Age and Ageing (1977) 6, Supplement
A COMPARISON OF TWO SEDATIVE/ HYPNOTIC DRUGS M. S. PATHY
St David's Hospital, Cardiff
Tabu I. Age distribution of patients completing the trial Age group (years)
No. of patients
Up to 60 61 to 70 71 to 80 More than 81
1 8 14 15
Total
38
Table III indicates the sequences in which the drugs were administered. All dosage forms were identical in shape, size and colour and taste and were administered at 10 pm. The trial period was 24 consecutive nights. All subjects had a three night run-in period during which placebo was given. This was followed by a seven-day period on 91
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There is a vast literature existing on the treatment of nocturnal insomnia and restlessness in the elderly and there is little doubt that there is, as we have already heard this afternoon and in the latter part of this morning, a considerable amount of over-prescribing of night sedation due to lack of adequate assessment of the factors preventing sleep or reducing restlessness. Notwithstanding this I suspect that not even the most doctrinaire amongst us will refuse to advise night sedation not infrequently. This study reports a double blind crossover comparison of chlormethiazole (Heminevrin), and dichloralphenazone, the active ingredient of Welldorm. Forty-seven non-confused male and female in-patients in our rehabilitation unit were studied and 38 subjects completed this trial. I perhaps should emphasize that this study was done some five years ago (Pathy 1975). Factors that led us to look at this preparation were that it had been used on the Continent for quite a long period for the treatment of alcohol withdrawal. It was noted to be an effective hypnotic in these patients, with few side-effects, and we felt that it might therefore become a useful hypnotic in the treatment of the elderly. Table I gives the age range of the patients studied: they are from 60 to over 80 and Table II indicates the diagnostic categories. Obviously this is a highly biased group due to the fact that they were basically in a rehabilitation unit as you will see from the diagnoses.
92
M. S. Pathy Table II. Diagnostic categories of patients Diagnosis
Total
1 8 8 1 1 1 2 6 2 2 1 2 1 1 1 38
Table III. Sequence in which drugs were administered Chlormethiazole treatment: 2 capsules each containing 192 mg chlormethiazole (base), plus 1 identical placebo capsule. Dichloralphenazone treatment: 3 capsules each containing 433 mg dichloralphenazone. Placebo administration: 3 capsules containing an inactive substance.
active preparations according to random allocations, a further three-day placebo period to eliminate possible crossover effect and a second seven-day period on an active preparation. The trial was concluded with a four-day period on placebo to assess possible persistent side-effects. In 9 of the 47 patients treatment was discontinued because of refusal to take any night sedation or because discharge from hospital was indicated. Among the 38 patients who completed the trial a high number of placebo reactors were recorded during the run-in period and with hindsight we can now say that all placebo reactors should be excluded from any comparative trial of hypnotics. Figure 1 shows those recorded as having heavy sleep. The difference is unfortunately small because of the large number of placebo reactors. Figure 2 shows a histogram representing the percentage of subjects who fell asleep within 60 min of administration of the drug. Table IV indicates the side-effects. As you will see the side-effects on active preparation are no different from those who received placebo. While this Btudy cannot claim to have shown that chlormethiazole is superior in all characteristics studied, the overall results do show that chlormethiazole is superior to both placebo and dichloralphenazone with regard to the indices of heavy sleep and time
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Varicose ulcers Amputation (lower limb) Cerebrovascular accident Pernicious anaemia Myocardial infarction Hypertension Congestive cardiac failure Fractured femur Bronchopneumonia Diabetes O8teomalacia Osteo-arthrosis Cerebral arteriosclerosis Cervical spondylosis Undiagnosed
Number
Comparison of Two Sedative/Hypnotic Drugs 100
-
90
-
80
93
73%
70
-
60
-
63% 57%
% 60 -
-
30
-
20
-
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40
10 -
r\
Chlormethiazole
Dichloralphenazone
Placebo
Fig. 1. Percentage of nights with heavy sleep (38 patients).
100 -
90 -
77%
80 -
72%
67.5%
70 60 -
% 60
-
40 30 20 10 0
Chlormethiazole
DSchloralphenazone
Placebc
Fig. 2. Percentage of nights with 'onset of sleep* ^60 min (38 patients). Table TV. Type and number of side-effects recorded in the overall material Side-effects reported: Number of times Symptoms Dizziness Headaches Gastrointestinal symptoms Nasal irritation
Placebo
Chlormethituole
Dichloralphetuuone
7 8 5 1
3 8 1
3 8 1 1
94
M. S. Pathy
of onset of sleep. The relatively short half-life of four hours probably accounts for the lack of manifest daytime drowsiness and hangover effect. During the last year in particular we have extensively used chlormethiazole edisylate as a syrup in 500-1000 mg doses and I am sorry to see that the makers recommend much smaller doses or a much smaller range of doses, because quite often one needs to go up to as much as 1000 mg. It is a particularly effective hypnotic in restless elderly patients, but it is also of considerable value in rational subjects because of its remarkable absence of daytime sedation. Though in our original trial patients we found no specific side-effects, in subsequent patients we found a very small percentage who complained of transient intense nasal irritation with sneezing which lasted for about 5 min. In these subjects the sideeffects were quite consistent each night and occurred within 15-20 min of administering the drug in syrup form but the nasal irritation is delayed if the drug is administered in tablet form.
