure 5.
An advert from the BMJ (23‐05‐64), emphasizing the lack of information presented
Companies marketing barbiturates did not immediately accept the premise that Librium had made their drugs redundant, and Lilly issued an advert for Tuinal (sodium amytal) in 1963, which included a quote from a BMJ review that ‘in any consideration of hypnotics, the barbiturates must take pride of place’, although it seemed to show that it belonged to a different era by quoting drug content in grains.
Also emphasizing changing patterns in the treatment of anxiety and insomnia was the 1964 Roche advertisement for their follow‐up benzodiazepine Valium (diazepam), a drug nearly three times as potent as chlordiazepoxide. The advert stressed that Valium had been tested in seven animal species and clinically evaluated by more than 900 physicians in over 21 000 patients before being made generally available to the medical profession. It also stated that there had been more than 250 reports in journals or read at scientific meetings, thereby emphasizing the likely efficacy and safety of this new drug. Both Librium and Valium continued to be advertised by Roche with no helpful information about their uses (BMJ, 02‐05‐64) and no separation of their properties; adverts for Valium stated that it was for ‘prisoners of the society of stress’ (showing a woman shopping) and that it ‘relaxes mind and body’ (their emphasis) (BMJ, 11‐05‐63), while 2 months later Librium was being advertised for the treatment of anxiety and tension. A later advert for Valium (BMJ, 12‐03‐66) informed the doctor that it was available in 2 mg and 5 mg tablets, but still gave no useful clinical information.
Roche further strengthened their market position by launching another benzodiazepine, nitrazepam (Mogadon) in 1966, focusing on its value as a hypnotic rather than an anxiolytic (BMJ, 02‐07‐66), a reasonable stance, given its shorter half‐life, although that was not mentioned. The advert merely emphasized the improved awakening condition of the patient after taking Mogadon compared with a barbiturate.
Although Roche had established themselves as leaders in the anxiolytic/hypnotic market, other companies were not giving up without a fight. May & Baker continued to market Soneryl, claiming ‘40 years and STILL the best answer for insomnia’ (their capitals), but nowhere does the advert mention that Soneryl contained a barbiturate (butobarbitone) (BMJ, 17‐09‐66). Wallace Laboratories promoted Miltown (meprobamate) as a treatment that they claimed would allow the anxious patient to stay in work (BMJ, 11‐01‐64). This was a major marketing shift from 1956 when the drug had been launched by Lederle as ‘promising much in mental illness’, with the comment that it was a powerful tranquillizer, accompanied by a picture of a high‐walled, gated, psychiatric hospital (BMJ, 10‐11‐56). Wyeth also sold meprobamate as Equanil, stating that it was a ‘standard tranquillizer producing fewer side‐effects, particularly sedation, than phenobarbitone’. Subsequent studies showed that meprobamate had similar pharmacology to barbiturates, including addictive properties, and by 1965 it had been classed as a sedative in the US and placed on the restricted drugs list.
In 1966 Wyeth launched their own benzodiazepine, oxazepam (Serenid), claiming effectiveness in all the expected areas (anxiety, tension, etc.), and additionally putting an unsubstantiated claim in inverted commas: ‘depression’ (BMJ, 19‐03‐66).
Roche continued to expand their market penetration by suggesting that anxiety featured as a problem in every field of medicine, ‘a complication and sometime a cause’, as they put it (BMJ, 14‐01‐67), and proposing that Librium would assist in the nine specialist hospital medical departments they listed.
Various phenothiazines were still regularly being advertised for treating anxiety, primarily thioridazine (Melleril), which was said to control ‘senile agitation’ (BMJ, 23‐04‐66), and trifluoperazine (Stelazine), which was claimed to be useful in treating ‘the chronic complainer’ (BMJ, 08‐10‐66) and as a treatment that allowed the patient to be relieved of tension and anxiety and therefore able to continue to work (BMJ, 04‐02‐67). Subsequent advertisements for Stelazine featured case histories of patients who had had various emotional problems resolved by use of the drug (e.g., BMJ, 22‐04‐67) and in 1972 it was advertised for patients who ‘needed the true tranquillizing effect and the invaluable alerting action of Stelazine’, which intuitively appear to be conflicting properties (BMJ, 08‐01‐72).
Another new drug first advertised in 1967 was Equipose (hydroxyzine panoate, Pfizer), which was stated to be neither a barbiturate nor a hypnotic, but rather a ‘psycho‐relaxant’ (BMJ, 01‐04‐67), a term lacking scientific rigour. The accompanying text would now also be challenged by both psychopharmacologists and pharmacokineticists, with its statements that, ‘it works almost exclusively in the hypothalamus, where the basic emotions of fear, anger and agitation are mediated’ and ‘there is little or no trespass [of the drug] to the cerebral or spinal cord areas’.
A two‐page advert from Roche in 1970 commented that it had been 10 years since the introduction of Librium and that since the decade had been very stressful (citing Biafra, Cuba, Vietnam), the drug had helped mankind meet these challenges (BMJ, 20‐06‐70). This audacious claim echoes the Rolling Stones' song ‘Mother's little helper’, the opening track on the UK version of their 1966 album Aftermath, which mentions ‘a little yellow pill’, generally believed to have been referring to meprobamate or diazepam.
A year later Roche stepped up the attack on barbiturates and their lack of safety in overdose with a series of adverts emphasizing the fact that patients attempting to commit suicide by ingesting Mogadon tablets had survived, with no evidence of harmful effects (BMJ, 23‐01‐71). A particularly hard‐hitting advert for Mogadon had a picture of a gravestone with the comment ‘Some patients stay on barbiturates until the day they die’ (Figure 6; BMJ, 02‐11‐74).
Figure 6.
An advert for nitrazepam (Mogadon), promoting its safety as a hypnotic when compared with a barbiturate (BMJ, 05‐10‐74)
Roche launched another benzodiazepine in 1971 (medazepam, Nobrium), with anxiety again as the indication and in 1974 they started marketing the hypnotic flurazepam (Dalmane; BMJ, 02‐03‐74). Wyeth began marketing lorazepam (Ativan) in 1973, with a quote from a published review that it was significantly superior to diazepam, but with no indication as to why this conclusion had been reached (BMJ, 08‐09‐73).
The only other novel hypnotic/anxiolytic non‐benzodiazepine compound advertised before 1980 was chlormethiazole (Heminevrin) from Astra, as a syrup for treating insomnia in elderly people. It was subsequently also used in different formulations to treat alcohol withdrawal and as an anticonvulsant, the latter indication being one it shared with both barbiturates and benzodiazepines.
