- Email: [email protected]
Endogenous opiates and the placebo effect
Journal of Psychosomatic Research 58 (2005) 115 – 120
Endogenous opiates and the placebo effect A meta-analytic review Marie D. Sauroa,*, Roger P. Greenbergb a
Department of Psychology, University of Massachusetts Dartmouth, 285 Old Westport Road, North Dartmouth, MA 02747, United States b Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, United States Received 15 March 2004; accepted 7 July 2004
Abstract Objective: A meta-analysis was performed to investigate the ability of placebo administration to reduce self-report of pain and to examine whether placebo-induced pain reduction might have physiological and psychological underpinnings. Method: Fortyfive effect sizes and 1183 participants from 12 studies were metaanalyzed for the effects of placebo and the opioid antagonist, naloxone, on self-report of pain. Results: Analyses showed that placebo administration was associated with a decrease in self-report of pain, and a hidden or blind injection of naloxone reversed placebo-induced analgesia. Furthermore, there were significant
between-group differences for type of pain (experimental vs. postoperative/clinical) for placebo studies. Conclusions: The results support the literature illustrating that the belief and expectation of analgesia induces discrete physiological changes, leading to relief from pain, and this response may be mediated by endogenous opioids. The implications of these findings are discussed in terms of the symbolic aspect of health care and mental health providers’ words and context, and their potential impact on the course of illness and well-being. D 2005 Elsevier Inc. All rights reserved.
Keywords: Pain; Patient–provider interaction; Placebo; Psychoneuroendocrinology; Psychopharmacology
Introduction The placebo response has received attention in many different areas of medicine and science. Its effects have been studied in the context of whether it is truly an appropriate control condition for clinical trials of drugs and other medical or surgical treatments. While some reports estimate that between 25% and 60% of patients report improvement with placebo treatment across various clinical conditions, such as pain, asthma, cardiovascular diseases, and depression [1,2], other reports have found little evidence supporting significant clinical effects [3]. The fact that physiological changes occur in response to an binertQ treatment, or a symbolic event, has important implications for many different therapeutic modalities. For example, it has been shown that medical context (i.e., all factors that comprise the atmosphere surrounding a patient, * Corresponding author. Tel.: +1 508 999 8380. E-mail address: [email protected] (M.D. Sauro). 0022-3999/04/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2004.07.001
including the specific wording of statements made by doctors) has profound effects on the outcome of medical treatment, and this effect is modulated by specific neurochemical messengers [4]. Others have suggested that placebo-like factors may play a role in determining treatment outcome for general medical outcomes [5], as well as specific conditions, such as Parkinsonism [6] and clinical depression [7,8]. For depression, these placebo-induced improvements can be mapped to changes in brain glucose metabolism [9,10] and electrical activity [11]. The physiological mechanisms underlying the placebo response have been studied extensively but are not well understood. The most well-studied phenomenon with respect to biochemical changes comes from studies examining placebo-induced analgesia. Mediators implicated include endogenous opioids (e.g., h-endorphin; 12–14), cholecystokinin [13], and dopamine [15]. Because studies in this literature are difficult to compare due to the variability of conditions, populations studied, and methodologies, there was a need to examine the significance
116
M.D. Sauro, R.P. Greenberg / Journal of Psychosomatic Research 58 (2005) 115 – 120
and consistency of effect sizes across the literature. Past reviews in this area have either been qualitative reviews [16], meta-analyses examining placebo effects in clinical trials collapsed across a variety of clinical conditions [3], or are somewhat outdated [17]. The main objective of this meta-analysis was to provide a focused quantitative review of the effects of placebo analgesia and the plausible mechanisms underlying this phenomenon (i.e., opiate related). For the primary analyses, it was hypothesized that placebo administration (i.e., administration of an inert agent along with verbal communication, that the individual would be receiving an analgesic agent) would decrease the subjective rating of both nonexperimental (postoperative/clinical) and experimentally induced pain. Second, it was hypothesized that the antagonism of opiate receptors (via the administration of naloxone) would attenuate placebo-induced analgesia. Third, as an exploratory analysis, it was hypothesized that there would be a difference in placebo-mediated analgesia among the different types of pain because the literature in this area is variable.