PATHY, M. S. (1975) A double-blind comparison of chlormethiazole & dichloralphenazone: a sedative/hypnotic in geriatric medicine. Curr. med. Res. Opin. 2, 648.
DISCUSSION 6 Professor Exton-Srmth: Could I just ask Dr Pathy did all the subjects in the trial require hypnotics. How did you determine whether they needed a hypnotic or not before putting them in the trial? Dr Pathy: These were patients who volunteered information saying they were unable to sleep without hypnotics, or who after two or three days in hospital had not slept. On this information the house officer decided that the subject needed an hypnotic and placed him in the trial. Unfortunately the criteria for using hypnotics in the very first place were probably not based on strict enough criteria and probably we should have decided a set number of days of sleeplessness before hypnotics were administered. Professor Williamson: Could we ask the psychiatrists to tell us of their experience with tardive dyskinesia? We all see this form from time to time but in my experience it is still rather rare and I wonder if the psychiatrists are seeing most of it? Perhaps they also create most of it! I have seen reports that, in some cases, the condition if caused by a phenothiazine can actually be controlled by giving an even larger dose of the offending drug which seems rather a pharmacological paradox, although I believe the explanation is that the phenothiazine acts by decreasing the dopamine levels in the brain. These receptors then become abnormally sensitive to the local dopamine and hence the dyskinesia. I have also read reports of good response of this distressing side-effect to thiopropazate and I have confirmed this in a few cases. Dr Robinson: It is a very real hazard of long-term therapy, particularly in the elderly. The patient with akathisia is especially in a dangerous situation because the diagnosis is often not appreciated and it is simply regarded as another rather extreme form of senile agitation. The most striking case I have seen was at the time when there was a
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REFERENCE
Discussion
95
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popular record about an amazing dancing bear. I always recall it as the 'dancing bear' syndrome because of that. I think that describes it very well. The other common presentation is the oro-facial-lingual variety and this too is often misinterpreted. The patient is continually protruding her tongue and licking her lips and sometimes there is facial grimacing as well. Once this has started I am very doubtful whether an increase in phenothiazines is justified in the elderly; it may damp down again temporarily. I have had some success in one or two cases using diazepam (Valium) having stopped the phenothiazine. There is no doubt that some patients are kept too long on phenothiazine and at too high a dosage. Many studies have shown that long term phenothiazines could be withdrawn in a proportion of stabilized patients without any adverse effect at all. I might add that there is some indication that extra-pyramidal disorder only occurs in patients who are sensitive. It may in fact be an idiosyncratic reaction and I feel therefore that it is not necessary or desirable to give anti-Parkinsonism drugs as a routine with phenothiazine even in the elderly. My policy with phenothiazines [and the one I am using mostly is trifluoperazine (Stelazine) and that not for dementia but for late paraphrenia with disturbing delusional or hallucinatory presentations] is to wait until the patient shows some flicker of cogwheel rigidity or a little facial immobility or other minor Parkinson signs. A lot of patients do not show anything of this sort at all; so it is only to those who do show incipient side-effects that I should give anti-Parkinson drugs. In these circumstances progress has to be carefully monitored. Professor Exton-Smith: Rosin and I described about 12 or 13 of these cases of the Earl-Hunter syndrome with oral-facial dyskinesia and we pointed out that it did tend to occur in brain-damaged people. I think perhaps why it is more common in the elderly is that they more often suffer from the effects of brain damage. I would not agree that you can control it by increasing the dose of all phenothiazines. The two which are most effective in controlling this are thiopropazate and perphenazine; in fact one has to choose the phenothiazines which have akinetic properties. Dr Robinson: Sometimes tetrabenazine can be helpful in the control of these disorders. Dr Arie: Dr Powell's paper was excellent but I would question one point on the use of antidepres8ants. If I have understood him right, he said if you give an antidepressant to a patient and he becomes confused you know that you are on the wrong lines and that you should stop within a few days. Confusion must always be watched very carefully, but a grossly slowed-up, apparently demented depressive may appear more confused as she begins to emerge from that state, and then you should go on for perhaps a month, and you may find that things are coming right and that you are on the right track. Dr Powell: Yes I would accept that. I am talking about the patient who is not obviously depressed and in many ways seems to be obviously demented, but one has the feeling that all is not quite right. The patient I first came across in this way, was 'dearly demented' except that she had been admitted to an old peoples' home three years previously from a psychiatric unit where she had been treated for depression. This just made me think that perhaps this was not a typical depression and so we gave her antidepressives. We then had to cardiovert her because of dysrhythmia from the amitryptiline . . . but these things happen! Dr Agate: Can I ask Dr Pathy, or anyone else who can enlighten me, exactly what we are treating with hypnotics? We are treating sleeplessness presumably; Dr Pathy said a moment or two ago he would perhaps start with patients who had real insomnia, let
96
Discussion
