- Email: [email protected]
THE PSYCHOPHYSICS OF CLINICAL PAIN
572 Vice-Marshal Sir Aubrey Rumball, and from the Civilian Consultant in Medicine, Dr. Kenneth Robson. We thank the Director-General Medical Services, Royal Air Force, for permission to publish. REFERENCES
Boijsen, E. (1959) Acta radiol. suppl. 183. Derrick, J. R., Tyson, R. T. (1960) Surgery, 42, 907. de Wardener, H. E. (1961) The Kidney; p. 22. London. Edling, N. P. G., Helander, C. G., Parsson, F., Asheim, A. (1959) Acta radiol. 57, 161. Edsman, G. (1957) ibid. suppl. 155. Graves, F. T. (1954) Brit. J. Surg. 42, 132. Houghton, B. J., Pears, M. A. (1957) Brit. med. J. i, 622. Marshall, A. G (1951) Lancet, ii, 701 (1953) Brit. J. Surg. 165, 38. (1956) J. Path. Bact. 71, 95. Platt, R. (1947) Quart. J. Med. 16, 111. (1948) ibid. 17, 83. Seldinger, S. I. (1953) Acta radiol. 39, 368.
"
"
pain-relief scores were calculated by subtracting the post-drug pain level from the pre-drug level. Thus, if a patient went from severe pain to slight pain, he got a score of 2 for that interview point. For each dose, the pain-relief score was Peak
calculated for the 1/2, 1, 2, 3, and 4 hour interviews after medication. The mean score for all doses was then calculated for each of these interview points, and the highest mean score was called the " peak " pain-relief score for the group. fi In fig. 1 are plotted the mean peak pain-relief scores achieved with morphine in fourteen individual experiments
post-
on
-
-
operative patients. Each
-
from twelve
to
THE PSYCHOPHYSICS OF CLINICAL PAIN
thirty patients (mean eighteen).
LOUIS LASAGNA
The ordinate is
M.D. Columbia MENTAL
THERAPEUTICS, JOHNS HOPKINS UNIVERSITY SCHOOL MEDICINE, BALTIMORE, MARYLAND
OF
DOES the efficacy of an analgesic drug depend upon how much pain the drug must relieve ? I have approached this question by analysing data from a series of experiments conducted during the past 4 years. These data are based on the performance of two standard treatments-morphine and a placebo-and the analyses are made with reference to the severity of the pretreatment pain. To evaluate
analgesic drugs, I have utilised an interviewing technique in which the severity of pain is graded according to the subjective report of patients with postoperative or postpartum discomfort. This subjective-severity rating is based on a scale ranging from no pain to very severe pain, with intermediate degrees of slight, moderate, and severe. Patients are asked to classify their pain in these terms, are given medication, and are then interviewed at stated intervals for a re-evaluation of their pain status (Lasagna et al. 1958). Changes from any one pain level to the next higher or lower pain level have arbitrarily been given equal value,* with positive scores for decrease in pain, and negative scores for increase in pain. Using this method, potent analgesics have, with reasonable consistency, been discriminated from placebo treatments or weak analgesics not only by me but by other investigators using similar techniques (Lasagna et al. 1958, Lasagna and De Kornfeld 1958, Houde et al. 1960). Analysis
For each experiment, mean pain-relief scores were computed. In patients with postoperative pain morphine (10 mg.), which is the standard medication, was alternated with the new agent under study, both being given subcutaneously under double-blind conditions-i.e., where neither patient nor interviewer is aware of the nature of a given medication. Each dose has been treated separately in the analysis, because the preinjection level of pain may vary considerably in a given patient from one dose to another, and past experience has revealed no important difference between the use of such scores and the use either of first doses only or of scores where each patient contributes a single score regardless of the number of doses received (Lasagna and De Kornfeld 1958). (In the studies of postpartum pain, to be discussed later, only one dose of medication is administered per patient.) -
At first, this was done because of ease of computation. The method was continued because attempts at discriminant-function analysis, and at psychophysical scaling (Lasagna 1960), failed to provide adequate justification for any weighting of decrements in pain for different initial levels of pain severity.
score,
the abscissa is the
premorphine pain severity of the patients (as a group) in the respective mean
experiments, on the basis of 1= slight pain, 2 moderate, 3
Fig. 1-Postoperative pain: morphine.
The good fit of the line, drawn according to the method of least squares (Wallis and Roberts 1956), is evident. The line has a slope of 0-68, with a standard severe, and 4 very severe.
error
Methods
*
=
pain-relief
ASSOCIATE PROFESSOR OF MEDICINE AND PHARMACOLOGY AND EXPERI-
-
point
represents data
of the
slope
of 0.104.
Analyses similar to the one described above were made for the results of the placebo administered to patients with postpartum pain. Fig. 2 shows the peak pain-reliefscores plot for thirty studies in which a placebo was included: The numbers of
fourteen
to
patients eighty-nine, with
in these studies ranged from a mean of forty-one. Again a significant linear correlation emerges between performance and challenge, with a slope of 0-46 and a standard error of the slope of 0-178.
In all the above analyses each ex-
periment allowed ate a
was
to gener-
single point
-amean pain-
relief Fig. 2-Postpartum pain: placebo.
each
score
mean
for
initial
pain score. An alternative (and perhaps tidier) approach would allow each experiment to generate four mean pain-relief scores, one for each of the four possible initial levels. This has been done in fig. 3 for all the fourteen postoperative experiments with morphine. Here the circles represent the mean t This procedure
was used instead of calculating the mean of the maximal pain-relief scores for all patients (regardless of time of such maximal relief) for several reasons: (1) the former " peak " score is the one customarily used in reporting analgesic effects in a group of patients, and (2) the use of the second measure (the mean maximal score) gives the maximal contribution of spontaneous temporary regression of pain. In point of " fact, an analysis of both kinds of peak " scores in the postoperative experiments to be described indicated little difference between the two, except for the expected tendency toward slightly lower mean scores with the method of choice.
