Pain, 38 (1989) 109-116

Elsevier

109

PAIN 01426

Conditioned response models of placebo phenomena: further support

Nicholas J. Voudouris, Connie L. Peck and Grahame Coleman

Department of Psychology, Lo Trobe University, Bunabora, Victoria 3083 (Australia)

(Received 24 January 1989, accepted 13 February 1989)

Following our earlier research [37], we further investigated a model that conceptualizes placebo phenomena as the

result of conditioning [40] and attempted to extend and replicate the fmding that placebo responses can be conditioned in human

subjects. Two groups of 10 subjects were told that they were receiving an analgesic which was in fact a placebo. During the

conditionin& placebo administration was surreptitiously paired with an increase in the painful stimulus for half of the subjects and

withadecrease for the other half. Subjects were tested pre and post conditioning for a placebo response. A second type of

experimental pain was also used to determine stimulus generalization. The results confumed a previous finding that placebo

responses can be conditioned in human subjects. The implications for clinical practice of a 1 earning model of placebo behavior are

discussed.

Key nerds: Conditioned response model; Placebo phenomena; (Human)

Introdwtion

Despite considerable research into placebo phe- nomena, the existing empirical data are incon- sistent and equivocal, marked by heterogeneous paradigms and failures to replicate. Grunbaum suggests that this situation has persisted because of ‘the ineptitude of customary terminology of placebo research’ [13] which has forced placebo research to remain fixed at the early inductive stages of heuristic fact gathering and construct formation. Consequently, there has been a paucity of theory and theory-based research. However, two recent developments in the placebo literature

Correspondence to: Dr. Cmmie Peck, Department of Psy- chology, La Trobe University, Bundoora, Victoria 3083, Australia.

have provided the opportunity to address the overdue task of advancing placebo research be- yond an inductive approach.

First, Gnmbaum [13] has proposed a more precise terminology to replace the obscure tradi- tional vocabulary in which the placebo phenome- non has been couched. A more recent analysis by Critelli and Neumann [7] has also supported the notion that the placebo concept can be adequately defined and that it retains conceptual and em-

pirical utility. These authors have more clearly delineated the boundaries of the construct and addressed the criticisms of the placebo that have in the past prompted a calling for its abandon- ment [17].

Second, Wickramasekera [40] has proposed a conditioning model of placebo behavior similar to a previous formulation by Ullman and Krasner [36]. This model, based on operant and classical

0304-3959/89/$03.50 0 1989 Elsevier Science Publishers B.V. (Biomedical Division)

conditioning, views the placebo phenomenon as a complicated, patterned psychophysiological re- sponse.

According to Wickramasekera [40], past in- stances of treatment in medical or experimental settings are construed as a complex stimulus con- figuration consisting of the therapist (or experi- menter) and the treatment (or experimental) set- ting (these comprise the conditioned stimulus, or CS), as well as the treatment administered (the unconditioned stimulus, or UCS). Relief of symp- toms or some change in the condition of the individual is the original, unconditioned response (UCR). Conditioning takes place through the re- peated pairing of the stimulus configuration and this (usually) salutary behavior, so that the latter occurs in response to the configuration even without the ‘active’ treatment component and may eventually generalize to other configurations.

The empirical support for a conditioning model of the placebo phenomenon comes primarily from animal studies [14,26,28,31,41]. Only one study to date has attempted to systematically condition placebo response in human subjects [37]. Follow- ing earlier work, we attempt to replicate and ex- tend these findings.

The current study had 2 aims. The first was to test Wickramasekera’s [40] conditioning hypothe- sis, by attempting to condition both analgesic (salutary) and algesic (exacerbatory) responses (CRs) to the administration of a placebo analgesic (CS) in the laboratory, with human subjects. A question of particular interest in this respect was whether, in the presence of expectations of pain relief, an exacerbatory response could in fact be conditioned to the placebo agent, thus placing expectancies in direct competition with condition- ing. This was done in order to explore Kirsch’s [18] recent contention that response expectancies are more important than conditioned responses in the genesis of placebo phenomena. The second aim of this experiment was to determine whether, if obtained, the conditioned learning would gener- alize to a second, different pain stimulus, since the demonstration of response generalization would lend weight to the conditioning explanation and to the validity of the conditioning paradigm em- ployed in this experiment.

Method

Subjects Twenty subjects, 12 females and 8 males,

voluntarily participated in the study and were paid $9.00 for taking part. The subjects were predominantly university students, their ages rang- ing from 20 to 42 years. Before participating, all subjects completed a consent form which ex- plained the nature of the noxious stimulation and warned people with heart conditions, hyperten- sion, or currently on medication, not to take part.