Between the mid‐1970s and 1980 anxiolytics and hypnotics were seldom advertised, although advertisements for Librium still appeared, with no useful information, other than that it was ‘a classic product of Roche research’, accompanying a picture of a pastoral English scene. In 1981 the research of Malcolm Lader and colleagues in particular 15 established that both dependence and withdrawal problems could occur in patients taking benzodiazepines, which, in time, markedly changed the way in which these drugs were prescribed by GPs.
Antidepressant drugs
At the beginning of the 1950s the only physical treatment that was likely to be efficacious in severe depressive illness was electroconvulsive therapy (ECT). Its use was restricted to inpatients and it was associated with a wide range of adverse effects, some serious, as it was administered without general anaesthetic and a muscle relaxant, both of which are standard practice today. Thus, the desire to be able to treat depression with a simple pharmacological approach would have been substantial. By 1952 amphetamine (Benzedrine) was being proposed by Smith, Kline & French, with the claim that it would ‘dispel the symptoms of fatigue, apathy and lowered mood’. A picture of a Swiss Army Knife was used to emphasize the claims of versatility in treating a bewildering assortment of other medical problems (depressive states, behavioural disorders of children, enuresis, post‐encephalitic Parkinsonism, psychopathic states, narcolepsy, alcoholism) (BMJ, 12‐01‐52).
The first true antidepressant drug was iproniazid (Marsalid), a hydrazine analogue of Roche's isoniazid, which was found to have mood‐elevating effects during treatment of tuberculosis. We found no advertisements in the BMJ for Marsalid. Hepatotoxicity led to its withdrawal, but the subsequent discovery that it inhibited monoamine oxidase (MAO) led to the development of other hydrazine and non‐hydrazine MAO inhibitors, which were advertised heavily in the early 1960s. Smith and Nephew advertised Drazine (phenoxypropazine) with the heading ‘A British monoamine oxidase inhibitor’ (BMJ, 29‐07‐61), a tag line then used for several years. The advert mentioned that clinical trials of Drazine were continuing and that they therefore recommended that its use be confined to consultants and hospitals. The claim that ‘it has remarkable low toxicity and incidence of side effects’ proved premature, as it was withdrawn in 1966 because of hepatotoxicity, a problem also encountered by other companies who developed hydrazine derivatives, such as nialamide (Nialamid, Pfizer). Nardil (phenelzine, Warner) was also being advertised in 1966, with claims that it acted selectively on the brain, that its adverse effects were minimal, and that it was ‘safe’, none of which, we now know, is true. The three‐quarter page engraving of Bedlam by Hogarth that accompanied this advertisement (BMJ, 12‐11‐60) would also certainly not be considered acceptable today.
The MAO inhibitor Actomol (mebanazine, ICI) was first advertised in 1964, and since this was shortly after the publication of the observation that a severe hypertensive crisis could be caused by the combination of an MAO inhibitor (MAOI) with cheese 16, a statement was included that ‘MAOIs potentiate the action of many drugs, so the risk of combining should be borne in mind’.
In 1966 a paper reporting the results of a major study on the efficacy of antidepressant treatments, sponsored by the Medical Research Council, cast doubt on the value of MAOIs in depressive illness 17. This result probably reflected the low dose of Nardil used in the study, although the results were also questioned by some psychiatrists, who complained that MAOIs were effective in reactive rather than endogenous depression (a distinction now seen to have little merit). Nevertheless, the results of this study together with the problems of drug–drug and drug–food interactions and the availability of the tricyclic antidepressants undoubtedly caused MAOIs to fall out of clinical favour, and a marked reduction in their advertising.
The non‐hydrazine MAOI tranylcypromine (Parnate, SK&F) was introduced in 1961, withdrawn in 1964, but later reintroduced with warnings about the possible problems of the ‘cheese reaction’. One advert in 1962 emphasized its distinction from the hydrazine drugs by reporting absence of liver problems. SK&F also marketed tranylcypromine combined with trifluoperazine, another of their drugs, as Parstelin (BMJ, 10‐02‐62), claiming it to be of value in patients suffering from both anxiety and depression. The then Committee on Safety of Medicines (CSM) withdrew its licence in 1999.
The late 1950s also saw the introduction of the tricyclic antidepressants. The first of these was imipramine, developed by Geigy scientists, who modified the chlorpromazine‐type structure in the search for new antihistamine drugs to treat major mental illness. Geigy released imipramine in the UK as Tofranil, and their first advert (BMJ, 07‐03‐59) called the drug a thymoleptic (a drug that modified mood), the first time the word had appeared in English, having been used previously in a German language article reporting on a clinical trial of Tofranil 18. The advert stated that ‘at the present time Tofranil is available only to Mental Hospitals and other psychiatric units, to allow full assessment of its therapeutic value in the treatment of mental illness’. A subsequent advertisement (BMJ, 09‐01‐60) is striking for the detail it contained, in contrast to most other contemporary adverts. It claimed that the drug was ‘a major breakthrough in the treatment of depression’, and stated that ‘it is neither a stimulant nor a tranquillizer, but modifies the basic properties of the depressive illness’. Data from a controlled trial on the efficacy of the drug were cited, which suggested that it was ‘therapeutically effective’ in 74% in endogenous depression and 59% in reactive depression, figures that have stood the test of time.
Other tricyclic antidepressants soon appeared on the market, and in 1962 two separate advertisements for amitriptyline appeared in the BMJ (13‐01‐62) from competing companies: Saroten from Warner and Tryptizol from MS&D. Both claimed that the unique value of the drug was its efficacy in depression, together with a favourable effect on associated anxiety. This assertion of efficacy in patients with depression coupled with anxiety was soon taken up by two companies marketing the tricyclic nortriptyline, perhaps not surprisingly, since nortriptyline is the major active metabolite of amitriptyline. These apparently competing companies, Lilly and Dista, used the respective trade names of Aventyl and Allegron for their preparations of nortriptyline. However, this was pseudo‐competition: Dista was a wholly owned subsidiary of Lilly, although their marketing approaches differed considerably. Aventyl was advertised with a large picture of an elderly depressed‐looking woman saying ‘Doctor, I feel awful’, with very little accompanying text about the drug, other than its effect on depression and anxiety (BMJ, 22‐08‐64), while the Allegron advert (BMJ, 19‐09‐63) was four pages long, with a substantial body of text on clinical evidence, indications, response rate, adverse effects, precautions and contraindications, and dosage. The mixture of good quality clinical pharmacology and what would now be considered weak science is striking. The section on adverse effects is good (including a list of major reported adverse events). In contrast, comparing the efficacy of Allegron with an anxiolytic (chlordiazepoxide) and an antipsychotic (chlorpromazine) would not now be considered valid.