573
severity (i.e., the average of the pretreatment pain severity and the pain severity present at the peak analgesic effect of the treatment). Such a function may, indeed, be unrelated to the analgesic performance of drugs, but it is unclear what biological meaning the function has,
value of pain
peak pain relief scores for the patients with different
degrees of predrug pain in the individual
experiments, while the
triangles
rep-
resent the means
for the
pooled data at each initial
severity level. This analysis confirms the linear Fig. 3-Morphine data: individual experiments stratified for initial pain level. relationship between pretreatment pain level and post-treatment pain-relief scores obtained with the other method of
analysis.
Discussion
Lawfulness of Pain Relief It is clear that pain-relief scores can be correlated with pretreatment pain levels when one uses an excellent analgesic drug, such as morphine, or a placebo. What is the importance of this observed " lawfulness " and are these correlations merely artefacts of the scoring system or the analysis ? The answer to this question is not simple. It is true that the points in fig. 1 are limited to an area whose upper limit is a straight line with a slope and intercept of 1, because patients with a slight " pain cannot obtain more than 1 relief unit, and patients with " moderate " pain A can only score 2 relief units if completely relieved, &c. population uniformly showing complete relief of pain at peak performance would, of course, yield a straight line (i.e., the limiting line described above). If even a fraction of the population shows spontaneous remission of pain, there will be a tendency to linearity (with a positive slope), provided that there is no differential propensity dependent on initial severity of pain. (A similar tendency would result from spontaneous increases in severity of pain to maximal levels.) But there is no compelling reason, on the other hand, why one ought to expect disappearance of severe pain as often as slight pain. In fact, an analysis of this point indicates that 92-11 % of sixty-three postoperative patients with slight pain experienced complete relief during the 4 hours after morphine, whereas the figures for moderate, severe, and very severe pain were, respectively, 62-3% (of a hundred and fifty-nine), 45-7% (of a hundred and eighty-six), and 32-3% (of ninety-six). Oldham (1962) has pointed out that one may be led to false conclusions by plotting changes (XCX2) against initial levels (xl), because even two sets of randomly chosen numbers, analysed in this way, will generate a "correlation"" by reason of the inevitable algebraic relation of the functions in question. His preference is for plotting the change (XCX2) against the mean of the initial and final values [(/2(Xi+Xa)], and then analysing for correlation. Such a function as 1/ 2(Xl + X2) will, to be sure, not be spuriously correlated with Xi-x, but it is not evident what such an analysis does tell one if no correla"
"
"
"
tion
"
be demonstrated. In the case of the data in this paper, 1/2(XI+X2) would represent an arbitrary mean can
" and such a lack of correlation does not rule out a real" relation between initial level of pain and pain relief. " A useful solution to this dilemma of " spurious correlation is to plot the level of pain at peak drug performance (x2) against the initial pain level (xl) and to analyse the resultant regression line. This slope will actually equal 1-b, where b equals the slope generated by plotting (XCX2) against Xl’ When one performs this manaeuvre for morphine and placebo, the resultant slopes " are still highly significant, indicating a true " relation between initial pain level and therapeutic effect achieved with either morphine or placebo.+ The approach of covariance analysis in this situation does not seem to be appropriate because the desire is not primarily to eliminate " initial severity of pain in the present analysis. Initial severity is here not a nuisance factor, but a variable of prime concern. "
"
Models of Pain Relief A basic difficulty regarding the question of artefact is that we do not know what the "true model" of untreated pain is. Because " medication " (placebos or drugs) was never withheld from patients so that they could be interviewed periodically in the absence of treatment, no data are available on the natural history of untreated postoperative or postpartum pain. The pain ultimately subsides under medication, and it would do so without medication; but we have no good estimate as to how most patients would fare, for example, during a given 4-hour period. The placebo data are our best estimate, though these results combine both spontaneous change and
suggestibility. One can postulate a variety of models. The simplest, perhaps, is that of no change in pain level without medication. A second model is to assume that patients show a random change in pain level over time, with pain either decreasing or increasing (within the limits of the categories used). A third model is to assume random change, but to eliminate the possibility of worsening of pain. Each of these models produces a linear relationship, but none seems reasonable for all patients any more than does the earlier postulated model for complete relief of pain for all patients. The most likely supposition is that clinical studies include elements of all these models-i.e., some patients will show no change in pain without medication, others will show spontaneous diminution or disappearance in pain even without drug, and still others will get worse if untreated. (Some patients report increased pain even after a drug.) That the observed changes in pain level are not entirely chance occurrences is clear. Controlled trials have, as stated above, usually distinguished with ease between powerful analgesics (such as morphine) and a placebo. Experience with aspirin (a weaker analgesic) in postpartum pain also testifies to this drug’s real contribution to pain relief scores: The results with aspirin 0-6 g. and placebo in twenty-three separate studies, each involving a total of thirty-five to a The utility of this approach is demonstrated by some data we have another therapeutic agent, where plotting x, yielded a highly significant slope, but plotting Xz against X, showed no relationship between initial and final pain levels.
accumulated
on
(Xi-Xa) against
574 hundred and
fifty-four (mean -= eightypatients eight), are summarised in fig. 4, where the mean peak pain-relief scores of both agents are simultaneously plotted in a scatter diagram. The diagonal line divides the diagram into two equal If aspirin and parts. placebo were in fact indistinguishable, the points should either fall on this line or be approximately Fig. 4-Postpartum pain: mean peak pain-relief scores for equally distributed on either placebo and aspirin in twentyside of it. As can be seen, three studies. all points but one are actually in the upper left half of the total area, indicating the analgesic superiority of aspirin, although individual points at times come quite close to the diagonal line.