Apparatus Iontophoretic pain. Noxious stimulation was ad-

ministered using a modified iontophoretic pain generator. Iontophoresis, by the repulsion of posi- tive potassium ions from the positive pole of an electric (DC) current, drives these ions into the skin, causing a prickling sensation at lower levels of stimulation and a cramping sensation at higher levels. The degree of noxious stimulation is depen- dent on the amount of current and the duration of administration and is independent of skin resis- tance [2].

The apparatus consisted of a plastic clamp, which is attached to the flexor surface of the forearm and which incorporates a small bowl on the upper surface. The bowl uses the upper surface of the arm as its base and is filled with a 3% solution of potassium chloride (the contact medium between the electrode and skin). Enclosed within the bowl is a metal anode plate. A gauze pad saturated with a 9% solution of sodium chlo- ride wrapped around a silver-silver chloride cathode plate is placed on the surface of the arm. This gauze base acts as an insulator. The source of the DC current is a series of batteries enclosed within a console, and this current is increased or decreased to the desired level by manipulating a potentiometer on the console. An electronic dis- play gives a constant readout on the level of stimulation, measured in milliamps (mA).

The modified generator delivers a continuous, ascending stimulus, commencing at 0 mA and increasing as a linear function up to the prescribed maximum as set by the potentiometer. The rate at which the current will be incremented is specifia-

ble (in set, to 3 decimal places), and this is achieved by means of a second potentiometer on the con- sole.

Ischemic pain. Noxious sedation was admin- istered using the submaximum effort tourniquet technique [32,33]. This technique produces pain by the occlusion of blood circulation in the limb using a blood pressure cuff as a tourniquet. With each subject’s non-dominant forearm extended vertically, an Esmarch bandage was placed around it to drain venous blood. A sphy~om~ometer cuff was next placed around the upper arm and inflated to a pressure of 250 mm Hg to act as a tourniquet. The bandage was immediately re- moved, and after 60 set, 20 isotonic contractions of the forearm were performed by squeezring a hand exerciser with attached counter at 2 set intervals. The exerciser required 7.72 kg of force for each contraction (after Smith et al. 1331). This produces an ‘aching’ type pain in the subject’s .arm which increases over time.

mounted. In this configuration - not unlike that of a traffic signal - the panels were colored white, yellow, orange, red, and purple from bot- tom to top and the subject controlled them using a handset wired to the control box. The panels signified: ‘no pain (white), ‘mild pain’ (yellow), ‘moderate pain (orange), ‘severe pain’ (red) and ‘intolerable pain’ (purple), and were labeled as such on the handset. When subjects activated the purple light indicating ‘intolerable pain,’ the ex- perimental pain procedure was terminated. Pain tolerance was measured in seconds.

Placebo. The placebo analgesic was in the form of a cream. Simple cold cream was mixed with linalol, which contained rub-down cream in the ratio 8 : 1, so that the cream would have a distinct smell. It was pink in color. The cream was re- moved by cleansing the skin with cotton soaked in a 70% alcohol solution.

Experimental design Pain measurement. A stopwatch was used to Table I shows the experimental design. Ten

time each pain procedure and a linear light ana- subjects were randomly assigned to each of 2 logue recorder [27] provided the subject with a grqups (designated as groups I and II). For both means of signaling that he or she could no longer groups, sessions 1 and 3 were identical and con- tolerate the pain. The linear light analogue re- sisted of pre- and post-tests to determine the corder consisted of a control box on which a effects of the conditio~g carried out in session 2. column of 5 colored lamp panels were vertically During these 2 sessions, tolerance to both ionto-

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TABLE I

EXPERIMENTAL DESIGN

IF = iontophoretic; Is = ischemic.

Treatment condition

Group 1 No placebo

Placebo

Group II No placebo

Placebo

Stimulation intensity

Session 1: pre-conditioning test Session 2: conditioning Session 3: post-conditioning test

Trials Ir value Trials Ir value Trials Ir value

@A/=4 @we4 (mA/s=)

Ir 0.5 Ir X 3 0.5 Ir 0.5 IS IS Ir 0.5 Ir X 3 0.1 Ir 0.5 Is IS

Ir 0.5 Irx 3 0.5 Ir 0.5 IS Is Ir 0.5 Ir X 3 2.0 Ir 0.5 IS IS

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phoretic and ischemic pain was assessed, with and without the presence of the placebo. A pain toler- ance task was chosen for this study rather than pain ratings based on the magnitude estimation of discrete stimuli which we have previously em- ployed [37]. This change is primarily a method- ological refinement since rating scale data can be complicated and problematic in psychophysical analyses [l] and involve the subject in a greater number of pain trials.

