The influence of anxiety and pain sensitivity on experimental pain in man

253

Pain, 4 (1978) 253-263 0 Elsevier/North-Holland

THE INFLUENCE EXPERIMENTAL

Biomedical

OF ANXIETY AND PAIN SENSITIVITY PAIN IN MAN

BEAT VON GRAFFENRIED, RENfi SPIEGEL (B.ll.G., E.N. Pharmaceutical University of (Switzerland) Frankfurt am

(Accepted

Press

ROLF ADLER,

KLAUS

ON

ABT, ERICH NUESCH

and

and R.S.) Experimental Therapeutics, Biological and Medical Research, Division, Sandoz Ltd., CH-4002 Basle, (R.A.) Medical Faculty of the Berne, Department of Medicine, Ilniversity of Berne, CH-3000 Berne and (K.A.) Department of Riostatistics, J. W. Goethe University, D-6 Main 70 (G.F.R.)

June 17th,

1977)

SUMMARY

A study was made of a number of factors that might be responsible for the unreliable results obtained in experimentally induced pain in man. In a randomised, double-blind, cross-over study on 32 healthy, male volunteers, the ischaemic pain test [14] and several psychological tests were performed. The influence of the following factors on the pain test results were examined: (a) ingestion of single, oral doses of 1000 mg aspirin (ASA) and placebo, (b) practice effect, (c) initial pain sensitivity, (d) anxiety, coping behaviour, attitude to the experiment and personality factors. The analgesic activity of ASA could not be demonstrated. An interaction between primary pain sensitivity and the sequence of drug administration was found. Furthermore, anxiety had a marked influence on the test results. Using experimental pain models reliable results are not to be expected as anxiety fluctuates intra- and interindividually in an unpredictable and uncontrollable manner.

INTRODUCTION

There is a need for a reliable experimental screening method in man to test new mild analgesics. Despite the invention of a wide variety of experimental pain models, the results obtained have been contradictory. The purpose of the present study was to investigate, in a systematic way, a number of the factors which might be responsible for the different results obtained in one test, namely the “submaximum effort tourniquet test (SETT) [13,14].

254

The factors which were investigated were: (a) practice effect when repeating the pain tests; (b) primary pain sensitivity which Moore et al. [ 111 have suggested to be important; and (c> psychologic~ factors like anxiety, coping behaviour, attitude to the experiment and personality which have been shown by Adler [3,4] to influence the ability to discriminate mild analgesics from placebo. ~~ATERIALS

AND METHODS

Popula lion and experimental design The study was performed as a double-blind, cross-over trial in 32 healthy, male students (age range 22-33 years). The effects of 1000 mg aspirin (ASA) and of placebo were compared. For all subjects, pain tests were carried out on 3 occasions: a pre-treatment trial session (I) and 2 treatment sessions (II, III). The interval between the sessions was always 2 weeks. For each subject the tests were performed on the same day of the week and at the same time of day. The subjects were asked to abstain from alcohol on the evening before the trials and to go to sleep at regular hours. Ingestion of any drugs was forbidden during and for the 24 h preceding each test. Session I began with each subject being individu~ly informed in a uniform manner by one investigator (BvG). Emphasis was laid on the harmlessness of the pain test. Immediately afterwards, the questionnaires (Q) 1 (Freiburg Personality Inventory (FPI) [S]) and Q 2 (state anxiety, coping behaviour, attitude toward experiment) were completed. The pain test was then performed, at the end of which an account of the test experience by the subject was recorded on tape. Finally Q 3 (similar to Q 2) was filled out. In sessions II and III the procedure was repeated with the following modifications. Immediately after arrival the subjects received orally a single dose of either 1000 mg ASA (2 X 500 mg capsules) or placebo (2 capsules), the interval since the last light meal being at least 1 h. The randomisation plan took into account the sequence of drug administration, the time of the test, and the initial pain sensitivity (see below). In session II the subjects were additionally required to complete Q 4 (Taylor Manifest Anxiety Scale (TMAS) [ 151). Sixty minutes after ingestion of the test substance, the same procedure was adhered to as in session 1. ~ec~n~~ue used for pain j~d~ct~on and evaluation procedure The “submaximum effort tourniquet technique” [14] was used with the modification that the “effort” was reduced from 20 to 10 squeezes in order to achieve a slower increase of pain intensity over time, thereby extending the time span during which a mild analgesic such as aspirin could be expected to be effective. Each subject rated his continuously increasing pain at fixed, but irregular intervals (1-2 min) on a visual analogue scale of 100 mm length. Its left end was marked with “no pain” (= 0 mm) and its right end with “unbearable pain” (= 100 mm). A new sheet was presented for each rating by the experimenter who was the same for all 96 tests. The trial