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us say having had no sleep for two or three nights. However, I do not believe that patients do stay awake for two or three nights on end, or even one night on end. If I ask my night staff whether people sleep or not they usually say "Yes they are asleep at certain hours'. These are fitful sleepers. I myself suffer a certain disability and am often restless at night; I go down stairs and have half a plate of cornflakes, glance at a soporific book, and go back to bed and sleep. Now, I do not reckon I should be treating myself with hypnotics I What are we treating elderly people for with hypnotics ? Are we treating them because they say 'Doctor, I do not sleep* ? Are we treating them because the night sister, at the moment she goes round does not find them asleep? In fact what are we doing? Dr Pathy: This is the nub of the problem. We made two assessments — a patient assessment and a nurse assessment, that is a subjective and an objective assessment. It was the amount of sleep or sleeplessness based on both the patients' subjective awareness of being awake and the nurse's objective statement in the chart that she had to fill in every hour. I suspect that unless she filled it in ineffectively, it did in fact record sleeplessness, or lack of adequate sleep. It should be added that all patients were assessed on placebo only for the first three days. Dr Judge: I would like to reinforce what Dr Powell said about phenothiazine paradoxical responses. The first time I saw this was many years ago with a small dose of chlorpromazine (Largactil). It was misinterpreted by me, and by everyone else, as an inadequate dose and the dose was pushed up and up and up with increasing restlessness. There is a very real danger in pushing the dose in a mistaken impression that this is a failed response. Dr Firth: Can I ask Dr Pathy the actual percentage of side-effects with chlormethiazole? He says that he used this substance for some time and has increased his dosage in certain circumstances and that it is a very safe drug. Does the nasal irritation he quotes amount to very much — does one have to stop medication? Dr Pathy: No, the patients complain that they get intense nasal irritation and they sneeze a lot but, contrary to Professor Hall's experience, they usually say it lasts for about 5 to 10 min and then passes off completely, so we have never had to stop the preparation. Actually it was seven patients who complained of this symptom in all, but that is out of about 150 patients outside this trial that we have treated with the syrup form of Heminevrin. Professor Hall: So it is not a very high percentage then. Dr Pathy: No, but it is quite intense. They complain about it but they will accept it if it is explained that this is expected in a few patients. Professor Hall: Have you tried increasing the dose? Dr Pathy: No we have not. That is, not in an attempt to overcome the nasal symptoms. Professor Hall: This is what I am told is effective. You go to sleep so rapidly having increased the dose, you do not feel the discomfort; that is the theory at any rate so the makers tell me, but certainly I experienced intense pain for about two and half hours with nasal congestion which was very unpleasant. Dr Hebbert: Could I ask Dr Powell about drugs causing dizziness and the use of antidepressants in chlorpromazine jaundice? Dr Powell: Firstly I do not think I have ever come across a patient with dizziness who has not been tried on prochlorperazine ('Stemetil'). By the time they get to me, it has
Discussion
97
• Pcrphenazine and nortriptyline interaction has been reported. In this situation, perphenazine causes hepatic enzyme inhibition and consequently nortriptyline metabolism is delayed thus producing nortriptyline intoxication with 'usual' doses of norlryptyline.
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always been tried. So it is very difficult in this group to know which came first. Concerning the chlorpromazine question and when one can start people on antidepressants: phenothiazine-induced jaundice is an hypereensitivity reaction with intra-hepatic obstructive jaundice. I would have thought that once the jaundice has cleared then you can start the antidepressant without any problem.* Dr Dall: We are all working empirically, some of us using high dosage and some using low dosage of a variety of drugs to try to achieve similar effects on a variety of patients. I wonder what situation we would be in when using the oral hypoglycaemic agents if we could not obtain blood sugar levels. We would be in a terrible mess and it would be a similar situation to that which we are in at the moment with hypnotics and tranquillizers and antidepressants. The mechanisms to measure drug effects and serum levels are now becoming available. It is high time we used these to try to achieve the same effect in two patients who may be of different sizes and different weights before we decide that one drug is better than the other. Dr Powell: I am not sure that serum levels at the moment are going to help us in how to use, for example, phenothiazines. The issues are too complicated. With tricyclics, it is a little clearer: one problem is when do you measure the serum levels? Is it when the person has started to respond to their depression, say three weeks after you have started the drug, or do you measure it after one dose of the drug? There is evidence (Davis & Janowsky 1974) that there is a correct dose range, however this is still a crude measurement. I quite accept that that would be a very useful development and perhaps in five or six years' time we shall not be prescribing drug 'X' without knowing appropriate levels in much the same way that one uses lithium at present. Professor Williamson: Could I revert to the subject raised earlier by Dr Agate — why do we prescribe night sedatives ? I do think this was adequately answered. Recently it was borne in upon me quite dramatically when I was talking to a final-year student who was doing a locum house officer post in our unit. He commented that there were several striking differences between the usages in the geriatric wards and what he was accustomed to. Thus he noticed that the patients were all dressed and out of bed for part of each day, the patients were not fed by the nurses and lastly 'you don't seem to use sedatives'. The same comment was volunteered by a student nurse and when we looked at the situation, it was in fact the case. This is partly, I think because we started this unit from scratch just over two years ago and in the two months before we opened our doors we had frequent seminars and discussions with all the new staff. We discussed all the important topics but we forget about sedatives and I think it was just as well — my advice is 'forget about sedatives' I Dr Powell: I would just make the point that when you do prescribe pentobarbitone (Nembutal) because the lady has been on it for 20 years, you are prescribing it for your own sake, because it makes life easier on the ward round 1 Dr Pathy: I think it is true to say that we do over-prescribe sedatives for a number of reasons. As has been said, partly for the benefit of the nursing staff, partly for the benefit of other patients in the ward. In certain situations where one has a restless, disturbed patient one is prescribing in that case not necessarily for the patient's benefit, but for the