Method Sample of studies Studies were obtained using a computer-based literature search. The databases used were Medline (1966 –2003), PsychINFO (1967–2003), and Mental Health Abstracts (1969–2003). Also searched were reference lists from review articles, empirical papers, and dissertations. Only studies available by June 2003 were included in the sample. Studies, or portions of studies, included in this metaanalysis met the following inclusion criteria: (a) a published study, (b) written in English, (c) included pain induction and measurement of pain, and (d) examined opiate pathway involvement either by the use of an antagonist or directly measuring endogenous opiates. Papers that did not measure both placebo analgesia and reversal by naloxone were not included. In addition, the study had to employ a protocol where the participant was not merely given a placebo, but was explicitly told that they would be receiving medication to alleviate pain. bPlaceboQ is operationalized by the following conditions: The substance is given in full view, with the suggestion that analgesia is being administered. Lastly, the study must have reported administration of naloxone via hidden injection (intravenously, out of participants’ view) or through a blinded procedure, where participants and experimenters were unaware of what substances were being administered to the participant (who previously agreed to receive injections of either saline or drugs).
gender of patients, (b) age, (c) year and form of publication, (d) measures used to assess pain (e.g., Numeric Rating Scale, NRS), (e) type of pain (postoperative/clinical or experimental), (f) type of experimental design (e.g., within and between group), (g) statistical test used, (h) n values for each group, (i) chronicity of pain, and (j) dose of antagonist. For the purpose of an exploratory analysis, the type of pain was chosen to be a correlate of the magnitude of the effect sizes for two reasons. First, the theoretical and empirical aspects of the literature suggest that the type of pain may influence the strength of the effect sizes. Second, although the literature suggests that the type of pain may be a moderator, there are inconsistencies in the data presented, which warrant further examination. Calculation of effect sizes Effect sizes, g, were defined as the difference between the mean of the experimental versus control group divided by the pooled standard deviation [18] and were computed using the meta-analytic software program DSTAT [19]. Positive gs indicated that either [1] placebo administration decreased the self-report of pain intensity versus control [2] or the administration of naloxone increased self-report of pain versus control. Some studies had multiple gs. When a study included two or more measures of the same variable, gs were calculated for each, and the results were combined according to the method of Rosenthal and Rubin [20]. Since g values can overestimate the population effect size, each g was converted to an adjusted Cohen’s d value, which corrects for this bias [21]. Analyses for placebo-induced analgesia, naloxone effects on analgesia, and placebo-induced h-endorphin secretion were calculated separately to avoid violating independence assumptions [22]. It was necessary to examine each of these parameters to study possible mechanistic changes accompanying placebo-induced analgesia. This methodology is similar to that used in other meta-analyses (e.g., 23–25). Analysis of effect sizes Study outcomes were separated into several analyses. Studies included both within (pre- vs. posttreatment) and between (placebo vs. control) group differences. Studies included the following: (a) placebo effect on self-report of pain and (b) effects of naloxone on the self-report of pain.
Table 1 Tests of population effect sizes Overall
k
d+
95% CI
r
N
P
Qw
P
N fs
Variables coded from each study
Placebo Naloxone
23 18
0.89 0.55
0.74 –1.04 0.39–0.72
.41 .27
609 574
.001 .001
51.11 31.81
.001 .016
41 21
For the primary analysis, the parameter of pain was coded (e.g., pain rating). Other information coded was (a)
Note: k = number of effect sizes; d+ = mean weighted effect size; CI = confidence interval; Q w = homogeneity statistic; N = number of participants; N fs = failsafe N.