255

was terminated 40 min after cessation of the “effort”, unless the subject reached the endpoint “unbearable” earlier. The subject was not able to check time in order to prevent him from trying to compare his performance with that of the preceding tests. The pain ratings (measured to the nearest mm) were plotted on a graph, thereby obtaining “pain curves” which were used for further analysis (Fig. 1). From these curves the time in minutes was read corresponding to the pain intensities 25 mm, 50 mm, 75 mm and 100 mm. In addition, an “analgesic index” (AI) was derived. For this purpose, only the range on the pain curves between the pain intensities 25-75 mm was used, which was divided into steps of 5 mm thereby providing 11 degrees of pain intensity_ The AI was obtained by counting how many points of intersection on the ASA curve with the 11 degrees of pain intensity were located to the right of the corresponding points on the placebo curve. This figure was expressed as a percentage of the maximum number possible (Il.). An AI of more than 50% means therefore that the subject experienced less pain during the ASA experiment than under placebo. By comparing the curves of the 3 trials (I, II, III) without taking into account the administered drugs,

o,, 0 1

,I,

,

,

3 4 5.5 7.5 9

Minutes

,,

,,

1112.514.516 13.5

,

18

,

,

f

20 21.5 23.5 22.5

Fig. 1. Example of a pain curve. Subject 19, S.U., 1953. AI = 0%: O/l1 points of intersection with the 5-mm pain intervals on the ASA curve are to the right of the placebo curve. AI III/II =: 100%: ll/ll points of intersection with the 5-mm pain intervals on test III curve are to the right of the test II curve.

256

the AI 11/I and III/II were calculated. Additionally, the time differences in minutes between the 11 points of equal pain intensity on the different curves were measured and the median calculated (At). The pain intensity range of O-25 mm (“very mild”) and 75-100 mm (“very severe”) was omitted for the derivation of AI. Assignment

of the subjects

to different

groups of pain sensitivity

Depending on the time that elapsed before the pain level of 75 mm was reached in test I (tTsI), the subjects were divided into 3 groups. Group 1 included the 8 subjects with the shortest tTsI (range 2.8-10.0 min) and designated the “high pain sensitive group”. Group 2 contained 16 intermediate subjects (range 10.3-19.4 min) and group 3 the 8 subjects with the longest tJ (range 19.5-40.0 min), the so-called “low pain sensitivity group”. Assessment

of psychological

factors

In addition to the above mentioned Q 1 (FPI) and Q 4 (TMAS), two questionnaires (Q 2 and Q 3) were used for the assessment of state anxiety, coping behaviour and attitudes towards the study and the investigator. Both questionnaires Q 2 and Q 3 were presented in the form of a visual analogue scale [ 51 (Tables I and II). Immediately after the pain test each subject was asked to give an account on tape of their experience during the test with respect to their feelings, thoughts and fears. The tapes were later analysed by one investigator (R.A.) under blind conditions. Anxiety (TR A), coping behaviour (TR C) and attitude-relationship (TR R) were rated on a 4-point scale (O-3) by means of rating scales previously described [ 3,4]. Statistical methods

The AI values were constructed as to have values of a rational scale, in contrast to the At data that belong to an ordinal scale. The main analysis was a non-orthogonal analysis of variance (NOVACOAl [l]) with the arc sin JAI transformed values testing the hypothesis of no sequence effect of drug application (oi = 0), no effect of the different groups TABLE