98
Discussion
SUMMARY
Professor Hall: I would like to begin by thanking both speakers for the high standard of their papers. That they have been very enjoyable, I think can be gauged by the excellent response that has come from the audience and I would like to thank you very much for also taking part In summarizing we come back to that most important factor, that accurate diagnosis is essential before we can treat. This theme has really gone through the whole session. We need to know exactly what we are doing when we treat a patient. Two most important points have been made, that drugs are not a substitute for diagnosis and correct treatment, and that every diagnosis does not need a drug. I think nevertheless there are one or
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benefit of the whole ward. That there is over prescribing of sedatives, I could not agree more. Professor Exton* Smith: I find it very difficult indeed now to carry out a trial of hypnotics since we have our nurses so well trained that when I am asked to carry out a trial we find that very few patients in our wards really do require them. This has always rather mystified me because several studies we have done have shown that 25 per cent or even more old people at home are receiving hypnotics nightly. What is happening to these people? I get the impression that many of them have acquired the hypnotic habit when they were in hospital and then they go home and the prescription is continued by their general practitioners. Dr Pathy: I think this largely came out of the initial part of this trial. As you will have noticed there were a large number of placebo reactors, that is those who slept perfectly well on the placebo. In fact when we took out this group who did sleep if they were on a placebo it left us with a very small number to analyse and this was a major difficulty of the analysis. It is important perhaps to note that there are a group who do not sleep if they are on placebo both as recorded by the nurse and the patient, but do so on an active preparation. So there clearly are a group of patients in hospital, despite Professor Williamson's observations, that we find do need a hypnotic and will not sleep on a placebo. Dr Andrews: The problem about drug usage, particularly sedatives, is that of laziness on the part of the medical staff. In the last year I have attempted to make sure that the housemen write up sedatives individually when needed. This has cut down the prescription rate to a minimum. We are carrying out a trial at the moment to assess, when patients are discharged whether they are familiar with the drugs they are taking home. I and the Senior Registrar inquire personally what each individual patient is being discharged on. I am sure that many patients still have sedatives prescribed because of the housemen having been taught, as students, by a non-geriatrician to give sedatives, and often the consultant does not know what the patient is being prescribed. Dr Hyams: Many old people living at home are taking hypnotics because they are some of the many thousands of old people with brain failure who are being kept in the community, but who have been doing interesting things at night that the relatives or neighbours do not want, whether it is bugle-playing, or wandering in the streets. One can see the GP faced with the problem of trying to ensure that they sleep at night so that they may be more manageable in general.
Discussion
99
REFERENCE DAVIS,
J. M. & JANOWSKY, D. S. (1974) Recent advances in the treatment of depression. British
Journal of Hospital Medicine 11, 219-228.
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two points which need further emphasis. We talked a lot this morning about the cerebral activators and really I think we ought to consider the ethics of using these drugs against the total background of the enormous problem which we face in the management of patients with dementing processes. Secondly I think that the pharmaceutical industry itself needs to think about the formulation of drugs. Are we giving the appropriate dose? Are tablets the right size for elderly patients? Colin Powell mentioned the importance of studying pharmacokinetics and he mentioned the problem of fast and slow acetylators. While this is an interesting subject we need equally to look at the whole problem of pharmacokinetics in the elderly and consequently understand how drugs are handled. What, for instance, is the effect of enzyme induction? We know that enzyme induction is delayed in the elderly, although not reduced. We must know much more about the handling of drugs, receptor sites, protein binding and similar problems. I am quite sure too that it is vitally important that whenever a new drug is introduced, which is going to be used in elderly subjects, that it has been studied in elderly subjects and in old animals first and not just in young dogs, rats or rabbits and then tried out on healthy young subjects. I think the industry has a big problem here and one that it definitely needs to tackle. Finally I would like to emphasize some of the points we have discussed. Do we really need to give drugs? Are hypnotics necessary? It is vitally important and necessary to monitor constantly the effectiveness of drugs which are being given to patients. It is essential to keep therapy under review and to stop it as soon as possible, but obviously it must be continued if necessary. Colin Powell did a very good job in emphasizing the harm and the effects that drugs can have in producing types of brain failure. This is of course recognized in the case of alcohol.