During sessions 1 and 3, the rate of increment in stimulation intensity for the iontophoretic stimuli (hereafter Ir) was fixed at 0.5 mA/sec, and remained at this level across trials in which the placebo cream was used as well as those where it was not. Ischemic tolerance procedures were iden- tical for both groups, independent of placebo ad- ministration.

In session 2 (conditioning) the Ir was manipu- lated without the subject’s knowledge. For group I, it was lowered to 0.1 mA/sec when the placebo was administered and remained at 0.5 mA when the placebo was not. For group II, the Ir was increased to 2.0 mA/sec when the placebo was administered and remained at 0.5 mA/sec when the placebo was not. Tolerance to ischemic pain was included only as a test of stimulus generaliza- tion and so was absent from session 2. Thus, the 2 groups differed only with regard to session 2, group I experiencing a favorable change in stimu- lation along with the placebo, and group II, an unfavorable change. Thus, any difference between placebo and no-placebo pain tolerance during the testing phases (sessions 1 and 3) could be consid- ered to be attributable to the pairing of the placebo cream with a change in stimulus intensity in ses- sion 2.

Procedure All subjects attended 3 sessions. Sessions were

held on consecutive days, and at the same time of day in order to avoid possible confounding effects of diurnal variations in the pain experience [29].

Sessions 1 and 3 (pre and post conditioning). Sessions 1 and 3 were identical. Prior to the com- mencement of testing, the subject completed a consent form and was seated in a comfortable chair in a bare room with the iontophoresis

equipment attached as previously described. The experimenter administered the stimuli and re- corded the subject’s responses through a l-way mirror in a small observation chamber adjacent to the experimental room. The subject was given a set of written instructions to be read in conjunc- tion with a tape recording of the same. Subjects were told that:

The purpose of this study is to investigate the action of an

experimental analgesic known for its ability to rapidly reduce

skin sensitivity and to act as a local pain killer. Recent data

have suggested that it may prove to be a harmless, yet highly

effective and umvenient local anesthetic.

They were also told that the preparation (in the form of a topical application) was not harmful and that its effects were fast-acting and short-lived. Each subject was instructed to indicate via the pain lights, at what point the pain could no longer be tolerated, at which time the pain was im- mediately terminated. Four tolerance trials were administered: two of iontophoretic and two of ischemic pain. Iontophoretic trials were always administered first, beginning with the no-placebo trial. The iontophoretic trials were separated by a gap of approximately 5 ruin, sufficient time, sub- jects were told, for the cream to ‘take effect.’ A 5 min break was also necessary following the second iontophoretic trial for the cream’s effect to ‘wear off.’ Between ischemic tolerance trials, the subject was given a 5 min rest period in addition to the above. The placebo cream preparation was ap- plied liberally to the subject’s forearm, concentrat- ing on those areas around the apparatus where the subject reported experiencing pain. The apparatus remained in place during the application of the cream but was removed while the skin was being cleansed.

Session 2 (conditioning). The subject was seated and prepared as in the first and third session. Six tolerance trials of iontophoretic stimuli were ad- ministered to the subject. The first 3 trials were administered consecutively without the placebo, and the following 3 trials with the placebo. Begin- ning with the no-placebo trials, the subject was once again required to indicate the point at which his or her pain became intolerable, using the pain

113

lights. With the exception of the third and fourth trials, the stimuli were separated by a period of approximately 5 min. Following the third trial, the experimenter administered the placebo and reset the iontophoretic Ir. For group I subjects, this was decreased to 0.1 mA/sec, while for group II sub- jects, the Ir was increased to 2.0 mA/sec. All subjects were debriefed at the conclusion of the study.

Results

Since any effect due to the conditioning would be manifest as a change in mean pain tolerance from the pre- to the post-test conditioning ses- sions, the analyses were based on difference scores (differences between prs and post-conditioning data). For each subject, 4 difference scores were calculated: 2 iontophoretic pain tolerance scores (placebo and no-placebo conditions), and 2

Gfoupl W

Gmupll ti

3.5

3.0 1

-25J I I p(aeb no pkmbo

Fig. 1. Mean diffexemes between pre and post-conditioning iontophretic pain tolerauce (in sac).

30-

20-

10-

O-

-lO-

-20 -

-30 -

-4o-

-5o-

-6O-

-7o-

- 80-

-90-

-100 -

Group1 u

Groupll A-A

I

placebo

1

rlc placebo

Fig. 2. Mean differences between pre- and post-conditioning ischemic pain tolerance (ii xc).

ischemic pain tolerance scores (placebo and no- placebo conditions). Difference scores in seconds of pain tolerance were derived by subtracting pre- conditioning from post-conditioning observations. The mean difference scores are presented in Figs. 1 and 2. Two analyses of variance were conducted, one for the iontophoretic and one for the ischemic pain tolerance data. Each was a 2-way (2 x 2) analysis of variance with one repeated measure. Factor A in both analyses represented the 2 placebo treatment conditions: positive or favor- able conditioning (group I), and negative or un- favorable conditioning (group II). Factor B repre sented the placebo/no-placebo repeated measure. The A and B factors alone are not meaningful within this design since it is the A x B interaction term which represents conditioning and is there- fore of interest.