I

QUESTIONNAIRE a) b) c) d) e) f)

Q 2 (BEFORE

PAIN

I am completely calm and relaxed This test is completely harmless I am extremely anxious I have not the slightest interest in the results of this study I am in a very bad mood today I will try to endure the pain as long as possible

TEST) -

____ I am very excited and tense This test carries great risks I am not anxious at all The results of this test interest me enormously I am in an excellent mood today The time for which I endure the pain is of absolutely no interest to me

257 TABLE

II

QUESTIONNAIRE

Q 3 (AFTER

PAIN TEST)

The items of Q 2 and Q 3 were measured from left to right to the nearest mm. The items Q 2a, b and c and Q 3a and c aimed at assessing anxiety, and were added to form anxiety indices: Q 2A = Q 2a + Q 2b + (100 - Q 2c) (scale O-300) and Q 3A = (100 - Q 3a) + Q 3c (scale O-200). a) b) c) d) e) f)

I was extremely anxious The pain was much worse than I had expected For a long time I was completely relaxed I find it inexcusable, that such tests are performed I have tried extremely hard to distract myself from the pain I was never successful in distracting my attention from the pain

-

I was not anxious at all The pain was not at all as bad as I had expected I was soon very excited

-

I have not the slightest objection to such tests I have in no way tried to distract myself from the pain For a long time I was very successful in distracting my attention from the pain

-

of pain sensitivity (flj = 0) or interaction 0) with the following statistical model: Y,k =

I-( + Qli +

flj + (~P)G +

Eijk ; Eijk = N (0,

between

those two factors ((afl)ij =

a2)

If the hypothesis of no interaction could be accepted, we tested the hypothesis of equal drug effect with the t-test of the transformed mean values of AI against the transformed value 0.5 (50%). One-way analysis of variance, the test of Kruskal and Wallis, the test of Wilcoxon, Mann and Whitney, Friedman’s test, Spearman’s p of rank correlation and linear multiple regression methods were used according to the scale niveau of the tested parameters to demonstrate interrelations between the psychological data, pain sensitivity and the pain test results [ 2,7,12]. RESULTS

Pain test data

Since the At data corresponded to the AI results, the former have not been presented. Effect of test drugs (Table III). It was not possible, either by examining the times corresponding to the 4 arbitrarily chosen pain intensity levels (25, 50, 75 and 100 mm), or by comparing the AI, to demonstrate an analgesic effect with 1000 mg ASA (mean AI = 45%, 95% confidence range 29-61s). Effect of order of sequence, interpreted as practice effect (Tables IV and V, Fig. 2). For the whole subject sample a small, non-significant continuous practice effect emerged. However, the different pain sensitivity groups behaved significantly slifferent. The highly pain-sensitive subjects became

258 TABLE

III

DRUG EFFECTS Median values pain intensities cebo (n = 32). .~I

(95% confidence range) of the time (mint elapsed for the induction of 4 (25, 50, 75, 100 mm) after the administration of 1000 mg ASA and pla-. __---_

---

Treatment

25 mm

50 mm

75 mm

100 mm

ASA

5.1 (4.1-7.6)

11.5 (8.8-14.2)

17.0 (12.2-21.5)

28.2 (21.5-32.6)

Placebo

6.9 (4.6-8.6)

12.4 (9.9-13.9)

17.1 (l-1.5----19.4) - “--- ..-____

27.3 (21.7-33.0)

more tolerant throughout all 3 tests (P < 0.05 for pain level 75 mm; r, = -0.51, P < 0.01 for AI II/I -tJ). The low pain-sensitive subjects, however, showed initially a large negative and later a considerable positive practice effect. The intermediate group developed a small, non-si~i~tcant practice effect in all tests.