Allegron was also recommended for patients as young as three years for treating ‘bed wetting, nail biting and tantrums etc’, with a suggested dose that appears to be merely a scaled down adult dose, based on body weight. The fact that a tricyclic antidepressant had been found to have efficacy in enuresis, by a mechanism that still remains unclear, was picked up by other companies, and by 1968 Tryptizol was being advertised as being available in a syrup for children with this problem (BMJ, 03‐02‐68). Geigy, clearly deciding that this new use might be counterintuitive to many doctors, had an advert for Tofranil that advised its use in both depression and enuresis, with the headline: ‘Not aiming to confuse but…’ (BMJ, 06‐12‐69).
Other antidepressants were also being launched and advertised during the mid‐1960s to 1970, including trimipramine (Surmontil, May and Baker), which was not claimed to have greater activity as an antidepressant, but was termed a ‘psycho‐sedative’ that did not need to be prescribed together with a sedative or tranquillizer (BMJ, 17‐12‐66). This sedative property contrasted with Concordin (protriptyline, MS&D), which was said to be a rapidly acting antidepressant free from sedative activity (BMJ, 27‐04‐67). In an advert that seems to have reflected an earlier era, Geigy promoted their tricyclic Pertofran (desipramine) in a whole‐page advert (BMJ, 06‐01‐68), which not only lacked the BAN/INN but also simply stated that the drug ‘Simplifies the treatment of depression in general practice’. No other information was given, apart from the chemical name and the fact that the tablets were pink.
It became clear over time that there was probably little difference in efficacy between the different tricyclics, as indicated in a Pfizer advert launching Sinequan (doxepin), which stated it to be effective in treating both depression and anxiety, thereby repeating a claim made for imipramine and nortriptyline nearly 10 years earlier. With unusual honesty Wyeth launched iprindole (Prondol), which has an atypical tricyclic structure, with the statement that it was ‘no more effective, but [has] lower anticholinergic effects’ (BMJ, 24‐08‐68).
Despite maintaining that the advertised antidepressants would treat depression and associated anxiety and had generally calming effects when given alone, companies were happy to produce combination formulations. Geigy combined imipramine with another drug in their portfolio, marketing ‘Tofranil with Promazine’ for the treatment of ‘depression with agitation and/or anxiety’ (BMJ, 04‐05‐63) and Allen and Hanburys combined amitriptyline with perphenazine (Triptafen) to treat ‘depression with an anxiety component’, even though amitriptyline was already stated to be effective for this indication (BMJ, 23‐10‐65). Amitriptyline was also combined with chlordiazepoxide as Limbritol (Roche), again with the indication of depression coupled with anxiety (BMJ, 24‐04‐69).
The 19 December 1970 issue of the BMJ carried no fewer than five adverts for different antidepressant drugs, although the number tapered rapidly in the following years. Nevertheless, new compounds continued to appear in the advertising pages, including Noveril (dibenzepin, Wander), with the claim not of greater efficacy, but fewer adverse effects than other tricyclics, and Anafranil (clomipramine, Geigy), with the comment that it was ‘an excellent supplement to the range of antidepressants available’. Thereafter, Anafranil was advertised extensively until the late 1970s. What is interesting about clomipramine is that it preferentially blocks serotonin reuptake rather than noradrenaline reuptake and can therefore be seen as a forerunner of the selective serotonin reuptake inhibitors (SSRI) like zimeldine (Zelmid, Astra) and fluoxetine (Prozac, Lilly), which were first marketed in the early 1980s.
Antipsychotic drugs
The current widespread use of the term ‘antipsychotic’ dates from the 1960s; previously such drugs were referred to by a variety of names, including ataraxics, neuroleptics, tranquillizers, and major tranquillizers. This changing nomenclature continued beyond the period of our study, with terms such as atypical antipsychotics, and first‐ and second‐generation antipsychotics, which partly reflect changing views about their therapeutic actions.
The discovery of the antipsychotic action of chlorpromazine, a phenothiazine, in the early 1950s by Rhône‐Poulenc scientists in France marked the start of the modern era of pharmacological treatment for psychiatric illness, sometimes called the psychopharmacology revolution 19. Following favourable reports of small uncontrolled trials, as were usual in that period, chlorpromazine became available in both Europe and the US, and its widespread use in the US resulted, in part, from an extensive advertising campaign by SK&F, who called it Thorazine. In the UK chlorpromazine was marketed by May and Baker (M&B) and called Largactil, apparently because it had a large number of actions. Largactil became available from the mid‐1950s, but we found no BMJ adverts before when it was advertised with the headline ‘Do you make full use of Largactil?’, with the suggestion that it was of use not only in ‘moderate to severe mental and emotional disturbances’ but also ‘prevention of nausea, vomiting and hiccough [sic]’ (BMJ, 02‐04‐60). At much the same time, SK&F were stating that their phenothiazine, Stelazine (trifluoperazine), was ‘an essential advance in chronic and acute schizophrenia’, while Sandoz had an impressively detailed advert for thioridazine (Melleril), another phenothiazine. The wide applications that were proposed for these drugs were emphasized by the advertisement in the BMJ on 6 August 1960 for Stelazine, which suggested its value in elderly patients suffering ‘anxiety, resentment or confusion’. Wyeth also felt that administering their drug Sparine (promazine) was justified in order to make the difficult elderly patient ‘co‐operative’ (BMJ, 20‐02‐60). The Largactil advert with the headline ‘Do you make full use of Largactil?’ had pictures of patients ranging from babies, through children, to the elderly. The drug was called ‘highly versatile’ but, apart from listing a range of medical specialities, no specific applications were mentioned (BMJ, 27‐07‐63).
Competition for the phenothiazines first appeared in 1961, with a new product announcement for haloperidol (Serenace, Searle). It was called the ‘first major advance in psychiatric chemotherapy since reserpine and the phenothiazines and the leader of a new class of drugs called the butyrophenones’ (BMJ, 02‐09‐61). Its use was focused on the ‘control of psychotic illness’.