A COMPARISON OF TWO SEDATIVE/ HYPNOTIC DRUGS M. S. PATHY
St David's Hospital, Cardiff
Tabu I. Age distribution of patients completing the trial Age group (years)
No. of patients
Up to 60 61 to 70 71 to 80 More than 81
1 8 14 15
Total
38
Table III indicates the sequences in which the drugs were administered. All dosage forms were identical in shape, size and colour and taste and were administered at 10 pm. The trial period was 24 consecutive nights. All subjects had a three night run-in period during which placebo was given. This was followed by a seven-day period on 91
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There is a vast literature existing on the treatment of nocturnal insomnia and restlessness in the elderly and there is little doubt that there is, as we have already heard this afternoon and in the latter part of this morning, a considerable amount of over-prescribing of night sedation due to lack of adequate assessment of the factors preventing sleep or reducing restlessness. Notwithstanding this I suspect that not even the most doctrinaire amongst us will refuse to advise night sedation not infrequently. This study reports a double blind crossover comparison of chlormethiazole (Heminevrin), and dichloralphenazone, the active ingredient of Welldorm. Forty-seven non-confused male and female in-patients in our rehabilitation unit were studied and 38 subjects completed this trial. I perhaps should emphasize that this study was done some five years ago (Pathy 1975). Factors that led us to look at this preparation were that it had been used on the Continent for quite a long period for the treatment of alcohol withdrawal. It was noted to be an effective hypnotic in these patients, with few side-effects, and we felt that it might therefore become a useful hypnotic in the treatment of the elderly. Table I gives the age range of the patients studied: they are from 60 to over 80 and Table II indicates the diagnostic categories. Obviously this is a highly biased group due to the fact that they were basically in a rehabilitation unit as you will see from the diagnoses.
92
M. S. Pathy Table II. Diagnostic categories of patients Diagnosis
Total
1 8 8 1 1 1 2 6 2 2 1 2 1 1 1 38
Table III. Sequence in which drugs were administered Chlormethiazole treatment: 2 capsules each containing 192 mg chlormethiazole (base), plus 1 identical placebo capsule. Dichloralphenazone treatment: 3 capsules each containing 433 mg dichloralphenazone. Placebo administration: 3 capsules containing an inactive substance.
active preparations according to random allocations, a further three-day placebo period to eliminate possible crossover effect and a second seven-day period on an active preparation. The trial was concluded with a four-day period on placebo to assess possible persistent side-effects. In 9 of the 47 patients treatment was discontinued because of refusal to take any night sedation or because discharge from hospital was indicated. Among the 38 patients who completed the trial a high number of placebo reactors were recorded during the run-in period and with hindsight we can now say that all placebo reactors should be excluded from any comparative trial of hypnotics. Figure 1 shows those recorded as having heavy sleep. The difference is unfortunately small because of the large number of placebo reactors. Figure 2 shows a histogram representing the percentage of subjects who fell asleep within 60 min of administration of the drug. Table IV indicates the side-effects. As you will see the side-effects on active preparation are no different from those who received placebo. While this Btudy cannot claim to have shown that chlormethiazole is superior in all characteristics studied, the overall results do show that chlormethiazole is superior to both placebo and dichloralphenazone with regard to the indices of heavy sleep and time
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Varicose ulcers Amputation (lower limb) Cerebrovascular accident Pernicious anaemia Myocardial infarction Hypertension Congestive cardiac failure Fractured femur Bronchopneumonia Diabetes O8teomalacia Osteo-arthrosis Cerebral arteriosclerosis Cervical spondylosis Undiagnosed
Number
Comparison of Two Sedative/Hypnotic Drugs 100
-
90
-
80
93
73%
70
-
60
-
63% 57%
% 60 -
-
30
-
20
-
Downloaded from http://ageing.oxfordjournals.org/ at UQ Library on June 5, 2016
40
10 -
r\
Chlormethiazole
Dichloralphenazone
Placebo
Fig. 1. Percentage of nights with heavy sleep (38 patients).
100 -
90 -
77%
80 -
72%
67.5%
70 60 -
% 60
-
40 30 20 10 0
Chlormethiazole
DSchloralphenazone
Placebc
Fig. 2. Percentage of nights with 'onset of sleep* ^60 min (38 patients). Table TV. Type and number of side-effects recorded in the overall material Side-effects reported: Number of times Symptoms Dizziness Headaches Gastrointestinal symptoms Nasal irritation
Placebo
Chlormethituole
Dichloralphetuuone
7 8 5 1
3 8 1
3 8 1 1
94
M. S. Pathy
of onset of sleep. The relatively short half-life of four hours probably accounts for the lack of manifest daytime drowsiness and hangover effect. During the last year in particular we have extensively used chlormethiazole edisylate as a syrup in 500-1000 mg doses and I am sorry to see that the makers recommend much smaller doses or a much smaller range of doses, because quite often one needs to go up to as much as 1000 mg. It is a particularly effective hypnotic in restless elderly patients, but it is also of considerable value in rational subjects because of its remarkable absence of daytime sedation. Though in our original trial patients we found no specific side-effects, in subsequent patients we found a very small percentage who complained of transient intense nasal irritation with sneezing which lasted for about 5 min. In these subjects the sideeffects were quite consistent each night and occurred within 15-20 min of administering the drug in syrup form but the nasal irritation is delayed if the drug is administered in tablet form.
