The Therapeutic Nightmare

The battle over the world's most controversial sleeping pill

John Abraham, Julie Sheppard

• Publisher: Routledge
• Year: 2014
• ISBN:
  9781134195817
• Edition: 1
• Topic: Droit
• Subtopic: Droit des consommateurs

How do drugs get to the market? What controls are there and what procedures for monitoring their effects? And how adequate are the regulators in protecting public health when new drugs have serious side effects? The Therapeutic Nightmare tells the story of the sleeping pill Halcion - a story which is far from over. First marketed in the 1970s, Halcion has been taken by millions of patients around the world. For many years it has been associated with serious adverse effects such as amnesia, hallucinations, aggression and, in extreme cases, homicide. Thirteen years after its first release, it was banned by the British government. It remains on sale in the United States and many other countries. This book explains why patients have come to be exposed to Halcion's risks and examines the corporate interests of the manufacturers, the professional interests of the scientists and medical researchers and the interests of patients in safe and effective medication. It reveals how these contending forces shape the regulatory decision-making process about drug safety. As the number of new drugs and health products grows, a major challenge facing regulators and the medical profession is how to put the interests of public health decisively and consistently above the commercial interests of the drugs industry, while becoming more accountable to patient and consumer organizations.

1

The Nature of Tranquillizing Drugs

Introduction

Drugs that have effects on mental function are known as psychotropic. There are many types of psychotropic drugs including antidepressants, antipsychotics (‘major’ tranquillizers) used in the management of psychosis, and ‘minor’ tranquillizers intended primarily for use in managing anxiety and insomnia. Tranquillizers have a long history dating back to the medicinal use of opium by Hippocrates in Ancient Greece. In the 19th century, opium and alcohol were used separately and in combination to treat ‘nervous restlessness’ and ‘sleeplessness’. A more refined and more potent form of opium, called morphine after the Greek god of sleep, Morpheus, was isolated in 1805 and by the middle of the 19th century was used by doctors in place of opium. Other tranquillizers with a significant impact in that century – and which came to replace opium – are the bromides which were used as sedatives, and chloral hydrate which was used as a hypnotic (ie to treat insomnia) and as an anaesthetic.¹

The early 20th century saw the development of a much more technically sophisticated pharmaceutical industry. This was reflected in the development of tranquillizers. In 1903 the first barbiturate, known as Veronal (barbitone), was manufactured. By mid century about 2500 kinds of barbiturates had been synthesized, of which about 50 were marketed for clinical use as sedatives or to induce sleep. During the 1930s the barbiturates came to replace the bromides and chloral hydrate because doctors believed that they were safer.² By the 1960s the modern minor tranquillizers, known as benzodiazepines, were being introduced. It is the benzodiazepine family of tranquillizers, of which Halcion (triazolam) is a member, that we are mostly concerned with in this book. Other well-known benzodiazepines are Valium (diazepam), Librium (chlordiazepoxide), Mogadon (nitrazepam), Ativan (lorazepam), Dalmane (flurazepam), Xanax (alprazolam) and Restoril (temazepam).

The benzodiazepines are central nervous system depressants. In this sense their clinical effects are similar to alcohol or barbiturates. Medically, the benzodiazepines are often defined as ‘sedative-hypnotics’ because they produce relaxation (sedation) at lower doses and sleep (hypnosis) at higher doses. At even higher doses, benzodiazepines can induce unconsciousness, which can make them useful as anaesthetics.³ Some benzodiazepines, such as Halcion, Dalmane, Mogadon and Restoril, which have been developed to treat insomnia, are known as hypnotics (ie sleeping pills). Others, such as Ativan and Valium, are called anxiolytics because they are used primarily to reduce anxiety. It is believed that drugs such as the benzodiazepines affect the body by acting on ‘receptors’ in the nerve endings which are sensitive to (or ‘receive’) the chemical compounds (or ‘signals’) called neurotransmitters which facilitate communication between the nerves of the body and the brain. Because of its resemblance to a neurotransmitter, a drug may interact with (or ‘bind’ to) the receptors and cause the nerves to respond as though they were being activated by the ‘sending’ nerves and their neurotransmitters. The benzodiazepines bind to particular receptors, and it is believed that the more effective a benzodiazepine is in relieving anxiety or inducing sleep, the more strongly it binds to those particular receptors. However, it is important to appreciate that the relationship between human behaviour and the biochemical processes in the brain – the so-called ‘mind-brain problem’ – remains highly controversial and we make no attempt to solve it in this book.