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Table 2 Tests of categorical models for type of pain as a moderator Placebo
Naloxone
Class
k
d+
95% CI
Type of pain Nonexperimental (postoperative/clinical) Experimental Between class
8 14
0.62 0.37– 0.87 1.06 0.86 –1.25 Q B(1) = 7.32, P = .007
Qw
k
d+
95% CI
11.03 32.62*
4 14
0.37 0.03– 0.70 0.62 0.43– 0.81 Q B(1) = 1.65, P = .20
Qw 0.37 29.79*
Note: k = number of effect sizes; d+ = mean weighted effect size; CI = confidence interval; Q w = homogeneity statistic; Q B = between-class effect statistic. * P = .01.
The study outcomes for each category were combined by averaging the d values, with each d weighted by the reciprocal of its variance to give the greatest weight to the studies with the largest sample sizes [21]. If the 95% confidence interval (calculated around the mean as a test of significance) did not include zero, it was concluded that d was greater than would be expected due to chance or error. To examine whether d values were consistent across the studies within a certain class, a homogeneity statistic, Q w, was calculated. Classes of a study also were defined to account for the variability in heterogeneous within-class ds, as well as to explore possible between-group differences. To determine the relationship between these classes and the magnitude of d, categorical models were tested using the between-classes statistic, Q B [21]. To address the bfile-drawerQ problem, a fail-safe N (N fs) was calculated. This value provides an estimate of the number of additional or unpublished studies that would be necessary to reverse the overall probability associated with the observed difference, to a level that is nonsignificant [22,26,27].
Results Description of study features This study meta-analyzed 45 final effect sizes from a total of 1183 participants. Methods of pain induction included ischemia, injection of capsaicin, mild electric shock, or postoperative pain/clinical. The age of the participants ranged from 18 to 59 years. Eight studies reported the number of
male (51%) and female (49%) participants by gender. Race and/or ethnicity were not reported in any study. Studies were analyzed separately for two different outcome variables: (a) self-report of pain response with placebo and (b) self-report of pain response with naloxone treatment. Primary analyses Table 1 shows the summary statistics for the primary analyses. In the first analysis, placebo administration was associated with a reduction in self-report of pain ( P = .001). Effect sizes were heterogeneous for type of pain ( P = .001). Also shown in Table 1 is the analysis illustrating the antianalgesic effects of naloxone on pain perception ( P = .001). Effect sizes in the naloxone studies were also heterogeneous ( P = .016). Exploratory analyses A model was fit for the type of pain. For placebo-induced analgesia studies, there was a significant difference between the mean ds for postoperative/clinical versus experimentally induced pain ( P = .007). Within the category of experimental pain, there was a significant degree of heterogeneity ( P = .003). When breaking experimental pain into discrete categories, it was found that the greatest amount of placebo relief was reported for pain induced by ischemia (d = 1.23; Table 2). Using a similar protocol, a model was fit for naloxoneinduced pain perception. There was no significant difference in the effects of naloxone in experimental versus post-
Table 3 Tests of categorical models for type of experimental pain as a moderator Placebo
Naloxone
Class
k
d+
Type of pain Nonexperimental (Postoperative/clinical) Experimental: ischemia Experimental: capsaicin Experimental: shock Between class
95% CI
8 11 2 2
0.62 0.37–0.87 1.23 1.00 –1.46 0.75 0.34 –1.16 0.53 0.02–1.04 Q B(3) = 15.12, P = .002
Qw
k
d+
11.03 22.87* 0.35 1.74
4 11 2 1
0.37 0.03– 0.70 0.44 0.21– 0.66 1.37 0.94 –1.79 0.30 0.45 –1.06 Q B(3) = 16.70, P = .001
95% CI
Qw 0.37 14.62 0.13 n/a
Note: k = number of effect sizes; d+ = mean weighted effect size; CI = confidence interval; Q w = homogeneity statistic; Q B = between-class effect statistic. * P = 0.01.
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operative/chronic pain; however, within the category of experimental pain, there was a significant between-group difference ( P = .001), with pain induced by capsaicin showing the greatest response to naloxone (d = 1.37; Table 3). Two studies examined the effects of placebo administration on h-endorphin secretion. An effect size of 0.22 was calculated, but was insignificant ( P = .36).
