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Assessment of analgesic drugs
Pharmac.Ther.Vol. 12. pp. 589-598
0163-7258 810401-0589$05.00 0
© Pergamon Press Lid 1981. Printed in Great Britain
Specialist Subject Editors: N. E. WILLIAMSand H. WILSON
ASSESSMENT
OF
ANALGESIC
DRUGS
J. W . DUNDEE a n d W . B. LOAN
Department of Anaesthetics, The Queen's University, Belfast, Northern Ireland
1. INTRODUCTION Despite notable recent advances in knowledge, pain remains a poorly understood phenomenon, and the precise mode of action of analgesic drugs is also, in many cases, uncertain. It is not therefore surprising that the evaluation of one unknown in the symptomatic treatment of another cannot be, in any real sense, quantitative. When variables such as severity and duration of the pain to be treated are superimposed, the problem becomes even more complex. To complicate the matter there is a great individual variation in appreciation of pain--or at least in description of its severity, and also the 'significance' of the pain to the sufferer affects his description of it. The basic stages of any study of pain relief (and assessment of analgesics) can, however, be summarized as standardization, control of bias and measurement.
2. STANDARDIZATION It is obvious that all administrations of the drug or drugs to be assessed must be presented with a comparable therapeutic challenge. It is probable that a very large number of variables may influence this factor. Some have been identified although rarely with complete confidence. 2.1.
POPULATION STUDIED
The investigator may select subjects conforming to specific criteria, thus producing a theoretically uniform population, each subject receiving one treatment ('between patient' study). Alternatively, he may employ the cross-over technique, in which each individual receives all treatments ('within patient' study). From the aspect of standardization the within patient approach has obvious attractions, but these may not be as real as they appear. Drug interactions (Macris et al., 1958), 'learning' effects (Lasagna and Meier, 1958) and variability of the base-line even within one patient (Swerdlow et al., 1963) have all been cited as disadvantages. It is probable that the ~ross over design has most to offer where long-standing clinical pain or experimentally induced stimuli are to be employed. In selecting subjects for 'between patient' studies, a number of factors have been found to be significant. Personality (Petrie, 1960), previous experience and up-bringing (Simpson and Parkhouse, 1961), continual psychological stress (Malmo, 1954; Swerdlow et al., 1963), cultural factors (Zborowski, 1952) and age, sex and race (Woodrow et al., 1972) have been identified among many others. Unfortunately the situation is complicated by the fact that Keats et al. (1950), and the present authors (Loan and Dundee, 1967a, b) were unable to relate the severity of postoperative pain to age, sex, operation, anesthesia or preanesthetic medication. Despite these uncertainties it is obviously wise to control these variables as far as is possible. 589
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J.W. DUNDEEand W. B. LOAN 2.2. THE OBSERVER
The observer may influence the results of a trial in two ways. Firstly, in as far as he forms a part of the patient's environment he may actually alter the outcome of treatment (Roe, 1963), or he may misinterpret or misrecord what occurs (Witts, 1959). Ideally the observer should have some 'training' before embarking on a large study of analgesics, and since it must be ensured that criteria do not change during the study, these should be carefully noted at the beginning (Dundee, 1969b). 2.3. THE ENVIRONMENT The influence of intense preoccupation with urgent matters, as in athletic contests or battle, is well known and often quoted. One of the authors has personal knowledge of a rugby footballer who did not complain of significant pain until some hours after his duodenum had been ruptured by a blow in the epigastrium. Distraction (Hardy et al., 1952) and the attitude of attendants (Keats, 1965; Roe, 1963; Egbert et al., 1964) have also been found to alter either pain threshold or response to analgesic drugs. Relatives and others can also influence the findings (Dundee, 1980) particularly in long-term studies. To minimize the possible influence of environment, attendants and observers, it is desirable that all these should be as constant as is possible throughout the study. It is probable that the number of observers, in particular, should be reduced to a minimum, and ideally to a single person. 2.4. NATURE OF PAINFUL STIMULI This is of great importance although many of the precise details are at present unknown. To quote an extreme case, Dundee (1960a) found sodium thiopentone to be antanalgesic where challenged by the tibial pressure stimulus, while Robson et al. (1965) classified the same agent as analgesic in action using the hot loop technique. Obviously there is a difference in response of drugs to 'deep' as compared with superficial pain (Keats, 1965). Similarly upper abdominal operations have usually been found to cause more subsequent pain than lower abdominal procedures (Parkhouse et al., 1961; Swerdlow et al., 1964; Loan and Morrison, 1967). Such cases have been used in a number of studies involving potent analgesics, usually given by intravenous injection (Gupta and Dundee, 1974; Dundee, 1969a). Patients having body surface operations form a discrete group with a lower severity of pain and incidence of postoperative vomiting which makes these suitable for assessment of the mild group of analgesics (Grainger et al., 1977). Chronic pain such as that associated with malignant disease (Houde and Wallenstein, 1953), or arthritis (Lee, 1978) may also be used but pain severity varies considerably with time, and standardization is correspondingly difficult (Dundee, 1960a). 2.5. METHOD OF DRUG ADMINISTRATION
That the route of administration should be standardized is self evident, but other variables may, at times, be significant and difficult to control. The influence of gastric pH on effective blood levels of morphinomimetic drugs after oral administration, or of local vasoconstrictor tone on the intramuscular route (Kety, 1949), have been demonstrated. It is possible, in fact, that the most meaningful assessment of analgesic efficacy could be related to blood level rather than dose administered. Where feasible, particularly in initial studies, drugs should be given intravenously. A relatively recent innovation is the use of the sublingual route (Robbie, 1979). The time factor is also important. Assessment must be so timed as to distinguish between drugs of differing pharmacokinetic profile, slow onset and prolonged action as opposed to rapid, transient action.
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2.6. STANDARDDRUG The inclusion of a standard drug whose properties are well known, helps not only to establish the sensitivity of the methodology used, but also permits continuous comparison of results from different trials. It is usually sufficient to give the standard drug at one dose level, whereas a dose response curve is essential for any new preparation which should be given in a minimum of three doses. It may prove necessary to alter the design of the trial, particularly in long term studigs, where the new drug is of agonist-antagonist type (Houde, 1979). Clearly these cannot be compared in cross-over studies with the usual standard drugs.
