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Placebo and Nocebo Responses, Cortisol, and Circulating Beta-Endorphin

From the Departments of Orthopedic Surgery (O.J.) and Clinical Chemistry (J.B.), The University Hospital of North Norway, and the Department of Psychology (M.A.F.), University of Tromsø, Norway

Address all communications to: Magne Arve Flaten, Professor Dr. Psychol., Department of Psychology, SV-Fak., University of Tromsø, N-9037 Tromsø, Norway. Telephone: +47-77644344. Fax: +47-77645291. Email: magnef{at}psyk.uit.no

	ABSTRACT

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OBJECTIVE: The experiment tested whether the placebo and nocebo responses could be mediated via modulation of stress.

METHODS: Ischemic pain was induced in healthy volunteers (N = 59). When pain reached "7" on a 10-point scale, two groups of subjects received information that a pain relieving (the Placebo group) or a pain increasing (the Nocebo group) substance was injected. All injections contained physiological saline. A third group received no information and no injection (the Natural History group). Pain ratings and blood samples for analysis of cortisol and beta-endorphin were obtained every 5 minutes after pain equal to seven until the experiment was terminated.

RESULTS: Pain increased in all groups, but there were significantly lower pain ratings in the Placebo group at 15 minutes after the injection, compared with the other two groups. Cortisol increased in all groups, but mostly so in the Nocebo group. Circulating beta-endorphin increased in all groups. Pain-ratings were not correlated with beta-endorphins or cortisol.

CONCLUSIONS: A placebo response, ie, a reduced pain level, was seen in the Placebo group at 15 minutes after the injection. The placebo response was not related to stress or to beta-endorphin. Expectation of a pain increase in the Nocebo group led to an increase in cortisol, but the expectation of pain increase and the resultant cortisol increase had no effect on pain.

Key Words: Placebo analgesia, • nocebo, • ischemic pain, • stress, • cortisol, • beta-endorphin.

Abbreviations: ACTH = adrenocorticotropic hormone;; VAS = visual analog scale.

	INTRODUCTION

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Providing information that an injection contains a painkiller has, in several studies (1–3), been shown to reduce pain, even when the injection contains only an inactive agent. This has been termed placebo analgesia. Providing information that a substance is a painkiller has also been shown to generate an expectancy of a decrease in pain levels (3), and expectancies is hypothesized to mediate the endorphin release. It is likely, however, that other psychological factors act as mediators of the placebo response, in addition to expectancy (eg, 4, 5). The present study investigates the hypothesis that providing information, to an individual that experiences pain, that a painkiller has been administrated, should reduce some of the stress associated with the pain. Increased stress and negative emotions have been shown to increase pain in humans (eg, 6), and it was hypothesized that a reduction in stress should be accompanied by a reduction in pain.

Placebo analgesia that is induced by verbal information can be completely (7) or partly reversed by administration of the opioid antagonist naloxone (1, 8). One study has found increased beta-endorphin in the cerebrospinal fluid of placebo-responders compared with placebo nonresponders (9), indicating that this form of placebo response is, at least partly, mediated via endogenous opioids that act in the central nervous system. However, there is evidence that peripheral beta-endorphin can reduce pain (10, 11) , and a second aim of the present study was to investigate whether changes in peripheral, circulating beta-endorphin could be related to placebo analgesia.

Nocebo hyperalgesia can be considered the opposite of placebo analgesia. Nocebo hyperalgesia is the induction of increased pain by information that a substance that increases pain has been administrated, and a role of stress and anxiety has been implicated in this type of nocebo response (12, 13).

The present experiment investigated the roles of stress, as indexed by cortisol, and beta-endorphin in placebo analgesia and nocebo hyperalgesia. Ischemic pain was induced by the submaximum effort torniquet technique (14, 15). One group received an injection with information that it contained a painkiller (the Placebo group) although a placebo was injected. Another group received information that it received an injection with a substance that increased pain (the Nocebo group). It was expected that cortisol should increase in this group. The natural history of pain was assessed by the Natural History group that received the pain stimulus, but not any injection and, of course, no information about pain relief or increase.