In addition, the time course of the observed changes in pain relief after medication bears witness to its nonrandom character. Thus, the mean pain-relief score 1-2 hours after morphine is greater than the score at either 1/2 or 4 hours after the drug, whether one looks at the data on patients initially complaining of slight pain, or of moderate, severe, or very severe pain. All these considerations thus lead to the opinion that the " lawfulness " described above is in part a result of the scoring system and of spontaneous changes in pain; but it is also attributable to a superimposed regularity derived from the ability of therapeutic agents to relieve pain. Conversely, the performance of an analgesic is determined by the severity of pretreatment pain in a way that is not contingent solely on the scoring system used to
quantify relief. It should be stressed that the linear relations described above do not necessarily indicate that placebo or morphine work " better " in severe pain than in mild pain. The pain relief scores are higher, certainly, in patients with severe pain before the drug was given, but this is a function of the system of scoring. A patient with slight pain is given a score of + 1 if morphine completely relieves the pain; a with very severe pain whose pain changes to patient " moderate " scores +2. Is the latter result " better " than the former ? Obviously, the semantics of this situation are formidable, but if one asks a simpler question, such as " What proportion of patients will be completely relieved of pain after morphine ?" (see above), there is
obviously a negative relationship between initial pain The technique currently severity and pain relief. employed in the Harvard Anesthesia Research Laboratory, by Beecher and his colleagues, for assessing pain relief accords a score of 3 for complete relief of pain, 2 for pain more than half gone ", 1 for " pain less than half gone ", and 0 for no relief, regardless of the initial level of pain. With this technique, again, a negative relation obtains between pain relief and initial level of pain-i.e., heroin and morphine provide higher scores in moderate than in more severe pain (Reichle et al. 1962). This technique appears closer to the question of complete relief ", and it agrees with my own data (Lasagna et al. 1958, and above). Certainly methods of interrogation, of assessment of relief, and of analysis of data may be important causes of apparent or real differences between "
"
laboratories. Other sources of variation can be listed, although none of them can be described in quantitative terms. There is,
first of all, the selection of patients. Some kinds of surgery, for example, cause little or no postoperative discomfort (Keats 1956), so that the pre-drug level of pain in patients subjected to such procedures will be low. Yet even with standard forms of surgery (Keats 1956), patients vary tremendously in their reported discomfort and requirement for drugs. Variability in group pain level before treatment (see figs. 1-3) is perhaps not surprising in the postoperative situation, where the groups are small, the types of operative procedures numerous, and the age, sex, and physical condition of the patient, the duration of anaathesia and of surgery, and the operative technique and personnel vary considerably. It is more surprising in the postpartum situation, where the patients are all women of similar age, race, and socioeconomic status, and where the type of pain is more uniform. Other sources of variance can be postulated (Keats 1956), of which the most important is probably changes of the interviewer. It is obviously not possible to be either satisfied or complacent about the variability in the data reported here and in data from other laboratories which study postoperative pain (Keats et al. 1950) or the chronic pain of malignant disease (Houde et al. 1960). That the variability is there and must be reckoned with seems clear.
Similarities between
Alorphine and Placebo
In work over the years I have been more impressed by the parallelisms in the analgesic performance of placebos and active drugs than by basic differences in the quality or temporal pattern of pain relief by these various agents (Lasagna et al. 1958). Such a view seems reasonable, because the performance of " active " drugs must contain within it, in some way, the performance of the placebo. (This, of course, is the primary reason for having a placebo control group to evaluate pharmacological efficacy.) Although placebo and morphine differ in relative efficacy and in the slopes of the lines achieved by plotting painrelief score against pain severity, both agents nevertheless show a positive correlation between pain relief and pretreatment pain level. Two further analyses bear on this point. The points in fig. 4 show a significant linear relation, and the least squares line has a positive slope of 1-06, with a standard error of 0-128. Thus, in these experiments, the pain-relief score of the placebo is high when that of aspirin is high, and low when that of aspirin is low. In addition, if one plots the difference (A-P) in peak pain-relief scores of aspirin and placebo (in each of these same twenty-three experiments) against mean severity of initial pain in the patients in each experimental group, a linear relationship emerges which, while not as impressive as the others described in this paper,§ nevertheless has a positive slope of 0-23, with a standard error of 0.127. Thus our best estimate of the relation between AA-p and the severity of pain suggests that AA-p approaches zero (i.e., the ability to discriminate between the placebo and aspirin diminishes) as the severity of the premedication pain decreases. These findings contrast with the results reported by Beecher (1956) in some patients with postoperative pain. This investigator demonstrated that, after a placebo, pain
§
One reason for this may lie in the difficulty of defining the abscissa with precision, because the pain severity for each point in this analysis is the mean of the average pain severities of two different groups of patients-i.e., those receiving a placebo and those receiving aspirin.