3. CONTROL OF BIAS Bias has been defined by Wilson (1962) as effects arising from sources other than the pharmacological actions of the drugs under trial and Modell (1963) has classified these errors, with their standard controls, as follows: (i) Experimenter and subject bias, controlled by double-blind administration. (ii) Psychic, symbolic and cultural implications of medication, controlled by administration of a dummy treatment. (iii) Extraneous factors, controlled by randomization.
3.1. DOUBLE-BLIND ADMINISTRATION
Double-blind administration implies that neither investigator nor patient knows the nature of the drug administered. This has been a widely accepted feature of drug trials for many years, but it is important to remember that it does not, in itself, ensure the accuracy of the trial. It is, in addition, rare to find an inert preparation which completely parallels the actions of the test drug in all respects except that under investigation; thus the investigator may be encouraged to guess and thus bias the outcome of the trial. Quite complex routines may be required for the administration of physically dissimilar drugs (Dundee, 1974). 3.2. ADMINISTRATION OF A DUMMY TREATMENT
The term 'dummy treatment' is more appropriate than 'placebo' as the objective in giving the drug is not to 'please the patient'. The practice of including such preparations is fundamentally repugnant to most people but is, nevertheless, of great importance in analgesic studies. Pharmacological actions are attributed to inert preparations for two basic reasons; either the patient has reacted to the administration of the 'drug' rather than to the active (or inactive) substances which it contains, or the method of investigation is insensitive. If a study can distinguish between a known analgesic and the dummy treatment, but not between the latter and the drug under trial, then the clinical usefulness of the unknown preparation is very doubtful. The ethical problems surrounding the use of dummy treatment can be reduced by careful explanation to patient, relatives and especially nursing staff, and by inclusion of a 'failure of therapy' clause in the protocol, the key being broken if pain is not relieved within a specified time. 3.3. RANDOMIZATION
The influence of factors which cannot be eliminated may be, to some extent, nullified by randomization. Truly random numbers must, however, be used and the allocation performed by a person other than those involved with administration or assessment.
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J.W. DUNDEEand W. B. LOAN 4. MEASUREMENT
Pain is probably unique among sensory perceptions in the degree to which it fulfils a warning role. While a sight, smell, sound or touch may produce fear or distress, these are usually acquired associations, specific to the individual concerned. Pain, on the other hand, evokes almost universally unwelcome reactions, and it is perhaps inevitable that the human mind should incorporate this menacing stimulus into a complex in which reception, interpretation and response are inseparably combined. The so-called reaction component can be regarded as the psychological modification of the initial stimulus produced by a composite of those personal characteristics mentioned above and, perhaps of even greater importance, the significance which the pain has for the subject. The reaction component also underlies many of the uncertainties concerning pain measurement. It touches upon controversial issues such as the degree to which pain should be considered physical perception or psychological experience, or the validity of employing artificially induced pain in analgesic assessment (Fig. 1). The subject has been discussed widely and is beyond the scope of the present article, but the place of clinical as opposed to experimental pain is of immediate importance. Pain measurement has usually been employed in the evaluation of drug action, so that the term has become almost synonymous with analgesic assessment. This would, however, only be correct if all analgesic drugs had the same mechanism of action and it has become quite clear that this is not the case. The most obvious example of this discrepancy is the largely peripheral action of the antipyretic analgesics as compared with the more centrally acting morphinomimetic agents. There is also some evidence, mentioned above, that the pain produced by different stimuli may be modified in dramatically opposed ways by the same drug. Of more subtle significance, however, is the interaction between the pain phenomenon and the action of the morphine-type analgesics. These agents probably produce at least some of their analgesic effect by modifying the reaction component. It can be argued that experimentally induced pain cannot have a true significance for the subject and that one aspect of drug activity is therefore untested. Despite efforts to create an artificial reaction component by employing very severe pain (Beecher, 1966) or an improved technique (Lahoda et al., 1977), or by using stimuli which mimic previously experienced clinical pain (Theobald et al., 1966; Gaensler, 1951) or by equating induced pain with existing clinical pain (Kast, 1962; Sternbach et al., 1974), the question remains unresolved. Alternatively, an attempt may be made to separate sensory and cognitive components by signal detection theory (Chapman and Butler, 1978) although the validity of this approach in pain measurement is uncertain (Rollman, 1977). In the present state of knowledge it is probably wise to employ stimuli as similar as possible to those against which the test drug will be used in clinical practice. Experimentally induced stimuli have, however, the attraction, in theory at least, of introducing one quantitative aspect into an otherwise distressingly subjective investigation. They probably have a part in the early assessment of analgesics, but on the limitations of the findings and the difficulty in quantitating them with a difficult situation must be appreciated. A very wide range of physical insults has been used as stimuli, including radiant heat (Woolf et al., 1940), contact heat (Lee and Pfeiffer, 1949), contact ultrasound (Yanaura et al., 1977), electric current to tooth filling (Goetzl et al., 1943), chemical stimulation of a blister base (Armstrong et al., 1951), muscle ischaemia (Lewis et al., 1929)
EXPE]R HENTAL STIMULusPAIN ~
CENTRAL APPRECIATION~ PATIENTS' SENSATION OF PAIN
PATHOLOGICAL PAIN
REACTION TOJ " v STINULUS
FIG. 1. Diagrammatic expression of the differencebetweenartificial and natural pain stimulus.