At this time unequivocal evidence of efficacy was not needed before a product was launched. Squibb, for instance, was able to advertise their phenothiazine Moditen (fluphenazine enanthate) as a depot formulation with the heading: ‘now undergoing trials in psychiatric units’. Depot formulations are administered intramuscularly at intervals of one week or more, which allowed Squibb to emphasize that one injection could control symptoms of schizophrenia for 2–4 weeks (BMJ, 26‐03‐66). Several years later Squibb started marketing a different salt, fluphenazine decanoate (Modecate) (BMJ, 27‐01‐73). Around that time, Lundbeck started selling another depot antipsychotic flupenthixol decanoate (Depixol) with an impressive advert that, in contrast to most of those of their competitors, provided considerable pharmacological detail, including the possible occurrence of extrapyramidal effects (BMJ, 01‐07‐72). However, although the advantage of depot formulations in achieving good adherence was highlighted, the inability to adjust dosages rapidly when adverse reactions occurred was not.
Advertising for antipsychotic drugs continued throughout the 1970s, but useful prescribing information was generally absent. Advertisements for Largactil generally highlighted its historical place in therapy, with text that said for example: ‘Largactil ushered in a new era of psychiatric treatment and stayed. Over the sixteen years the major tranquillizers have proliferated but Largactil remains unsurpassed’. Serenace was claimed to offer ‘tranquillity without sedation’, presumably to emphasize that it was not merely acting as a sedative.
The only novel drug launched in the 1970s through the pages of BMJ was Orap (pimozide, Janssen). Orap was claimed to be ‘a quiet revolution in the treatment of schizophrenia’, and it was emphasized that it was neither a phenothiazine nor a butyrophenone, was not sedative, could be given once daily, and ‘rarely gives rise to parkinsonism’ (BMJ, 23‐01‐71). The last claim soon proved to be unfounded, and this problem, together with reports of other significant adverse effects, ensured that pimozide never became a popular antipsychotic drug.
Drugs for Parkinson's disease
The 20 years from 1950 saw few adverts for the pharmacological treatment of Parkinson's disease, reflecting the dearth of effective medications for this and other neurological diseases. In 1952 a full‐page advert from Burroughs Wellcome, headed ‘NEW treatment for Parkinsonism’ (their capitals), reported that initial trials for Kemadrin (only the full chemical name was given; it is now known as procyclidine, an anticholinergic drug) were ‘sufficiently favourable’ to allow immediate marketing, a prime example of the lack of any rigorous pre‐market testing being required. It was maintained that it produced fewer adverse effects than traditional remedies, such as belladonna alkaloids (BMJ, 27‐02‐52). Two years later, Lederle were advertising another anticholinergic drug, Artane (benzhexol), stating that it had been extensively tested and had become the accepted treatment for Parkinsonism. Benzhexol continues to have a place in treating Parkinson's disease today.
In 1970 a two‐page announcement from Roche heralded a major advance in the treatment of Parkinson's disease, making bold claims. Following the discovery of a major loss of dopamine in the substantia nigra of patients with the disease 20, several academic groups had, in the 1960s, tried to alleviate its symptoms by administering large doses of l‐DOPA, the dopamine precursor, with reasonable success. Consequently, several years later Roche began marketing l‐DOPA as Larodopa, initially promoting it in a two‐page ‘Roche Medical Information Service’ announcement, stating that the drug had limited availability and was being supplied to the Department of Health (BMJ, 13‐06‐70). By September, Roche stated that continued trials were providing encouraging results, while also admitting that treatment created ‘many side effects’. It was asserted that close control of dosage reduced the problems (BMJ, 26‐09‐70). Only a week later, another Roche advertisement informed readers that 50 years earlier one of their chemists had first described a simplified route for synthesizing l‐DOPA, and that they were now making the drug available to GPs. Dosing schedules and benefits were described, together with the somewhat concerning statement that ‘long term safety and efficacy has yet to be established’. This clever rolling out of the drug established Roche as the l‐DOPA experts. This was further emphasized by the subsequent offer of educational monographs, and in March 1971 readers were told that they would soon receive an invitation to see a film, which ‘shows, with a clarity and conviction unachievable in any other medium, the dramatic – sometimes almost incredible – responses achieved when Parkinson's disease is treated with Larodopa’.
We have found no other example in the 1950–1980 period of such a dramatic launch of a new drug, and Roche must have assumed that they had cornered the market in the treatment of Parkinson's disease. The problem was, however, that l‐DOPA was a far from perfect drug. Large doses (6–8 g day−1) had to be given, and most of the dose was metabolized peripherally, giving rise to many adverse effects.
Only three years later, a three‐page advert appeared from MS&D, headed ‘The most significant advance in the treatment of Parkinsonism since levodopa’, heralding the launch of Sinemet (levodopa plus carbidopa). The advert continued ‘Sinemet reduces or eliminates many of the adverse reactions seen in treatment with plain levodopa’ (BMJ, 06‐04‐74). Clever pharmacological thinking, coupled with equally clever medicinal chemistry, had resulted in carbidopa, a drug that inhibited peripheral, but not central, dopa decarboxylase. Consequently, l‐DOPA was not metabolized peripherally, but entered the brain, where it was mainly metabolized to dopamine, allowing the dose of levodopa to be reduced, and many of the adverse effects resulting from its peripheral metabolism to be minimized. As a later advert for Sinemet stated: ‘Sinemet puts levodopa in its place – in the brain’. Not surprisingly, Roche scientists had been thinking along the same lines, but the company lost its primacy in the market, since their product Madopar (l‐DOPA plus the decarboxylase inhibitor benserazide), with the tagline ‘Another breakthrough in Parkinsonism from Roche’, was not launched until later the same year.
While other drugs for Parkinson's disease appeared subsequently, including the dopamine receptor agonist bromocriptine (Parlodel, Sandoz), none achieved similar market penetration to Sinemet or Madopar, both of which continue to play a major role in treating Parkinson's disease.
Cardiovascular drugs
The first advert we found for a drug to treat hypertension was from Riker Laboratories in early 1952. This company was particularly interested in extracts of alkaloid substances and had a full‐page advertisement for Veriloid (BMJ, 12‐04‐52), an intravenous solution of alkaloids of Veratrum viride, also known as Indian Hellebore, an extremely toxic plant. The extract of veratrum alkaloids was a potent antihypertensive agent (acting by adrenoceptor antagonism, although that was not known at the time), and the advert suggested that intravenous Veriloid was the treatment of choice when dealing with a hypertensive crisis. A tablet formulation was also available for long‐term use. The advert commented that it was a very potent agent and added that it should not be used before careful study of the instructions.
