Renewable Revolution

Continued from previous post by Dr. as well as a Prof) Ashton


History of My Benzodiazepine Withdrawal Clinic

My own involvement with benzodiazepines started at this time. One day in 1981 a lady came hobbling on crutches into my general pharmacology clinic. She had been involved in a road traffic accident. She had two broken limbs in plaster and had been prescribed the benzodiazepine Ativan for muscle relaxation (1mg tds). She had noticed as she recovered that when the time for each dose of Ativan approached she experienced a strong craving for the next pill, along with anxiety, restlessness and muscle cramps. "I think I am addicted," she said. "Can you help me?" Naively I said "yes" although I had no experience in drug addiction at that time. She duly underwent a withdrawal process, during which she suffered many symptoms including anxiety, insomnia, hallucinations; tremor, muscle cramps and many other symptoms now (but not then) recognised as typical benzodiazepine withdrawal symptoms.

Following this lady's appearance at my clinic there was a trickle of others which soon grew to a stream and finally a flood of patients referred by their doctors because they wished to stop their benzodiazepines. As a result, I had to start a dedicated benzodiazepine withdrawal clinic. I continued this clinic single-handedly for 12 years at two sessions every week until 1994 when I had to retire (you have to retire at 65 from clinical work under the National Health Service). Strangely, none of my medical colleagues wished to become involved in this clinic or to take it over in 1994, so the clinic closed down. I think that the current medical training did not equip most doctors for listening to anxious patients with many complaints, patients who were time-consuming and required repeated consultations. I myself spent most of the time simply listening to the patients and learning from them how to come off benzodiazepines.

Adverse Effects of Long-Term Benzodiazepine Use

Over 300 patients passed through this clinic and over 90% successfully withdrew.

Morbidity in 50 Patients
Slide 3
This slide shows some of the symptoms in the first 50 patients attending the clinic. They had been on prescribed, so-called "therapeutic" doses of benzodiazepines for 1–22 years (mean, 10 years) and wished to withdraw. They ranged from 20 to 72 years of age, (mean age 46 yrs); 40 were females.

•20% had taken drug overdoses requiring hospital admission in suicide attempts (illustrating that benzodiazepines cause or exacerbate depression)

•20% had developed incapacitating agoraphobia (in addition to the majority who had panic attacks)

•18% had undergone GI investigations (irritable bowel) (a condition closely linked to anxiety)

•10% had undergone neurological investigations (3 wrongly diagnosed with MS on the basis of muscle weakness and tremor, blurred vision and patches of numbness — signs often associated with anxiety states)

•62% had been prescribed other psychotropic drugs, mainly antidepressants, since starting benzodiazepines

•28%  were taking a combination of two benzodiazepines, the second added after the first become insufficient.

This illustrates the development of tolerance and dosage escalation with benzodiazepines.

These symptoms were not the original cause for starting benzodiazepines but developed during the course of prolonged use. It seems clear that long-term benzodiazepines actually aggravate or cause further anxiety and depression. In the 90% of patients in this series who successfully withdrew, and I followed for 10 years, there were no more overdoses; the agoraphobia, panic attacks, depression and neurological symptoms, including the alleged MS, disappeared. The fact that patients improve after withdrawal is a strong argument that symptoms are related to the benzodiazepines and are not due to some underlying psychiatric disorder, as many psychiatrists have claimed. 

Some of these patients developed withdrawal symptoms while coming off benzodiazepines. Between 1980 and 1985 a number of controlled trials by Lader, Tyrer and others showed that withdrawal symptoms from regular therapeutic doses of benzodiazepines were real and that they indicated dependence on these drugs.

Benzodiazepine Withdrawal Symptoms

Withdrawal Symptoms
Slide 4
These have since been described by many authors and include a range of symptoms common to all anxiety disorders (such as panic attacks, agoraphobia, insomnia, nightmares, tremors and muscle tension) and some relatively specific to benzodiazepines (such as perceptual distortions, hallucinations, sensory hypersensitivity and sometimes psychotic symptoms). However, these symptoms are not obligatory if withdrawal is carried out slowly and carefully — as I shall describe later. They nearly always improve after some weeks although in a small proportion the symptoms may be protracted.

Protracted Withdrawal Symptoms
Slide 5
Anxiety, depression and gastrointestinal symptoms may persist for many months, though gradually declining. A number of neurological symptoms including tinnitus, motor and sensory symptoms and global cognitive impairment may be very long-lasting and raise the question of whether benzodiazepines may cause permanent neurological damage.

The publicity surrounding benzodiazepines in the 1980s resulted in a reduction of benzodiazepine prescribing levels in the UK from its height of 32 million in 1976 (for a population of 50 million) down to about 18 million in 2000. And by 2000 the benzodiazepine problem was largely perceived to have gone away. National Health withdrawal clinics had shut down, the media no longer found benzodiazepines newsworthy and self-help groups closed down because of lack of public financial support.

Skeleton in the Closet: Costs of Inappropriate Prescribing

But the problem has not gone away.
Skeleton Surveying Skull
Slide 6
The skeletons were merely shut in the closet and now some worms are beginning to crawl out of the coffin. For example, there are still nearly one million long-term benzodiazepine users in the UK and four million or more in the US. There is a growing problem of benzodiazepine abuse — benzodiazepines are taken by over 90% of alcohol and illicit drug abusers and sometimes in their own right. Benzodiazepines are inappropriately prescribed at all stages of life — from the elderly who take them chronically as sleeping pills or are given them to keep them quiet in retirement homes and psychiatric units; to discharged psychiatric patients still taking benzodiazepines prescribed in hospital; to women still being prescribed them in pregnancy, and to their developing fetuses and newborn infants.

