The Ativan Story

Dr Vernon Coleman

The world’s biggest and most damaging addiction problem doesn’t involve heroin or cocaine or painkillers. It involves benzodiazepine tranquillisers such as lorazepam (also known as Ativan).

The benzodiazepine scandal has existed for over 50 years now. No one has been punished and little or no support has been made available for benzodiazepine sufferers.

Today, countless thousands of patients struggle to cope without help or support because prescription-happy doctors over prescribed, and money hungry drug companies over promoted.

And in the UK, the drug companies and overprescribing doctors have always been protected and enabled by the medical establishment – which is effectively owned by the drug industry.

Here is the story of Ativan – one of the most addictive benzodiazepine drugs.

The Ativan story begins in 1971 when the drug company John Wyeth and Brother Ltd produced a new benzodiazepine called lorazepam.

The results of the first real clinical trials were published in 1971.

Dr Ijaz Haider, who was at the time working at the Welsh National School of medicine, selected fifty patients from the inpatients at Whitechurch Hospital and the out patients at the Cardiff Royal Infirmary. The patients, whose ages ranged from 16 to 65, were all suffering from anxiety or anxiety and depression. Haider then compared the new drug lorazepam with the original and best known benzodiazepine, diazepam.

When describing his experiment in the British Journal of Psychiatry, Dr Haider reported that the diazepam was slightly more effective than lorazepam but that the lorazepam caused less sedation than the diazepam. Haider concluded that "Lorazepam would therefore appear to have a definite place in the treatment of anxiety states in hospital and general practice."

Another early trial was reported in The Journal of Clinical Pharmacology in late 1971 and conducted by Annmarie Hedges and Dr P. Turner of the Department of Clinical Pharmacology at St Bartholomew's Hospital in London and Dr T.V.A. Harry of the drug company Wyeth. Once again the researchers said that their studies showed that lorazepam had similar central depressant effects to diazepam.

By 1973, Wyeth had done enough research to launch their new drug in Britain. They clearly hoped to be able to take a share of the rapidly growing market for benzodiazepines.

But the drug was not received everywhere with enthusiasm.

In 1973, the Drug and Therapeutics Bulletin reviewed the new drug. The drug, by now called Ativan, had at first been made available only to psychiatrists but Wyeth made no secret of the fact that the drug was soon to be marketed to general practitioners.

`Lorazepam...has the characteristic pharmacological properties of the benzodiazepine group of drugs,’ said the Drug and Therapeutics Bulletin. `But its advantages over the five available benzodiazepines are obscure’.

The Drug and Therapeutics Bulletin, published by the Consumers Association, concluded: `Lorazepam is yet another benzodiazepine which is a hypnotic and sedative. As five drugs of this group are already in clinical use, i.e. chlordiazepoxide, diazepam, medazepam, nitrazepam and oxazepam, the manufacturers should show that the new agent has advantages over established drugs. No such evidence has been published and there is no valid reason for preferring the drug to the other available benzodiazepines for any type of patient.’

At the time no one knew that lorazepam would prove to be an extremely addictive drug. I have been unable to find any evidence to suggest that any testing was done to find out if lorazepam was more or less addictive than any of the other benzodiazepines.

But when the drug was launched to general practitioners, Wyeth did give a hint of problems to come in the official data sheet which they published and distributed to general practitioners. Under the heading Side Effects, Wyeth warned doctors: `Daytime drowsiness may be seen initially and is to be anticipated in the effective treatment of anxiety. It will normally diminish rapidly and may be minimised in the early days of treatment by giving the larger proportion of the day's dose before retiring. Similarly it is advisable to avoid abrupt discontinuation of Ativan as some sleep disturbance may result. This applies especially where high doses have been given for prolonged periods.’

I very much doubt if anyone at Wyeth had any idea that some of the patients starting the drug in 1973 would still be taking it fifteen years later. No one at the company could have known what would happen to patients who took the drug for that long. But the hint of problems to come appears in the penultimate sentence in the paragraph I have quoted above. Wyeth already knew that stopping Ativan suddenly could lead to problems.

Other side effects of which Wyeth warned doctors in 1973 included: occasional confusion, hangover, headache on waking, drowsiness or dizziness, blurred vision and nausea.

During 1973, an important paper was published by a Belgian consultant psychiatrist called Dr de Buck. After a study of 30 patients, in which he compared lorazepam and diazepam both with one another and with a dummy, placebo drug Dr de Buck reported that two of his patients had convulsions after a relatively high dose of lorazepam was withdrawn.

Should Wyeth have done more trials on their new drug before they released it for general use? Certainly, the Drug and Therapeutics Bulletin seemed to think so. The authors of their review article stated that `Controlled studies of the hypnotic effects of lorazepam have not been reported and the suggestion that it may be more effective as a hypnotic than as an anxiolytic is not supported by good evidence. Adequate comparisons with the other benzodiazepine hypnotics have not been published’.

During the next few years there were other signs that not all doctors were totally enthusiastic about this new benzodiazepine. Articles about the drug gradually started to appear in medical and scientific journals around the world.

Dr B Novis from the famous Groote Schuur Hospital wrote warning other doctors about a hazard he had noticed with lorazepam. He said: `We should like to warn of the danger of using this form of premedication (lorazepam) in out-patients, particularly those who may have to drive a car home or even take public transport, as they are liable to drop off to sleep when left alone.’

By 1975, Wyeth were advertising the drug to general practitioners with enthusiasm. One of their advertisements read: `Your anxious patients will be more successfully controlled by Ativan than by any previous benzodiazepine.’ The advertisement included photographs of five contented, smiling patients, all presumably happy and calm on Ativan. In later advertisements, Wyeth would emphasize what they saw as the merits of the drug. `Ativan - the simple solution to the complicated problem of treating the anxious patient’, read one advertisement. `Minimal side effects’ said a bright and cheerful headline.