Assessment of analgesic drugs
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FIG. 2. Three types of analogues of pain scores. and skin pressure (von Frey, 1897; Dundee, 1960b). None of these are very recent references, and it can be seen that there was much controversy about this topic. Where, however, the decision is made to use naturally occurring pain, such as that following surgery, or myocardial infarction, or association with malignant disease, while it can be argued that the findings will be of greater validity, although the design of the trial and the actual process of measurement are more difficult. Other attempts to increase the objective, if not necessarily quantitative aspects of clinical pain measurement have included the use of trained observers and visual analogues. The trained observer may record his impressions (Parkhouse and Holmes, 1963) or evaluate selected criteria such as bodily movement or facial expression (as in Table 1) (Steinhaus et al., 1964; Dundee, 1980). This approach can be regarded as a useful supplement to the patient's own assessment. The visual analogue has been used quite widely in an attempt to bridge the communication gap between subject and investigator. The pain scale usually ranges from 'no pain' to 'as bad as it can be' (Fig. 2) and may be more accurate than conventional pain scales (Berry and Huskisson, 1972; Revill et al., 1976). Theoretically, the method may be further improved if descriptive terms are placed at intervals along the analogue scale (Scott and Huskisson, 1976), but this really converts it into a pain score approach and most patients will put the mark at one of the marked grades. Figure 2 shows the single line and two modifications, but none of the latter offer any real advantage over the original. Analogues can also be used, perhaps less successfully, in grading pain relief. The patient places a mark on a line ranging nil to complete. The various modifications shown in Fig. 2 can also be adopted here. The remaining methods will rely, in one form or another, on the testimony of the patient. This is a difficult area of pain methodology and involves essentially three stages: (i) The conversion from abstract to parametric. (ii) Comparison of estimates thus derived before and after treatment. (iii) Communication of estimates from patient to observer. G a d d u m (1954) has defined three basic methods for the comparison of different drugs under such circumstances. (a) Direct assay. Incremental doses are administered until a predetermined end point is reached (Paxson, 1932; G o r d o n and Moran, 1965; Gawley et al., 1976). More recently the principle has been expanded further in the self-administration of analgesics by patients (Evans et al., 1976). The principal difficulties would appear to be selection of suitable end points and when to make the decision to accept failure. When drugs have a slight latent period to peak TABLE1. Grading Scheme for Pain Severity Patient estimate
Pain score or grade
Very severe Severe Moderate Slight None
5 4 3 2 1
E D C B A
Observer estimate Patientwrithing, sweating and/or distressed Patientwith strained facial expression Patientstill and avoiding movement Patientdozing off and on, not completelyat ease No discomfort, patient completelyat ease, moving
594
J . W . DUNDEE and W. B. LOAN
action, as in the case of analgesics, this may be difficult as either a too rapid or too slow an injection will underestimate potency. (b) Measurement of responses (or use of graded scales). These were popularized by Keele 0948) and called 'pain scores'. A typical example involving observer as well as patient estimate is given in Table 1. They have been widely used in various forms, including the substitution of numbers for grades. This is legitimate if limited to comparison of mean scores, especially where large differences are included, but standard deviation (or SE) should not be used for the conventional Student 't' test. Preferably, scores can be grouped and analysed by the X 2 method ridit analysis (Bross, 1958) or other form of parametric analysis. Grouping does, however, require large numbers of patients and some pooling of groups may be required for statistical analysis. Pain severity has also been expressed as a percentage, 100% being very severe, or as pain relief graded on a scale from little or none to complete. Graded scales can also be used to quantitate pain relief; these use varying grades ranging from nil to complete. This is less satisfactory than quantitating pain, as the subject may not remember the initial pain severity. An interesting development of the pain scale concept is its expansion into a multidimensional form (Melzack and Torgensen, 1971; Reading et al., 1979). Words are selected which have near universal significance within the proposed study population, and the individual then employs them to describe pain simultaneously in respect of sensory, affective, temporal, spatial evaluations or other components. (c) Quantal methods. These procedures differ from that described above in that the proportion of patients relieved is regarded as the index of analgesic efficacy rather than the mean improvement of each patient. Great advances in the knowledge of the physiology of pain have been made in recent years but their significance in its measurement have not yet been fully assessed. It is possible that current measurement techniques may have to be modified due to recent or future discoveries, or indeed that the converse may apply as certain inconsistencies in the results of pain studies have acted as a stimulus to more basic research.
5. OTHER METHODS OF ASSESSMENT These include tests which reflect but do not measure analgesic activity. These are mostly used in postoperative patients where deep respiration is inhibited by wound pain, and it is suggested that good analgesia will enable the patient to breathe deeply. Arterial blood gas estimations (oxygen and carbon dioxide) are of limited value in this field but measurements of tidal volume and FEV1 can be used. The problems of patient cooperation, accuracy of measurement and the sedative effect of analgesia have led to the almost complete abandonment of these tests in the assessment of analgesics. Sometimes the respiratory tests may be combined with the patient's assessment and the opinion of a trained observer in evaluating pain relief. Predetermined criteria for 'analgesia' have to be fulfilled before pain can be said to be relieved and the resulting incidence of 'success' or 'failure' is treated on a quantal basis. More complicated combinations of subjective and objective tests can be used (Hill et al., 1967) but these have little place in the assessment of analgesic drugs. Various respiratory parameters have also been recorded simultaneously with alteration in galvanic skin response and blood pressure, using the polygraph technique usually employed in crime detection (Schklair, 1977). This technique would appear to offer most promise in evaluating precipitated episode pain but some difficulty could be experienced in evaluating the base-line state. Some alterations in blood chemistry have been related to the experience of pain, e.g. a fall in serum lipo-proteins and cholesterol (Keele and Stern, 1973), or a fall in urinary catecholamines when pain is relieved (Huskisson, 1974). The place of these in the assessment of analgesics has not been assessed.
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6. TOXICITY This is an important aspect of the assessment of analgesic drugs--in fact most new drugs are introduced with the hope that they will produce fewer side effects than the standard preparations. While side effects should be looked for during the evaluation of analgesia, the respiratory and cardiovascular side effects of analgesics may not be detected unless specifically precipitated by, e.g., a carbon dioxide challenge or tilting. Thus there are good reasons for studying these effects in volunteers or in different groups of patients. Side effects are generally related to the plasma concentration of a drug, rather than to the dose given, and are thus most likely to occur following intravenous injection. Their severity is usually more marked in ambulant patients and as far as the emetic effects are concerned, women are more prone to sickness than men. Ambulation will also increase the hypotensive effect of analgesics. In contrast, the respiratory depressant effects are more marked in undisturbed recumbent patienis. To complicate matters, patients recovering from upper abdominal operations, who make particularly good subjects for assessment of potent analgesics are particularly unsuitable for respiratory and possibly for cardiovascular studies; 'splinting' of the diaphragm and residual curarization will impair ventilation, while the possibility of hypovolaemia will affect the response of the cardiovascular system. Furthermore, repeated blood sampling or other accompanying manoeuvres will, by distraction, interfere with the assessment of analgesics. Volunteers may be needed for studies of the effects of analgesics on vital functions, unless there is access to patients requiring analgesics who have arterial cannulae in position, such as in an intensive therapy unit. Simple readings of tidal volume and respiratory rate are useful as preliminary studies but they are of limited value in assessing the degree of respiratory depression whereas arterial blood gas estimations and a CO2 response curve will give more useful data. This latter can be either measurement of the response to the inhalation of a fixed concentration of carbon dioxide or response to the patient's own carbon dioxide. Arterial pressure and cardiac output readings and response to postural changes are some of the accepted studies of cardiovascular function. Expert advice should be sought on these topics (Jennett et al., 1968). The apparently simple topic of evaluating the emetic effects of analgesics is nonetheless demanding, because steps must be taken to reduce extraneous factors which influence the incidence of sickness. Again one may have to divorce toxicity and analgesic studies. The legitimate use of analgesics as preanesthetic medication offers facilities for such studies, since the preoperative period is suitable for observing the toxic effects of the drugs, which can be given in a range of doses, while, under certain circumstances the postoperative period is equally useful (Morrison et al., 1971 ; Dundee, 1977). Their premedicant use also affords an opportunity of evaluating the soporific effects of analgesics and the incidence of dizziness (Morrison et al., 1968, 1969). As has already been pointed out in this article, new analgesics must be compared with standard preparations under comparable conditions. This is particularly important in relation to toxicity. The fact that a new analgesic is 100 times more potent (w/w) than morphine does not ensure its merit, if it is also 50-100 times more toxic. Differences will have to be very real to justify introducing new compounds. The incidence of side effects found, under standard test conditions, with both the test drug and the drug under investigation may be much higher than the actual incidence under clinical conditions, but generally speaking the relative frequency with the two compounds will apply under all conditions. Likewise the introduction of new opiate analgesics of the mixed agonist-antagonist variety (such as pentazocine or buprenorphine) because of their lower addictive potential must be treated with caution. Drug dependence is not a problem of real clinical importance with the proper use of analgesics but it must be ensured that these compounds can produce effective analgesia.