There are large and uncounted socioeconomic costs associated with benzodiazepines. 



Reasons for Inappropriate Benzodiazepine Prescribing

Why are benzodiazepines still so commonly prescribed inappropriately? One factor is that doctors have failed to follow guidelines limiting them to short-term usage. In the short-term, that is 2–4 weeks only or intermittent use, benzodiazepines have many excellent therapeutic, even life-saving properties, illustrated here (enumerate).

Therapeutic Actions of Benzodiazepines (Short-Term)
Slide 8
(enumerate)
 Used long-term, however, they can produce many adverse effects that I have no time to describe in detail. They include: (enumerate)

Adverse Effects of Benzodiazepines (Long- Term)
Slide 9
Doctors have been slow to give up the idea that benzodiazepines are so benign that they can be continued for life. 

Secondly, doctors and drug companies have been slow to recognise the difference between different benzodiazepines, both in rates of elimination and in relative potency.  This slide shows equivalent potencies and elimination rates of some anxiolytics.

Equivalent potencies of different benzodiazepines

Half-lives and Equivalent Potencies of Benzodiazepine Anxiolytics
Slide 10
Explain slide (elimination half-lives and approximate clinical potency of some benzodiazepines compared to diazepam).

The three most potent in this group of anxiolytics are alprazolam, clonazepam and lorazepam which are 10–20 times more potent than diazepam. This difference is often disregarded and the drugs prescribed in excessive dosage. For example, I have recently seen patients prescribed alprazolam in daily doses of 4–6mg — equivalent to 80–120mg of diazepam. Alprazolam is no longer prescribed under the NHS in the UK though it can be prescribed privately. I have also recently seen lorazepam prescribed in 6, 10, and over 12mg daily doses — again in equivalence up to 120mg diazepam. Both these drugs are fairly short-acting and have to be taken 3–4 times a day. Patients often suffer mini-withdrawal symptoms between doses. Clonazepam is also very potent, 10–20 times the strength of diazepam. In the UK it is only officially indicated as an anticonvulsant for epilepsy but it is popular in the US and British doctors are following suit and prescribing it for anxiety.

All these three drugs are highly addictive;  dependence develops rapidly and they are particularly hard to withdraw from. This difficulty is partly due to the relatively excessive dosage used, partly I suspect from their potency which probably means that they bind particularly avidly to GABA/BZ receptors, partly because equivalent potencies are not adhered to when switching patients to other benzodiazepines such as Valium or Librium in attempts at withdrawal, and partly because they are not available in small enough dosage strengths to allow for gradual dosage reduction. In the UK Ativan is only available in 2.5mg or 1mg tablets. The 1mg tablet is equivalent to 10mg diazepam. Even if you halve it you are withdrawing by decrements of 5mg in diazepam equivalents, which can be a big drop for some people. Strangely, 0.5mg Ativan tablets are available in the US and Canada, but all attempts to get the drug company (Wyeth) to supply this in the UK have failed.

Many physicians in the US switch patients on alprazolam or lorazepam onto clonazepam for withdrawal in the belief that its longer half-life will make withdrawal easier. However, clinical experience shows that clonazepam is also difficult to withdraw from, and patients do much better switching onto diazepam which has a much longer half-life including active metabolites for up to 200 hours, allowing a smoother and slower fall in blood concentration. Also diazepam comes in 1mg tablets which can be halved allowing very small dosage decrements. Yet for some reason I have found that American doctors are very reluctant to prescribe diazepam. 

I will describe withdrawal methods in more detail later. First you may ask how these equivalents were arrived at. Most were determined by direct clinical titration. In about 1983 Professor Michael Rawlins and I in Newcastle titrated the dose of diazepam required to substitute, in terms of anxiety symptoms, in 20 anxious patients on various doses of lorazepam. The mean came to an equivalence of 9.8mg diazepam for 1mg lorazepam. This is close to the equivalence of 1:10mg now officially accepted in most texts. Similar clinical tests were conducted for other benzodiazepine such as alprazolam though some equivalents are based on clinical experience during withdrawal of patients on various benzodiazepines who were switched to diazepam. Some equivalents were derived from animal work and human trials by drug companies. There is now a general consensus, at least in the UK, about equivalent potencies for both anxiolytic and hypnotic benzodiazepines. They are quoted in the British National Formulary produced by the British Medical Association and the Royal Pharmaceutical Society circulated to all doctors and in many published papers. Unfortunately, not all doctors read or heed this advice!

Half-lives and Equivalent Potencies of Some Benzodiazepine Hypnotics
Slide 11
This slide shows the equivalences and half lives of some benzodiazepine hypnotics. Triazolam is very potent, again 20 times the strength of diazepam and very short acting. It can give rise to withdrawal symptoms the next day, and it was removed from the UK formulary in 1995. Flunitrazepam is also potent but long-acting. It gained general popularity as a “date-****” drug, because of the prolonged amnesia it induces. Nitrazepam, temazepam and flurazepam are less potent and have a medium duration of action but can cause a hangover the next day.

All these equivalencies are of course approximate. There is considerable individual variation in how people react to benzodiazepines. In addition, there are subtle differences in the pharmacological profiles of different drugs, and the equivalences do not always work at higher doses. For example, in my clinical experience diazepam is rather more sedative than lorazepam (Ativan) which is more anxiolytic. So if you abruptly change someone on say 6mg Ativan to 60mg of diazepam, he is likely to become very sleepy but may still be anxious. However, you can accomplish a changeover if you do it gradually and stepwise, dose by dose, titrating each dose to the clinical response. People also have differences in the speed at which they metabolise drugs, but on the whole the equivalences apply generally, except possibly in the case of benzodiazepines which have active metabolites such as diazepam where the half-lives of these can vary from 36–200 hrs.