A year later Riker were also advertising Rauwiloid (BMJ, 28‐11‐53), a combination product of Veriloid with an extract of Rauwolfia alkaloids, Rauwolfia serpentina being a plant that had been used for centuries in India as a sedative. It was suggested that the two extracts had a synergistic action, owing to the ‘calming action’ of the Rauwolfia alkaloid. A very small line of print informed the reader that each batch was tested in dogs for its effectiveness in producing hypotension, bradycardia, and sedation, and a dosing regimen was given. The monoamine‐depleting effect of reserpine, both centrally and peripherally, was unknown at that time, so a synergistic effect of the two extracts would have occurred, but probably not because of any sedating effect of the reserpine.
By the early 1960s, drugs acting on the sympathetic nervous system were being introduced. Burroughs Wellcome advertised Darenthin (bretylium tosylate) (BMJ, 20‐02‐60) as a new compound with a selective action on post‐ganglionic sympathetic fibres, that did not produce various adverse reactions, such as constipation and blurred vision, that occurred with other ganglion blockers, presumably meaning guanethidine and debrisoquine. Guanethidine was marketed by Ciba as Ismelin (BMJ, 20‐02‐63) and debrisoquine was sold as Declinax (Roche), although we found no adverts for the latter. All these drugs were in competition with another drug that was to play a major role in the treatment of hypertension over the next 20 years; the MS&D compound α‐methyldopa (Aldomet), which inhibits the peripheral sympathetic nervous system by an indirect central mechanism. The first Aldomet advert (BMJ, 17‐03‐62) was headlined ‘Important Announcement’ and cited a Lancet paper. It continued with the comment that journal papers had aroused considerable interest in this ‘major advance in therapeutics’ and stated that it would be made available initially to hospitals and later to GPs.
MS&D scientists were also responsible for the first of another entirely new class of antihypertensive agents that became available in the early 1960s, the thiazide diuretics. Other companies were soon producing their own related compounds. There was some enthusiasm for combining thiazide diuretics with other drugs, particularly alkaloids. MS&D marketed Salupres, a combination of hydrochlorothiazide with reserpine and potassium chloride (BMJ, 06‐07‐63), and Abbott marketed not only Enduron (BMJ, 04‐05‐63), methyclothiazide, but also Enduronyl, a combination of methyclothiazide and a Rauwolfia alkaloid called deserpidine. Similarly, Riker combined their alkaloid Veriloid with epithiazide (Thiaver), claiming that it was safer than ganglion‐blocking drugs or adrenergic agents (BMJ, 27‐04‐63).
Two more novel antihypertensives appeared in the advertising pages of the BMJ before the end of 1963. The first was pargyline, brand name Eutonyl, marketed by Abbott. The company had observed that this non‐hydrazine MAO inhibitor had, in common with other MAO inhibitors, a hypotensive effect. The text suggested that the drug, when combined with their other drug Enduron (methyclothiazide), allowed a lowering of the dose of Eutonyl (BMJ, 12‐10‐63). The selling point of Eutonyl was ‘lowers blood pressure, brightens emotional outlook’. The antidepressant effect of the MAO inhibitors was, at that time, being increasingly recognized (see section on Antidepressants). What had not then been reported was the severe drug interactions between MAO inhibitors and some other drugs and foodstuffs that can lead to a severe, or even fatal, hypertensive crisis 16, making the marketing of an MAO inhibitor as an antihypertensive drug inappropriate.
Another novel drug, first advertised by ICI Pharmaceuticals in late 1963, was Alderlin, the chemical name of which was stated, but not its generic name, pronethalol. This drug resulted from the research activities of James Black that focused on producing compounds that were β‐adrenoceptor antagonists. This fact was detailed in the advert (BMJ, 23‐11‐63), which stated that it: ‘antagonises the sympathetically induced changes in heart rate by its unique blocking action on the adrenergic β‐receptor mechanism’, a pleasing example of serious pharmacological science appearing in advertising information, even though, as Black et al. 21 subsequently commented, ‘clinicians and endocrinologists did not talk about receptors and their antagonists’. The speed at which compounds progressed from discovery to the marketplace at that time resulted in rapid withdrawal of Alderlin when longer term toxicity testing in mice showed that it had carcinogenic properties.
A more potent and safe compound from the same research project soon replaced it. Propranolol (Inderal) was launched as ‘an important new discovery resulting from ICI original research’ in a BMJ advert (25‐09‐65, Figure 7). Two weeks after this advert another full‐page advert emphasized the value of Inderal in treating angina, but with a note pointing out that since the pharmacological action was quite new, it would be advisable to study the detailed literature before using the drug, but with no information as to how this information might be obtained.
Figure 7.
The first advertisement for Inderal (propranolol) (BMJ, 25‐09‐65)
Over the next few years Inderal was advertised primarily for the treatment of angina, but in 1969 an advertisement for Inderal‐80 showed a multi‐image picture of a woman getting out of bed, with the statement that the drug ‘reduces blood pressure without causing postural hypotension’ (BMJ, 28‐06‐69). Over the same period there had been a large number of advertisements for Aldomet, claiming that it was effective over the whole range of severity of hypertension. Adverts for Aldomet continued, even after it lost patent protection, with the claim that generic formulations of methyldopa might vary, so that: ‘to be certain your hypertensive patient receives Aldomet, please be sure to prescribe Aldomet by name’ (BMJ, 10‐02‐73).
Some companies marketing the older antihypertensive drugs fought back against the newer compounds. Riker, for example, compared Rauwiloid to both a paper clip and a safety pin, in similarly having a design that had not been bettered (BMJ, 19‐03‐66), and Wellcome stated that fewer patients complained of adverse reactions when taking their drug bethanidine (Estebal) than when taking guanethidine or methyldopa (BMJ, 11‐01‐69). However, these drugs were advertised less and less often over time, particularly after 1970, when a new range of beta‐blockers began to reach the market.