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J.W. DUNDEE and W. B. LOAN
7. PRACTICAL ASPECTS There is a need for expert statistical advice in the design of trials of analgesics, not only to ensure comparability of standard and test drug on patients but also to make sure that measurements are made in units which are amenable to statistical analysis. Advice is needed on the number of patients in each series, the number of categories of drug effects, the use of (or need for) placebos, range of dosage etc. The handling of nonparametric pain scores has already been mentioned, together with the limitations of mean scores and variance scores, although these have been used by Parkhouse et al. (1979) in analgesic studies. Small numbers in different categories require pooling and this poses particular problems. For ethical reasons, or unavailability of suitable subjects, one may have to handle these small numbers and extract the maximum amount of useful data from them. There may be a temptation to use the sequential design in comparison of new and standard drugs, particularly at the beginning of a study but this is of very limited value. Not only will the preference be limited to one aspect of drug action, but it is not possible to say whether, for example, one drug is half or quarter as effective as another. In practice we can only conclude that in the patients under study, in the doses used, one drug is superior or inferior to another. If the two doses are approximately equianalgesic then there will be a large number of 'tied pairs" which are lost in the final analysis. If, however, the drugs effects are recorded in detail, then analysis by more orthodox methods can be carried out in very strictly comparable groups of subjects.
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HILL, G. B., LOAN, W. B. and DUNDEE, J. W. (1967) The use of a discriminant function in the assessment of analgesic drugs. Clin. Pharmacol. Ther. 8: 543-547. HOUDE, R. W. (1979) Analgesic effectiveness of the narcotic agonist-antagonists. Br. J. Clin. Pharmacol. 7: 297S--308S. HOUDE, R. W, and WALLENSTEIN,S. L. (1953) A method for evaluating analgesics in patients with chronic pain. Drug Addict. Narcot. Bull. Appendix F: 660-682. HUSKISSON, E. C. (1974) Catecholamine excretion and pain. Br. J. Clin. Pharmacol. 1: 80-82. JENNETT,S., BARKER, J. G. and FORREST, J. B. (1968) A double-blind controlled study of the effects on respiration of pentazocine, phenoperidine and morphine in normal man. Br. J. Anaesth. 40: 864-875, KAST, E. C. (1962) The measurement of pain, a new approach to an old problem. New Drugs 2: 6. KEATS, A. S. (1965) Pain, analgesia and anti-analgesia. Anesthesiology 26: 1-2. KEATS, A. S., BEECHER, H. K. and MOSTELLER, F. C. 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Heart 15: 359. LOAN, W. B. and DUNDEE, J. W. (1967a) The clinical assessment of pain. Practitioner 198: 759-768. LOAN, W. B. and DUNDEE, J. W. (1967b) The value of the study of postoperative pain in the assessment of analgesics. Br. J. Anaesth. 39: 743-750. LOAN, W. B. and MORRISON, J. D. (1967) Incidence and severity of postoperative pain. Br. J. Anaesth. 39: 695~598. MACRIS, S. G., GRAVENSTEIN,J. S., REICHLE, C. W. and BEECHER, H. K. (1958) Drug synergism (potentiation) in pain relief in man; papaverine and morphine. Science 128: 84. MALMO, R. B. (1954) Higher functions of the nervous system. Ann. Rev. Physiol. 16: 371-390. MELZACK, R. and TORGENSEN, W. S. (1971) On the language of pain. Anesthesiology 34: 50. MODELL, W. (1963) Seminar on the clinical evaluation of drugs. The protean control of clinical pharmacology. Clin. Pharrnacol. 4:371 379. MORRISON, J. D., HILL, G. B. and DUNDEE, J. W. (1968) Studies of drugs given before anaesthesia. XV: Evaluation of the method of study after 10,000 observations. Br. J. Anaesth. 40: 890-900. MORRISON, J. D., LOAN, W. B. and DUNDEE, J. W. (1971) Controlled comparison of the efficacy of fourteen preparations in the relief of postoperative pain. Br. Med. J. 3: 287-290. MORRISON, J. D., LOAN, W. B., DUNDEE, J. W., McDOWELL, S. A. and BROWN, S. S. (1969) Studies of drugs given before anaesthesia. XVIII: The synthetic opiates. Br. d. Anaesth. 41: 987-993. PARKHOUSE, J. and HOLIES, C. M. (1963) Assessing postoperative pain relief. Proc. Roy. Soc. Med. 56: 579-585. PARKHOUSE, J., LAMBRECHTS, W. and SIMPSON, B. R. J. (1961) The incidence of postoperative pain. Br. J. Anaesth. 33: 345-353. PARKHOUSE, J., PLEUVRy, B. F. and RUES, H. M. H. (1979) Analgesic Drugs. Blackwell, London. PAXSON, N. F. (1932) Obstetrical anaesthesia with sodium iso-ammyl ethyl barbiturate and nitrous oxide oxygen. Results in obstetrical practice. Curt. Res. Anesth. 