575
optimal early and minimal late in the postoperative period; whereas a reverse relationship obtained for morphine. Beecher assumed that postoperative pain is relief
ANTINUCLEOLAR ANTIBODIES
was
first, on the average, and diminishes with seems reasonable and can easily be which stand time-a the related to performance of morphine in his data. But the difference between morphine and the placebo was least when the pain was presumably most severe, and greatest as pain was allegedly tapering off. It should be pointed out that Beecher did not actually attempt to estimate the severity of pain in the patients he studied, but rather he recorded the incidence of significant pain relief; in addition, his experiments involved postoperative pain rather than the postpartum pain used in the analysis above. But my data on postoperative pain (Lasagna et al. 1958), and those of Keats (referred to in Lasagna et al. 1958) in similar patients, are also at variance with those of Beecher. One cannot easily reconcile these several reports, though one wonders whether the particular patients studied by Beecher (who were alternately exposed to morphine and a placebo) might not have shown a gradually increasing ability to discriminate between active and inactive treatments. Such a phenomenon (discussed but dismissed by Beecher), taken in conjunction with a waning of pain over time, could conceivably explain his results. Later Beecher (1960) stressed instead the increased effectiveness of both placebo and morphine in relieving pain of pathological origin as contrasted with experimentally induced pain. The reports summarised by Beecher are not readily integrated into an attempted correlation between analgesic efficacy and severity of " stress ". There are obviously many differences between experimental and pathological pain states other than severity of pain or amount of distress ". Variability in the level of pain owing to spontaneous remission, for example, seems more likely in clinical situations; and it might contribute to a higher placebo success-rate in the clinical reports cited, because the placebo response but also spontaneous measures not only " suggestibility changes in symptoms. But Beecher, in this second paper, marshals an impressive body of evidence which accords entirely with one of the major conclusions of my worknamely, that the placebo and morphine show a remarkable similarity in the pattern of their analgesic effects.
J. SWANSON BECK M.B., B.Sc. Glasg., F.R.F.P.S., M.R.C.P.E.
most severe at
"
"
Summary
and Conclusions
Pain relief after
morphine or a placebo can be correlated with pretreatment pain severity. These correlations appear to be only partly contingent upon the method used for scoring pain relief; and they depend on a lawfulness " and regulatory action provided by the ability of therapeutic agents to relieve pain. Models of pain relief, with and without medication, and the similarities in performance of a placebo and morphine "
are
LECTURER
J. R. ANDERSON M.D., B.Sc. St. And., F.R.F.P.S., M.R.C.P. SENIOR LECTURER
A.
J. MCELHINNEY
RESEARCH ASSISTANT
UNIVERSITY DEPARTMENT OF WESTERN
M.B. CONSULTANT
INFIRMARY,
PATHOLOGY,
GLASGOW
N. R. ROWELL Durh., M.R.C.P., D.C.H.
DERMATOLOGIST,
GENERAL
INFIRMARY,
LEEDS
ANTIBODIES to isolated cell nuclei and various constituents of cell nuclei such as deoxyribonucleoprotein, deoxyribonucleic acid, histone, and a phosphate-bufferextractible protein have been identified in the serum of with systemic patients erythematosus and the other " connective-tissue diseases " by conventional immunological techniques, such as complement fixation (Robbins et al. 1957), precipitation reactions (Ceppellini et al. 1957, Seligmann 1957), latex agglutination (Christian et al. 1958), tanned-cell agglutination (Miescher and Strassle 1957), Coombs’ consumption test (Miescher 1955), and passive cutaneous anaphylaxis (Deicher et al. 1960). The reaction of such antibodies with the nuclei in tissue sections has also been detected by the fluorescent-antibody technique (Friou 1957, 1958, Holborow et al. 1957, Holman and Kunkel 1957, Alexander and Duthie 1958). In a previous communication (Beck 1961) it was shown by the fluorescent-antibody technique that various patients’ sera may cause one or other of two different patterns of nuclear
lupus
"
"
staining, the homogeneous representing anti-deoxyribonucleoprotein (anti-D.N.P.) whereas the speckled " represented an antibody to a soluble protein of the nucleus. "
In that paper the existence of antinucleolar antibodies was first postulated from the observation that one serum caused nucleolar staining by the fluorescent-antibody technique. Subsequently, Fennell et al. (1962) described three sera which also caused nucleolar staining from patients with progressive systemic sclerosis. We review here our experience of eleven sera which contained antinucleolar antibodies and discuss the associated clinical and immunological abnormalities. Clinical and Laboratory Findings In a search for antinucleolar antibodies in the sera of 358 patients with various connective-tissue diseases by the
sandwich fluorescent-antibody technique (Beck 1961), eleven sera were found which caused nucleolar staining. None of the sera from an unselected group of 490 hospital " " patients with diseases other than the autoimmune group caused nucleolar staining. The specificity of the fluorescein-conjugated rabbit
discussed.
I am indebted to H. K. Beecher, J. Cornfield, A. W. Kimball, V. G. Laties, P. Meier, F. C. Mosteller, P. D. Oldham, and B. Weiss for their incisive criticisms. Their comments have helped me greatly, but they are not to be blamed for any errors, statistical or otherwise. This work was supported in part by a grant (B-865) from the National Institutes of Health, and in part by grants awarded by the Committee on Drug Addiction and Narcotics, National Academy of Science, National Research Council, from funds contributed by a group of pharmaceutical manufacturers.