Discussion Overall, the data quantitatively support several decades of literature suggesting that the expectation of analgesia does indeed affect self-report of pain. It was found that a substance administered in full view of the individual, with the suggestion that the substance would alleviate pain, induced a significant reduction in the experience of pain, whether pain was experimentally induced or created by surgical experience. The effect size of 0.89 indicates that the average person treated with placebo for pain was better off than 81% of those who did not receive placebo. More specifically, this means that the distributions of the placebo and nonplacebo groups are separated by 0.89 standard deviations at their means or centers, placing the median of the placebo group curve above 81% of the area under the control-group curve. The data also support the notion that placebo analgesia is mediated, in part, by an endogenous opiate-related mechanism. That is, when naloxone was administered by hidden injection, it was found to augment pain response in those receiving placebo analgesia, but had no effect in those individuals who had no expectation of pain reduction (i.e., were not specifically told that they were receiving a painkiller). Moreover, the type of pain moderated the effects of placebo analgesia. There are several plausible reasons for this. First, it is possible that higher levels of endorphins are released during experimental pain. Second, postoperative pain may be greater in intensity than experimental pain to begin with, such that less relief is reported. In addition, experimental pain is induced under more controlled conditions where the amount of pain delivered is tolerable to most. However, studies examined do suggest that the response can be generalized to a natural setting, where the amount of pain and suffering is not as well controlled. It is also unclear if differences in responses were merely a reflection of differences in the emotional aspect of painsuffering (i.e., the physical sensation plus the emotion and affect evoked by the sensation), as opposed to the physiological sensation only [28]. The placebo response, not surprisingly, can be defined as having opiate and non-opiate-mediated components [13,15,29,30]. It is postulated that while the expectation of analgesia was more suggestive of an opiate-mediated event, drug conditioning may activate other subsystems [29]. Furthermore, placebo analgesia may be mediated by other neurotransmitter/modulator systems, such as cholecystoki-
nin [13] and dopamine [15] or by the inhibition of prostaglandin-related pathways [29]. Data support the notion that the bplacebo responseQ is more than just that of an inert, nonspecific factor, but instead, the result of discrete, although multiple, physiological events [4]. Others have proposed that it is personal expectances and a desire for an attenuation of pain that is important [31]. These expectancies are important for the delivery of medical, as well as psychological, treatments. Brody [32] suggests a broader definition of placebo response from inert, nonspecific factors to physiological changes attributable to the symbolism of treatment. More recent evidence, using functional magnetic resonance imaging (fMRI), showed that placebo analgesia was related to decreased brain activity in parts of the brain mediating pain, suggesting that placebos actually alter the experience of pain [33]. Critique and future directions Most studies included in our review adhered to stringent methodology, with several criteria, as outlined by Grevert et al. [14]. These criteria included [1] a no-treatment control group [2], a hidden injection of naloxone to ensure that it is not the awareness of the injection influencing pain rating [3], a between-group design [4], and an appropriate dose of naloxone. Additionally, as previously mentioned, placebo administration should be in full view of the participant, with (or without an additional control condition) the suggestion that pain medication is being administered. While the studies examined showed extremely well-planned methodologies, a glaring omission in the literature is the direct measurement of endogenous opiate levels (e.g., h-endorphin). Only two studies, to our knowledge, utilized this methodology [34,35]. Inasmuch as there were only two studies, we did not include these as part of a formal analysis, but an effect size of 0.22 was calculated. Although this was not significant ( P = .36), most likely due to the lack of statistical power, it calls attention to the need for further studies with similar measurements. These findings also highlight the importance of context, words, and attitudes of medical and mental health providers. Studies show that, while a good therapeutic relationship plays an important role in outcome (e.g., better communication may enhance compliance), the symbolic impact of health care and mental health providers’ words and context can affect the course of illness [4]. Within the field of mental health, for example, it has been shown that many antidepressants are, at best, only marginally more effective than placebo is [7,8,36] and that between 25% and 60% of those treated with placebo report a decrease in depressive symptoms [1,2]. Others have found that placebo administration in depressed individuals who report an improvement in depressive symptoms show concurrent changes in brain function similar to those on antidepressant medication [9,11]. Perceptions are influenced by general beliefs about the environment and world [37]. A thorough understanding of
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the power of the spoken word and the resulting psychoneuroendocrine mechanisms involved in placebo responding will hopefully lead to better communication and improved interactions between psychologists/physicians and clients and significantly improve treatment outcome.