In 1970 Ciba began advertising the non‐selective β‐adrenoceptor antagonist oxprenolol (Trasicor) as a ‘new and better beta‐blocker’, claiming it had a ‘mild stimulating effect on heart muscle fibres’, but with no supporting citations (BMJ; 18‐07‐70). However, one suspects that this launch was overshadowed by a two‐page advert by ICI three months later for practolol (Eraldin; BMJ, 03‐10‐70) that emphasized that it ‘shields the heart – and the heart alone – against excessive sympathetic stimulation’ and pointed out, albeit not very prominently, that it could be used in patients with asthma or bronchitis, but failed to state that this property was because the drug was a selective β1‐adrenoceptor antagonist. By 1974 information was accumulating that Eraldin was producing serious adverse reactions, including the oculomucocutaneous syndrome. This was the first major drug‐related scandal in the UK after thalidomide over 10 years before, but unlike thalidomide it was the company that withdrew the drug from the market, rather than the regulatory authority. Fortunately it was a problem specific to practolol rather than beta‐blockers in general, and the next year ICI, perhaps to emphasize this fact, ran a major advert for Inderal, which consisted of a page saying only ‘Inderal: Britain's most tried and trusted beta blocker’, followed by ‘How can ICI support a claim like that?’ The following two pages emphasized that the claim was supported by 10 years of clinical experience and a mass of documentation (over 5000 published papers) (BMJ, 24‐05‐75).
One feels that with the practolol setback and the arrival of several other beta‐blockers on the market, ICI had to act forcefully to protect their market position, by emphasizing the accumulated knowledge about Inderal. Duncan Flockhart had begun advertising Beta‐Cardone (sotalol), a non‐selective beta blocker, in July 1974, and Bristol‐Myers started to advertise the same drug in February of the next year, under the name Sotacor, suggesting that it was ‘specifically designed for the management of hypertension’. MS&D were also presenting their new beta‐blocker Blocadren (timolol) in 1974 in a detailed advert over three pages, recommending it for both hypertension and angina (BMJ, 19‐10‐74). Ciba had also decided that more information should be presented in adverts for beta‐blockers, as seen in the advert for oxprenolol (Trasicor; BMJ, 08‐02‐75), which included comparator graphs on reduction of tachycardia with oxprenolol, propranolol, tolamolol and practolol.
The failure of practolol had not halted the search for β1‐adrenoceptor selective antagonists, two of which entered the market in 1975 and a third in 1976. The first was the May and Baker compound acebutolol (Sectral), which was described as cardioselective and recommended purely for angina, with good prescribing details (BMJ, 12‐04‐75). The second was metoprolol, discovered by Astra, but marketed by Geigy in the UK as Lopressor. Their first advert (BMJ, 14‐06‐75), headed ‘Lopressor, new β 1 selective beta blocker’, listed its clinical benefits and a suggested dose for angina and hypertension. It also gave a brief pharmacological profile, including some pharmacokinetic data, such as protein binding and plasma half‐life. This advert continued almost every week for some months.
The following year ICI re‐entered the cardioselective beta‐blocker market with a third new compound, atenolol (Tenormin), albeit marketing it under the name of a subsidiary company, Stuart Pharmaceuticals (BMJ, 12‐09‐76). Tenormin used the tag line ‘one daily for hypertension, the chances are they'll take it’, and it was presumably the once‐daily dosing that encouraged the company to subsequently release a 28‐day calendar pack (BMJ, 14‐01‐78), an idea followed soon after by May and Baker, with a higher strength of acebutolol (Sectral 400) (BMJ, 03‐03‐79), and by Geigy, with Lopressor (BMJ, 25‐08‐79).
The beta blockers were not without competition in the late 1970s, as can be seen not only by the continued advertising of Aldomet, but also because an antihypertensive drug with a totally different mechanism appeared in the market place. The first advert by Carlo Elba for prazosin appeared in the BMJ on 28‐09‐74. It was stated that the drug, under the brand name Sinetens, was unique and acted ‘through cellular metabolism, relaxing smooth muscle without significant impairment of sympathetic function’. One week later the company repeated the advert, with the heading: ‘Sinetens controls hypertension like nothing else can’. Oddly, this advert followed a full page from Pfizer with a detailed pharmacological description of how prazosin worked in hypertension and stating that they were marketing it under the name Hypovase. This detailed description focused on phosphodiesterase inhibition as the mechanism by which prazosin acted as an antihypertensive, rather than the now generally accepted explanation of α1‐adrenoceptor antagonism. Indeed, Pfizer suggested that adrenoceptor antagonism would lead to adverse reactions. Later studies found that phosphodiesterase inhibition occurred only at doses above those required for the therapeutic effect. At the beginning of the following year Pfizer gave some clinical details on the use of Hypovase, stating that it gave ‘smooth control of all grades of benign hypertension’, with few distressing haemodynamic effects, and perhaps wisely restricted their description on its mechanism of action to suggesting that it produced specific relaxation of arterial smooth muscle to reduce peripheral resistance (BMJ, 11‐01‐75).
Respiratory drugs
There were few pharmacological options for treating asthma during the 1950s, as indicated by the lack of advertisements. Isoprenaline was an option, as indicated by a Boots advert, which gave it no brand name but called it ‘the pharmacological approach to asthma’ (BMJ, 01‐04‐50). Isoprenaline was available as a spray for inhalation or as sublingual tablets. The advertisement stated that while adrenaline could have both excitatory and inhibitory effects, isoprenaline possessed only the inhibitory action, thereby producing relaxation of smooth muscle. The advert did not mention the seminal paper of Ahlquist on the existence of adrenoceptor subtypes that had appeared two years earlier 22. The short half‐life of isoprenaline (2 min) meant that it was generally given by either inhalation or injection during an acute attack, and in 1960 Benger Laboratories introduced Lomupren, isoprenaline delivered in a cartridge as an inhalant spray (BMJ, 20‐02‐60), and therefore a medicine essentially similar to that advertised by Boots 10 years earlier.
Another approach was to use combination drugs such as sustained‐release capsules for oral medication. Expansyl (SK&F; BMJ, 13‐01‐62), combined ephedrine, diphenylpyraline and trifluoperazine, with the claim that this produced ‘sustained bronchodilation, anti‐allergic reaction and control of psychological factors’, and reflected Wander's approach with Asmac years earlier which contained allobarbitone, ephedrine, caffeine and ipecacuanha (BMJ, 15‐08‐53).
In 1963 Boehringer Ingelheim were advertising their new approach to treatment of an acute attack, marketing metaproterenol, a preferential β2‐adrenoceptor agonist in a metered‐dose inhaler (Alupent) (BMJ, 06‐04‐63). Metered‐dose equipment subsequently became familiar to generations of asthmatic sufferers, their value becoming rapidly recognized. The BMJ issue of 27‐04‐63 carried adverts by Riker for their Prenomiser Plus, which delivered isoprenaline plus atropine, and by Moore Medicinal Products with the same combination (Iso‐Brovon); both companies claimed sustained action. In August (BMJ, 10‐08‐63) Riker presented their delivery system of isoprenaline as the Medihaler, a name that subsequently became almost generic for this type of delivery system, and the next year they produced a Manufacturer's Information Sheet about the Medihaler‐Bron, with details of contents (isoprenaline and atropine), indications, dosages and cautions, and stating unequivocally that ‘side effects have NOT been observed’ (their capitals). Four years later it was obvious that problems had arisen, as they published a full‐page advert headed ‘Important announcement. New dosage recommendations for Medihaler products’. It continued: ‘recent reports in the medical press and the Committee on Safety of Medicines have drawn attention to the need for careful supervision of asthmatic patients’. Patients had been using the Medihaler more often than recommended and new guidelines were given for maximum tolerated doses. The advert also mentioned that an instructional pamphlet would be included in packs in the future.
