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Rapid Responses: Rapid Responses published:
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Morphine is a safe, effective treatment for patients with refractory dyspnoea
- Simon G Williams (5 September 2003)
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Morphine for breathlessness - greater degrees of improvement possible?
- Andrew Wilcock, Jackie Frisby (Specialist Registrar) (27 September 2003)
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There are no outcome data
- Richard G Fiddian-Green (28 September 2003)
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A caution on opiate use in COPD
- James W Berrill, Seamus J Linnane (Consultant Respiratory Physician) (3 October 2003)
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Morphine for the treatment of breathlessness
- Peter N Black, Peter N Black,Morphine for the Phillippa J Poole. (4 October 2003)
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Should morphine be abandoned in the management of dyspnoea?
- Richard G Fiddian-Green (27 October 2003)
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HOW DOES MORPHINE WORK
- PRADEEP KV KRISHNAMURTHY, WS2 9XS (24 December 2003)
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Simon G Williams, Specilaist Registrar Cradiothoracic Centre, Thomas Drive, Liverpool, L14 3 PE
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EDITOR –There is a general lack of consensus regarding the use of morphine to relieve the symptom of refractory dyspnoea in patients with chronic obstructive airways disease and chronic heart failure. Concerns have been voiced about the potential detrimental effect on respiration and over-sedation. The paper by Abernethy et al.1 showed that in patients with chronic obstructive airways disease, low dose oral morphine provided a significant improvement in dyspnoea. Side effects were minimal and no evidence of respiratory depression was found. Two recent studies (both were randomised, double blind, placebo-controlled) have shown low dose morphine to be safe and provide significant benefit in the symptoms and exercise capacity in patients with chronic heart failure.2,3 Hence, low dose morphine has been shown to be safe and effective in providing relief for the distressing symptom of dyspnoea in patients with chronic obstructive airways disease and chronic heart failure. Careful prescribing of morphine can now be widely adopted as a cheap, effective and appropriate treatment for the relief of refractory symptoms in patients with these conditions. References 1. Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. Br Med J 2003;327:523-8. 2. Williams SG, Wright DJ, Marshall P, Tzeng B, Reese A, Coats AJS, Tan LB. Effects of low dose diamorphine on ventilation and oxygen consumption during exercise in patients with chronic heart failure. Heart 2003;89:1085 -6 3. Johnson MJ, McDonagh TA, Harkness A, McKay SE, Dargie HJ. Morphine for the relief of breathlessness in patients with chronic heart failure-a pilot study. Eur J Heart Fail 2002;4:753-6. Competing interests: None declared |
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Andrew Wilcock, Macmillan Reader in Palliative Medicine and Medical Oncology Hayward House Specialist Palliative Care Unit, Nottingham City Hospital, Nottingham, NG5 1PB, Jackie Frisby (Specialist Registrar)
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Editor – palliative care trials pose many challenges and Abernethy et al. are to be congratulated on their recent trial of morphine for intractable breathlessness.1 They state they plan further studies in this area and we offer the following observations that we hope are helpful. The group they studied had variable degrees of breathlessness with a range of 2-92mm as measured by visual analogue scale (VAS). This may have contributed to the small reduction of 7-10mm they found as some subjects would have limited capacity to respond to an intervention. At the other end of the spectrum, those with the most severe breathlessness may show the least response to a fixed-dose of morphine.2 It would be interesting to know if a differential response is seen if Abernethy et al. analyse their results according to the severity of breathlessness. In future studies, restricting the study population to those with moderate or severe symptoms and allowing dose-titration would focus on those with the greatest symptom burden and may allow a larger reduction in breathlessness intensity to be achieved. Finally, repeatability data for the use of a VAS for patients with intractable breathlessness at rest are available.3 Our calculations suggest that 17 patients are required to detect a change in ‘breathlessness right now’ of 25% in a within subject between day study powered at 80%. 1. Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. Br Med J 2003;327:523-8. 2. Allard P, Lamontagne C, Bernard P, Tremblay C. How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomised continuous sequential clinical trial. J Pain Symptom Manage 1999;17:256-265. 3. Wilcock A, Crosby V, Clarke D, Tattersfield A. Repeatability of breathlessness measurements in cancer patients. Thorax 1999;54:375. Competing interests: None declared |
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Richard G Fiddian-Green, None None
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Having frequently prescibed codiene phosphate or codiene sulfate to reduce the number of bowel movements in the early weeks after control closing the temporary ileostomy performed after an ileo-anal anastomosis, I can confirm the apparent safety of these oral medications. What I cannot confirm is that the medications might have increased the likelihood of the patients developing organ dysfunction or even dying should they have developed an acute illness. Excitation may precede depression in hypoxia. Morphia appears to impair mitochondrial oxidative phosphorylation independently of any antecedent suppression of respiratory depression and might even induce respiratory depression by impairing ox-phos. Relief of dyspnoea per se does not, therefore, exclude the possibility that morphia might have induced or increased in severity of an impairment of ox-phos. As an impairment of ox-phos appears to be the principle if not the sole reason for developing organ dysfunctions, undoubtedly including acute respiratory failure, morphine could make patients worse or even kill them as in the Shipman deaths. Competing interests: None declared |