PATHY, M. S. (1975) A double-blind comparison of chlormethiazole & dichloralphenazone: a sedative/hypnotic in geriatric medicine. Curr. med. Res. Opin. 2, 648.
DISCUSSION 6 Professor Exton-Srmth: Could I just ask Dr Pathy did all the subjects in the trial require hypnotics. How did you determine whether they needed a hypnotic or not before putting them in the trial? Dr Pathy: These were patients who volunteered information saying they were unable to sleep without hypnotics, or who after two or three days in hospital had not slept. On this information the house officer decided that the subject needed an hypnotic and placed him in the trial. Unfortunately the criteria for using hypnotics in the very first place were probably not based on strict enough criteria and probably we should have decided a set number of days of sleeplessness before hypnotics were administered. Professor Williamson: Could we ask the psychiatrists to tell us of their experience with tardive dyskinesia? We all see this form from time to time but in my experience it is still rather rare and I wonder if the psychiatrists are seeing most of it? Perhaps they also create most of it! I have seen reports that, in some cases, the condition if caused by a phenothiazine can actually be controlled by giving an even larger dose of the offending drug which seems rather a pharmacological paradox, although I believe the explanation is that the phenothiazine acts by decreasing the dopamine levels in the brain. These receptors then become abnormally sensitive to the local dopamine and hence the dyskinesia. I have also read reports of good response of this distressing side-effect to thiopropazate and I have confirmed this in a few cases. Dr Robinson: It is a very real hazard of long-term therapy, particularly in the elderly. The patient with akathisia is especially in a dangerous situation because the diagnosis is often not appreciated and it is simply regarded as another rather extreme form of senile agitation. The most striking case I have seen was at the time when there was a
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REFERENCE
Discussion
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popular record about an amazing dancing bear. I always recall it as the 'dancing bear' syndrome because of that. I think that describes it very well. The other common presentation is the oro-facial-lingual variety and this too is often misinterpreted. The patient is continually protruding her tongue and licking her lips and sometimes there is facial grimacing as well. Once this has started I am very doubtful whether an increase in phenothiazines is justified in the elderly; it may damp down again temporarily. I have had some success in one or two cases using diazepam (Valium) having stopped the phenothiazine. There is no doubt that some patients are kept too long on phenothiazine and at too high a dosage. Many studies have shown that long term phenothiazines could be withdrawn in a proportion of stabilized patients without any adverse effect at all. I might add that there is some indication that extra-pyramidal disorder only occurs in patients who are sensitive. It may in fact be an idiosyncratic reaction and I feel therefore that it is not necessary or desirable to give anti-Parkinsonism drugs as a routine with phenothiazine even in the elderly. My policy with phenothiazines [and the one I am using mostly is trifluoperazine (Stelazine) and that not for dementia but for late paraphrenia with disturbing delusional or hallucinatory presentations] is to wait until the patient shows some flicker of cogwheel rigidity or a little facial immobility or other minor Parkinson signs. A lot of patients do not show anything of this sort at all; so it is only to those who do show incipient side-effects that I should give anti-Parkinson drugs. In these circumstances progress has to be carefully monitored. Professor Exton-Smith: Rosin and I described about 12 or 13 of these cases of the Earl-Hunter syndrome with oral-facial dyskinesia and we pointed out that it did tend to occur in brain-damaged people. I think perhaps why it is more common in the elderly is that they more often suffer from the effects of brain damage. I would not agree that you can control it by increasing the dose of all phenothiazines. The two which are most effective in controlling this are thiopropazate and perphenazine; in fact one has to choose the phenothiazines which have akinetic properties. Dr Robinson: Sometimes tetrabenazine can be helpful in the control of these disorders. Dr Arie: Dr Powell's paper was excellent but I would question one point on the use of antidepres8ants. If I have understood him right, he said if you give an antidepressant to a patient and he becomes confused you know that you are on the wrong lines and that you should stop within a few days. Confusion must always be watched very carefully, but a grossly slowed-up, apparently demented depressive may appear more confused as she begins to emerge from that state, and then you should go on for perhaps a month, and you may find that things are coming right and that you are on the right track. Dr Powell: Yes I would accept that. I am talking about the patient who is not obviously depressed and in many ways seems to be obviously demented, but one has the feeling that all is not quite right. The patient I first came across in this way, was 'dearly demented' except that she had been admitted to an old peoples' home three years previously from a psychiatric unit where she had been treated for depression. This just made me think that perhaps this was not a typical depression and so we gave her antidepressives. We then had to cardiovert her because of dysrhythmia from the amitryptiline . . . but these things happen! Dr Agate: Can I ask Dr Pathy, or anyone else who can enlighten me, exactly what we are treating with hypnotics? We are treating sleeplessness presumably; Dr Pathy said a moment or two ago he would perhaps start with patients who had real insomnia, let
