Postgrad Med J: first published as 10.1136/pgmj.40.460.103 on 1 February 1964. Downloaded from

POSTGRAD. MED. J. (I964), 40, 103 Clinical Trial

DOUBLE BLIND TRIAL OF DEXTROMORAMIDE, AND IN THE TREATMENT OF SEVERE PAIN *S. G. FLAVELL MATTS, M.B., Ch.B., M.R.C.P.(Ed.) C. H. J. SWAN, M.B., Ch.B. The Royal Hospital, Wolverhampton B. A. WHARTON, M.B., Ch.B., D.C.H., The Middlesex Hospital, London, W. i

SEVERE pain is a recurrent problem in the treatment TABLE i-Dextromoramide IO mg. and its relief is an of many diseases, important part Length of the management of the illness. Many of are in existence but few are really effective in effects therapy. Most people are still agreed that the drugs Diagnosis (hours) Side-effects of the group are probably the most effective for pain relief. Unfortunately, the use of these Raynaud's disease 3 Nil

-drugs is marred by the occurrence of unpleasant Diabetic gangrene 3 Nil by copyright. and sometimes dangerous side-effects, particularly Pleurisy 4 Nil respiratory depression, nausea, vomiting and addic- Carcinomatosis 3 Nil Subarachnoid hoemorrhage 4 Nil tion. It is extremely difficult to design a good clinical Pleurisy 6 Dizziness trial to discriminate between drugs used in the relief Coronary thrombosis 6 Nausea of pain. Uncontrolled trials are of no value because Scleroderma 5 Nil they depend too much on the subjective impressions Subarachnoid hemorrhage 12 Nil of the patient and observers. Controlled trials are Carcinomatosis No Nausea difficult to organise because of their time-consuming effects nature, difficulties with the D.D.A. regulations and Severe rheumatoid arthritis 5 Nil the problems of assessing degrees and duration of Diabetic gangrene 4 Nil Angina 4 Nil pain relief. Many of these difficulties have been Cervical spondylosis 6 Nil stressed in excellent reviews of the subject by Coronary thrombosis 6 Nil http://pmj.bmj.com/ Swerdlow and Murray (I962), and Swerdlow, Pleurisy 4 Nil Murray and Daw (I963). In view of the importance Subarachnoid hoemorrhage 3 Nil of obtaining accurate information on this subject, Cerebral tumour .. .. 3 Dizziness we felt that an investigation employing a double Severe migraine .. 4 Nil blind technique would be the best method of Cerebral hemorrhage .. 6 Nil oavoiding false clinical bias and erroneous impres- Subarachnoid hxemorrhage 12 Nil Gangrene .. .. 4 Nil sions. It was felt that a comparison of three Carcinomatosis . . .. commonly used oral analgesics would determine, Nil Coronary thrombosis .. 2 Faintness and on October 1, 2021 by guest. Protected by this method, any difference between them. dizziness Pethidine is very widely used and was therefore one Pleurisy .. 4 Nil of the drugs chosen. Methadone, which is another Lumbar spondylosis .. 4 Nil well-established and widely-used , was the Carcinomatosis .. 3 Nil second drug included in the trial. For the third Gangrene ...... 2 Nil drug we chose the relatively new analgesic dextro- Pleurisy .. .. I Nil moramide (Palfium), which originated in Belgium Subarachnoid haemorrhage 8 Nil and had been described by Janssen and Jageneau Summary (1957, 1958). The use of dextromoramide has been 30 patients; 29 obtained relief of from I to 12 hours, described in this country by Cope and Jones (I959), 5 patients developed side-effects-no respiratory Gavin (I960), Kagan (I96I) and Matts (I962); and depression. it has been found to be an effective and safe anal- gesic in clinical practice. Method *In receipt of a Research Grant from the Birmingham Three lots of tablets were prepared externally com- JRegional Hospital Board. pletely identical. Each tablet contained either 5 mg. of Postgrad Med J: first published as 10.1136/pgmj.40.460.103 on 1 February 1964. Downloaded from 104 POSTGRADUATE MEDICAL JOURNAL