Anxiety in the pain test situation. Significant and highly significant correlations between the different anxiety parameters (Q 2A, Q 3A, TR A) were found and were, therefore, combined by simple addition to give a “total anxiety index” (TA):

TA=Q2A+Q3A++RAXloo 3

3

2

(scale 0-300)

Additions significant correlations were found between anxiety items and Q 2e, Q 36, Q 3f, TR C and TR R (rS values 0.35-0.80; P < 0.05-0.001). It appears, therefore, that bad mood (Q 2e), objections to the pain test (Q 3d),

TABLE EFFECT

IV OF ORDER

Median values pain intensities Test no. I II III

OF SEQUENCE

(practice

effect)

(95% confidence range) of the time (mm) elapsed for the induction (25, 50,75, 100 mm) in test I-III (n = 32). .--25 mm 50 mm 75 mm 100 mm __-5.2

9.7 (8.4-12.2) 11.8 (9.4-12.9) 12.7 (9.5-14.2)

(2.2-6.9) (k-7.5) 7.5 (4.1-8.8)

-

14.4 (11.4-19.0) 17.1 (13.3-19.4) 17.1 (14.5-20.9)

27.7 (21.4-20.5) 27.8 (21.7-34.5) 28.8 (21.1-36.2) --

of 4 --

-

259 TABLE

V

EFFECT

OF ORDER

OF SEQUENCE

(practice

effect)

Mean values of AI (W) II/I and III/II. AI % II/I All subjects Group Group Group

(95%

confidence

58

range)

1 n = 8 (high sensitivity) 2 n = 16 (intermediate) 3 n = 8 (low sensitivity)

Group

1 lhlghly

sensitlvei

AI % III/II

(41-73)

;:6-76)

74 64 30

57 53 73

a

n

mm

B

Test

I

c--d

Test

II

c.4

Test

Ill

I

Group

2 iintermedlatei

n

16

Group

3 AOW sensltlvel

n

a

I

30

40 ml”

30

40 ml”

mv

25

Tlrr

0

10

20

Fig. 2. Effect of order of sequence (practice elapsed for the intluction of 4 pain intensities; tivity groups.

effect). subjects

Median values of the time (min) separated into different pain sensi-

260

extensive use of coping manoeuvres (Q 3f, TR C) and negative attitude towards the experiment (TR R) also indicate anxiety. In the course of the 3 sessions, anxiety diminished continuously for the subjects as a whole group (TA I 83.5 (95% confidence range 55-89), TA II 75.0 (34-88), TA III 52.0 (26-91)). Again, however, the 3 sensitivity groups reacted differently. The highly pain-sensitive subjects had significantly higher anxiety scores in the third trial than in the second trial (H = 6.07, P < 0.05) (Fig. 3). The increase of anxiety in the two treatment trials correlated with pain sensitivity (r, = 0.36, P < 0.05). On the other hand, there was no difference in anxiety between the 3 groups in the pre-treatment trial, e.g., the highly sensitive subjects were not more anxious a priori. A correlation matrix, in which all data of the 3 tests and their changes from one test to the next were taken into account (174 items for each subject), contained 1296 correlations between the different state-anxiety parameters and the pain test results. Of these, 107 were found to be significant (P < 0.05-0.001). Without exception, these relations could be interpreted in the same manner: the more anxiety increased from one test to the next, the shorter was the time taken to reach an identical pain level, i.e., the subject was less pain tolerant. Subjects who were not anxious, i.e., decreased their anxiety in the course of the trials, became more pain tolerant as the trial progressed and, therefore, showed a positive practice effect. This applied to anx-

TA

mm

Group highly n 8

1 sensltlve

60 Group 2 IntermedIate n 16 Group 3 low sensitive n 8

i

Test

,_.____.._

Test I’I

Test III

* p

0.05

__.___.^_ ______._--;

Fig. 3. Anxiety pain sensitivity

(TA) in the 3 sessions. groups.

