Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Clinical Practice is as good as Evidence Based Practice
- Vijaya Murali (26 June 2002)
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The treatment for non-compliance must improve
- Sir Nil (28 June 2002)
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Committee on Safety of Medicines' gave bad advice on "gradual" withdrawal
- Dinah KC Murray (30 June 2002)
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Balancing the risks
- Ann F. Bisset (12 July 2002)
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Response to Davied et al and Murray from the MCA
- Dinah KC Murray (12 July 2002)
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What happened to Thioridazine?
- Pernia Arshad, Mary Morcos, Baskaran Sridharan (12 July 2002)
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Disconuation of thioridazine > Primary care experience
- Paul H Driscoll, Sheffield S2 3 AJ (24 July 2002)
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Discontinuation of thioridazine: guidelines should consider indications of drugs beyond their licens
- Georgina Walker, Andrew Wilcock (25 July 2002)
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Vijaya Murali, Specialist Registrar in Psychiatry Cossham Hospital,Lodge Road, Kingswood, Bristol, BS15
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Editor- I am sure that many clinicians like me would have relished the article by Dr.Davies et al as they have voiced their views regarding the use of Thioridazine in day to day clinical practice.(ref:1) It was a time when the committee on Safety of Medicines restricted the licensed indications for thioridazine, when not only the patients but also professionals including GPs were expressing their anguish at the decision made. It is interesting to note that the National Institute for Clinical Excellence (NICE)(ref:2)has now come out with the guidance on the use of newer (atypical) antipsychotic drugs for the treatment of Schizophrenia. However, NICE does not recommend change to one of the atypical antipsychotic drugs if a patient is currently taking typical antipsycotics that are controlling the symptoms of schizophrenia and are not causing unacceptable side effects. It is undeniable that it is important to work with the patient in determining the care and medication following a discussion on the relative benefits of each of the drugs and their side- effects. In that case, will the directives allow clinicians greater flexibility in their clinical practice to continue established drug regimes with careful and adequate monitoring? Dr.V.Murali
1. Simon JC Davies, Leila B Cooke, Alan G Moore, John Potokar. Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs. BMJ 2002;324:1519-21 2. NICE Technology Appraisal Guidance - No.43, National Institute for Clinical Excellence. (www.nice.org.uk) |
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Sir Nil, Patient activist http://hem.passagen.se/sir.nil/
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Dear Sirs, As a sufferer of schizophrenia, I am delighted that The Committee on Safety of Medicines restricted the indications for thioridazine, although FDA gave similar recommendations 6 months earlier in United States. In Sweden, for instance the Medical Product Agency (MPA) has done nothing to restrict it's use and they have recently told me that such decisions are based on national adverse effect reports and it is difficult to get enough evidence to make such restrictions. In Sweden, year 2001 20 % of the Drug Committees recommended thioridazine against psychosis, which seems not very appropriate regarding the risk of cardiac side effects and the fact that schizophrenia seems to have an increased cardiac mortality.1 Concerning this article, it is naturally very interesting although the number of patients involved seems rather small. The results, however, suggests that the majority can change to a less harmful drug and also the general importance of a careful choice of drugs to the group of learning disabilities. In some countries, I am sure that this group of patients are often treated by GP:s, who might lack this awareness. What I lack in this article is the strategy they adopted with the patients that had problems to change from Mallorol. At Schizophrenia sites on Internet, I often meet desperate family members of schizophrenia patients that wants advice how to convince him/her to comply with the medication and care. The usual advice is buy the book "I Am Not Sick, I Don't Need Help! Helping the Seriously Mentally Ill Accept Treatment: A Practical Guide for Families and Therapists" by Xavier Amador, Ph.D., with Anna-Lisa Johanson. After a year or so of recommending this book, I have started to wonder, if the care have read it and what strategy they uses in such cases. Doctors have prescribed drugs for several houndred years, but still is not able to treat patients that refuse medication. This suggests that more education and research should be directed to the problem with non-compliance and it is especially urgent in schizophrenia. Yours truly Sir Nil Founder of the site: Whisper - about schizophrenia Information source, Meeting point,Whistle-blower http://hem.passagen.se/sir.nil/ 1. Allebeck, P Schizophrenia: A life shortening disease Schizophrenia Bullentin, 1989, 15: 81-89 |