TABLE 2-Methadone IO mg. TABLE 3-Pethidine IOO mg. Length Length of of effects effects Diagnosis (hours) Side-effects Diagnosis (hours) Side-effects Pleurisy ...... I Nil Coronary thrombosis 3 Nil Severe angina .. 3 Nil Pleurisy I Dizziness Cerebral,tumour .. 4 Sweating and Angina 4 Dizziness drop in B.P. Diabetic gangrene 6 Sweating Diabetic gangrene .. I Vomiting Pleurisy 3 Respiratory Severe rheumatoid arthritis 8 Nil depression Subarachnoid heemorrhage 4 Nil Sciatica ...... No Nil Coronary thrombosis .. 3 Dizziness effects Pleurisv ...... 6 Dizziness Carcinomatosis .. .. 2 Nil Carcinomatosis .. .. 8 Respiratory Paget's disease .. .. 8 Nil depression Angina ...... 3 Vomiting Diabetic gangrene . . Nil Coronary thrombosis .. 5 Nil Carcinomatosis .. .. 3 Respiratory Arteriosclerotic gangrene .. 4 Nil depression Subarachnoid hamorrhage 3 Nil Subarachnoid hemorrhage 3 Nil Severe migraine .. .. No Nil Acute peptic ulcer .. 4 Nil effects Arteriosclerotic gangrene .. No Nil Severe migraine .. .. 3 Nil effects Osteo-arthritis .. .. 6 Respiratory Severe Raynaud's depression phenomena .. .. 2 Sweating Pleurisy ...... 7 Nil Severe migraine .. .. 3 Nil Diabetic gangrene .. 3 Nil Pleurisy ...... 4 Nil Severe rheumatoid arthritis 4 Nil Coronary thrombosis .. 5 Vomiting Acute peptic ulcer .. 5 Sweating Cerebral tumour .. .. 3 Nil Coronary thrombosis .. 9 Nil Coronary thrombosis .. 4 Dizziness Angina ...... No Nil

Severe rheumatoid arthritis 3 Nil effects by copyright. Pleurisy .. .. 4 Nil Subarachnoid hemorrhage No Nil Carcinoma of thyroid .. 5 Nil effects Subarachnoid hemorrhage 4 Nil Carcinomatosis .. .. 8 Collapse with Severe angina .. .. 3 Nil sweating Diabetic gangrene .. 4 Nil Pleurisy . .. .. 4 Nil Sciatica *. . .. 3 Nil Cervical spondylosis .. 5 Nil Osteoporotic vertebral Coronary thrombosis .. 3 Nil collapse ...... 3 Nil Cerebral tumour .. .. Nil Angina ...... Nil Sciatica ...... 4 Nil Carcinomatosis .. .. 4 Nil Carcinomatosis .. .. No Nil effects Summary Axillary abscess .. .. 30 patients; 29 obtained relief of pain from I to 12 3 Nil hours, 9 experienced side-effects, two of which were Summary http://pmj.bmj.com/ respiratory depression. 30 patients; 25 obtained relief of pain from I to 9 hours, 8 developed side-effects, 2 of which were res- piratory depression. dextromoramide, 5 mg. of methadone or 50 mg. of pethidine. The dosage range of dextromoramide is from 5 to io mg., of methadone 5 to io mg., and of either analgesic A, B or C. The results of therapy were pethidine 50 to IOO mg. In order to obtain a standard recorded from the observations of the medical staff, nursing staff and the statements of effect it was decided to give the upper range of dosage the patients them- on October 1, 2021 by guest. Protected and therefore all patients would be treated with either selves as regards their feeling of relief from pain, the IO mg. of dextromoramide, IO mg. of methadone or Ioo duration of this relief and the'occurrence of any side- mg. of pethidine, this dose being contained in two effects. An analysis of the results can be seen in Tables tablets. Thus all the patients were prescribed two I, 2, 3 and 4. tablets of one of these analgesics, which were identified by letters A, B or C. Only the pharmacist knew which Results was which of these and this knowledge was not re- As can be seen from the tables, differences between vealed until after the entire trial was completed. Thus the three groups were not great. A total of go patients neither doctors, nurses nor patients were aware of the in all were included in the trial. In the dextromoramide contents of the tablets at the time of the trial and group (30 patients) 29 patients obtained relief from assessment. The patients were those admitted to a pain and five patients developed side-effects, none of general medical ward and were suffering with a variety these being respiratory depression. In the methadone of conditions which had produced severe pain. They group (30 patients) 29 patients obtained relief of pain, were assessed by the authors and were adjudged as 9 patients experienced side-effects, two of these being being in need of a powerful analgesic because of this respiratory depression. In the pethidine group (30 severe pain. Having thus been included in the trial patients) 25 patients obtained relief of pain and eight they were prescribed, by a method of random selection, patients developed side-effects, two of which were Postgrad Med J: first published as 10.1136/pgmj.40.460.103 on 1 February 1964. Downloaded from February I964 FLAVELL MATTS, SWAN and WHARTON: Double Blind Trial of Dextromoramide Io5