The demand for a quiet life

Modern societies have made great strides in raising the health of their populations. In particular, public health measures, antibiotics and vaccines have all made a contribution to reducing the prevalence of infectious diseases. On the other hand, the increasing complexities and fragmentation of modernity, combined with our growing expectations about quality of life, have made us vulnerable to psychic distress and disorders. Some people are more vulnerable than others; but, as Professor George Brown and his colleague Tirril Harris have shown, this is by no means limited to the biological make up of the brain. They found that women in Britain were much more vulnerable to depression if they lacked a close relationship/lover, had lost their mother in early childhood, had more than two children living at home and/or were unemployed.⁴ Moreover, research on healthy, young and educated British civil servants in 1983 found that about one third reported impaired concentration, fatigue and anxiety.⁵

It is difficult to know how many people are suffering mental distress in our communities because of the imprecise nature of diagnosis. In 1979 Morton Kramer showed that a patient admitted to mental hospital in Britain with a particular set of symptoms would be ten times more likely to be diagnosed as a manic depressive than someone with identical symptoms in the US.⁶ Another good example of this is the treatment of depression with tranquillizers. It might be expected that depression would be treated with antidepressants rather than tranquillizers, which are themselves depressants of the central nervous system. However, there is evidence of widespread use of tranquillizers for the treatment of depression. In a series of studies of hundreds of depressed women in the UK in the late 1970s and early 1980s, it was found that they were more likely to be prescribed a minor tranquillizer than an antidepressant when they sought medical help.⁷

While the American Psychiatric Association (APA) and the World Health Organization (WHO) have done much to improve diagnostics in this field since the late 1970s, it remains an inexact science.⁸ In 1993, a Dutch survey of general practice found that doctors were much more likely to prescribe tranquillizers for women than for men, even when neither their symptoms nor the diagnosis warranted such drug treatment. Doctors frequently diagnosed women with symptoms such as headache and general fatigue as suffering from anxiety, stress or insomnia, and thus as candidates for benzodiazepines.⁹

According to Inglis, it was estimated that in 1981, in the Western industrialized countries, about a third of all patients in hospitals had been admitted for psychiatric treatment, although currently in the US the figure is closer to 6 per cent.¹⁰ Moreover, a large number of non-hospitalized patients are treated by general practitioners for milder psychotic, neurotic or stress-related symptoms such as anxiety, depression, irritability, sleep disturbance, impaired concentration and fatigue. According to Professor Anthony Clare, in one year, ‘an average British general practitioner will deal with around 200 minor emotional illnesses, at least 12 patients will present with severe depression, and approximately 55 of his/her patients will be suffering from chronic mental illness and will be living in the community’.¹¹ In 1990 in the US, the National Institute of Mental Health declared that anxiety afflicted 8 per cent of the population, including three million people suffering from panic disorders or recurrent attacks of anxiety and 11 million suffering from phobias, obsessions, compulsions and/or chronic levels of apprehension.¹² It was estimated in 1997 that there was a 10 per cent prevalence of chronic insomnia in the American adult population, with an associated annual cost of US$90–107 billion.¹³

Apart from patients’ demands for tranquillizers, it has been cynically suggested that these drugs had a greater effect on the psychiatrists and psychiatric nurses working in hospitals than on the patients because, at last, these health professionals could relax and treat their inmates as patients rather than as prisoners.¹⁴ Others have commented that outside the hospital context, doctors are ‘hooked on medicalizing’ social and psychological problems and diagnosing them as if they can be treated with drugs. These commentators tend to reject entirely the treatment of anxiety and sleep disturbance with tranquillizers.¹⁵

Yet some patients certainly benefitted from more community-based mental health care, which was made possible partly by the use of psychotropic drugs. Moreover, long-term users of psychotropic drugs have found them useful for travelling, shopping, mixing with people, running the home, work, family problems, marriage, financial matters and housing problems.¹⁶ Here again research has revealed the significance of social differences in the vulnerability to long-term desire for medication in our communities. Long-term users of tranquillizers are more likely to be divorced and not to have children living at home; they are more likely to be women; and if they are living with partners or children, they are more likely to find those relationships unsupportive.¹⁷