DR. LASAGNA: REFERENCES
Beecher, H. K. (1956) Amer. J. Physiol. 187, 163. (1960) Science, 132, 91. Houde, R. W., Wallenstein, S. L., Rogers, A. (1960) Clin. Pharmacol. 1, 163 Keats, A. S. (1956) J. chron. Dis. 4, 72. — Beecher, H. K., Mosteller, F. C. (1950) J. appl. Physiol. 3, 35. Lasagna, L. (1960) Ann. N.Y. Acad. Sci. 86, 28. De Kornfeld, T. J. (1958) J. Pharmacol. 124, 260. Laties, V. G., Dohan, J. L. (1958) J. clin. Invest. 37, 533. Oldham, P. D. (1962) J. Chron. Dis. (in the press). Reichle, C. W., Smith, G. M., Gravenstein, J. S., Macris, S. G., Beecher, H. K. (1962) J. Pharmacol. 136, 43. Wallis, W. A., Roberts, H. V. (1956) Statistics: A New Approach. Glencoe, Ill. -
-
-
Boijsen, E. (1959) Acta radiol. suppl. 183. Derrick, J. R., Tyson, R. T. (1960) Surgery, 42, 907. de Wardener, H. E. (1961) The Kidney; p. 22. London. Edling, N. P. G., Helander, C. G., Parsson, F., Asheim, A. (1959) Acta radiol. 57, 161. Edsman, G. (1957) ibid. suppl. 155. Graves, F. T. (1954) Brit. J. Surg. 42, 132. Houghton, B. J., Pears, M. A. (1957) Brit. med. J. i, 622. Marshall, A. G (1951) Lancet, ii, 701 (1953) Brit. J. Surg. 165, 38. (1956) J. Path. Bact. 71, 95. Platt, R. (1947) Quart. J. Med. 16, 111. (1948) ibid. 17, 83. Seldinger, S. I. (1953) Acta radiol. 39, 368.
"
"
pain-relief scores were calculated by subtracting the post-drug pain level from the pre-drug level. Thus, if a patient went from severe pain to slight pain, he got a score of 2 for that interview point. For each dose, the pain-relief score was Peak
calculated for the 1/2, 1, 2, 3, and 4 hour interviews after medication. The mean score for all doses was then calculated for each of these interview points, and the highest mean score was called the " peak " pain-relief score for the group. fi In fig. 1 are plotted the mean peak pain-relief scores achieved with morphine in fourteen individual experiments
post-
on
-
-
operative patients. Each
-
from twelve
to
THE PSYCHOPHYSICS OF CLINICAL PAIN
thirty patients (mean eighteen).
LOUIS LASAGNA
The ordinate is
M.D. Columbia MENTAL
THERAPEUTICS, JOHNS HOPKINS UNIVERSITY SCHOOL MEDICINE, BALTIMORE, MARYLAND
OF
DOES the efficacy of an analgesic drug depend upon how much pain the drug must relieve ? I have approached this question by analysing data from a series of experiments conducted during the past 4 years. These data are based on the performance of two standard treatments-morphine and a placebo-and the analyses are made with reference to the severity of the pretreatment pain. To evaluate
analgesic drugs, I have utilised an interviewing technique in which the severity of pain is graded according to the subjective report of patients with postoperative or postpartum discomfort. This subjective-severity rating is based on a scale ranging from no pain to very severe pain, with intermediate degrees of slight, moderate, and severe. Patients are asked to classify their pain in these terms, are given medication, and are then interviewed at stated intervals for a re-evaluation of their pain status (Lasagna et al. 1958). Changes from any one pain level to the next higher or lower pain level have arbitrarily been given equal value,* with positive scores for decrease in pain, and negative scores for increase in pain. Using this method, potent analgesics have, with reasonable consistency, been discriminated from placebo treatments or weak analgesics not only by me but by other investigators using similar techniques (Lasagna et al. 1958, Lasagna and De Kornfeld 1958, Houde et al. 1960). Analysis
For each experiment, mean pain-relief scores were computed. In patients with postoperative pain morphine (10 mg.), which is the standard medication, was alternated with the new agent under study, both being given subcutaneously under double-blind conditions-i.e., where neither patient nor interviewer is aware of the nature of a given medication. Each dose has been treated separately in the analysis, because the preinjection level of pain may vary considerably in a given patient from one dose to another, and past experience has revealed no important difference between the use of such scores and the use either of first doses only or of scores where each patient contributes a single score regardless of the number of doses received (Lasagna and De Kornfeld 1958). (In the studies of postpartum pain, to be discussed later, only one dose of medication is administered per patient.) -
At first, this was done because of ease of computation. The method was continued because attempts at discriminant-function analysis, and at psychophysical scaling (Lasagna 1960), failed to provide adequate justification for any weighting of decrements in pain for different initial levels of pain severity.
score,
the abscissa is the
premorphine pain severity of the patients (as a group) in the respective mean
experiments, on the basis of 1= slight pain, 2 moderate, 3
Fig. 1-Postoperative pain: morphine.
The good fit of the line, drawn according to the method of least squares (Wallis and Roberts 1956), is evident. The line has a slope of 0-68, with a standard severe, and 4 very severe.
error
Methods
*
=
pain-relief
ASSOCIATE PROFESSOR OF MEDICINE AND PHARMACOLOGY AND EXPERI-
-
point
represents data
of the
slope
of 0.104.
Analyses similar to the one described above were made for the results of the placebo administered to patients with postpartum pain. Fig. 2 shows the peak pain-reliefscores plot for thirty studies in which a placebo was included: The numbers of
fourteen
to
patients eighty-nine, with
in these studies ranged from a mean of forty-one. Again a significant linear correlation emerges between performance and challenge, with a slope of 0-46 and a standard error of the slope of 0-178.
In all the above analyses each ex-
periment allowed ate a
was
to gener-
single point
-amean pain-
relief Fig. 2-Postpartum pain: placebo.
each
score
mean
for
initial
pain score. An alternative (and perhaps tidier) approach would allow each experiment to generate four mean pain-relief scores, one for each of the four possible initial levels. This has been done in fig. 3 for all the fourteen postoperative experiments with morphine. Here the circles represent the mean t This procedure
was used instead of calculating the mean of the maximal pain-relief scores for all patients (regardless of time of such maximal relief) for several reasons: (1) the former " peak " score is the one customarily used in reporting analgesic effects in a group of patients, and (2) the use of the second measure (the mean maximal score) gives the maximal contribution of spontaneous temporary regression of pain. In point of " fact, an analysis of both kinds of peak " scores in the postoperative experiments to be described indicated little difference between the two, except for the expected tendency toward slightly lower mean scores with the method of choice.
