Journal of Psychosomatic Research, Vol. 20, pp. 289-301. Pergamon Press, 1976. Printed in Great Britain

DIURNAL VARIATION AND INDIVIDUAL DIFFERENCES IN TBE PERCEPTION OF INTRACTABIE PAIN

Simon Folkard

MRC Perceptual and Cognitive Performance Unit, University of Sussex, Brighton.

C.J. Glynn and J.W. Lloyd

Pain Relief Unit, Abingdon Bospital, Abingdon, Oxfordshire.

A number of studies have indicated that there is a circadian (around 24 hours) rhythm in the sensitivity to painful stimuli, The earlier studies in this area used electric shocks applied to either the teeth or skin, and found the sensitivity to these shocks to show a similar circadian rhythm to body temperature. Thus sensitivity was found to be lowest at 04.00, and to increase over most of the day reaching a maximum at 18.00. These early studies are reviewed by Kleitman (1963), who also reports that in one of the studies there was a direct relationship between the circadian variations in body temperature and those in pain sensitivity in the two subjects studied. These subjects also showed a relationship between pain sensitivity and changes in body temperature mediated by their activity.

More recent work by Procacci and his associates using thermal stimulation has confirmed the presence of a circadian rhythm in pain sensitivity (e.g. Procacci et al, 1974), but has failed to explore the relationship between pain sensitivity end body temperature. Further, it has followed the early work in examining the sensitivity of normal healthy adults to an externally applied painful stimulus. It is unclear as to whether a similar circadian rhythm exists in the sensitivity to pain secondary to organic disease. Thus the main aim of the present study was to determine whether there is a circadian rhythm in the intensity of the pain experienced by patients with intractable pain. As the experience of such pain is essentially subjective (Merskey, 1973), we were forced to rely on the patients ratings of their pain rather than on objective measures. Since this necessitated measures being taken only when the patients were awake, the study was strictly one of diurnal variation (variation over the 'waking day') rather than of circadian rhythm.

The present study was also concerned with the consistency of the relationship between pain sensitivity and body temperature (reported by Kleitman, 1963) in these patients, and with examining the possibility of a relationship between pain sensitivity and alertness. Although there appears to be no evidence for the presence of this latter relationship, hospital staff frequently comment that patients seem to experience most pain when they are trying to get to sleep and are presumably relatively drowsy. Finally, the study was concerned with whether the diurnal variation in pain intensity, if it existed, differed for different patients. While this question would appear to have received no consideration in the work on shock sensitivity, it is well established that individual differences dc exist in the circadian variation Of a variety of measures. Thus, for example, both the temperature and alertness ratings of introverts start rising earlier in the day than those of extraverts (Blake,

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1967; Folkard, 1975). If temperature or alertness proved to be related to pain intensity, then a similar difference might be expected in the diurnal variation of pain. From a practical point of view it was also clearly important to determine whether differences in the diurnal variation of pain were associated with any other easily identified characteristic of the patients

TRE PATIENTS

The 41 patients who produced sufficiently complete records for their results to be included in the analysis had an age range of 16 to 78 years. They were all suffering from intractable pain and were outpatients of the Pain Relief Unit at Abingdon Hospital. 8 were suffering from post-herpetic nemalgia, 5 from cancer, 8 from low back pain, and the remaining 20 from a variety of conditions including phantom limb, atypical facial neuralgia, causalgia etc. 25 of them were male and 16 female, while 18 went out to work and 23 typically stayed at home during the day.

PROCEDURE

A number of patients with intractable pain were asked to report on its intensity every two hours from 08.00 to 22.00, for seven successive days, using a visual analogue scale (Merskey, 1973). They were also asked to record their subjective alertness using a similar scale, and their oral temperature using a standard mercury thermometer inserted sublingually for three minutes. The visual analogue scale consisted of a 10 cm horizontal line with its ends labelled Pnonel and 'greatest' in the case of pain, and 'drowsiest' and 'alertest' in the case of alertness. For the pain scale subjects were told that the extreme left of the line represented no pain, and the extreme right the greatest pain they had experienced. They were instructed to put a mark on the line to indicate how intense their pain was at the time. Similar instructions were given for the alertness scale.