11: 116. PETRIE, A. (1960) Some psychological aspects of pain and the relief of suffering. Ann. N.Y. Acad. Sci. 86: 13. READING, A. E., REED, C. and NEWTON, J. R. (1979) A card cost method for pain assessment in gynecology: a multi-dimensional approach. Acta Obstet. Gynaec. Scand. 58: 105-113. REVlLL, S. 1., ROBINSON, J. O., ROSEN, M. and HOGG, M. I. (1976). The reliability of a linear analogue for evaluating pain. Anaesthesia 31:1191. ROBmE, D. S. (1979) A trial of sublingual buprenorphine in cancer pain. Br. J. Clin. Pharmacol. 7: 315S-317S. ROBSON, J. G., DAVENPORT,H. T. and SUGIYAMA,R. (1965) Differentiation of two types of pain by anaesthetics. Anesthesiology 26: 31-36. ROE, B. B. (1963) Are postoperative narcotics necessary? Arch. Surg. 87: 912. ROLLMAN, G. B. (1977) Signal detection theory measurement of pain: a review and critique. Pain 3: 187. SCHKLAIR,E. (1977) Use of polygraph techniques in the measurement of patient anxiety, pain and sensitivity during the use of two prophylaxis instruments. Periodont. Oral Hygiene 12: 1. SCOTT, J. and HUSKISSON, E. C. (1976) Graphic representation of pain. Pain 2: 175. SIMPSON, B. R. J. and PARKHOUSE, J. (1961) The problem of postoperative pain. Br. J. Anaesth. 33: 336--344. STEINHAUS,J. E., BEVAN, W., WEBB,S. and THOMPSON, W. R. (1964) Evaluation of analgesics by the rating of patient behaviour. Anesthesiology 25: 64. STERNBACH,R. A., ~URPHY, R. W. and TIMMERMANS,G. (1974) The severity of clinical pain. In: Advances in Neurology, vol. 4, p. 281, BONICA, J. I. (ed.). Raven Press, New York. SWERDLOW, M., MURRAY, A. and DAW, R. H. (1963) A study of postoperative pain, Acta. Anaesth. Scand. 7: 11-19. SWERDLOW, M., STARMER,G. and DAw, R. H. (1964) A comparison of morphine and phenazocine in postoperative pain. Br. J. Anaesth. 36: 782. THEOBALD, G. W., MENZIES, n . N. and BRYANT, G. H. (1966) Critical electrical stimulus which causes uterine pain. Br. Med. J. !: 716-718.
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VON PREY, M. (1897) Untersuchungen tiber die Linearfunktionen der menschlichen. Haut: Druckempfindungen und Schmerz. Abh. Sacho. Ges. (Akad) Wiss. 23: 169. WILSON, C. W. M. (1962) An analysis of factors contributing to the placebo response. Proc. Roy. Soc. Med. 55: 780. WITTS, L. J. (1959) Some methods and applications of group research in medicine. In: Medical Surveys and Clinical Trials, p. 39. University Press, London. WOLFF, H. G., HARD',', J. D. and GOODELL, H. (1940). Studies on pain, measurement of the effect of morphine, codeine, and other opiates on the pain threshold and an analysis of their relation to the pain experiences. J. Clin. Invest. 19: 659. WOODROW, K. M., FRIEDMAN,G. D.. SIEGELAUB,A. B. and CULLEN, M. F. (1972). Pain tolerance. Differences according to age, sex and race. Psychosom. Med. 34: 548-556. YANAURA,S.. YAMATAKE,Y. and MISAWA,H. (1977) Clinical assessment of analgesics using ultrasound stimulation--a new method. Jap. 3. Pharmacol. 27:501 508. ZaOROWSKL N, (1952) Cultural components in response to pain. J. Social Issues 8: 16.
0163-7258 810401-0589$05.00 0
© Pergamon Press Lid 1981. Printed in Great Britain
Specialist Subject Editors: N. E. WILLIAMSand H. WILSON
ASSESSMENT
OF
ANALGESIC
DRUGS
J. W . DUNDEE a n d W . B. LOAN
Department of Anaesthetics, The Queen's University, Belfast, Northern Ireland
1. INTRODUCTION Despite notable recent advances in knowledge, pain remains a poorly understood phenomenon, and the precise mode of action of analgesic drugs is also, in many cases, uncertain. It is not therefore surprising that the evaluation of one unknown in the symptomatic treatment of another cannot be, in any real sense, quantitative. When variables such as severity and duration of the pain to be treated are superimposed, the problem becomes even more complex. To complicate the matter there is a great individual variation in appreciation of pain--or at least in description of its severity, and also the 'significance' of the pain to the sufferer affects his description of it. The basic stages of any study of pain relief (and assessment of analgesics) can, however, be summarized as standardization, control of bias and measurement.
2. STANDARDIZATION It is obvious that all administrations of the drug or drugs to be assessed must be presented with a comparable therapeutic challenge. It is probable that a very large number of variables may influence this factor. Some have been identified although rarely with complete confidence. 2.1.