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Dinah KC Murray, Tutor Distance Education Dept /WebAutism Birmingham University B15 2TT
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Davies et al are right to raise concerns about the discontinuation of thioridazine in patients with learning disabilities. However, there are reasons for questioning some of their interpretations of the problems which have arisen in carrying out advice from the Committee on Safety of Medicines. Thioridazine’s high anticholinergic activity may be associated with severe withdrawal syndromes for some people. The Chief Medical Officer refers to these as “nausea, vomiting, gastric upset, trembling, dizziness, anxiety, agitation and insomnia, as well as transient dyskinetic signs or the re-emergence of psychotic symptoms.” ‘Gradual’ withdrawal is advised in pursuance of their avoidance. Unfortunately, prevalent definitions employed by prescribers refer to periods of between one week and four weeks as “gradual withdrawal”. For drugs which may have been taken for decades this is an abrupt and not a gradual change. In my own observation, discontinuing Thioridazine in people with learning disabilities after longterm use without a long taper can have catastrophic effects [1]. Dramatic weight loss, severe disruption of sleep patterns, pronounced almost incessant agitation and restlessness with distressed vocalisations are features of these abrupt withdrawals which may last for months after rapid onset coinciding with drug discontinuation. Sovner found a similar pattern in his cases of thioridazine withdrawal, with anxiety and insomnia prominent[2] . Here is what a veteran pharmacist who spent decades specialising in psychiatric drugs says about antipsychotic withdrawal, "All the problems, like benzodiazepines, occur when withdrawal is attempted in a few days or few weeks"[3] . There are a number of reasons for suspecting that a proportion of the patients who had problematic withdrawal from thioridazine in the study by Davies et al were undergoing withdrawal reactions, with or without eventual re-emergence of a baseline pathology. One reason is the speed of onset of disturbed behaviour, one is the appearance of psychotic like symptoms in people who did not initially have a diagnosis of psychosis, one is the cases where switching to another antipsychotic did not curtail the problem behaviours, one is the case of NMS , and finally it would be surprising if nobody experienced a withdrawal syndrome when after only 37 weeks of antipsychotic treatment even monkeys show disturbed behaviours after discontinuation for as long as seven weeks before beginning to return to baseline [4]. This view is also supported by the findings of May et al that “of 23 severely and profoundly mentally retarded adult male patients undergoing slow "diagnostic" neuroleptic taper, it was determined that at least 60% could eventually be managed without psychoactive medication. However, many of these demonstrated a remarkably long, but nonetheless transient, period of worsening” (my emphasis)[5]. Davies et al remark that, “Although the adverse consequences for the seven patients who stopped taking thioridazine could be viewed as being attributable to poor management of change, the clinicians involved felt they had little option but to follow the Committee on Safety of Medicines' advice”. A significant defect in that advice was its characterisation of “gradual withdrawal”. Strangely, when that advice appears as from the Committee’s Chair, Professor Alan Breckenridge, (online) it is thus: “When discontinuing thioridazine a gradual reduction in dosage over several weeksone to two weeks is recommended “[sic][6] . Did someone alter the original statement and replace “several weeks” with “one to two”? If so, they may be responsible for widespread distress, often leading to “prescribing cascades”[7] . An ideally slow taper would be no faster than 10% every two to three months, especially after chronic use of thioridazine or other neuroleptics. footnotes 1.Murray DKC 1999, “Potions Pills and Human Rights”, Good Autism Practice April 1999, pp.1-13. 2.Sovner,R. 1995, “Thioridazine withdrawal induced behavioral deterioration treated with clonidine: Two case reports”. Mental Retardation, 33, 221-225. 3.Stuart Baker http://www.apana.supanet.com/links.htm 4. Amore M, Zazzeri N. 1995 Neuroleptic malignant syndrome after neuroleptic discontinuation. Prog Neuropsychopharmacol Biol Psychiatry ;19(8):1323-34 5. May P, London EB, Zimmerman T, Thompson R, Mento T, Spreat S. 1995 “A study of the clinical outcome of patients with profound mental retardation gradually withdrawn from chronic neuroleptic medication.” Ann Clin Psychiatry. Dec;7(4):155-60. 6. www.doh.gov.uk/cmo/cmo00_18.htm 7. See Webb, OJ. 1996, Medication use patterns in IHC community homes. NZ Fam Physician; 23: 4-6. and Murray DKC 1999, “Potions Pills and Human Rights”, Good Autism Practice April. |
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Ann F. Bisset, medical adviser Public Health Medicine, Information & Statistics division, Trinity Park House, Edinburgh EH5 3SQ