Each patient was issued with seven booklets, one for each day of the study. A separate pege was used for each reading in an attempt to minimise the degree to which the readings were influenced by one another. Provision was made on the 'temperature pages' for the patients to comment on any of the readings. All the patients were shown examples of how to use the scales, and were given detailed verbal instructions. The visual analogue scales were scored by measuring the distance of the patient's mark in centimetres (to the nearest millimetre) from the extreme left hand end of the line. Thus the possible range of scores was 0.0 to 10.0, with high scores indicating higher levels of alertness cr pain than low scores. In order to examine potential day of the week effects, unconfounded by possible 'practice' effects, approximately equal numbers of patients started the study on each day of the week.

The patients also completed an Eysenck Personality Inventory (Eysenck & Eysenck, 1963) which yields scores on the personality dimensions of Extra- version, Neuroticism, and 'Social Conformity'. Details were kept of the sex and age of the patients, as well as whether they typically went out to work during the day or stayed at home. In addition, details were available on the cause of their pain and the type of treatment they were receiving during the study.

RESULTS

Complete records were obtained from 39 patients, while a further 2 patients

completed all but the temperature records. Any patient who had omitted more than 2 readings at any one time of day having been excluded. Three lines of

analysis were undertaken. The first was concerned with establishing whether

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there was a diurnal variation in the measures recorded. The second with the relationship between pain intensity, oral temperature, and alertness; and the third with individual differences in the diurnal variation of pain intensity.

Diurnal variation

The diurnal variation in the three measures was enalysed in two ways. First, analyses of variance were performed in order to determine -whether there was any reliable time of day effect. Theseanalysesalso examined the possibility of there being (a) day of the week effects, and (b) interactions between time of day, and day of week. Secondly, a form of analysis commonly used in circadian rhythm studies was performed. This involves the computation of the sine curve with a 24 hour period that best fits the data. While this form of analysis makes a number of assumptions about the nature of the circadian rhythm, it yields estimates of both the amplitude and acrophase (or 'pesk') of the rhythm. In the present study the method used was that described hy Fort & Mills (1970).

FIG. 1. The diurnal variation in pain intensity (solid line ,

1 and the best fitting 24 hour sine curve (broken

line .

The analysis of variance based on the reported pain scores indicated that there was a highly reliable diurnal variation, (F = 4.99; df = 7,280; p<O.OOl) but no effect of day of week, and no suggestion that the diurnal variation differed with the day of the week. The diurnal variation in the pain scores, and the corresponding portion of the best fitting sine curve are shown in Figure 1. The reported pain clearly increased over most of the day, with the exception of two slight 'peaks at 12.00 and 18.00. The best fitting sine curve showed a highly significant fit (F = 66.26, df = 2,53; p< O.OOl), and estimated the acrophase (or 'peek') of the rhythm to occur at 20.27 hours. The shape of this diurnal variation in reported pain intensity is similar to that reported for the sensitivity to painful electric shock, except that while Kleitman

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(1963) reports sensitivity to be at a maximum at 18.00, and to decrease after that time, the patients in the present study reported their maximum pain intensity somewhat later.

The temperature readings also showed a highly significant diurnal variation (F = 16.65; df = 7,266; p<O.OOl), and were well fitted by a 24 hour sine curve (F = 77.43; df = 2,55; p-~O.O01). This is shown in Figure 2. The sine curve analysis estimated the acrophase of the temperature rhythm to occur at 19.02. While this is over an hour earlier than that of the pain intensity rhythm, in general these two rhythms were fairly similar, suggesting that these measures might be related.