POPULATION STUDIED
The investigator may select subjects conforming to specific criteria, thus producing a theoretically uniform population, each subject receiving one treatment ('between patient' study). Alternatively, he may employ the cross-over technique, in which each individual receives all treatments ('within patient' study). From the aspect of standardization the within patient approach has obvious attractions, but these may not be as real as they appear. Drug interactions (Macris et al., 1958), 'learning' effects (Lasagna and Meier, 1958) and variability of the base-line even within one patient (Swerdlow et al., 1963) have all been cited as disadvantages. It is probable that the ~ross over design has most to offer where long-standing clinical pain or experimentally induced stimuli are to be employed. In selecting subjects for 'between patient' studies, a number of factors have been found to be significant. Personality (Petrie, 1960), previous experience and up-bringing (Simpson and Parkhouse, 1961), continual psychological stress (Malmo, 1954; Swerdlow et al., 1963), cultural factors (Zborowski, 1952) and age, sex and race (Woodrow et al., 1972) have been identified among many others. Unfortunately the situation is complicated by the fact that Keats et al. (1950), and the present authors (Loan and Dundee, 1967a, b) were unable to relate the severity of postoperative pain to age, sex, operation, anesthesia or preanesthetic medication. Despite these uncertainties it is obviously wise to control these variables as far as is possible. 589
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J.W. DUNDEEand W. B. LOAN 2.2. THE OBSERVER
The observer may influence the results of a trial in two ways. Firstly, in as far as he forms a part of the patient's environment he may actually alter the outcome of treatment (Roe, 1963), or he may misinterpret or misrecord what occurs (Witts, 1959). Ideally the observer should have some 'training' before embarking on a large study of analgesics, and since it must be ensured that criteria do not change during the study, these should be carefully noted at the beginning (Dundee, 1969b). 2.3. THE ENVIRONMENT The influence of intense preoccupation with urgent matters, as in athletic contests or battle, is well known and often quoted. One of the authors has personal knowledge of a rugby footballer who did not complain of significant pain until some hours after his duodenum had been ruptured by a blow in the epigastrium. Distraction (Hardy et al., 1952) and the attitude of attendants (Keats, 1965; Roe, 1963; Egbert et al., 1964) have also been found to alter either pain threshold or response to analgesic drugs. Relatives and others can also influence the findings (Dundee, 1980) particularly in long-term studies. To minimize the possible influence of environment, attendants and observers, it is desirable that all these should be as constant as is possible throughout the study. It is probable that the number of observers, in particular, should be reduced to a minimum, and ideally to a single person. 2.4. NATURE OF PAINFUL STIMULI This is of great importance although many of the precise details are at present unknown. To quote an extreme case, Dundee (1960a) found sodium thiopentone to be antanalgesic where challenged by the tibial pressure stimulus, while Robson et al. (1965) classified the same agent as analgesic in action using the hot loop technique. Obviously there is a difference in response of drugs to 'deep' as compared with superficial pain (Keats, 1965). Similarly upper abdominal operations have usually been found to cause more subsequent pain than lower abdominal procedures (Parkhouse et al., 1961; Swerdlow et al., 1964; Loan and Morrison, 1967). Such cases have been used in a number of studies involving potent analgesics, usually given by intravenous injection (Gupta and Dundee, 1974; Dundee, 1969a). Patients having body surface operations form a discrete group with a lower severity of pain and incidence of postoperative vomiting which makes these suitable for assessment of the mild group of analgesics (Grainger et al., 1977). Chronic pain such as that associated with malignant disease (Houde and Wallenstein, 1953), or arthritis (Lee, 1978) may also be used but pain severity varies considerably with time, and standardization is correspondingly difficult (Dundee, 1960a). 2.5. METHOD OF DRUG ADMINISTRATION
That the route of administration should be standardized is self evident, but other variables may, at times, be significant and difficult to control. The influence of gastric pH on effective blood levels of morphinomimetic drugs after oral administration, or of local vasoconstrictor tone on the intramuscular route (Kety, 1949), have been demonstrated. It is possible, in fact, that the most meaningful assessment of analgesic efficacy could be related to blood level rather than dose administered. Where feasible, particularly in initial studies, drugs should be given intravenously. A relatively recent innovation is the use of the sublingual route (Robbie, 1979). The time factor is also important. Assessment must be so timed as to distinguish between drugs of differing pharmacokinetic profile, slow onset and prolonged action as opposed to rapid, transient action.
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2.6. STANDARDDRUG The inclusion of a standard drug whose properties are well known, helps not only to establish the sensitivity of the methodology used, but also permits continuous comparison of results from different trials. It is usually sufficient to give the standard drug at one dose level, whereas a dose response curve is essential for any new preparation which should be given in a minimum of three doses. It may prove necessary to alter the design of the trial, particularly in long term studigs, where the new drug is of agonist-antagonist type (Houde, 1979). Clearly these cannot be compared in cross-over studies with the usual standard drugs.
3. CONTROL OF BIAS Bias has been defined by Wilson (1962) as effects arising from sources other than the pharmacological actions of the drugs under trial and Modell (1963) has classified these errors, with their standard controls, as follows: (i) Experimenter and subject bias, controlled by double-blind administration. (ii) Psychic, symbolic and cultural implications of medication, controlled by administration of a dummy treatment. (iii) Extraneous factors, controlled by randomization.
3.1. DOUBLE-BLIND ADMINISTRATION
Double-blind administration implies that neither investigator nor patient knows the nature of the drug administered. This has been a widely accepted feature of drug trials for many years, but it is important to remember that it does not, in itself, ensure the accuracy of the trial. It is, in addition, rare to find an inert preparation which completely parallels the actions of the test drug in all respects except that under investigation; thus the investigator may be encouraged to guess and thus bias the outcome of the trial. Quite complex routines may be required for the administration of physically dissimilar drugs (Dundee, 1974). 3.2. ADMINISTRATION OF A DUMMY TREATMENT
The term 'dummy treatment' is more appropriate than 'placebo' as the objective in giving the drug is not to 'please the patient'. The practice of including such preparations is fundamentally repugnant to most people but is, nevertheless, of great importance in analgesic studies. Pharmacological actions are attributed to inert preparations for two basic reasons; either the patient has reacted to the administration of the 'drug' rather than to the active (or inactive) substances which it contains, or the method of investigation is insensitive. If a study can distinguish between a known analgesic and the dummy treatment, but not between the latter and the drug under trial, then the clinical usefulness of the unknown preparation is very doubtful. The ethical problems surrounding the use of dummy treatment can be reduced by careful explanation to patient, relatives and especially nursing staff, and by inclusion of a 'failure of therapy' clause in the protocol, the key being broken if pain is not relieved within a specified time. 3.3. RANDOMIZATION
The influence of factors which cannot be eliminated may be, to some extent, nullified by randomization. Truly random numbers must, however, be used and the allocation performed by a person other than those involved with administration or assessment.