By 1979, lorazepam was the fifth most popular benzodiazepine in Britain. Two million prescriptions were written for it that year. During subsequent years, lorazepam would do even better. It reached third place in 1980 and by 1982 doctors were writing nearly three and a half million prescriptions for the drug.

By the 1980s, articles were beginning to appear in medical journals suggesting that lorazepam might be causing more problems than some other benzodiazepines. For example, in The Lancet in 1980, a doctor from the General and Marine Hospital in Ontario, Canada reported that he had seen four cases of withdrawal convulsions in patients coming off benzodiazepines. Two of those patients had been taking lorazepam

As the 1980s progressed, more and more warnings about lorazepam began to appear. For example, in 1984, the journal `Psychiatry in Practice’ published an article in which Zahed Subhan, Research Associate in the Human Psychopharmacology Research Unit at the University of Leeds reported that lorazepam seemed to have an adverse effect on human memory.

It was, however, in 1985 that the first really serious warning about lorazepam appeared in the Drug and Therapeutics Bulletin under the heading: `Lorazepam - a benzodiazepine to choose or avoid?’

Sales of the drug were worth many millions of pounds a year (one source puts the sales of lorazepam in the United States as being worth $220 million in 1987 alone) and Ativan was one of the best selling drugs in the world.

`Lorazepam is an effective anxiolytic,’ said the Drug and Therapeutics Bulletin, `but there is great concern about its potential to produce physical and psychological dependence; severe withdrawal symptoms may make it more difficult to stop treatment with lorazepam than with diazepam. The reason for this is unknown.’

`Lorazepam shares the usual reversible dose related unwanted effects of all benzodiazepines,’ continued the Drug and Therapeutics Bulletin. `...lorazepam may impair memory more than other benzodiazepines. After abrupt discontinuation of oral lorazepam given for weeks or months withdrawal symptoms are common, and withdrawal fits have been reported. Withdrawal should therefore always be gradual.’

The Drug and Therapeutics Bulletin concluded that: `lorazepam is now the second most commonly prescribed anxiolytic benzodiazepine in this country, but it has no important advantages over other benzodiazepines and is widely believed to carry a greater risk of dependence. Its oral use as an anxiolytic is best limited to courses of treatment of a week or two, to intermittent use and to particular groups of patients such as those with poor liver function. Sudden discontinuation can produce severe withdrawal reactions.’

One might have imagined that this severe warning would have led to doctors abandoning lorazepam. But they didn't. Maybe they didn't read the warning. Or maybe their patients were too hooked on the drug to stop it. Or maybe no one cared?

The article in the Drug and Therapeutics Bulletin was not the only warning about lorazepam.

In the same year the medical newspaper `Pulse’ carried a number of letters about lorazepam.

Dr Michael Ross, a general practitioner in Liverpool, said: `For the last 18 months I have been communicating with the Committee on Safety of Medicines about what I believe are the unequivocal risks of dependence and marked withdrawal symptoms associated with lorazepam. In my opinion this can occur even with low dosage short courses and for many months after cessation of therapy.’

Dr Ross complained that the Committee on Safety of Medicines had rejected this claim - arguing that they had received few reports of lorazepam being a problem.

Dr Ross invited any doctors who had noticed problems with lorazepam to submit reports to the committee on safety of medicines.

Underneath Dr Ross's letter, Pulse carried a reply from Dr Maurice Cohen, the medical director of Wyeth Laboratories, the manufacturers of lorazepam. Dr Cohen claimed that `there is no indication there is a major problem with this particular product’ and went on to argue that `If it were, in fact, a major problem for a large number of doctors its use would obviously decline. From the sales figures this is not the case’.

Dr Cohen, not surprisingly perhaps, misses the point that if patients had difficulty in stopping the drug then the sales figures would inevitably remain high.

Dr Ross did not go unsupported.

Letters from three doctors supporting him appeared in Pulse in a subsequent issue.

At this point it is perhaps worth taking a look at the data sheets that Wyeth had published to describe its drug Ativan to prescribing doctors in Britain. Data sheets are the most important `official’ warnings that doctors see. On its data sheet cards a drug company is expected to provide doctors with an honest appraisal of the advantages and risks of its drugs.

I've already described the warning Wyeth included on its 1973 data sheet. However, by 1981, Wyeth were warning doctors that `prolonged or excessive use of benzodiazepines may occasionally result in the development of some psychological dependence with withdrawal symptoms on sudden discontinuation. Treatment in these cases should be withdrawn gradually. Careful usage seldom results in the development of dependence’.

And by 1983, Wyeth were saying: "Prolonged or excessive use of benzodiazepines may occasionally result in the development of some psychological dependence with withdrawal symptoms on sudden discontinuation. This is more likely in patients with a history of alcoholism, drug abuse or in patients with marked personality disorders. Treatment in all patients should be withdrawn gradually. Careful monitoring of all patients is essential.’

In addition, Wyeth were warning that: `The use of benzodiazepines may release suicidal tendencies in depressed patients. Other rarely reported behavioural effects of the benzodiazepines include paradoxical aggressive outbursts, excitement and confusion.’

The warning seems clear enough. Wyeth were clearly aware of the problems associated with lorazepam.

Unfortunately, many doctors prescribing the drug didn't read the warnings.

And if they read them they didn't take any notice of them. Thousands of patients were betrayed by their doctors.

This extract was taken from The Benzos Story by Vernon Coleman

Copyright Vernon Coleman June 2022

Vernon Coleman’s latest book about the benzodiazepines is called `The Benzos Story’. It is available as a paperback.