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FIG. 2. The diurnal variation in oral temperature (solid line), and the best fitting 24 hour sine curve (broken line).

The diurnal variation in alertness (Figure 3) was also highly significant (F = 33.71; df = 7,280; p<O.OOl) as was the fit of the sine curve (F = 174.63; df = 2,55; p40.001). However, consistent with previous studies (e.g. Folkard,

1975), alertness showed a far earlier peak than either pain or temperature, the acrophase of the fitted sine curve occuring at 14.53.

Relationship between measures

In order to determine whether a relationship existed between the reported pain intensity and either subjective alertness or oral temperature, correlation coefficients were computed for each of the 39 patients with complete records between their 56 pain ratings, alertness ratings, and temperature scores. Of these patients, ten showed significant (~(0.05) correlations between their pain ratings and their oral temperatures. Eight of these 10 patients showed a positive correlation indicating a tendency for higher pain ratings to be associated with higher oral temperatures. The remaining two showed a negative correlation, indicating that for them higher pain ratings tended to be associated with lower oral temperatures. Thus four times as many patients showed a statistically reliable positive correlation as showed a reliable

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FIG. 5. The diurnal variation in alertness ratings (solid line), end the best fitting 24 hour sine curve (broken line).

negative correlation. While this find& tends to support that of Kleitman (1963), that temperature and pain sensitivity show a direct relationship, it has to be offset against the fact that this relationship was reliable for less then a quarter of the patients studied. Indeed the average of the 39 correlations between pain and temperature was effectively zero (+0.05), indicating that there was little consistency in the relationship between these measures.

Rather more patients (17 out of 39) showed reliable (pcO.05) correlations between their pain ratings and their subjective alertness scores. Of these seventeen, IO showed a positive relationship (higher pain associated with higher alertness), and 7 a negative relationship (higher pain associated with lower alertness). The average of the correlations between pain and alertness was again effectively zero (+0.02) indicating that there was little consistency in the relationship between pain and alertness. Nevertheless, the fact that a reasonable proportion of the patients showed a reliable relationship between these two measures, together with the fact that some showed the opposite relationship to others, suggests quite strongly that there may be marked individual differences in the diurnal variation of the measures taken.

Individual differences in the diurnal variation of pain

This third line of analysis was concerned with whether the nature of the diurnal variation in pain described above was general to all the patients studied, or whether there were differences between easily identifiable sub- groups of patients. The factors by which these subgroups were identified can be conveniently classified under three main headings, (i) medical, (ii) personality and (iii) general. In all cases comparisons between the various subgroups were made using analyses of variance with pooled within-subject

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error terms, since there was no significant heterogeneity of the error mean squares.

(i) Medical Factors

Two 'medical' factors were considered, the first being the organic cause of the pain, and the second being whether or not the patients were taking some form of treatment, and if so whether this was on a regular or irregular basis.

There was no significant difference in the diurnal variation of the pain associated with the differences in the organic cause of the pain descri.bed above. However, since there were relatively few patients with any given complaint, it is not possible to conclude that the organic cause of the pain has no effect on its diurnal variation. Nevertheless, if such an effect does exist, it would appear to be relatively small in comparison to those discussed below. Nor was there any significant difference between the patients taking no treatment to relieve their pain, and those who were; or between those patients who received regular treatment (i.e. at 4 to 6 hourly intervals) and those who took analgesics or used a trans-cutaneous stimulator only when required. this is not to say that a difference would not be found in a larger sc~~~~udy.

(ii) Personality Factors

The Eysenck Personality Inventory administered to the patients in this study yields scores on the personality dimensions of Extraversion (E) and Neuroticism (N). It also yields scores on a 'Lie scale' (L) which is essentially a check on whether people *fake good' on the E and N scales. These L scores can be considered as a measure of social conformity. However, since preliminary analysis indicated that there were no differences in the diurnal variation of pain associated with the L scores, when the influence of other factors had been controlled for, this factor was ignored in the following analysis.