592
J.W. DUNDEEand W. B. LOAN 4. MEASUREMENT
Pain is probably unique among sensory perceptions in the degree to which it fulfils a warning role. While a sight, smell, sound or touch may produce fear or distress, these are usually acquired associations, specific to the individual concerned. Pain, on the other hand, evokes almost universally unwelcome reactions, and it is perhaps inevitable that the human mind should incorporate this menacing stimulus into a complex in which reception, interpretation and response are inseparably combined. The so-called reaction component can be regarded as the psychological modification of the initial stimulus produced by a composite of those personal characteristics mentioned above and, perhaps of even greater importance, the significance which the pain has for the subject. The reaction component also underlies many of the uncertainties concerning pain measurement. It touches upon controversial issues such as the degree to which pain should be considered physical perception or psychological experience, or the validity of employing artificially induced pain in analgesic assessment (Fig. 1). The subject has been discussed widely and is beyond the scope of the present article, but the place of clinical as opposed to experimental pain is of immediate importance. Pain measurement has usually been employed in the evaluation of drug action, so that the term has become almost synonymous with analgesic assessment. This would, however, only be correct if all analgesic drugs had the same mechanism of action and it has become quite clear that this is not the case. The most obvious example of this discrepancy is the largely peripheral action of the antipyretic analgesics as compared with the more centrally acting morphinomimetic agents. There is also some evidence, mentioned above, that the pain produced by different stimuli may be modified in dramatically opposed ways by the same drug. Of more subtle significance, however, is the interaction between the pain phenomenon and the action of the morphine-type analgesics. These agents probably produce at least some of their analgesic effect by modifying the reaction component. It can be argued that experimentally induced pain cannot have a true significance for the subject and that one aspect of drug activity is therefore untested. Despite efforts to create an artificial reaction component by employing very severe pain (Beecher, 1966) or an improved technique (Lahoda et al., 1977), or by using stimuli which mimic previously experienced clinical pain (Theobald et al., 1966; Gaensler, 1951) or by equating induced pain with existing clinical pain (Kast, 1962; Sternbach et al., 1974), the question remains unresolved. Alternatively, an attempt may be made to separate sensory and cognitive components by signal detection theory (Chapman and Butler, 1978) although the validity of this approach in pain measurement is uncertain (Rollman, 1977). In the present state of knowledge it is probably wise to employ stimuli as similar as possible to those against which the test drug will be used in clinical practice. Experimentally induced stimuli have, however, the attraction, in theory at least, of introducing one quantitative aspect into an otherwise distressingly subjective investigation. They probably have a part in the early assessment of analgesics, but on the limitations of the findings and the difficulty in quantitating them with a difficult situation must be appreciated. A very wide range of physical insults has been used as stimuli, including radiant heat (Woolf et al., 1940), contact heat (Lee and Pfeiffer, 1949), contact ultrasound (Yanaura et al., 1977), electric current to tooth filling (Goetzl et al., 1943), chemical stimulation of a blister base (Armstrong et al., 1951), muscle ischaemia (Lewis et al., 1929)
EXPE]R HENTAL STIMULusPAIN ~
CENTRAL APPRECIATION~ PATIENTS' SENSATION OF PAIN
PATHOLOGICAL PAIN
REACTION TOJ " v STINULUS
FIG. 1. Diagrammatic expression of the differencebetweenartificial and natural pain stimulus.
Assessment of analgesic drugs
593
NO PAIN F NO
I:~IN
:
I :
:
:
:
:
:
:
:
:
:
:
:
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:
:
:
:
~
:
|
AS
AS
iT
COULD
NO PAIN I
mild
~,,r~
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FIG. 2. Three types of analogues of pain scores. and skin pressure (von Frey, 1897; Dundee, 1960b). None of these are very recent references, and it can be seen that there was much controversy about this topic. Where, however, the decision is made to use naturally occurring pain, such as that following surgery, or myocardial infarction, or association with malignant disease, while it can be argued that the findings will be of greater validity, although the design of the trial and the actual process of measurement are more difficult. Other attempts to increase the objective, if not necessarily quantitative aspects of clinical pain measurement have included the use of trained observers and visual analogues. The trained observer may record his impressions (Parkhouse and Holmes, 1963) or evaluate selected criteria such as bodily movement or facial expression (as in Table 1) (Steinhaus et al., 1964; Dundee, 1980). This approach can be regarded as a useful supplement to the patient's own assessment. The visual analogue has been used quite widely in an attempt to bridge the communication gap between subject and investigator. The pain scale usually ranges from 'no pain' to 'as bad as it can be' (Fig. 2) and may be more accurate than conventional pain scales (Berry and Huskisson, 1972; Revill et al., 1976). Theoretically, the method may be further improved if descriptive terms are placed at intervals along the analogue scale (Scott and Huskisson, 1976), but this really converts it into a pain score approach and most patients will put the mark at one of the marked grades. Figure 2 shows the single line and two modifications, but none of the latter offer any real advantage over the original. Analogues can also be used, perhaps less successfully, in grading pain relief. The patient places a mark on a line ranging nil to complete. The various modifications shown in Fig. 2 can also be adopted here. The remaining methods will rely, in one form or another, on the testimony of the patient. This is a difficult area of pain methodology and involves essentially three stages: (i) The conversion from abstract to parametric. (ii) Comparison of estimates thus derived before and after treatment. (iii) Communication of estimates from patient to observer. G a d d u m (1954) has defined three basic methods for the comparison of different drugs under such circumstances. (a) Direct assay. Incremental doses are administered until a predetermined end point is reached (Paxson, 1932; G o r d o n and Moran, 1965; Gawley et al., 1976). More recently the principle has been expanded further in the self-administration of analgesics by patients (Evans et al., 1976). The principal difficulties would appear to be selection of suitable end points and when to make the decision to accept failure. When drugs have a slight latent period to peak TABLE1. Grading Scheme for Pain Severity Patient estimate
Pain score or grade
Very severe Severe Moderate Slight None
5 4 3 2 1
E D C B A
Observer estimate Patientwrithing, sweating and/or distressed Patientwith strained facial expression Patientstill and avoiding movement Patientdozing off and on, not completelyat ease No discomfort, patient completelyat ease, moving
594
J . W . DUNDEE and W. B. LOAN
action, as in the case of analgesics, this may be difficult as either a too rapid or too slow an injection will underestimate potency. (b) Measurement of responses (or use of graded scales). These were popularized by Keele 0948) and called 'pain scores'. A typical example involving observer as well as patient estimate is given in Table 1. They have been widely used in various forms, including the substitution of numbers for grades. This is legitimate if limited to comparison of mean scores, especially where large differences are included, but standard deviation (or SE) should not be used for the conventional Student 't' test. Preferably, scores can be grouped and analysed by the X 2 method ridit analysis (Bross, 1958) or other form of parametric analysis. Grouping does, however, require large numbers of patients and some pooling of groups may be required for statistical analysis. Pain severity has also been expressed as a percentage, 100% being very severe, or as pain relief graded on a scale from little or none to complete. Graded scales can also be used to quantitate pain relief; these use varying grades ranging from nil to complete. This is less satisfactory than quantitating pain, as the subject may not remember the initial pain severity. An interesting development of the pain scale concept is its expansion into a multidimensional form (Melzack and Torgensen, 1971; Reading et al., 1979). Words are selected which have near universal significance within the proposed study population, and the individual then employs them to describe pain simultaneously in respect of sensory, affective, temporal, spatial evaluations or other components. (c) Quantal methods. These procedures differ from that described above in that the proportion of patients relieved is regarded as the index of analgesic efficacy rather than the mean improvement of each patient. Great advances in the knowledge of the physiology of pain have been made in recent years but their significance in its measurement have not yet been fully assessed. It is possible that current measurement techniques may have to be modified due to recent or future discoveries, or indeed that the converse may apply as certain inconsistencies in the results of pain studies have acted as a stimulus to more basic research.