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James W Berrill, House Officer, Medicine Llandough Hospital, Penarth, Cardiff, CF64 2XX, Seamus J Linnane (Consultant Respiratory Physician)
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Editor – In their article relating to the use of morphine for the management of refractory dyspnoea, Abernethy et al (1), have examined an important area of palliative care. They correctly identify that hypercapnia and respiratory depression are seen as impediments to the use of opiates in patients with chronic obstructive pulmonary disease (COPD) yet they do little to allay those concerns in their report. The majority (88%) of their patients were reported to have COPD. This is a diagnosis based on spirometric assessment (2). It may be assumed that such information existed for this diagnosis to be made but none is presented. Spirometric data would allow for classification of these patients according to the severity of airflow limitation providing prognostic information and also possibly selection criteria for the intervention. The authors state that measurement of pulmonary function would be neither generisable nor ethical. We strongly disagree with this contention. Spirometry is easily performed and widely available in most health care settings. We see no ethical bar to performing this simple test. They also suggest that spirometry is an invasive procedure which we believe to be simply incorrect. Of critical importance is the absence of data on respiratory depression. The authors state that respiratory depression was not identified however they present no data to support this. They report measurements of oxygen saturation and respiratory rate, which cannot address this issue. Respiratory depression will result in a reduction in alveolar ventilation, which is a function of both respiratory rate and tidal volume. Reporting of only one of these variables is insufficient. Oxygen saturation is a function of inspired oxygen and it appears from the discussion that patients may have had some freedom in the use of supplemental oxygen. The only valid parameter to assess respiratory depression is arterial carbon dioxide (PaCO2) and while we agree that arterial blood gas sampling is an invasive procedure, minimally invasive approaches such as capillary blood sampling or capnography would have provided useful information. Increases in PaCO2 are associated with adverse outcomes. This is particularly relevant since it seems from the discussion that some patients used non-invasive ventilation, presumably for hypercarbic respiratory failure. We welcome this paper and the important issues it addresses however given the concerns outlined above we suggest that for refractory dyspnoea opiates continue to be used with extreme caution, in COPD at least. 1. Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. Br Med J 2003;327:523-8. 2. BTS guidelines for the management of chronic obstructive pulmonary disease. The COPD Guidelines Group of the Standards of Care Committee of the BTS. Thorax. 1997 Dec;52 Suppl 5:S1-28. Competing interests: None declared |
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Peter N Black, Associate-Professor Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand., Peter N Black,Morphine for the Phillippa J Poole.
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Abernethy et al report that four days of treatment with slow release morphine led to a significant reduction in breathlessness in their patients, most of whom had COPD(1). They suggest that their findings are generalisable but we believe that caution should be exercised before the results of a short term study are used as evidence that morphine is effective and well tolerated in the long term treatment of breathlessness in patients with COPD. Abernethy and colleagues cite a recent systematic review as further evidence that opioids are effective for the treatment of breathlessness(2) but most of the studies included in the review were single dose studies. There were only three studies where subjects took opioids regularly for two or more weeks and we do not believe that these studies support the wider use of opioids in COPD. In one of these studies we treated 16 patients with severe COPD using a double-blind, randomised, placebo controlled, crossover design. Slow release morphine was titrated up to 10mg b.d. and then continued for another four weeks. Despite a small, non -significant improvement in the dyspnoea subscale of the Chronic Respiratory Disease Questionnaire (CRQ) with morphine there was no difference in the overall CRQ scores. The score for the mastery subscale of the CRQ was significantly worse with morphine as was the six minute walk distance and almost all of the subjects experienced adverse effects including constipation, nausea and sedation. Nine patients elected to continue morphine after the study but only 4 were still taking it three months later. In another study of patients with COPD, Eiser et al(3) studied 14 subjects and compared 2.5mg of diamorphine, 5 mg of diamorphine and placebo six hourly for 2 weeks. The VAS scores for dyspnoea was slightly worse with diamorphine although the difference was not statistically significant. Several subjects were troubled by constipation and nausea. In the third study, Woodcock et al treated 16 subjects with 30mg of dihydrocodeine t.i.d. for 2 weeks and 60mg t.i..d. for 2 weeks(4). Five of the 16 subjects did not complete the study because of nausea and vomiting. In the remaining 11 subjects there was a small but significant reduction in breathlessness with 30mg of dihydrocodeine but no benefit at all was seen with the 60mg. Until further studies are undertaken the widespread use of morphine for the long term treatment of dyspnoea in patients with COPD cannot be recommended. 1.Abernethy AP, Currow DC, Frith P, Fazekas PS, McHugh A, Bui C. Randomised, double-blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ 2003; 357: 523-528. 2.Poole PJ, Veale AG, Black PN. The effect of sustained-release morphine on breathlessness and quality of life in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 175: 1877- 1880. 3.Eiser N, Denman WT, West C, Luce P. Oral diamorphine: lack of effect on dyspnoea and exercise tolerance in the "pink puffer"syndrome. Eur Respir J 1991; 4: 926-931 4.Woodcock AA, Johnson MA, Geddes DM. Breathlessness, alcohol and opiates. N Engl J Med 1982; 306: 1363-4. Peter Black Associate-Professor Phillippa Poole Associate-Professor Department of Medicine University of Auckland Private Bag 92019 Auckland, New Zealand Competing interests: None declared |