In the present sample of patients, 18 had E scores of 15 or less and could thus be considered to be relatively introverted, while 19 had E scores of 15 or more and could be considered as being relatively extraverted. Of these 57 patients, 18 had N scores of 15 or more and could be considered as relatively neurotic, while 19 had N scores of 11 or less and could be considered as relatively stable. By excluding one patient with an E score of 15 and an N score of 11, four subgroups, i.e. stable-extraverts, stable-introverts, neurotic-extraverts, and neurotic-introverts, of 9 patients each were formed. It should be emphasised that these terms are used in a relative sense, only five of the 41 patients failing to appear in one or other subgroup.

The analysis of variance indicated that there was a significant interaction between extraversion and time of day in the pain scores (F = 2.62; df = 731760; p co.05). !&is interaction appears to be largely due to the fact that the introverts reported rather more pain than the extraverts between the hours of 10.00 and 14.00 but approximately the seme amount at other times of day (Figure 4). in alternative way of expressing this difference, which is more consistent with the differences known to exist between the circadian rhythms of introverts and extraverts in both body temperature (Blake, 1967) and subjective alertness (Folkard, 1975), is to say that the curve of extraverts is 'phase shifted' relative to that of introverts, i.e. while the main rise in pain for introverts took place between 08.00 and 12.00, that for extraverts took place between 14.00 and 18.00; approximately six hours later. This interpretation could also account for the fact that the pain ratingsof extra-

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verts, but not introverts, dropped from 08.00 to 10.00 since a difference in phase would imply that the extraverts should show a later fall, as well as rise, than the introverts in their pain ratings.

There was also a significant interaction between neuroticism and time of day in the pain scores (F = 2.96; df = 7,176O; p< 0.01). As in the case of the difference associated with extraversion, the difference between 'neurotics' and 'stables' is perhaps best described as a phase shift (Figure 5) with the latter group's diurnal variation showing a zatherlaterrise. This difference is somewhat unexpected since there is little evidence in the literature that the circadian rhythms of these groups differ. Nevertheless the difference is fairly large and cannot be accounted for in terms of the other factors found to influence the diurnal variation in pain. Finally, there was no evidence of an interaction between extraversion, neuroticism, and time of day. Thus the difference between introverts end extraver-;;s would appear to be independent of that between neurotics and stables.

(iii) General factors

The general factors examined were age, se:&, and whether the patient typically went out to work or stayed at home duri%> the day. Originally this last factor was concerned with whether the patient had retired or was still working. However, a preliminary inspection of the results suggested that the important factor was not work per se, but whether the patient went out to work. !rhus houseworking females showed a diurnal v.Ariation in their pain that was far more similar to that of females who had retired, than to that of females who went out to work.

A comparison of the 21 patients who were 55+ with the 20 patients who were less than 55 indicated that there was uo significant effect of age on the diurnal variation in pain intensity, when other factors had been controlled for. However, an analysis of variance comparing the 16 female with the 25 male patients indicated both that the females rated their pain as more intense overall (F = 5.96; df = 1,39; p<O.O5), and that there was a highly significant interaction between sex and time of 'day (F = 6.31; df = 7,2145; p<O.OOl).

It is clear from Figure 6 that, while both sexes reported a similar pain intensity at 08.00, the increase in pain scores over the day was far greater in females than males. However, since the main difference between the sexes was clearly in the magnitude of the time of day effect, rather than its 'Shilpe', it is possible that it was due to differing interpretations of the visual analogue scale rather than to.sny 'real' difference in the intensity of the pain experienced. Thus the males may have been less willing than females to admit to high levels of pain, especially since all the experimenters were male.