In 1964 Lilly released Vortel, which, as with other anti‐asthmatic drugs, was a combination of disparate compounds, an isoprenaline derivative (clorprenaline), methapyrilene, an antihistamine, and ethomoxane, a hypotensive drug. Apart from announcing that the drug (available as a syrup or capsule) was a powerful anti‐asthmatic, no other information was given (BMJ, 11‐04‐64). Similarly, the Boehringer advert in the same issue for Alupent was sparse in terms of information, other than stating that it was a metered aerosol for asthma. The advert even failed to give the INN name for the active substance (orciprenaline, a β‐adrenoceptor agonist). Adequate information about Vortel did subsequently appear in a detailed Manufacturer's Information Sheet (BMJ, 02‐05‐64).
Products containing either theophylline (Tedral, Warner) or the theophylline derivative proxyphylline (Thean, Astra) were advertised in 1967–1968, but it was during 1968 and the beginning of 1969 that major advances in the treatment of asthma finally appeared, with two different ground‐breaking products.
The first novel compound was Intal (sodium cromoglycate), launched with the tagline ‘a product of original British research from Fisons Pharmaceuticals’. Fisons emphasized that the drug was not a bronchodilator, an antihistamine or a corticosteroid. It was inhaled with an insufflator device developed by the company called a Spinhaler, the powdered drug being introduced into the device in a capsule (BMJ, 11‐05‐68, Figure 8). Over the next few years advertisements for Intal appeared regularly. In August 1968 readers were given information as to how it worked: ‘reduces the asthmatic response to allergen exposure’. Subsequently, it was also stated (BMJ, 06‐01‐73) that Intal, unlike steroids, bronchodilators and antihistamines, was not a symptomatic treatment but actually prevented attacks by preventing the release of spasmogens. Fisons also cited studies that indicated that patients with late‐onset obstructive airway disease also benefited from Intal, even when there appeared to be no defined allergic component (BMJ, 03‐11‐73).
Figure 8.
The launch of Intal, showing the administration inhaler and some clinical information, including journal references (BMJ, 11‐05‐68)
The second product that was first advertised at the beginning of 1969 was Ventolin (salbutamol) a product of Allen and Hanburys’ research. In an impressively detailed two‐page advert (BMJ, 11‐01‐69, Figure 9) details were given about its mechanism of action, selective β2‐adrenoceptor agonism, so that, unlike isoprenaline, it would not affect the heart. Details of animal studies, clinical studies, pharmacology, and contraindications were provided. Two weeks later the advert was repeated, but with the addition of graphs showing forced expiratory volume, heart rate and pulse pressure after salbutamol and isoprenaline. By June the same year, Ventolin became available in tablet form with the phrase ‘For bronchodilatation without cardiac stimulation’, and a year after that it was being sold in a strawberry flavoured syrup for children.
Figure 9.
The launch of Ventolin, with a very detailed modern style of advertisement, including much clinical and pharmacological detail (BMJ, 11‐01‐69)
The approach of treating asthma with a selective β2‐adrenoceptor agonist had clearly been researched by other companies, as a year after the first adverts for Ventolin appeared, Riker were presenting details of Numotac, a tablet containing the short‐acting β2‐adrenoceptor agonist isoetarine and in 1972 Bricanyl (terbutaline, Astra) became available in tablets, a syrup and an inhaler. One wonders therefore why Allen and Hanburys felt able in 1973 to advertise that ‘Ventolin is the only adrenergic bronchodilator that is indicated in patients with concomitant heart disease or hypertension’, since that was clearly not true.
Allen and Hanburys were also responsible for the entry of a novel steroid in 1972. Stating that their Becotide inhaler delivered beclomethasone in aerosol form, the advert asserted that the drug gave ‘steroid control without steroid side effects’. The delivery of beclomethasone directly to the lungs avoided systemic steroid effects. Considerable detail on administration, particularly in patients already taking steroids, was given in a full page of instructions, as part of the three‐page advert (BMJ, 25‐11‐72).
Fisons continued advertising Intal during 1973 as the only drug to prevent acute attacks of asthma, and this may have encouraged Allen and Hanburys to compare Intal with Ventolin (BMJ, 17‐11‐73), taking data from a study that had been published in the British Journal of Diseases of the Chest the year before, in which patients with asthma used a bicycle ergometer. However, the very low patient numbers (six in one part of the study) and the lack of statistical analysis would almost certainly have prevented publication of this study by any current journal. An advert for Becotide early the next year, citing a Lancet publication that reported the drug's efficacy in extrinsic asthma on the basis of four patients, would now also be considered totally unacceptable (BMJ, 19‐01‐74).
Gastrointestinal drugs
Horlicks Pharmaceutical were regularly advertising Nulacin tablets in the 1950s for relief from the pain and discomfort of peptic ulcer, and claiming that the tablets assisted the healing process (BMJ, 27‐02‐54). The adverts remained little changed for many years and were a credit to the company when compared with most pharmaceutical product advertising, both then and for many years thereafter, as they presented graphs on in vitro gastric acidity in the presence and absence of the drug and references to clinical and experimental studies. The major component was a milk preparation combined with antacid substances (magnesium carbonate, calcium carbonate, magnesium trisilicate, and magnesium oxide). Advertisements for other products containing antacids, such as the Beecham product Prodexin (aluminium glycinate plus magnesium carbonate) and the Wyeth product Aludrox (aluminium hydroxide), were also printed regularly during 1950–1970, the latter with the claim that ‘ulcer symptoms simply disappear’ (BMJ, 04‐01‐64).