573
severity (i.e., the average of the pretreatment pain severity and the pain severity present at the peak analgesic effect of the treatment). Such a function may, indeed, be unrelated to the analgesic performance of drugs, but it is unclear what biological meaning the function has,
value of pain
peak pain relief scores for the patients with different
degrees of predrug pain in the individual
experiments, while the
triangles
rep-
resent the means
for the
pooled data at each initial
severity level. This analysis confirms the linear Fig. 3-Morphine data: individual experiments stratified for initial pain level. relationship between pretreatment pain level and post-treatment pain-relief scores obtained with the other method of
analysis.
Discussion
Lawfulness of Pain Relief It is clear that pain-relief scores can be correlated with pretreatment pain levels when one uses an excellent analgesic drug, such as morphine, or a placebo. What is the importance of this observed " lawfulness " and are these correlations merely artefacts of the scoring system or the analysis ? The answer to this question is not simple. It is true that the points in fig. 1 are limited to an area whose upper limit is a straight line with a slope and intercept of 1, because patients with a slight " pain cannot obtain more than 1 relief unit, and patients with " moderate " pain A can only score 2 relief units if completely relieved, &c. population uniformly showing complete relief of pain at peak performance would, of course, yield a straight line (i.e., the limiting line described above). If even a fraction of the population shows spontaneous remission of pain, there will be a tendency to linearity (with a positive slope), provided that there is no differential propensity dependent on initial severity of pain. (A similar tendency would result from spontaneous increases in severity of pain to maximal levels.) But there is no compelling reason, on the other hand, why one ought to expect disappearance of severe pain as often as slight pain. In fact, an analysis of this point indicates that 92-11 % of sixty-three postoperative patients with slight pain experienced complete relief during the 4 hours after morphine, whereas the figures for moderate, severe, and very severe pain were, respectively, 62-3% (of a hundred and fifty-nine), 45-7% (of a hundred and eighty-six), and 32-3% (of ninety-six). Oldham (1962) has pointed out that one may be led to false conclusions by plotting changes (XCX2) against initial levels (xl), because even two sets of randomly chosen numbers, analysed in this way, will generate a "correlation"" by reason of the inevitable algebraic relation of the functions in question. His preference is for plotting the change (XCX2) against the mean of the initial and final values [(/2(Xi+Xa)], and then analysing for correlation. Such a function as 1/ 2(Xl + X2) will, to be sure, not be spuriously correlated with Xi-x, but it is not evident what such an analysis does tell one if no correla"
"
"
"
tion
"
be demonstrated. In the case of the data in this paper, 1/2(XI+X2) would represent an arbitrary mean can
" and such a lack of correlation does not rule out a real" relation between initial level of pain and pain relief. " A useful solution to this dilemma of " spurious correlation is to plot the level of pain at peak drug performance (x2) against the initial pain level (xl) and to analyse the resultant regression line. This slope will actually equal 1-b, where b equals the slope generated by plotting (XCX2) against Xl’ When one performs this manaeuvre for morphine and placebo, the resultant slopes " are still highly significant, indicating a true " relation between initial pain level and therapeutic effect achieved with either morphine or placebo.+ The approach of covariance analysis in this situation does not seem to be appropriate because the desire is not primarily to eliminate " initial severity of pain in the present analysis. Initial severity is here not a nuisance factor, but a variable of prime concern. "
"
Models of Pain Relief A basic difficulty regarding the question of artefact is that we do not know what the "true model" of untreated pain is. Because " medication " (placebos or drugs) was never withheld from patients so that they could be interviewed periodically in the absence of treatment, no data are available on the natural history of untreated postoperative or postpartum pain. The pain ultimately subsides under medication, and it would do so without medication; but we have no good estimate as to how most patients would fare, for example, during a given 4-hour period. The placebo data are our best estimate, though these results combine both spontaneous change and
suggestibility. One can postulate a variety of models. The simplest, perhaps, is that of no change in pain level without medication. A second model is to assume that patients show a random change in pain level over time, with pain either decreasing or increasing (within the limits of the categories used). A third model is to assume random change, but to eliminate the possibility of worsening of pain. Each of these models produces a linear relationship, but none seems reasonable for all patients any more than does the earlier postulated model for complete relief of pain for all patients. The most likely supposition is that clinical studies include elements of all these models-i.e., some patients will show no change in pain without medication, others will show spontaneous diminution or disappearance in pain even without drug, and still others will get worse if untreated. (Some patients report increased pain even after a drug.) That the observed changes in pain level are not entirely chance occurrences is clear. Controlled trials have, as stated above, usually distinguished with ease between powerful analgesics (such as morphine) and a placebo. Experience with aspirin (a weaker analgesic) in postpartum pain also testifies to this drug’s real contribution to pain relief scores: The results with aspirin 0-6 g. and placebo in twenty-three separate studies, each involving a total of thirty-five to a The utility of this approach is demonstrated by some data we have another therapeutic agent, where plotting x, yielded a highly significant slope, but plotting Xz against X, showed no relationship between initial and final pain levels.
accumulated
on
(Xi-Xa) against
574 hundred and
fifty-four (mean -= eightypatients eight), are summarised in fig. 4, where the mean peak pain-relief scores of both agents are simultaneously plotted in a scatter diagram. The diagonal line divides the diagram into two equal If aspirin and parts. placebo were in fact indistinguishable, the points should either fall on this line or be approximately Fig. 4-Postpartum pain: mean peak pain-relief scores for equally distributed on either placebo and aspirin in twentyside of it. As can be seen, three studies. all points but one are actually in the upper left half of the total area, indicating the analgesic superiority of aspirin, although individual points at times come quite close to the diagonal line.