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Until the Committee on Safety of Medicines (CSM) restricted the use of Thioridazine in 2000, it was the most widely used anti-psychotic in the UK, with 50 million years’ of safe patient use world-wide. In Scotland in 1999, there were 250,808 prescriptions dispensed in primary care (hospital data not available, but CSM reports it was the most widely used anti- psychotic in hospital as well). This dropped to 39,177 in 20012. Is Thioridazine safer, cheaper and more effective than alternative anti-psychotic drug treatments for anxiety, agitation, mania and hypomania? There is simply not enough evidence to answer this because thioridazine has been very widely used for 30 years – before the days of rigorous Randomised Controlled Trials. Lack of evidence is not evidence of no benefit. Conversely, there is only evidence of a handful of adverse cardiac events, some of which may not have been directly caused by Thioridazine, or may have been due to combination with other drugs. While the reported cardiac deaths are lamentable, it appears that Thioridazine is very much safer than other effective drugs such as Aspirin, which continues to be sold over the counter. Even if there is some under-reporting of adverse events, there is far more practical evidence of long-term safety for Thioridazine compared to much more expensive and much less tried and tested drugs. A recent JAMA study3 noted that many new drugs have a high rate of serious side-effects which go undetected until late in post-marketing surveillance. CSM needs to balance these relative risks. The manufacturers of Thioridazine have raised few objections to the restricted use of Thioridazine because it is an extremely cheap drug, costing only a few pence compared with newer anti-psychotics, which may be up to a hundred times more expensive, as well as having different and sometimes distressing side-effects. The cost of anti-psychotic prescriptions has risen sharply in the last two years in Scotland2. Anecdotally, considerable numbers of patients with hypomania, anxiety and agitation are having considerable problems in adjusting to a change of drugs, and, as Davies points out, informed consent may be a problem1. It would be very helpful if NICE or Health Technology Board for Scotland reviewed the evidence, risks and benefits of Thioridazine, and considered more humane guidelines for its future use. It seems quite wrong to deprive so many patients of a well-tried drug. 1. Davies SJC, Cooke LB, Moore AG, Potokar J. Discontinuation of Thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs. BMJ 2002:324: 1519-21. 2. Information from Primary Care information Unit, Information & Statistics Division, Trinity Park House, Edinburgh EH5 3SQ 3. Lasser K, Allen P et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002: 287:2215-20 Ann F Bisset
No competing interests. |
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Dinah KC Murray, Tutor Autism Distance Education, WebAutism Education Dept Birmingham University B15 2TT
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BMJ readers may be interested in this reply from the Medicines Control Agency to my last letter MCA ref: HPO2690 8 July 2002 Dear Dr. Murray, Thank you for the copy of your response to the article by Davies et al in the BMJ 324:1519-1521 entitled ‘Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs’ published on June 22 2002. The wording which was issued from the Medicines Control Agency (MCA) can be found as follows: 1) MCA Press release, 2) Message from Professor Alasdair Breckonridge, Chairman of CSM, 3) Advice on prescribing information and 4) DOH on the following web links: 1. http://www.mca.gov.uk/whatsnew/pressreleases/thioridazinepressrelease.htm 2. http://www.mca.gov.uk/mca/csm/thiolet.pdf 3. http://www.mca.gov.uk/mca/csm/thisspc.pdf 4. http://www.doh.gov.uk/cmo/cemcmo200018.pdf The website which you have cited in your response (http://www.doh.gov.uk/cmo/cmo00_18.htm) is the only one to contain the garbled english that you have highlighted. As all the others are consistent with the original communications cascaded from the MCA we do not know how this has happened. We will notifiy the DOH of this dichotomy in their website. The points that you have raised in your response about gradual withdrawal and that were also highlighted in the original BMJ article are well made. Should any similar issues arise in the future then such points and suggestions will be taken into account when seeking advice from the CSM and will be important features of future communications. The communication issues arising from the restriction of thioridazine have provoked numerous comments for future consideration and we are grateful to you for your contribution. Yours sincerely, Dr. A. Horsfall Scientific Assessor Pharmacovigilance Post Licensing Division |
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Pernia Arshad, Consultant in Learning Disability Psychiatry Department of Psychological Medicine,Meadowbrook Unit,Salford, M6 8HG, Mary Morcos, Baskaran Sridharan
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The article by Davies raised some important issues on Thioridazine discontinuation in Learning Disability population.1 As against the author's experience, we had successful withdrawal of Thioridazine in our services at Salford district. We looked at the following issues before withdrawal of Thioridazine: 1.Initial Diagnosis before Thioridazine was prescribed.