Appendix. Studies Included in the Meta-analysis Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: Expectation-activated opioid systems versus conditioning-activated subsystems. J Neurosci 1999; 19:484 –494. Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: A role for non-specific activation of endogenous opioids. Pain 2001; 90:205 –215. Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996; 64:535 –543. Benedetti F, Arduino C, Amanzio M. Somatotopic activation of opioid systems by target-directed expectations of analgesia. J Neurosci 1999; 19:3639–3648. Gracely RH, Dubner R, Wolskee PJ, Deeter WR. Placebo and naloxone can alter post-surgical pain by separate mechanisms. Nature 1983; 306:264 –265. Grevert P, Albert LH, Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain 1983; 16:129 –143. Hersh EV, Ochs H, Quinn P, MacAfee K, Cooper SA. Narcotic receptor blockade and its effects on the analgesic response to placebo and ibuprofen after oral surgery. Oral Surg Oral Med Oral Pathol 1993; 75:539 –546. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978:654 –657. Levine JD, Gordon NC. Influence of the method of drug administration on analgesic response. Nature 1984; 312: 755 –756. Pollo A, Vighetti S, Rainero I, Benedetti F. Placebo analgesia and the heart. Pain 2003; 102:125 –133. Posner J, Burke CA. The effects of naloxone on opiate and placebo analgesia in healthy volunteers. Psychopharmacol 1985; 87:468 – 472. Roelofs J, ter Riet G, Peters ML, Kessels AGH, Ruelen JPH, Menheere PPCA. Expectations of analgesia do not affect nociceptive R-III reflex activity: An experimental study into the mechanism of placebo-induced analgesia. Pain 2000; 89:75 –80.
References [1] Shapiro AK, Shapiro E. The powerful placebo: from ancient priest to modern physician. Baltimore7 Johns Hopkins Univ Press, 1997. [2] Quitkin FM. Placebos, drug effects, and study design: a clinician’s guide. Am J Psychiatry 1999;156:829 – 36. [3] Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344(21):1594 – 602.
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[4] Benedetti F. How the doctor’s words affect the patient’s brain. Eval Health Prof 2002;25(4):369 – 86. [5] Starfield B, Wray C, Hess K, Gross R, Birk PS, D’Lugoff BC. The influence of patient–practitioner agreement on outcome of care. Am J Publ Health 1981;71:127 – 32. [6] Shetty N, Friedman JH, Keiburtz K, Marshall FJ, Oakes D. The placebo response in Parkinson’s disease. Parkinson study group. Clin Neuropharmacol 1999;22:207 – 12. [7] Greenberg RP, Bornstein RF, Greenberg MD, Fisher S. A meta-analysis of antidepressant outcome under bblinderQ conditions. J Consult Clin Psychol 1992;60(5):664 – 9. [8] Greenberg RP, Fisher S. Mood-mending medicines: probing drug, psychotherapy, and placebo solutions. In: Fisher S, Greenberg RP, editors. From placebo to panacea: putting psychiatric drugs to the test. New York7 Wiley, 1997. pp. 115 – 72. [9] Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA. The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002;159(5):728 – 37. [10] Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia—imaging a shared neural network. Science 2002;295: 1737 – 40. [11] Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002;159:122 – 9. [12] Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978:654 – 7. [13] Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996;64:535 – 43. [14] Grevert P, Albert LH, Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain 1983;16:129 – 43. [15] de la Fuente-Fernandez R, Stoessl AJ. The biochemical bases for reward: implications for the placebo effect. Eval Health Prof 2002;25: 387 – 98. [16] Benedetti F, Amanzio M. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 1997; 51:109 – 25. [17] ter Riet G, de Craen AJM, de Boer A, Kessels AGH. Is placebo analgesia mediated by endogenous opioids? A systematic review. Pain 1998;76:273 – 5. [18] Cohen J. Statistical power analysis for the behavioral sciences. New York7 Academic Press, 1969. [19] Johnson BT. DSTAT: software for the meta-analytic review of research literatures. Hillsdale (NJ)7 Erlbaum, 1989. [20] Rosenthal R, Rubin D. Meta-analytic procedures for combining studies with multiple effect sizes. Psychol Bull 1986;99:400 – 6. [21] Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando7 Academic Press, 1985. [22] Wolf FM. Meta-analysis: quantitative methods of research synthesis. Newbury Park7 Sage Publications, 1986. [23] Benschop RJ, Geenen R, Mills PJ, Naliboff BD, Kiecolt-Glaser JK, Herbert TB, van der Pompe G, Miller GE, Matthews KA, Godaert GLR, Gilmore SL, Glaser R, Heijnen CJ, Dopp JM, Bijlsma JM, Solomon GF, Cacioppo JT. Cardiovascular and immune responses to acute psychological stress in young and old women: a meta-analysis. Psychosom Med 1998;60:290 – 6. [24] Jorgensen RS, Johnson BT, Kolodzeij ME, Schreer GE. Elevated blood pressure and personality: a meta-analytic review. Psychol Bull 1996; 120:293 – 320. [25] Rossy LA, Buckelew SP, Dorr N, Haggland KJ, Thayer JF, McIntosh MJ, Hewett JE, Johnson JC. A meta-analysis of fibromyalgia treatment interventions. Ann Behav Med 1999;21:180 – 91. [26] Rosenthal R. The bfile-drawerQ problem and tolerance for null results. Psychol Bull 1979;86:638 – 41. [27] Orwin RG. A fail-safe N for effect size. J Educ Stat 1983;8:157 – 9. [28] Beecher HK. Relationship of significance of wound to pain experienced. J Am Med Assoc 1956;161:1609 – 13.
120
M.D. Sauro, R.P. Greenberg / Journal of Psychosomatic Research 58 (2005) 115 – 120
[29] Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioningactivated subsystems. J Neurosci 1999;19:484 – 94. [30] Price DD, Soerensen LV. Endogenous opioid and non-opioid pathways as mediators of placebo analgesia. In: Guess HA, Kleinman A, Kusek JW, Engel LW, editors. The science of the placebo. London7 BMJ Books, 2002. pp. 183 – 206. [31] Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 1999;83:147 – 56. [32] Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract 2000;49(7):649 – 54. [33] Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in
[34]
[35]
[36] [37]
fMRI in the anticipation and experience of pain. Science 2004;303: 1162 – 7. Lipman JJ, Miller BE, Mays KS, Miller MN, North WC, Byrne WL. Peak beta endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response. Psychopharmacology 1990;102:112 – 6. Roelofs J, ter Riet G, Peters ML, Kessels AGH, Ruelen JPH, Menheere PPCA. Expectations of analgesia do not affect nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia. Pain 2000;89:75 – 80. Kirsch I, 1999. The placebo effect: an interdisciplinary exploration. Cambridge (MA)7 Harvard Univ Press, 1999. Houston BK, 1986. Personality dimensions in reactivity and cardiovascular disease. New York7 Wiley, 1986.