In addition, the time course of the observed changes in pain relief after medication bears witness to its nonrandom character. Thus, the mean pain-relief score 1-2 hours after morphine is greater than the score at either 1/2 or 4 hours after the drug, whether one looks at the data on patients initially complaining of slight pain, or of moderate, severe, or very severe pain. All these considerations thus lead to the opinion that the " lawfulness " described above is in part a result of the scoring system and of spontaneous changes in pain; but it is also attributable to a superimposed regularity derived from the ability of therapeutic agents to relieve pain. Conversely, the performance of an analgesic is determined by the severity of pretreatment pain in a way that is not contingent solely on the scoring system used to
quantify relief. It should be stressed that the linear relations described above do not necessarily indicate that placebo or morphine work " better " in severe pain than in mild pain. The pain relief scores are higher, certainly, in patients with severe pain before the drug was given, but this is a function of the system of scoring. A patient with slight pain is given a score of + 1 if morphine completely relieves the pain; a with very severe pain whose pain changes to patient " moderate " scores +2. Is the latter result " better " than the former ? Obviously, the semantics of this situation are formidable, but if one asks a simpler question, such as " What proportion of patients will be completely relieved of pain after morphine ?" (see above), there is
obviously a negative relationship between initial pain The technique currently severity and pain relief. employed in the Harvard Anesthesia Research Laboratory, by Beecher and his colleagues, for assessing pain relief accords a score of 3 for complete relief of pain, 2 for pain more than half gone ", 1 for " pain less than half gone ", and 0 for no relief, regardless of the initial level of pain. With this technique, again, a negative relation obtains between pain relief and initial level of pain-i.e., heroin and morphine provide higher scores in moderate than in more severe pain (Reichle et al. 1962). This technique appears closer to the question of complete relief ", and it agrees with my own data (Lasagna et al. 1958, and above). Certainly methods of interrogation, of assessment of relief, and of analysis of data may be important causes of apparent or real differences between "
"
laboratories. Other sources of variation can be listed, although none of them can be described in quantitative terms. There is,
first of all, the selection of patients. Some kinds of surgery, for example, cause little or no postoperative discomfort (Keats 1956), so that the pre-drug level of pain in patients subjected to such procedures will be low. Yet even with standard forms of surgery (Keats 1956), patients vary tremendously in their reported discomfort and requirement for drugs. Variability in group pain level before treatment (see figs. 1-3) is perhaps not surprising in the postoperative situation, where the groups are small, the types of operative procedures numerous, and the age, sex, and physical condition of the patient, the duration of anaathesia and of surgery, and the operative technique and personnel vary considerably. It is more surprising in the postpartum situation, where the patients are all women of similar age, race, and socioeconomic status, and where the type of pain is more uniform. Other sources of variance can be postulated (Keats 1956), of which the most important is probably changes of the interviewer. It is obviously not possible to be either satisfied or complacent about the variability in the data reported here and in data from other laboratories which study postoperative pain (Keats et al. 1950) or the chronic pain of malignant disease (Houde et al. 1960). That the variability is there and must be reckoned with seems clear.
Similarities between
Alorphine and Placebo
In work over the years I have been more impressed by the parallelisms in the analgesic performance of placebos and active drugs than by basic differences in the quality or temporal pattern of pain relief by these various agents (Lasagna et al. 1958). Such a view seems reasonable, because the performance of " active " drugs must contain within it, in some way, the performance of the placebo. (This, of course, is the primary reason for having a placebo control group to evaluate pharmacological efficacy.) Although placebo and morphine differ in relative efficacy and in the slopes of the lines achieved by plotting painrelief score against pain severity, both agents nevertheless show a positive correlation between pain relief and pretreatment pain level. Two further analyses bear on this point. The points in fig. 4 show a significant linear relation, and the least squares line has a positive slope of 1-06, with a standard error of 0-128. Thus, in these experiments, the pain-relief score of the placebo is high when that of aspirin is high, and low when that of aspirin is low. In addition, if one plots the difference (A-P) in peak pain-relief scores of aspirin and placebo (in each of these same twenty-three experiments) against mean severity of initial pain in the patients in each experimental group, a linear relationship emerges which, while not as impressive as the others described in this paper,§ nevertheless has a positive slope of 0-23, with a standard error of 0.127. Thus our best estimate of the relation between AA-p and the severity of pain suggests that AA-p approaches zero (i.e., the ability to discriminate between the placebo and aspirin diminishes) as the severity of the premedication pain decreases. These findings contrast with the results reported by Beecher (1956) in some patients with postoperative pain. This investigator demonstrated that, after a placebo, pain
§
One reason for this may lie in the difficulty of defining the abscissa with precision, because the pain severity for each point in this analysis is the mean of the average pain severities of two different groups of patients-i.e., those receiving a placebo and those receiving aspirin.