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us say having had no sleep for two or three nights. However, I do not believe that patients do stay awake for two or three nights on end, or even one night on end. If I ask my night staff whether people sleep or not they usually say "Yes they are asleep at certain hours'. These are fitful sleepers. I myself suffer a certain disability and am often restless at night; I go down stairs and have half a plate of cornflakes, glance at a soporific book, and go back to bed and sleep. Now, I do not reckon I should be treating myself with hypnotics I What are we treating elderly people for with hypnotics ? Are we treating them because they say 'Doctor, I do not sleep* ? Are we treating them because the night sister, at the moment she goes round does not find them asleep? In fact what are we doing? Dr Pathy: This is the nub of the problem. We made two assessments — a patient assessment and a nurse assessment, that is a subjective and an objective assessment. It was the amount of sleep or sleeplessness based on both the patients' subjective awareness of being awake and the nurse's objective statement in the chart that she had to fill in every hour. I suspect that unless she filled it in ineffectively, it did in fact record sleeplessness, or lack of adequate sleep. It should be added that all patients were assessed on placebo only for the first three days. Dr Judge: I would like to reinforce what Dr Powell said about phenothiazine paradoxical responses. The first time I saw this was many years ago with a small dose of chlorpromazine (Largactil). It was misinterpreted by me, and by everyone else, as an inadequate dose and the dose was pushed up and up and up with increasing restlessness. There is a very real danger in pushing the dose in a mistaken impression that this is a failed response. Dr Firth: Can I ask Dr Pathy the actual percentage of side-effects with chlormethiazole? He says that he used this substance for some time and has increased his dosage in certain circumstances and that it is a very safe drug. Does the nasal irritation he quotes amount to very much — does one have to stop medication? Dr Pathy: No, the patients complain that they get intense nasal irritation and they sneeze a lot but, contrary to Professor Hall's experience, they usually say it lasts for about 5 to 10 min and then passes off completely, so we have never had to stop the preparation. Actually it was seven patients who complained of this symptom in all, but that is out of about 150 patients outside this trial that we have treated with the syrup form of Heminevrin. Professor Hall: So it is not a very high percentage then. Dr Pathy: No, but it is quite intense. They complain about it but they will accept it if it is explained that this is expected in a few patients. Professor Hall: Have you tried increasing the dose? Dr Pathy: No we have not. That is, not in an attempt to overcome the nasal symptoms. Professor Hall: This is what I am told is effective. You go to sleep so rapidly having increased the dose, you do not feel the discomfort; that is the theory at any rate so the makers tell me, but certainly I experienced intense pain for about two and half hours with nasal congestion which was very unpleasant. Dr Hebbert: Could I ask Dr Powell about drugs causing dizziness and the use of antidepressants in chlorpromazine jaundice? Dr Powell: Firstly I do not think I have ever come across a patient with dizziness who has not been tried on prochlorperazine ('Stemetil'). By the time they get to me, it has
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• Pcrphenazine and nortriptyline interaction has been reported. In this situation, perphenazine causes hepatic enzyme inhibition and consequently nortriptyline metabolism is delayed thus producing nortriptyline intoxication with 'usual' doses of norlryptyline.
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always been tried. So it is very difficult in this group to know which came first. Concerning the chlorpromazine question and when one can start people on antidepressants: phenothiazine-induced jaundice is an hypereensitivity reaction with intra-hepatic obstructive jaundice. I would have thought that once the jaundice has cleared then you can start the antidepressant without any problem.* Dr Dall: We are all working empirically, some of us using high dosage and some using low dosage of a variety of drugs to try to achieve similar effects on a variety of patients. I wonder what situation we would be in when using the oral hypoglycaemic agents if we could not obtain blood sugar levels. We would be in a terrible mess and it would be a similar situation to that which we are in at the moment with hypnotics and tranquillizers and antidepressants. The mechanisms to measure drug effects and serum levels are now becoming available. It is high time we used these to try to achieve the same effect in two patients who may be of different sizes and different weights before we decide that one drug is better than the other. Dr Powell: I am not sure that serum levels at the moment are going to help us in how to use, for example, phenothiazines. The issues are too complicated. With tricyclics, it is a little clearer: one problem is when do you measure the serum levels? Is it when the person has started to respond to their depression, say three weeks after you have started the drug, or do you measure it after one dose of the drug? There is evidence (Davis & Janowsky 1974) that there is a correct dose range, however this is still a crude measurement. I quite accept that that would be a very useful development and perhaps in five or six years' time we shall not be prescribing drug 'X' without knowing appropriate levels in much the same way that one uses lithium at present. Professor Williamson: Could I revert to the subject raised earlier by Dr Agate — why do we prescribe night sedatives ? I do think this was adequately answered. Recently it was borne in upon me quite dramatically when I was talking to a final-year student who was doing a locum house officer post in our unit. He commented that there were several striking differences between the usages in the geriatric wards and what he was accustomed to. Thus he noticed that the patients were all dressed and out of bed for part of each day, the patients were not fed by the nurses and lastly 'you don't seem to use sedatives'. The same comment was volunteered by a student nurse and when we looked at the situation, it was in fact the case. This is partly, I think because we started this unit from scratch just over two years ago and in the two months before we opened our doors we had frequent seminars and discussions with all the new staff. We discussed all the important topics but we forget about sedatives and I think it was just as well — my advice is 'forget about sedatives' I Dr Powell: I would just make the point that when you do prescribe pentobarbitone (Nembutal) because the lady has been on it for 20 years, you are prescribing it for your own sake, because it makes life easier on the ward round 1 Dr Pathy: I think it is true to say that we do over-prescribe sedatives for a number of reasons. As has been said, partly for the benefit of the nursing staff, partly for the benefit of other patients in the ward. In certain situations where one has a restless, disturbed patient one is prescribing in that case not necessarily for the patient's benefit, but for the