5. OTHER METHODS OF ASSESSMENT These include tests which reflect but do not measure analgesic activity. These are mostly used in postoperative patients where deep respiration is inhibited by wound pain, and it is suggested that good analgesia will enable the patient to breathe deeply. Arterial blood gas estimations (oxygen and carbon dioxide) are of limited value in this field but measurements of tidal volume and FEV1 can be used. The problems of patient cooperation, accuracy of measurement and the sedative effect of analgesia have led to the almost complete abandonment of these tests in the assessment of analgesics. Sometimes the respiratory tests may be combined with the patient's assessment and the opinion of a trained observer in evaluating pain relief. Predetermined criteria for 'analgesia' have to be fulfilled before pain can be said to be relieved and the resulting incidence of 'success' or 'failure' is treated on a quantal basis. More complicated combinations of subjective and objective tests can be used (Hill et al., 1967) but these have little place in the assessment of analgesic drugs. Various respiratory parameters have also been recorded simultaneously with alteration in galvanic skin response and blood pressure, using the polygraph technique usually employed in crime detection (Schklair, 1977). This technique would appear to offer most promise in evaluating precipitated episode pain but some difficulty could be experienced in evaluating the base-line state. Some alterations in blood chemistry have been related to the experience of pain, e.g. a fall in serum lipo-proteins and cholesterol (Keele and Stern, 1973), or a fall in urinary catecholamines when pain is relieved (Huskisson, 1974). The place of these in the assessment of analgesics has not been assessed.
Assessment of analgesicdrugs
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6. TOXICITY This is an important aspect of the assessment of analgesic drugs--in fact most new drugs are introduced with the hope that they will produce fewer side effects than the standard preparations. While side effects should be looked for during the evaluation of analgesia, the respiratory and cardiovascular side effects of analgesics may not be detected unless specifically precipitated by, e.g., a carbon dioxide challenge or tilting. Thus there are good reasons for studying these effects in volunteers or in different groups of patients. Side effects are generally related to the plasma concentration of a drug, rather than to the dose given, and are thus most likely to occur following intravenous injection. Their severity is usually more marked in ambulant patients and as far as the emetic effects are concerned, women are more prone to sickness than men. Ambulation will also increase the hypotensive effect of analgesics. In contrast, the respiratory depressant effects are more marked in undisturbed recumbent patienis. To complicate matters, patients recovering from upper abdominal operations, who make particularly good subjects for assessment of potent analgesics are particularly unsuitable for respiratory and possibly for cardiovascular studies; 'splinting' of the diaphragm and residual curarization will impair ventilation, while the possibility of hypovolaemia will affect the response of the cardiovascular system. Furthermore, repeated blood sampling or other accompanying manoeuvres will, by distraction, interfere with the assessment of analgesics. Volunteers may be needed for studies of the effects of analgesics on vital functions, unless there is access to patients requiring analgesics who have arterial cannulae in position, such as in an intensive therapy unit. Simple readings of tidal volume and respiratory rate are useful as preliminary studies but they are of limited value in assessing the degree of respiratory depression whereas arterial blood gas estimations and a CO2 response curve will give more useful data. This latter can be either measurement of the response to the inhalation of a fixed concentration of carbon dioxide or response to the patient's own carbon dioxide. Arterial pressure and cardiac output readings and response to postural changes are some of the accepted studies of cardiovascular function. Expert advice should be sought on these topics (Jennett et al., 1968). The apparently simple topic of evaluating the emetic effects of analgesics is nonetheless demanding, because steps must be taken to reduce extraneous factors which influence the incidence of sickness. Again one may have to divorce toxicity and analgesic studies. The legitimate use of analgesics as preanesthetic medication offers facilities for such studies, since the preoperative period is suitable for observing the toxic effects of the drugs, which can be given in a range of doses, while, under certain circumstances the postoperative period is equally useful (Morrison et al., 1971 ; Dundee, 1977). Their premedicant use also affords an opportunity of evaluating the soporific effects of analgesics and the incidence of dizziness (Morrison et al., 1968, 1969). As has already been pointed out in this article, new analgesics must be compared with standard preparations under comparable conditions. This is particularly important in relation to toxicity. The fact that a new analgesic is 100 times more potent (w/w) than morphine does not ensure its merit, if it is also 50-100 times more toxic. Differences will have to be very real to justify introducing new compounds. The incidence of side effects found, under standard test conditions, with both the test drug and the drug under investigation may be much higher than the actual incidence under clinical conditions, but generally speaking the relative frequency with the two compounds will apply under all conditions. Likewise the introduction of new opiate analgesics of the mixed agonist-antagonist variety (such as pentazocine or buprenorphine) because of their lower addictive potential must be treated with caution. Drug dependence is not a problem of real clinical importance with the proper use of analgesics but it must be ensured that these compounds can produce effective analgesia.
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7. PRACTICAL ASPECTS There is a need for expert statistical advice in the design of trials of analgesics, not only to ensure comparability of standard and test drug on patients but also to make sure that measurements are made in units which are amenable to statistical analysis. Advice is needed on the number of patients in each series, the number of categories of drug effects, the use of (or need for) placebos, range of dosage etc. The handling of nonparametric pain scores has already been mentioned, together with the limitations of mean scores and variance scores, although these have been used by Parkhouse et al. (1979) in analgesic studies. Small numbers in different categories require pooling and this poses particular problems. For ethical reasons, or unavailability of suitable subjects, one may have to handle these small numbers and extract the maximum amount of useful data from them. There may be a temptation to use the sequential design in comparison of new and standard drugs, particularly at the beginning of a study but this is of very limited value. Not only will the preference be limited to one aspect of drug action, but it is not possible to say whether, for example, one drug is half or quarter as effective as another. In practice we can only conclude that in the patients under study, in the doses used, one drug is superior or inferior to another. If the two doses are approximately equianalgesic then there will be a large number of 'tied pairs" which are lost in the final analysis. If, however, the drugs effects are recorded in detail, then analysis by more orthodox methods can be carried out in very strictly comparable groups of subjects.
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