Median

values; subjects

separated

into different

261

iety evaluated both before (Q 2) and after the pain test (Q 3, TR). TMAS (trait anxiety). The TMAS scores showed no close correlations with the state-anxiety parameters of trials II and III. However, there was a significant correlation of TMAS to Q 2A (r, 0.56, P < 0.01) and TA (r, 0.37, P< 0.05) in the pre-treatment trial I. As Q 2 I was completed before the first pain test, and hence included trait anxiety, this correlation was to be expected and validated the questionnaire. TMAS correlated well with TR C (P < O.Ol), i.e., anxious subjects had a strong tendency to distract themselves from pain. Coping manoeuures. Beside the above-mentioned relationship to TMAS and state anxiety a positive correlation was found to primary pain sensitivity (TR C - t,,I r, = 0.40, P < 0.05; Q 3f - t,,I rp,= 0.57, P < 0.01). “Relation” items and the FPI contriOther psychological parameters. buted nothing to the main goals of the study. No personality pattern, which would have been typical for pain sensitivity, practice effect or psychological behaviour in the pain situation, could be demonstrated. Discrimination between ASA and placebo The 15 subjects who had an AI of more than 50%, i.e., those subjects who experienced less pain under ASA than under placebo were designated as discriminators. Significant correlations between their ability to recognise the active drug and several psychological parameters (Table VI) showed that the discriminators were calm, not anxious, did not distract themselves from pain and were in a good mood.

TABLE

VI

SIGNIFICANT

CORRELATIONS

Sp = rank order correlation Items

TO “DISCRIMINATORS”

(Spearman);

U-test = U-test of Mann and Witney.

P<

Test

AI AI

TMAS TMAS

0.05 0.05

SP U-test

rs = -0.36 z = 2.00

AI

TR C II

0.05

SP

rs = -0.44

AI

TRCF

0.05

,SP

rs = -0.36

AI AI

FPI(1) FPI(l)

0.05 0.05

SP U-test

rs = -0.39 z = 2.06

AI AI

0.05 0.01

SP SP

rs = rs =

0.40 0.49

AI

Q 3e II Q 3e III II + III Q 3eT

0.01

SP

rs =

0.48

AI

II + III Q 3eT

0.05

U-test

z =

2.47

AI

Q3fv

0.05

U-test

z =

2.15

262 However, these conclusions have a limitation, because the sequence of drug administration was not balanced among the discriminators (9 times placebo-ASA, 6 times ASA-placebo). DISCUSSION Although a high degree of standardization was achieved in respect to procedures and instruction of a homogeneous group of subjects and although the randomisation controlled possible influences of sequence of drug administration, time of day and primary pain sensitivity, we were, like Moore et al. [ 111, not successful in demonstrating the analgesic effect of 1000 mg of ASA using the ischaemic pain test (SETT). Contrary to Smith [13,14] and other authors [9] we feel that the SETT is not a reliable experimental method for testing mild analgesics in man. Two factors have emerged from the present study which might explain the contradictory results obtained not only with SETT but also with most conventional experimental pain models: the influence of primary pain sensitivity and of certain unstable psychological factors, mainly anxiety. Moore et al. [ll] have suggested that their failure to replicate the results of Smith et al. [14] might have been due to their sample of prisoner-volunteers, who were less pain sensitive than the students tested by Smith et al. [14]. In the present study it is clear that the 3 groups with different pain sensitivity showed different patterns with regard to the effect of practice. Whereas at the first repetition of the pain test, the highly pain-sensitive subjects became more pain tolerant and the low pain-sensitive less pain tolerant, the low pain-sensitive group had the largest practice effect at the second repetition. The formation of groups with different pain sensitivity and randomisation of the medication within each group was therefore advantageous as it prevented the practice effect from being interpreted as drug related. The second interfering factor in the pain test situation was anxiety. The degree of anxiety immediately before beginning each pain test (Q 2) had a considerable and highly significant effect on the pain-intensity time curve. The greater the increase of anxiety, the shorter was the time which elapsed before a certain pain level was reached; the greater the decrease of anxiety from one trial to the next, the greater was the practice effect. The pre-treatment trial did not stabilize the anxiety level as had been hoped, but instead it decreased sequentially from one trial to the next when the sample was significant differences existed considered as a whole. Again, however, between the 3 pain sensitivity groups but this time, the inter- and intraindividual changes were erratic. Anxiety appeared, therefore, to be an important but, unfortunately, uncontrollable variable which was not predictable by the psychological tests employed (TMAS, FPI). As in earlier studies (Adler et al. [ 3,4]), subjects who were able to discriminate mild analgesics from placebo showed the following characteristics: they were calm, showed a low degree of anxiety, were not engaged in distracting themselves from the pain situation and showed a positive attitude towards