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Professor Hall: I would like to begin by thanking both speakers for the high standard of their papers. That they have been very enjoyable, I think can be gauged by the excellent response that has come from the audience and I would like to thank you very much for also taking part In summarizing we come back to that most important factor, that accurate diagnosis is essential before we can treat. This theme has really gone through the whole session. We need to know exactly what we are doing when we treat a patient. Two most important points have been made, that drugs are not a substitute for diagnosis and correct treatment, and that every diagnosis does not need a drug. I think nevertheless there are one or
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benefit of the whole ward. That there is over prescribing of sedatives, I could not agree more. Professor Exton* Smith: I find it very difficult indeed now to carry out a trial of hypnotics since we have our nurses so well trained that when I am asked to carry out a trial we find that very few patients in our wards really do require them. This has always rather mystified me because several studies we have done have shown that 25 per cent or even more old people at home are receiving hypnotics nightly. What is happening to these people? I get the impression that many of them have acquired the hypnotic habit when they were in hospital and then they go home and the prescription is continued by their general practitioners. Dr Pathy: I think this largely came out of the initial part of this trial. As you will have noticed there were a large number of placebo reactors, that is those who slept perfectly well on the placebo. In fact when we took out this group who did sleep if they were on a placebo it left us with a very small number to analyse and this was a major difficulty of the analysis. It is important perhaps to note that there are a group who do not sleep if they are on placebo both as recorded by the nurse and the patient, but do so on an active preparation. So there clearly are a group of patients in hospital, despite Professor Williamson's observations, that we find do need a hypnotic and will not sleep on a placebo. Dr Andrews: The problem about drug usage, particularly sedatives, is that of laziness on the part of the medical staff. In the last year I have attempted to make sure that the housemen write up sedatives individually when needed. This has cut down the prescription rate to a minimum. We are carrying out a trial at the moment to assess, when patients are discharged whether they are familiar with the drugs they are taking home. I and the Senior Registrar inquire personally what each individual patient is being discharged on. I am sure that many patients still have sedatives prescribed because of the housemen having been taught, as students, by a non-geriatrician to give sedatives, and often the consultant does not know what the patient is being prescribed. Dr Hyams: Many old people living at home are taking hypnotics because they are some of the many thousands of old people with brain failure who are being kept in the community, but who have been doing interesting things at night that the relatives or neighbours do not want, whether it is bugle-playing, or wandering in the streets. One can see the GP faced with the problem of trying to ensure that they sleep at night so that they may be more manageable in general.
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REFERENCE DAVIS,
J. M. & JANOWSKY, D. S. (1974) Recent advances in the treatment of depression. British
Journal of Hospital Medicine 11, 219-228.
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two points which need further emphasis. We talked a lot this morning about the cerebral activators and really I think we ought to consider the ethics of using these drugs against the total background of the enormous problem which we face in the management of patients with dementing processes. Secondly I think that the pharmaceutical industry itself needs to think about the formulation of drugs. Are we giving the appropriate dose? Are tablets the right size for elderly patients? Colin Powell mentioned the importance of studying pharmacokinetics and he mentioned the problem of fast and slow acetylators. While this is an interesting subject we need equally to look at the whole problem of pharmacokinetics in the elderly and consequently understand how drugs are handled. What, for instance, is the effect of enzyme induction? We know that enzyme induction is delayed in the elderly, although not reduced. We must know much more about the handling of drugs, receptor sites, protein binding and similar problems. I am quite sure too that it is vitally important that whenever a new drug is introduced, which is going to be used in elderly subjects, that it has been studied in elderly subjects and in old animals first and not just in young dogs, rats or rabbits and then tried out on healthy young subjects. I think the industry has a big problem here and one that it definitely needs to tackle. Finally I would like to emphasize some of the points we have discussed. Do we really need to give drugs? Are hypnotics necessary? It is vitally important and necessary to monitor constantly the effectiveness of drugs which are being given to patients. It is essential to keep therapy under review and to stop it as soon as possible, but obviously it must be continued if necessary. Colin Powell did a very good job in emphasizing the harm and the effects that drugs can have in producing types of brain failure. This is of course recognized in the case of alcohol.