575
optimal early and minimal late in the postoperative period; whereas a reverse relationship obtained for morphine. Beecher assumed that postoperative pain is relief
ANTINUCLEOLAR ANTIBODIES
was
first, on the average, and diminishes with seems reasonable and can easily be which stand time-a the related to performance of morphine in his data. But the difference between morphine and the placebo was least when the pain was presumably most severe, and greatest as pain was allegedly tapering off. It should be pointed out that Beecher did not actually attempt to estimate the severity of pain in the patients he studied, but rather he recorded the incidence of significant pain relief; in addition, his experiments involved postoperative pain rather than the postpartum pain used in the analysis above. But my data on postoperative pain (Lasagna et al. 1958), and those of Keats (referred to in Lasagna et al. 1958) in similar patients, are also at variance with those of Beecher. One cannot easily reconcile these several reports, though one wonders whether the particular patients studied by Beecher (who were alternately exposed to morphine and a placebo) might not have shown a gradually increasing ability to discriminate between active and inactive treatments. Such a phenomenon (discussed but dismissed by Beecher), taken in conjunction with a waning of pain over time, could conceivably explain his results. Later Beecher (1960) stressed instead the increased effectiveness of both placebo and morphine in relieving pain of pathological origin as contrasted with experimentally induced pain. The reports summarised by Beecher are not readily integrated into an attempted correlation between analgesic efficacy and severity of " stress ". There are obviously many differences between experimental and pathological pain states other than severity of pain or amount of distress ". Variability in the level of pain owing to spontaneous remission, for example, seems more likely in clinical situations; and it might contribute to a higher placebo success-rate in the clinical reports cited, because the placebo response but also spontaneous measures not only " suggestibility changes in symptoms. But Beecher, in this second paper, marshals an impressive body of evidence which accords entirely with one of the major conclusions of my worknamely, that the placebo and morphine show a remarkable similarity in the pattern of their analgesic effects.
J. SWANSON BECK M.B., B.Sc. Glasg., F.R.F.P.S., M.R.C.P.E.
most severe at
"
"
Summary
and Conclusions
Pain relief after
morphine or a placebo can be correlated with pretreatment pain severity. These correlations appear to be only partly contingent upon the method used for scoring pain relief; and they depend on a lawfulness " and regulatory action provided by the ability of therapeutic agents to relieve pain. Models of pain relief, with and without medication, and the similarities in performance of a placebo and morphine "
are
LECTURER
J. R. ANDERSON M.D., B.Sc. St. And., F.R.F.P.S., M.R.C.P. SENIOR LECTURER
A.
J. MCELHINNEY
RESEARCH ASSISTANT
UNIVERSITY DEPARTMENT OF WESTERN
M.B. CONSULTANT
INFIRMARY,
PATHOLOGY,
GLASGOW
N. R. ROWELL Durh., M.R.C.P., D.C.H.
DERMATOLOGIST,
GENERAL
INFIRMARY,
LEEDS
ANTIBODIES to isolated cell nuclei and various constituents of cell nuclei such as deoxyribonucleoprotein, deoxyribonucleic acid, histone, and a phosphate-bufferextractible protein have been identified in the serum of with systemic patients erythematosus and the other " connective-tissue diseases " by conventional immunological techniques, such as complement fixation (Robbins et al. 1957), precipitation reactions (Ceppellini et al. 1957, Seligmann 1957), latex agglutination (Christian et al. 1958), tanned-cell agglutination (Miescher and Strassle 1957), Coombs’ consumption test (Miescher 1955), and passive cutaneous anaphylaxis (Deicher et al. 1960). The reaction of such antibodies with the nuclei in tissue sections has also been detected by the fluorescent-antibody technique (Friou 1957, 1958, Holborow et al. 1957, Holman and Kunkel 1957, Alexander and Duthie 1958). In a previous communication (Beck 1961) it was shown by the fluorescent-antibody technique that various patients’ sera may cause one or other of two different patterns of nuclear
lupus
"
"
staining, the homogeneous representing anti-deoxyribonucleoprotein (anti-D.N.P.) whereas the speckled " represented an antibody to a soluble protein of the nucleus. "
In that paper the existence of antinucleolar antibodies was first postulated from the observation that one serum caused nucleolar staining by the fluorescent-antibody technique. Subsequently, Fennell et al. (1962) described three sera which also caused nucleolar staining from patients with progressive systemic sclerosis. We review here our experience of eleven sera which contained antinucleolar antibodies and discuss the associated clinical and immunological abnormalities. Clinical and Laboratory Findings In a search for antinucleolar antibodies in the sera of 358 patients with various connective-tissue diseases by the
sandwich fluorescent-antibody technique (Beck 1961), eleven sera were found which caused nucleolar staining. None of the sera from an unselected group of 490 hospital " " patients with diseases other than the autoimmune group caused nucleolar staining. The specificity of the fluorescein-conjugated rabbit
discussed.
I am indebted to H. K. Beecher, J. Cornfield, A. W. Kimball, V. G. Laties, P. Meier, F. C. Mosteller, P. D. Oldham, and B. Weiss for their incisive criticisms. Their comments have helped me greatly, but they are not to be blamed for any errors, statistical or otherwise. This work was supported in part by a grant (B-865) from the National Institutes of Health, and in part by grants awarded by the Committee on Drug Addiction and Narcotics, National Academy of Science, National Research Council, from funds contributed by a group of pharmaceutical manufacturers.
DR. LASAGNA: REFERENCES
Beecher, H. K. (1956) Amer. J. Physiol. 187, 163. (1960) Science, 132, 91. Houde, R. W., Wallenstein, S. L., Rogers, A. (1960) Clin. Pharmacol. 1, 163 Keats, A. S. (1956) J. chron. Dis. 4, 72. — Beecher, H. K., Mosteller, F. C. (1950) J. appl. Physiol. 3, 35. Lasagna, L. (1960) Ann. N.Y. Acad. Sci. 86, 28. De Kornfeld, T. J. (1958) J. Pharmacol. 124, 260. Laties, V. G., Dohan, J. L. (1958) J. clin. Invest. 37, 533. Oldham, P. D. (1962) J. Chron. Dis. (in the press). Reichle, C. W., Smith, G. M., Gravenstein, J. S., Macris, S. G., Beecher, H. K. (1962) J. Pharmacol. 136, 43. Wallis, W. A., Roberts, H. V. (1956) Statistics: A New Approach. Glencoe, Ill. -
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