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Richard G Fiddian-Green, None None
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One of the primary functions of my father, RMO in the 8th Army fighting Rommel, was to give morphia to the wounded to relieve their anxiety and pain. Did his actions improve outcome or did it have and adverse effect upon outcome? The sedation score introduced by Ramsay and subsequently refined by De Jonghe and others (1) has allowed the level of sedation to be measured like the level of anaesthesia. In fact there is very little difference between them sedated patients becoming unconscious and not suffering pain just like anaesthetised patients. I have no doubt that my late father would have judged this state a desirable one. Watt and Ledingham drew attention to the potnetial dangrs of sedation observing that the mortality of patients who had suffered multiple trauma increased from 28% to 77% (p<0.005) after they had changed their sedation regimen (2). They attributed the change to an adverse effect restricted to etomidate. Parke et al subsequently reported five fatal cases of metabolic acidosis (indicative of unreversed ATP hydrolysis) and heart failure after administering propofol (3). Terao et al have subsequently shown that post- operative sedation reduces oxygen consumption and energy expenditure (possibly indicative of an impairment of tissue oxygenation) in a dose- related manner (4). Kollef et al found that the duration of mechanical ventilation to be significantly longer for patients receiving continuous i.v. sedation compared with patients who did not receive continuous i.v. sedation (148 h [95% confidence interval: 121, 175 h] vs 78.7 h [95% confidence interval: 68.9, 88.6 h]; p<0.001) (5). Yeager et al (6) conducted a randomized controlled clinical trial to evaluate the effect of epidural anesthesia and postoperative analgesia (EAA) on postoperative morbidity in a group of high-risk surgical patients. When compared to control patients, patients who received EAA had a reduction in the overall postoperative complication rate (P = 0.002) and in the incidence of cardiovascular failure (P = 0.007) and major infectious complications (P = 0.007). These authors conclude that EAA exerted a significant beneficial effect on operative outcome in a group of high risk surgical patients. The beneficial effect might more appropriately attributed to the avoidance of the systemic effects of the analgesia. As admirable as the induction of unconsciousness and relief of pain may be from a humanitarian perspective it may have an adverse effect upon outcome in the majority of patients unless it is administered in doses that do not compromise mitochondrial oxidative phosphorylation. I know of no data that has related sedative and analgesic effects to the adequqcy of mitochondrial oxidative phosphorylation. The same argument applies to the use of morphine in the management of dyspnoea as suggested in my earlier communication. It is imperative that this study be repeated in a large enough group of dyspnoeic patients to detect the potentially adverse effects of morphine upon outcome. 1. De Jonghe B, Cook D, Griffith L, Appere-de-Vecchi C, Guyatt G, Theron V, Vagnerre A, Outin H. Adaptation to the Intensive Care Environment (ATICE): development and validation of a new sedation assessment instrument. Crit Care Med. 2003 Sep;31(9):2344-54. 2. Watt I, Ledingham IM. Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia. 1984 Oct;39(10):973-81. 3. Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ, Waldmann CS, Verghese C. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ. 1992 Sep 12;305(6854):613-6. 4. Terao Y, Miura K, Saito M, Sekino M, Fukusaki M, Sumikawa K. Quantitative analysis of the relationship between sedation and resting energy expenditure in postoperative patients. Crit Care Med. 2003 Mar;31(3):830-3. 5. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998 Aug;114(2):541-8. 6. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology. 1987 Jun;66(6):729-36. 7. Amy P Abernethy, David C Currow, Peter Frith, Belinda S Fazekas, Annie McHugh, and Chuong Bui Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea BMJ 2003; 327: 523-528 Competing interests: None declared |
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PRADEEP KV KRISHNAMURTHY, SHO medicine MANOR HOSPITAL, WALSALL, WS2 9XS
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Firstly, we all know how morphine helps breathlessness in heart failure especially in the acute states, but, I would like to know how morphine works in relieving the sensation of breathlessness in these patients, by which i mean the pathophysiology involved in its mechanism of action.If it works by reducing anxiety and panic, would there be any role for benzodiazepines/buspirone, or if the mechanism is different, is there any point in using fentanyl patch, all of which are much safer than morphine especially in the community? Secondly, were the patients in the study (n=38) given morphine only for the study period or have they preferred continuing morphine, considering the results of your study? If the latter is true how many of them are still on it and what is their present state? Thirdly, if the Therapeutic Guidelines Group in Palliative Care, Australia, advice the use of opioids in these patients, is that what is commonly practiced in Australian hospitals? Because if the evidence is not totally convincing, which is a fact in this case, we may be in dangerous grounds recommending it.The only way to get such evidence is to obtain scientific results like blood gases rather than base our decisions on visual analogue scales. Answering the above questions would be much appreciated as it may give us a chance to reconsider our opinions. Competing interests: None declared |
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