A further analysis of variance was performed comparing the pain scores of the patients who typically stayed at home with those of the patients who went out to work. This indicated both that those who stayed at home reported more pain (F = 5.94; df = 1,39; p< 0.05), and that there was an interaction between whether or not the patient went out to work and time of day (F = 6.74; df = 7,2145; p<O.OOl). This difference is shown in Figure 7, from which it is clear that these two groups showed very different time of day effects. The reported pain of these two groups was similar at 08.00. However, while that of the 'home' group rose rapidly to 12.00 endthenremained relatively constant over the rest of the day, that of the 'work' group decreased from 08.00 to 10.00 and remained relatively low until 18.00. Indeed even in the evening, when both groups were presumably at home, the 'work' group rated their pain as rather less intense than the 'home' group.

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FIG. 4. The diurnal variation in pain for introverts (n = 18) and extraverts (n = 18).

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FIG. 5. The diurnal variation in pain for neurotics (n = 18) and stables (n = 18)

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. .’

FIG. 6. The diurnal variation in pain for males (n = 25) and females (n = 16).

FIG. 7. The diurnal variation in pain for those patients who stayed at home (n = 23) compared to those who went out to work (n = 18).

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This difference in the pain experienced by these two groups clearly emphasises the fact that pain is 'something that happens in the mind' (Merskey, 1973). Thus, although pain is normally attributed to physical events affecting the body, its experience is subjective and presumably dependent on the degree to which it is attended to. Indeed, it has been argued that we have to 'learn' to experience it (Merskey, 1970).

The difference between the home and work groups would also appear to be largely responsible for the inconsistencies in the relationship between the alertness and pain ratings. The majority (7 out of 10) of the patients who showed a reliable positive correlation between alertness and pain typically stayed at home, while 5 of the 7 patients who showed a reliable negative correlation between these measures went out to work.

A final analysis of variance indicated that there was no significant inter- action between sex, 'home' versus 'work', and time of day. Thus the difference in the time of day effect between males and females occurred whether or not

FIG. 8. !Jhe diurnal variation in pain for Females at home

~&=N~:!~ at work (n = 13) Females at work (n = 5), Males at home (n = 12)

.

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they stayed at home or went out to work. !t%is can be seen quite clearly in Figure 8 in which the time of day effect is plotted separately for these four subgroups. It should be noted that the 'Females at work' curve is based on only 5 patients and may thus be rather less representative than the other three curves. Nevertheless it is clear from Figure 8 that females, whether or not they went out to work, showed a far greater rise in pain ratings over the day than males. For those females who stayed at home the main rise occurred between 08.00 and 12.00, while for those who went out to work it was rather later. The males who stayed at home showed a similar, but less pronounced, time of day effect to the females who stayed at home. In contrast, the pain ratings of the males who went out to work showed a marked decrease from 08.00 to 10.00, and. remained below the 08.00 level until 18.00, by which time most of them had returned home. Indeed the pain ratings of 'males at work' appear to have been rather more influenced by whether or not they were at work than by the time of day. Thus, only in this subgroup were the 08.00 and evening readings virtually the same.

Finally, a check was made to detkrmine whether the sex, and 'home' versus sworkf, differences were confounded with the personality differences reported above. There were no significant differences between these pairs of groups on either the E or N scores. Thus the differences in the time of day effect associated with personality, sex, and 'home' versus 'work' would appear to be independent of one another.

DISCUSSION

These results clearly indicate that there is a diurnal variation in the intensity of the pain experienced by patients with intractable pain. Since the nature of this diurnal variation was unaffected by the organic cause of the Pain, it seems probable that this variation reflects changes in the sensitivity to Pain, rather than changes in the organic disease associated with the circadian rhythm of various physiological processes.

In general the diurnal variation in the pain intensity ratings was similar to that reported by Kleitman (1963) for the sensitivity to painful stimuli. However, there was little evidence to support Kleitman's claim of a direct relationship between pain sensitivity and body temperature. While a few of the subjects did show such a relationship, there was little consistency from subject to subject. This lack of consistency was even more marked in the case of the relationship between the pain and alertness ratings, but in this case there was some evidence that the inconsistency was due to individual differences in the diurnal variation of reported pain intensity.