Cortisol and circulating beta-endorphin, as well as pain ratings, were recorded every five minutes after administration of a placebo injection. Cortisol is a reliable indicator of stress (eg, 16), and cortisol has been shown to increase after induction of ischemic pain (17). Circulating beta-endorphin is also released during stress, since beta-endorphin and cortisol share the same precursor molecule, pro-opiomelanocortin (POMC), which is found centrally and also in lymphocytes (18, 19). Corticotropin releasing factor (CRF) produced within hypothalamus and also in cells of the immune system (10) releases beta-endorphin and adrenocorticotropic hormone (ACTH). The function of ACTH is to release cortisol from the adrenal cortex. Beta-endorphin may be involved in the regulation of different functions including analgesia (10, 20). One previous study (21) measured circulating beta-endorphin after a placebo manipulation, but the placebo response was not seen in that study, and the study provides, therefore, no information on the relationship of the placebo response to circulating beta-endorphin.

	METHODS

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Subjects were 59 drug-free healthy men (age range 19–30 years). One additional subject was excluded due to experimenter error and one subject withdrew from the experiment due to nausea. All subjects were run between 0900 and 1330 hours to reduce diurnal variability in beta-endorphin and cortisol release. Subjects were recruited through advertisements at Tromsø University and The University Hospital of North Norway. All subjects went through a medical examination performed by the first author before being assigned to the study. Only subjects without previous or present serious disease, and who were not on prescription drugs, were admitted to the study. The study was approved by the Regional Committee for Medical Research Ethics in Health Region V in Norway (project number 14/98). Written informed consent was obtained from all participants.

On the day of the experiment the subjects met at the Department of Clinical Research at The University Hospital of North Norway for a light breakfast at 0800 hours. The subjects were instructed not to eat before arrival at the Hospital, and not to drink caffeinated beverages, or use alcohol- or nicotine-containing products for 12 hours before the start of the experiment. The subjects were run, one at a time, at 0900, 1000, 1100, or 1200 hours in a room at the Department of Clinical Research.

Blood samples were drawn from an indwelling Veneflon in the median basilic or cubital vein continuously infused with a solution of isotonic sodium chloride. The dominant arm was used. At sampling times the infusion was stopped. After discharging the first 2 ml of blood from each sampling, 10 ml of blood was collected in gel-free tubes. Serum was prepared 30 minutes after sampling by spinning the sample tubes at 1500 g for 10 minutes. The serum samples were pipetted off and kept frozen at -20°C in 2-ml plastic tubes until analyzed. Serum for beta-endorphin was analyzed by a RIA kit (RIK-8616 beta-endorphin (Human), Peninsula Laboratories, Inc.). The rabbit antiserum cross-reactivity with human beta-endorphin was 100%. The 50% inhibitory concentration (IC₅₀) was 3.5 pmol/tube. Unextracted plasma was used. Cortisol in serum was analyzed by a heterogeneous competitive magnetic separation assay in Technicon Immuno 1 system, using monoclonal antibodies. Absorbance, due to the formation of para-nitrophenoxide, was monitored at 405 nm. The sensitivity of the assay was 0.2 µg/dl, with analytical range up to 60.0 µg/dl (5.5–1656.0 nmol/l). The coefficient of variation of the assay was 5%.

All injections were performed by uniformed nurses who were blind to the purpose of the experiment, and who were informed that the subjects would receive a painkiller or a substance that increased pain. The informed consent form stated that the experiment investigated a treatment for pain, and described the pain stimulus. The form did not mention the possibility that some subjects received a placebo. Information about the type of treatment that each subject received, ie, whether the drug acted to decrease or increase pain, was delivered orally before the injection.

After arrival at the laboratory each subject was placed in a supine position on a bed, and a blood sample was drawn for analyses of beta-endorphin and cortisol. The submaximum effort tourniquet technique (14, 15) was used for induction of pain, and the procedure used here is similar to that of Benedetti (1), with one exception: the present experiment used a cuff pressure of 200 mm Hg, whereas Benedetti (1) used a pressure of 250 mm Hg. The nondominant forearm was extended vertically. Venous blood was drained from the arm by the use of a bandage, and a sphygmomanometer cuff was placed around the upper nondominant arm and inflated to 200 mm Hg. The bandage was removed and the hand placed by the subject’s side. One minute later the subject squeezed a hand exerciser 12 times with a 2-second pause between each squeeze. After this, the subject rated his pain verbally every 5 minutes on a visual analogue scale (VAS) from 0 (no pain) to 10 (unbearable pain). When pain reached "7," the experiment proper began: The 59 subjects were randomly allocated to three groups (N=19 in the Placebo group, N=20 in the Nocebo and Natural History groups). The Placebo group received an injection in the dominant arm and was told that it was a painkiller. The Nocebo group received an identical injection, but was told that it was a substance that would increase the pain. All injections contained physiological saline. The Natural History group did not receive any injection and no information was provided to this group. Pain ratings were obtained every 5 minutes after pain had reached "7." Immediately after each pain rating, a blood sample was obtained. When pain reached 10, the cuff was removed from the arm of the subject and a blood sample was drawn. The cuff was removed from the arm after a maximum of 30 minutes after the injection, even if the pain level had not reached "10." Five minutes after removal of the cuff, the subject rated his pain again. The subjects stayed at the Department of Clinical Research for 30 minutes after the completion of the experiment.