Results indicated that out of 175 patients under the care of a Learning Disability Psychiatrist, 28 of them received Thioridazine. The majority (23 patients) received small doses (50 - 100 mg) for many years. The main indication for use was marked Challenging Behaviour (12 patients). Based on the above information, a decision was made to gradually reduce (12 patients) or suddenly stop Thioridazine (16 patients). Alternative tranquilliser was prescribed for all 28 patients. Risperidone was the most commonly used atypical antipsychotic because of some evidence of its effectiveness in challenging behaviour.2 A review of patients' mental state three months after the substitution of tranquillisers indicated that: 21 patients either remained stable or improved 7 patients deteriorated These 7 patients subsequently improved, either by a change to a different psychotropic drug or by adjusting the dose of existing drugs. No patient required to restart Thioridazine. Review of previous psychiatric treatment helped us to identify instances of rebound increase in behavioural problems when Thioridazine was stopped. It also prompted us to avoid using those Neuroleptics which were either ineffective or caused unacceptable side effects. Evidence of rebound aggression on stopping neuroleptics was also observed by Mos et al .3 This lead us to withdraw Thioridazine gradually in most cases. In our opinion risk associated with the withdrawal of Thioridazine was carefully managed and minimised by taking into account the diagnosis, the dose and duration and consequences of previous reduction in medication followed by a careful strategy of either gradual reduction or sudden stoppage with replacement of alternative tranquillisers in appropriate doses. Dr. Pernia Arshad
Dr. Mary Marcos
Dr. B.Sridharan
References: 1.Simon J C Davies, Leila B Cooke, Alan G Moore, and John Potokar.Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs. BMJ 2002 : 324: 1519-21. (22nd June 2002) 2.Vander Ben Borre R. Risperidone as add- on therapy in behavioural disturbances in mental retardation: a double blind placebo-controlled Cross- over study. Acta Psychiatrica Scandinavica 1993: 87, 167-71. 3.Mos,J., Van Aken, H.H., Van Oorschot,R. & Olivier,B. Chronic treatment with Eltoprazine does not lead to tolerance in its anti- aggressive actions, in contrast to Haloperidol. European Neuropsychopharmacology 1996 : 6, 1-7. Competing interests- None |
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Paul H Driscoll, General Practitioner Heeley Green Surgery, 302 Gleadless Rd, Sheffield S2 3 AJ
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Dear Editor The article by Dr SJ Davies et al (1) struck a chord with us. We are a general practice of 5,500 patients and had 11 patients well controlled on thioridazine, 6 with learning delay and the rest with mixed mental health problems. We look after two hostels for those with learning disabilities and some sheltered accomodation , where most of our patients lived (7/11). Our experience was that it was that in 8 out of the 11 there were significant problems with the changeover, most notably an increase in agitation, severe in some and distressing to both carers and patients alike One patient was admitted to a hospital under a section from February 2001 to May 2001,, another from October 2001 who is still an inpatient, and another who I had seen 5 times in 2000 had 41 surgery consults in 2001. The total number of consults for all patients at the GP surgery was 153 for 2000 amd 149 for 2001, but this does not include phone calls, out of hours contacts and hospital appointments, all of which were increased. Infromation re alternative medications was poor. The initial local suggestion of promazine was not appropriate as it had little sedative effect , relative tom thioridazine. , We also ran out of it here in Sheffield and patients had to be prescribed large volumes of syrup, Only one of the eleven was finally stabilised on it . I agree with their comments that balancing cardiovascular risk against the psychological and pharmacological impact of changing drugs can be difficult but feel that in this case the MCA/CSM guidance,(2) was too proscriptive to the detriment of our patients , and I believe our evidence supports theirs, as to the distress caused, by this and also the substantioal workload. generated in both primary and secondary care services. As generalists, we felt the guidance was so strong that we were obliged to change our patients over, as it would be hard to defend not doing so at that time. Davies SJC, Cooke LB, Moore AG, Potokar J. Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs. BMJ 2002; 1519-1521. (22 June ) Medicines Control,Agency/Committee on Safety of Medecines. QT interval prolongation with antipsychotics. Current problems in pharmacovigilance 2001.1: 27: 4 Paul Driscoll General Practitioner, Heeley Green Surgery, 302 Gleadless Rd, Sheffield S2 3AJ 0114 2500326 |
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Georgina Walker, SpR Palliative Medicine Hayward House, Specialist Palliative Care Unit, Nottingham City Hospital, Nottingham, NG5 1PB, Andrew Wilcock
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Editor – The article by Davies et al(1) highlights the difficulties encountered resulting from thioridazine being restricted due to its association with prolonged QT interval and cardiac arrhythmia. Several other drugs e.g. cisapride, droperidol, have been withdrawn for the same reason. In palliative care, thioridazine and cisapride were of use in the management of symptoms, usually for an unlicensed indication, as are other commonly used antipsychotics, e.g. haloperidol and tricyclic antidepressants, e.g. amitriptyline, that also prolong the QT interval(2). Given the growing safety concerns relating to prolonged QT and the lack of information regarding the extent to which it is a problem in palliative care patients, we routinely carry out an ECG on all new referrals to a specialist palliative care unit, except those deemed to be imminently dying. Of 200 patients with cancer, based on EMEA definitions(3), 26 (13%) had prolonged QTc (QT corrected for heart rate) and only 1 (0.5%) had a seriously prolonged QT of over 500 milliseconds. Compared to those with normal QTc interval, those with prolonged QTc had a greater male:female ratio (p=0.001) and a higher incidence of cardiac disease (p=0.01), otherwise demographics, biochemistry, use of ‘at risk’ drugs, survival and incidence of sudden ‘unexpected’ death were similar. The prevalence of prolonged QTc in palliative care patients appears similar to psychiatric patients (8-23%), higher than reported in non-malnourished hospital patients (4%) and less than reported in malnourished hospital patients (23%)(4-6). However, severely prolonged QT appears to be relatively rare. For any drug treatment, balancing the potential benefit against the risk of harm is part of the prescribers’ responsibilities and is aided by an understanding of the magnitude of the risk. We agree with Davies that guidelines should provide flexibility to continue established regimes where the benefits outweigh the potential harm but would add that they also pay cognisance to the sometimes extensive use of these drugs for indications beyond the license. No competing interests 1. Davies SJC, Cooke LB, Moore AG et al. Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs. British Medical Journal 2002; 324: 1519-1521. 2. Haverkamp W, Breithardt G, Camm AJ et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. European Heart Journal 2000; 21: 1216-1231. 3. Anonymous. Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. European Agency for the Evaluation of Medicinal Products (EMEA); Committee for Proprietary Medicinal Products: CPMP/986/96. 4. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SHL. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. The Lancet 2000; 355: 1048-1052. 5. Warner JP, Barnes TRE, Henry JA. Electrocardiographic changes in patients receiving neuroleptic medication. Acta Psychiatr Scand 1996; 93: 311-313. 6. Da Cunha DF, De Carvalho Da Cunha F, Ferreira TPS et al. Prolonged QTc intervals on the electrocardiograms of hospitalized malnourished adults. Nutrition 2001; 17: 370-372. |
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