263

the experiment and the investigator. These qualities correspond very well with the criteria which are known to be of importance in the selection of patients for clinical trials of mild analgesics. Even if not stated explicitly, they seem to have been effective in 2 experimental studies by other authors

[6,101. In conclusion, even if maximal standardization of the methodology is achieved, conventional experimental pain techniques do not seem to be suited for the investigation of the effect of mild analgesics. In addition to the primary pain sensitivity and the order of drug administration, a number of variables which determine the ability of the subjects to discriminate are unstable and unpredictable. Conventional screening tests like TMAS or personality inventories do not permit the behaviour and attitude of a subject in the pain test situation to be predicted. This, however, would appear to be vital for the selection of suitable subjects. REFERENCES 1 Abt,

2

3

4

5 6 7 8 9 10

11

12 13 14

15

K., The Method and Use of NOVACOM, a Program for “Non-orthogonal” Analysis of Variance and Covariance, U.S. Naval Weapons Laboratory Technical Report No. 2108,1967. Abt, K., Gemill, G., Herring, T. and Shade, R., DA-MRCA: a FORTRAN IV Program for Multiple Linear Regression, U.S. Naval Weapons Laboratory Technical Report No. 2036,1966. Adler, R., Gervasi, A., Holzer, B. and Hemmeler, W., Mild analgesics evaluated with II. The influence of a tranquilizer on the “submaximum effort tourniquet technique”. their effect, Psychopharmacologia (Berl.), 38 (1974) 357-362. Adler, R. and Lomazzi, F., Mild analgesics evaluated with the “submaximum effort tourniquet technique”. I. The influence of psychological factors on their effect, Psychopharmacologia (Berl.), 38 (1974) 351-356. Aitken, R.C.B., Measurement of feelings using visual analogue scales, Proc. roy. Sot. Med., 62 (1969) 989-993. Benjamin, F.B., Effects of Aspirin on suprathreshold pain in man, Science, 128 (1958) 303-304. Conover, W.J., Practical Nonparametric Statistics, Wiley, New York (1971). Fahrenberg, J., Selg, H. und Hampel, R., Das Freiburger Personlichkeitsinventar FPI, Hogrefe, Gottingen, 1970. Ferguson, R.K., Drug-test interaction in the submaximum effort tourniquet technique, Proc. Sot. exp. Biol. (N.Y.), 134 (1970) 1015-1019. Hill, H.E., Kornetsky, C., Flanary, H. and Wikler, A., Effects of anxiety and morphine on discrimination of intensities of painful stimuli, J. clin. Invest., 31 (1952) 473480. Moore, J.D., Weissman, L., Thomas, G. and Whitman, E., Response of experimental ischemic pain to analgesics in prisoner volunteers, J. clin. Pharmacol., 11 (1971) 433439. Sachs, L., Statistische Auswertungsmethoden, Springer, Berlin, 1969. Smith, G.M. and Beecher, H.K., Experimental production of pain in man: sensitivity of a new method to 600 mg of Aspirin, Clin. Pharmacol. Ther., 10 (1969) 213-216. Smith, G.M., Egbert, L.D., Markowitz, R.A., Mosteller, F. and Beecher, H.K., An experimental pain method sensitive to morphine in man: the submaximal effort tourniquet technique, J. Pharmacol. exp. Ther., 154 (1966) 324-332. Taylor, J.A., A personality scale of manifest anxiety, J. abnorm. sot. Psychol., 48 (1953) 285-290.