Endogenous opiates and the placebo effect A meta-analytic review Marie D. Sauroa,*, Roger P. Greenbergb a
Department of Psychology, University of Massachusetts Dartmouth, 285 Old Westport Road, North Dartmouth, MA 02747, United States b Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, United States Received 15 March 2004; accepted 7 July 2004
Abstract Objective: A meta-analysis was performed to investigate the ability of placebo administration to reduce self-report of pain and to examine whether placebo-induced pain reduction might have physiological and psychological underpinnings. Method: Fortyfive effect sizes and 1183 participants from 12 studies were metaanalyzed for the effects of placebo and the opioid antagonist, naloxone, on self-report of pain. Results: Analyses showed that placebo administration was associated with a decrease in self-report of pain, and a hidden or blind injection of naloxone reversed placebo-induced analgesia. Furthermore, there were significant
between-group differences for type of pain (experimental vs. postoperative/clinical) for placebo studies. Conclusions: The results support the literature illustrating that the belief and expectation of analgesia induces discrete physiological changes, leading to relief from pain, and this response may be mediated by endogenous opioids. The implications of these findings are discussed in terms of the symbolic aspect of health care and mental health providers’ words and context, and their potential impact on the course of illness and well-being. D 2005 Elsevier Inc. All rights reserved.
Keywords: Pain; Patient–provider interaction; Placebo; Psychoneuroendocrinology; Psychopharmacology
Introduction The placebo response has received attention in many different areas of medicine and science. Its effects have been studied in the context of whether it is truly an appropriate control condition for clinical trials of drugs and other medical or surgical treatments. While some reports estimate that between 25% and 60% of patients report improvement with placebo treatment across various clinical conditions, such as pain, asthma, cardiovascular diseases, and depression [1,2], other reports have found little evidence supporting significant clinical effects [3]. The fact that physiological changes occur in response to an binertQ treatment, or a symbolic event, has important implications for many different therapeutic modalities. For example, it has been shown that medical context (i.e., all factors that comprise the atmosphere surrounding a patient, * Corresponding author. Tel.: +1 508 999 8380. E-mail address: [email protected] (M.D. Sauro). 0022-3999/04/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2004.07.001
including the specific wording of statements made by doctors) has profound effects on the outcome of medical treatment, and this effect is modulated by specific neurochemical messengers [4]. Others have suggested that placebo-like factors may play a role in determining treatment outcome for general medical outcomes [5], as well as specific conditions, such as Parkinsonism [6] and clinical depression [7,8]. For depression, these placebo-induced improvements can be mapped to changes in brain glucose metabolism [9,10] and electrical activity [11]. The physiological mechanisms underlying the placebo response have been studied extensively but are not well understood. The most well-studied phenomenon with respect to biochemical changes comes from studies examining placebo-induced analgesia. Mediators implicated include endogenous opioids (e.g., h-endorphin; 12–14), cholecystokinin [13], and dopamine [15]. Because studies in this literature are difficult to compare due to the variability of conditions, populations studied, and methodologies, there was a need to examine the significance
116
M.D. Sauro, R.P. Greenberg / Journal of Psychosomatic Research 58 (2005) 115 – 120
and consistency of effect sizes across the literature. Past reviews in this area have either been qualitative reviews [16], meta-analyses examining placebo effects in clinical trials collapsed across a variety of clinical conditions [3], or are somewhat outdated [17]. The main objective of this meta-analysis was to provide a focused quantitative review of the effects of placebo analgesia and the plausible mechanisms underlying this phenomenon (i.e., opiate related). For the primary analyses, it was hypothesized that placebo administration (i.e., administration of an inert agent along with verbal communication, that the individual would be receiving an analgesic agent) would decrease the subjective rating of both nonexperimental (postoperative/clinical) and experimentally induced pain. Second, it was hypothesized that the antagonism of opiate receptors (via the administration of naloxone) would attenuate placebo-induced analgesia. Third, as an exploratory analysis, it was hypothesized that there would be a difference in placebo-mediated analgesia among the different types of pain because the literature in this area is variable.