Data analysis
Because subjects terminated the experiment at different points in time after the injection, overall, ANOVAs that involved tests performed toward the end of the experiment could not be performed, and group differences were evaluated by the Newman-Keuls test. Other statistics were performed by the Pearson product-moment correlation. An alpha value of 0.05 was chosen.

	RESULTS

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The mean time (±1 SEM) from the cuff was inflated until pain equal to "7" was reported was 16.7 (±1.9), 14.3 (±1.2), and 14.4 (±1.1) minutes for the Placebo, Nocebo, and Natural History groups, respectively (F<1, NS). Pain ratings increased in all subjects after administration of the injection. The mean time from the injection at pain equal to "7," and until the experiment was terminated was 12.1 (±1.0), 11.5 (±1.4), and 12.3 (±1.7) minutes for the Placebo, Nocebo, and Natural History groups, respectively.

Three of the 59 subjects did not reach a pain level of "10" within 30 minutes after the injection (one in the Nocebo group and two in the Natural History group). All other subjects terminated the experiment 21 minutes or less after the injection.

Pain was lower in the Placebo group compared with the Nocebo and Natural History groups at 15 minutes after the injection (means of 9.15 (±0.43), 9.62 (±0.15), and 9.70 (±0.15), respectively, p values = .031 and .018). There were no other significant between-group differences in the pain ratings (Figure 1).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Mean pain ratings in the three groups from pain = 7, for every 5 minutes after pain = 7, and 5 minutes after removal of the tourniquet. At pain = 7, the Placebo group received an injection with information that it was a painkiller, and the Nocebo group received an injection with information that it would increase the pain. The Natural History group did not receive the injection and information. Error bars indicate ±1 standard error of the mean (SEM).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Mean beta-endorphin in the three groups before the start of the experiment, at pain = 7, for every 5 minutes after pain = 7, and 5 minutes after removal of the tourniquet. Error bars indicate ±1 SEM.

View larger version (23K): [in this window] [in a new window]   Fig. 3. Mean cortisol in the three groups before the start of the experiment, at pain = 7, for every 5 minutes after pain = 7, and 5 minutes after removal of the tourniquet. Error bars indicate ±1 SEM.

Cortisol and beta-endorphin levels were not correlated with pain ratings. However, low variability in pain ratings could have decreased correlations.

	DISCUSSION

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The main findings of the present study were as follows: Pain was significantly reduced in the Placebo group at 15 minutes after the injection, compared with the Nocebo and Natural History groups. This is evidence that a placebo response was elicited in the Placebo group. Cortisol was significantly increased in the Nocebo group compared with the other groups at 15 minutes after VAS equal to seven, indicating that the nocebo response involves an increase in stress. In addition, pain increased cortisol and beta-endorphin in all groups.

It was hypothesized that placebo analgesia was related to a reduction in stress after information that a painkiller had been injected. However, the placebo analgesia seen at 15 minutes after the injection in the Placebo group was not associated with lower cortisol levels, since cortisol levels were comparable in the Placebo and Natural History groups. Cortisol increased in the Nocebo group, on the other hand, indicating that stress was increased in this group, but pain levels were comparable in the Nocebo and Natural History groups. Thus, the present findings indicate that pain increases stress as indexed by cortisol, as could be expected, but changes in cortisol do not have a modulating effect on pain. Subjective stress was not assessed, since it was assumed that this could have interfered with the pain ratings. Future research could consider the use of subjective stress measures. The present study did not employ a manipulation check on whether the subjects believed the drug-related information, and this should also be included in future studies.