For a few profits more

On the whole, the pharmaceutical industry may be said to be research-based and highly profitable. It is the large research-based companies which dominate the market. For example, in terms of sales, the top 25 companies out of about 10,000 in the world are all research-based. This relatively small number of huge companies accounts for about 45 per cent of the market. With the growing tendency towards mergers between large companies, this concentration of market influence is on the increase. Moreover, average pre-tax profits in the industry are about 17 per cent, though profits on sales can be as high as 29 per cent in the most commercially successful companies.¹⁸

Dominance by large companies is partly due to the extensive costs, equipment, materials and organization required in new drug research and development (R&D). These, too, have been increasing steadily over the years. In the UK in 1963, a typical new drug would take three years and cost UK£3 million to develop and bring to the market; by the late 1980s it took seven to ten years and cost UK£50 million. Similar trends can be found in the US and other Western countries. Globally, it is estimated that the pharmaceutical industry spends about US$15 billion on R&D.¹⁹ For example, in 1994, GlaxoWellcome spent UK£1197 million on R&D, more than any other company – with Roche a close third spending UK£1160.²⁰

Yet the huge number of barbiturates that saturated the market in the 1950s illustrates the mismatch between the modern pharmaceutical industry’s research activities and therapeutic need. Many of the barbiturates were ‘me-too’ drugs, which were very similar to existing compounds and offered little or no therapeutic advantage over what was already on the market. Such drugs are sufficiently inventive to obtain patents even though they may be superfluous to medical need because patents are awarded on the basis of chemical uniqueness. A patent protects a new chemical entity’s use by competitors for many years, providing its manufacturer with an exclusive market whether or not it turns out to be an especially safe or effective medicine. Bearing this in mind, it is not so surprising to find estimates that one fifth of the barbiturates marketed would have been sufficient to meet therapeutic needs.²¹

More generally, numerous studies in the 1980s have found that the number of therapeutically significant new drug products in Western industrialized countries is only about 4 to 10 per cent of the drugs introduced within those markets.²² While therapeutic breakthroughs for common illnesses or diseases are bound to be profitable, they are also rare and usually require very considerable time and expenditure on R&D. Thus, the industry’s motivation for the development of me-too drugs is that they are relatively safe financial ventures involving a modest amount of time and research, and that they enable the industry to maintain high levels of profits while engaging in the high-risk activity of searching for genuinely innovative medicines. As a former medical director of Squibb pharmaceutical company put it:

The incidence of disease cannot be manipulated and so increased sales volumes must depend at least in part on the use of drugs unrelated to their real utility or need.²³

Research-based as the industry certainly is, it is also important to appreciate that its expenditure on R&D is only about 10 per cent of sales and 60 per cent of net profits. This compares with an expenditure on product promotion and other marketing techniques of between 15 and 20 per cent of sales.²⁴ In other words, on average, the industry spends twice as much on promotion and marketing as it does on R&D. Thus, there is certainly scope for more R&D into genuine therapeutic advances and for less promotion of me-toos.

The highly competitive nature of the pharmaceutical sector fuels aggressive marketing. Two important structural aspects of the industry explain why companies place such importance on promotional activities. Firstly, while most Western countries grant patents for 15 to 20 years, it may take eight to 12 years to get a drug marketed, especially in the US. Once the patent expires, competing companies can begin marketing that drug without having invested in its R&D. Consequently, manufacturers run a race against time in order to recover their R&D costs before the patent expires. One way to achieve this is to reach the largest market possible as rapidly as possible, which means extensive promotion. And secondly, because there are so many me-too products, various new drugs will not find their place on the doctor’s prescription pad purely on the basis of their exceptional safety or effectiveness. Vigorous promotion, which emphasizes any conceivable, and sometimes inconceivable, advantages of such products is needed to make up the therapeutic shortfall, and to gain a market advantage over competitors.

The manufacturers of tranquillizers have not been shy about promoting their products to doctors for a wide and loosely defined range of psychic distress. In 1969 McNeil advertised the barbiturate Butisol (sodium butabarbital) as a ‘daytime sedative for everyday situational stress’ in the Journal of the American Medical Association and Roche ran an advertisement in the British Medical Journal which read:

WHATEVER THE DIAGNOS...