Abbott (BMJ, 24‐02‐51) combined pentobarbitone (‘relieves psychic tension’) with belladonna (‘alleviates spasm and diminishes the secretion of hydrochloric acid’) and Searle also saw the possible advantage of treating peptic ulcer by relieving anxiety; their advertisement for Pro‐Banthine (BMJ, 25‐03‐61) showed a businessman clutching his stomach and stated that ‘where anxiety plays a part’ the drug would relieve the pain. Absolutely no details were given, other than stating that the tablet contained Dartalan (thiopropazate, a phenothiazine antipsychotic). Presumably the main ingredient was the anticholinergic drug propantheline, and Pro‐Banthine subsequently underwent a significant change of formulation, with the phenothiazine being removed so that it contained only the anticholinergic. The use of an anticholinergic to reduce acid secretion was also the approach of Pfizer with their drug Daricon, which contained oxyphencyclimine (BMJ, 27‐04‐63). Concurrently, AH Robbins were marketing the anticholinergic, glycopyrronium, either alone (Robinul) or together with phenobarbitone (Robinul‐PH). No information was provided as to whether one product might be better than the other in any specific patient (BMJ, 21‐04‐64).
In 1967, and for some considerable time thereafter, Berk advertised Biogastrone (carbenoxolone) as ‘the only drug conclusively shown to heal gastric ulcers’, quoting papers from the BMJ and the journal Gut (BMJ, 16‐12‐67). Carbenoxolone is a glycyrrhetinic acid derivative of compounds found in the root of the liquorice plant. Later reviews cast some doubt on this healing claim, mainly because of the high rate of spontaneous healing 23. Caved‐S (Tillotts) also contained a liquorice derivative, although the first advert (BMJ, 06‐01‐73) merely claimed three times that ‘Caved‐S heals peptic ulcers’, giving no clue as to content, or even in what form the drug was supplied. The quality of this advertisement is much worse than any others of the period. Subsequent adverts only stated that Caved‐S was deglycyrrhizinized liquorice (and therefore the opposite of Biogastrone). One suspects that the other constituents, aluminium hydroxide, sodium bicarbonate, magnesium carbonate, frangula (buckthorn), and bismuth subnitrate (which later adverts finally reported the formulation to contain) were the key medicaments. Later adverts also gave some details about dosing (BMJ, 03‐03‐79).
One Caved‐S advert emphasized that there were important differences between it and histamine H2 receptor antagonists (BMJ, 18‐12‐76), but with little pharmacological information, and later adverts tended to emphasize price differences. What is particularly interesting is that we were unable to find any adverts for the histamine H2 receptor antagonist cimetidine in the BMJ at that time, although, as the Caved‐S advert acknowledged, prescribers must have been well aware of a ground‐breaking new medicine that had just been launched, namely Tagamet (cimetidine, SK&F). The first advert we found for Tagamet was in World Medicine (20‐04‐77, Figure 10), where further adverts appeared regularly thereafter.
Figure 10.
An advertisement from World Medicine (20‐04‐77), with detailed pharmacology and journal references included
Serious competition for cimetidine only appeared after 1980; ranitidine, another H2 histamine receptor antagonist (Zantac, Glaxo), was launched in 1981 and the proton pump inhibitor omeprazole (Losec, Astra) in 1989.
Discussion
In an article on advertising in his magazine ‘The Idler’ (20‐01‐1759), Samuel Johnson wrote ‘promise, large promise, is the soul of an advertisement’. We saw little in our perusal of pharmaceutical advertising published around 200 years later that would lead us to question the accuracy of his comment. In some cases, later clinical evidence resulted in the promise not being fulfilled and, as we discussed, this was due in no small part to the very different regulations that existed in the period under review when developing a drug for the market. However, what is also evident is that the large number of novel compounds first marketed from the late 1950s and before 1980 were major advances in therapeutics, and many of them (or their class successors) continue to play an important part in modern drug therapy and appear in the WHO list of essential medicines. From that perspective, it is reasonable to conclude that much that was promised was fulfilled over time.
What was also striking to us was the way that drugs were made available and advertised when so little was known about them, both preclinically and clinically. Some drugs were advertised with the expectation that wide availability would lead to confirmation of promising evidence that they would prove efficacious (for example isoniazid, chlorpromazine, levodopa) and further trials indeed confirmed their early promise. Others were subsequently withdrawn because of significant toxicity discovered either preclinically (pronethalol) or clinically (thalidomide and practolol).
Pharmaceutical companies have been much criticized for the fact that they spend much more on advertising than research. Gagnon and Lexchin 24 reported data from 2004, and recently recalculated data shows that this continues to be the case 25. It is a truism that the best drug in the world will not sell without advertising, and companies require sales revenue to undertake further research. What the ‘appropriate’ ratio of spend on advertising and research is beyond the scope of this article and is complicated by the fact that some drugs are licensed‐in by the marketing company.
Our research suggests that while some of the most successful drugs (in terms of market penetration) were also those most advertised (Aldomet, Intal, Tenormin, Anafranil), this was not always the case. Haloperidol (Serenace), for example, was little advertised in the BMJ following its launch in 1961, while extensive advertising was often seen on drugs with little or no novelty. A preliminary study (Aronson and Green, unpublished) of advertising in World Medicine (Volume 1, 1965–1966) found that the company advertising most often was Fisons, although none of its advertised products had novelty. The products advertised included an iron supplement (for anaemia), paracetamol plus codeine (for pain), and isoprenaline (for bronchospasm), indicating that some advertising had the purpose of maintaining a high product profile. Patterns of which companies advertised the most also changed over the period we examined. In 1965–1966 around 70 different companies were advertising. However, the many subsequent mergers and closure of companies renders any comparison with current activities of specific companies meaningless.
It is clear is that there is little relationship between the early drug advertising, which emphasized arresting pictures, extravagant claims and a paucity of useful information, and current advertisements, where half the page is covered with information detailing safety, efficacy and much more in small print (often actually difficult to read, but now mandatory). Advertisements have become much more accurate but much less interesting, and it would be a fascinating investigation to find out what proportion of physicians actually read the small print and whether providing this information has made prescribing safer.
Competing Interests
There are no competing interests to declare.
A.R.G. and J.K.A. thank the British Pharmacological Society for a Paton Historical Award to help defray the costs of this study. We thank Michael S. Kinch (Washington University in St Louis, Mo, USA) for providing the raw data from his study 4 , which allowed us to present the results in a modified form. We are also grateful to the staff of the Bodleian Library, Oxford, for friendly assistance during our investigations.
Green, A. R. , Haddad, P. M. , and Aronson, J. K. (2018) Marketing medicines: charting the rise of modern therapeutics through a systematic review of adverts in UK medical journals (1950–1980). Br J Clin Pharmacol, 84: 1668–1685. 10.1111/bcp.13549.
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