TABLE 4 dextromoramide is particularly valuable and the Average duration of reduction in the number of dangerous side-effects a Drug pain relief (hours) feature which adds greatly to the safety, because the patients will not normally be under continuous "Dextromoramide IO mg. .. 4.4 surveillance, as they would be from the nursing Methadone io mg. .. .. 3.8 staff in a hospital. The fact that there are so many I!ethidine Ioo mg. .. .. 3.6 oral analgesics makes it even more important that one should choose the best available drug for the type of pain experienced by the patient, taking into 'respiratory depression. The best average duration of account the presence of various disease entities relief of pain was dextromoramide with 4.4 hours, which may make other analgesics undesirable for methadone came second with 3.8 hours and pethidine various reasons (i.e. respiratory depression un- last with 3.6 hours. desirable in pneumonia or pleurisy etc.). Discussion Although it is said that 'man made , 4 The use of oral analgesics is considerably larger came from heaven', a patient suffering than those given by injection because of their ease severe side-effects from morphine may well feel of administration. It is therefore important to know that the direction of origin of morphine may have the relative efficacy and dangers of analgesics in been reversed! For this reason alternatives to common use. The trial results appear to confirm morphine should always be considered, and of the clinical impression held by many people that these the three employed in this trial are acceptable, there is little difference between the more powerful with the evidence pointing to a marginal advantage oral analgesics. However, dextromoramide does to dextromoramide, particularly in cardio- show marginal advantages over the other two respiratory or cerebral conditions. agents. The average duration of pain relief was slightly higher, the incidence of side-effects lower Summary and there were no cases in which respiratory de- A double-blind trial of dextromoramide, pethi- pression was a feature. These findings may be of dine and methadone in severe pain was carried out. particular value outside hospital practice where The results are not strikingly different, but marginal patients will take analgesics as and when necessary advantages in favour of dextromoramide do by copyright. for their pain in their own homes. In these circum- emerge, particularly for home use or in cardio- Kstances the increased duration of pain relief with respiratory or cerebral cases. REFERENCES COPE, E., and JONES, P. 0. (I959): Relief of Post-operative Pain, Brit. med. J3., i, 2II. GAVIN, R. (I960): The Alleviation of Intractable Pain, Ibid., ii, 1917. JANSSEN, P. A. J., and JAGENEAU, A. H. (1957): A New Series of Potent Analgesics, J. Pharm. Pharmacol., 9, 38I. (1958): A New Series of Potent Analgesics, Ibid, IO, I4. KAGAN, G. (I96I): Dextromoramide: a New Analgesic, Med. Press, 245, 154. MATTS, S. G. F. (I962): Dextromoramide Analgesia in the Acute General Medical Patient, Practitioner, I88, 524. SWERDLOW, M., and MURRAY, A. (I962): 'Some Difficulties in the Assessment of Post-operative Pain', European

F Congress of Anmesthiology (Vienna), I962. http://pmj.bmj.com/ and DAW, R. H. (I963): A Study of Post-operative Pain, Acta anaesth. scand., 7, I. on October 1, 2021 by guest. Protected