Fairly large and reliable individual differences in the diurnal variation of reported pain were found to be associated with the sex of the patient and with whether the patient went out to work. Rather smaller, but still reliable, differences were associated with the personality dimensions of EMraversion and Neuroticism. Thus from a practical point of view these findings suggest not only that patients require different amounts ofanalgesics at different times of day, but also that factors such as whether the patients go out to work, their sex, and their personality should be taken into account. Of these factors, the first two would. seem to be the more important since rather larger differences were associated with them. In addition, taking account of personality is complicated by the fact that it is known to be associated with differences in drug sensitivity (e.g. Claridge, 1974).

There are also complications in taking account of the diurnal variation in pain, and the influence of sex and going out to work. Thus, for example, there may be individual differences in the relationship bet-n the time elapsed since administering analgesics, and their blood level. Effective analgesia

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will only result if the maximum blood level occurs at the same time as the peak in pain. Nevertheless it is clear that the taking of drugs should anticipate periods of high pain intensity, rather than wait for them to occur. Despite such complications, the present results do have implications for the effective treatment of pain. It is clearly advisable to make patients aware of the diurnal variation they are likely to experience in the intensity of their pain, and to encourage those who take drugs when required to anticipate, rather than wait for, peaks in their pain. It would also seem advisable to encourage patients, wherever possible, to engage in some form of activity during the day that gets them out of their homes and in contact with other people

In conclusion, these results emphasise the need for patients with intractable pain to receive 'individually optimised treatement', and give some indication as to how this might be achieved by pointing to some of the important factors to be taken into account.

41 patients with intractable pain rated its intensity on a visual analogue scale at two hourly intervals, from 08.00 to 22.00, for seven successive days. These pain ratings were found to exhibit a marked diurnal variation. Differences in this diurnal variation were associated with the personality and. sex of the patient, and with whether or not the patient typically went out to work during the day. For the majority of the patients the variations in reported pain intensity were unrelated to those in oral temperature and alertness ratings. The implications of these results for the effective relief of pain are discussed.

Acknowledgements

We should like to express OUT gratitude to all the patients who took part in this study, to Ann Fort who allowed us to use her sine curve program, and to Timothy H. Monk who implemented it.

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Blake, M.J.F. (1967) Relationship between circadian rhythm of body temperature and introversion-extraversion. Nature, m, 896-897.

Clariclge, G. (1974) Individual differences in drug response. Paper presented to 18th Annual Conference of Sot. Psychosom. Res.

Conroy, R.T.W.L. & Mills, J.N. (1970) Human Circadian Rhythms. London: Churchill.

Eysenck, H.J. & Eysenck, S.B.G. (1963) Eysenck Personality Inventory. London: University of London Press.

Folkard, S. (1975) The nature of diurnal variations in performance and their implications for shift work studies. In P. Colquhoun, S. Folkard, P. Knauth, and J. Rutenfranz (eds), Experimental studies of shift work. Westdeutscher

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Fort, A. & Mills, J.N. (1970) Fitting sine curves to 2qh urinary data. Nature, 226, 657-658.

Kleitmsn, N. (1963) Sleep and wakefulness. Chicago: University of Chicago

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Merskey, H. (1970) On the development of pain. Headache, IO, 116-123.

zskey, H. (1973) The perception and measurement of pain. J. Psychosom. s., 2, 251-255. -

Moore Ede, M.C. (1963) Circadian rhythms of drug effectiveness and toxicity. Clinical Pharmacology and Therapeutics, 14, 925-935.

Procacci, P., Carte, M.D., Zoppi, M. & Maresca, M. (1974) Rhythmic changes of the cutaneous pain threshold in man. A general review. Chronobiolo~ia, ?_, 77-96.