For the iontophoretic tolerance data, the analy- sis confirmed a sign&ant AX B interaction (F,,, i8) = 23.51, P -z 0.05), reflecting that a condi-

tioning effect was obtained. Examination of Fig. 1 shows that subjects in group I experienced an increase in mean pain tolerance under the-placebo condition following conditioning. Also of particu- lar interest is a decrease in mean pain tolerance under the no-placebo condition for these subjects. Group II subjects showed a decrease in mean pain tolerance following conditioning in the placebo condition and a corresponding increase in mean pain tolerance in the no-placebo condition. This apparent rebound effect may be of interest.

The ischemic pain tolerance data also revealed a significant A X B interaction (5,. i8) = 7.00, P -z 0.05). Fig. 2 shows a small decrease in mean pain tolerance following conditioning for the group I subjects under the placebo condition and also a decrease under the no-placebo condition. For group II subjects, a decrease in placebo mean pain tolerance is present, and following conditioning the no-placebo mean pain tolerance appears to increase in group II subjects. Thus while,group II does appear to show a stimulus generalization effect, group I does not seem to show generaliza- tion.

Discussion

The results of the present study concur with our earlier research [37] and suggest that both salutary and exacerbatory placebo behavior (CR) can be conditioned in the human subjects by pairing increased or decreased length of noxious stimulation (UCS) with a neutral therapeutic agent (CS). In group II, learning appears to override the subjects’ expectation of a salutary effect when the placebo agent was administered. The ischemic tolerance data - intended as a measure of stimu- lus generalization - only occurred in group II where the treatment effects violated the expectan- cies held by the subjects. It did not occur in group I where, in the presence of expectancies consonant with subsequent learning, treatment effects would (intuitively at least) be expected to be more pro- nounced. It is possible, however, that conditioned learning which was clearly at odds with expectan- cies somehow had more impact for the group II subjects (perhaps by increasing anxiety) than an

experience which was predictable (as was the case for the group I subjects).

An unexpected and interesting result concerns the effect of conditioning on the subjects’ no- placebo pain tolerance for both groups. While the ‘manipulation’ of stimulus tolerance during ses- sion 2 applied only to trials where the placebo was administered, the effect of this learning appears to have also modified the subjects’ pain tolerance in the no-placebo condition at session 3. Thus, at session 3, the subjects in group I tolerated less pain without the placebo than they did in the first session without it, though the iontophoretic pain had identical Ir characteristics to that of session one. Similarly, subjects in group II appear to tolerate more pain without the placebo following conditioning despite the fact that the session 3 pain again had Ir characteristics identical to those of the pain of session 1. This trend is pronounced and is evident for both types of pain.

While there are limitations to experimental ana- logues of clinical phenomena, these data may have important implications for treatment. Any ther- apeutic theory that advocates the use of a particu- lar treatment modality for the remediation of a specific illness should take cognizance of the indi- vidual’s conditioning history for that treatment. This should be done not only with regard to what Grunbaum [13, p. 1591 has termed the treatment’s ‘characteristic components’ - for example the characteristic pharmacological action of a drug - but also the ‘non-characteristic components’ of the treatment (here conceived of as the complex CS configuration).

Such influences may be particularly powerful for patients with a long history of failure for a particular treatment. New treatments, with prom- ising characteristic constituents (new drugs with impressive pharmacological effects, for example) may experience poor results because the patient’s conditioned response to the non-characteristic constituents might mitigate against the action of its characteristic constituents. This notion of an interaction between (in the old parlance) ‘active’ and ‘placebo’ components of treatments has been empirically substantiated in the past [8,9].

Recognition of the patient’s treatment history has often been a neglected consideration in the

115

past. If future placebo behavior can be predicted from treatment history, then the prescription of treatment must take this into account to maximize the selection, application and development of re- medial measures.

Conclusion

The data obtained in this experiment provide support for Wickramasekera’s [40] conditioned learning theory of placebo phenomena since both salutary and exacerbatory responses were condi- tioned. Exacerbatory responses also demonstrated stimulus generalization. Moreover, the data pro- vide preliminary evidence to refute Kirsch’s [18] assertion that response expectancies are more im- portant than conditioned learning in their contri- bution to the occurrence of placebo phenomena.

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