Circulating beta-endorphin was not related to placebo analgesia. A number of studies have shown that blockade of endorphin action by naloxone decreases (2, 8) or under certain circumstances completely abolishes (7) placebo analgesia, indicating that endorphins are important mediators of placebo analgesia. The present findings indicate that circulating beta-endorphin is not essential in this process. It has also been shown that placebo analgesia can be induced at one body location whereas other body locations do not display placebo analgesia (22). This indicates that placebo analgesia is mediated via central nervous system mechanisms, and cannot be accounted for by circulating hormones alone.

Beta-endorphin levels increased as pain increased. Since beta-endorphin was positively correlated with cortisol, and both hormones are the result of CRH activation, increased circulating beta-endorphin seemed to be part of the response to pain and/or stress. Stress has been shown to induce analgesia in man through endogenous opioid activation (23), but there was no relationship between cortisol and pain in the present study. There could be several reasons for this: Firstly, the low variability in pain scores made it difficult to detect a correlation between pain and cortisol. Secondly, pain was relatively intense when the injection and information were administrated. The analgesic effect of beta-endorphin could be larger if it acted before pain reached high levels.

Pain was induced, in the present experiment, in a way similar to that of Smith et al. (14, 15) and Benedetti (1). The present study did, as did Benedetti (1), find evidence of placebo analgesia. However, there are two important differences between the results in the studies. Firstly, the development of pain was substantially slower in Benedetti et al. (1) compared with Smith et al. (14, 15) and the present study. Smith et al. (14, 15) found a mean time from inflation of the cuff to "unbearable" pain of 13 to 14 minutes in one experiment, and about 20 minutes in three other experiments in subjects receiving placebo. The present study, that used a lower cuff pressure (200 mm vs. 250 mm) compared with Smith et al.(14, 15), found a mean time to "unbearable" pain of about 27 minutes. Benedetti (1) seems to have obtained substantially longer time periods from inflation of the cuff to "unbearable" pain, since he reported a mean of about 23 minutes from inflation of the cuff to a pain equal to "7" was reached (the corresponding value for the present experiment was about 15 minutes), and data for the natural history group were reported for another 35 minutes after that point in time.

Secondly, the placebo analgesia in Benedetti (1) was significantly different from a natural history group at 10 minutes and more after the injection with information that it was a painkiller. Placebo analgesia in the placebo responders increased across the duration of the experiment, and reached a maximum of about five points on a 10-point scale at about 35 minutes after the injection. The present study observed a placebo response of 0.55 cm on a 10-cm scale. About 26% of the subjects in Benedetti (1) displayed reduced pain after information that they received a painkiller, whereas no subject in the present study displayed reduced pain after any form of information. Thus, the placebo analgesia observed by Benedetti (1) was substantially stronger than the placebo analgesia observed in the present study.

Even if the placebo analgesia observed in the present study was statistically significant, a reduction in pain of 5.5 mm cannot be termed clinically significant (24). However, some authors have observed considerably stronger placebo analgesia, and it is of interest in future studies to investigate the factors that contribute to the magnitude of the placebo response. The magnitude of the placebo response in the present study was similar to the magnitude of placebo responses of 5.6 mm obtained by Price et al. (3) for thermal pain after a "weak" placebo manipulation, and about 4 mm for iontophoretic pain (25), but stronger than the 1-mm difference for chronic pain between a neutral and positive expectancy group (26). However, a number of studies have reported substantially larger placebo analgesia magnitudes than the present study (eg, 1, 2, 8). The knowledge the experimenter had about the substances that could be provided to the subjects could have contributed to this large variability in placebo effects: Gracely et al. (27) found that if the experimenter knew that the subjects could receive a placebo, pain was increased compared with a condition where the experimenter knew that the subjects only received active drugs. Similar findings have also been obtained by other researchers (2). The present experiment was conducted by nurses who were informed that the subjects might receive a substance that would increase pain, or a placebo. This knowledge could have reduced placebo effects. Moreover, interaction that was not specified in the experimental procedure was kept at a minimum, eg, no emotional support was provided. Earlier studies have not stated whether such contact between experimenter and subject took place. Thus, it is possible that emotional factors could have contributed to the variability seen in the placebo response across studies.

	ACKNOWLEDGMENTS

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The present study was supported by a grant from the Norwegian Science Council to Dr. Flaten. The research was conducted at the Department of Clinical Research at the University Hospital of North Norway.

Received for publication September 12, 2002.

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