Method Sample of studies Studies were obtained using a computer-based literature search. The databases used were Medline (1966 –2003), PsychINFO (1967–2003), and Mental Health Abstracts (1969–2003). Also searched were reference lists from review articles, empirical papers, and dissertations. Only studies available by June 2003 were included in the sample. Studies, or portions of studies, included in this metaanalysis met the following inclusion criteria: (a) a published study, (b) written in English, (c) included pain induction and measurement of pain, and (d) examined opiate pathway involvement either by the use of an antagonist or directly measuring endogenous opiates. Papers that did not measure both placebo analgesia and reversal by naloxone were not included. In addition, the study had to employ a protocol where the participant was not merely given a placebo, but was explicitly told that they would be receiving medication to alleviate pain. bPlaceboQ is operationalized by the following conditions: The substance is given in full view, with the suggestion that analgesia is being administered. Lastly, the study must have reported administration of naloxone via hidden injection (intravenously, out of participants’ view) or through a blinded procedure, where participants and experimenters were unaware of what substances were being administered to the participant (who previously agreed to receive injections of either saline or drugs).
gender of patients, (b) age, (c) year and form of publication, (d) measures used to assess pain (e.g., Numeric Rating Scale, NRS), (e) type of pain (postoperative/clinical or experimental), (f) type of experimental design (e.g., within and between group), (g) statistical test used, (h) n values for each group, (i) chronicity of pain, and (j) dose of antagonist. For the purpose of an exploratory analysis, the type of pain was chosen to be a correlate of the magnitude of the effect sizes for two reasons. First, the theoretical and empirical aspects of the literature suggest that the type of pain may influence the strength of the effect sizes. Second, although the literature suggests that the type of pain may be a moderator, there are inconsistencies in the data presented, which warrant further examination. Calculation of effect sizes Effect sizes, g, were defined as the difference between the mean of the experimental versus control group divided by the pooled standard deviation [18] and were computed using the meta-analytic software program DSTAT [19]. Positive gs indicated that either [1] placebo administration decreased the self-report of pain intensity versus control [2] or the administration of naloxone increased self-report of pain versus control. Some studies had multiple gs. When a study included two or more measures of the same variable, gs were calculated for each, and the results were combined according to the method of Rosenthal and Rubin [20]. Since g values can overestimate the population effect size, each g was converted to an adjusted Cohen’s d value, which corrects for this bias [21]. Analyses for placebo-induced analgesia, naloxone effects on analgesia, and placebo-induced h-endorphin secretion were calculated separately to avoid violating independence assumptions [22]. It was necessary to examine each of these parameters to study possible mechanistic changes accompanying placebo-induced analgesia. This methodology is similar to that used in other meta-analyses (e.g., 23–25). Analysis of effect sizes Study outcomes were separated into several analyses. Studies included both within (pre- vs. posttreatment) and between (placebo vs. control) group differences. Studies included the following: (a) placebo effect on self-report of pain and (b) effects of naloxone on the self-report of pain.
Table 1 Tests of population effect sizes Overall
k
d+
95% CI
r
N
P
Qw
P
N fs
Variables coded from each study
Placebo Naloxone
23 18
0.89 0.55
0.74 –1.04 0.39–0.72
.41 .27
609 574
.001 .001
51.11 31.81
.001 .016
41 21
For the primary analysis, the parameter of pain was coded (e.g., pain rating). Other information coded was (a)
Note: k = number of effect sizes; d+ = mean weighted effect size; CI = confidence interval; Q w = homogeneity statistic; N = number of participants; N fs = failsafe N.
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Table 2 Tests of categorical models for type of pain as a moderator Placebo
Naloxone
Class
k
d+
95% CI
Type of pain Nonexperimental (postoperative/clinical) Experimental Between class
8 14
0.62 0.37– 0.87 1.06 0.86 –1.25 Q B(1) = 7.32, P = .007
Qw
k
d+
95% CI
11.03 32.62*
4 14
0.37 0.03– 0.70 0.62 0.43– 0.81 Q B(1) = 1.65, P = .20
Qw 0.37 29.79*
Note: k = number of effect sizes; d+ = mean weighted effect size; CI = confidence interval; Q w = homogeneity statistic; Q B = between-class effect statistic. * P = .01.
The study outcomes for each category were combined by averaging the d values, with each d weighted by the reciprocal of its variance to give the greatest weight to the studies with the largest sample sizes [21]. If the 95% confidence interval (calculated around the mean as a test of significance) did not include zero, it was concluded that d was greater than would be expected due to chance or error. To examine whether d values were consistent across the studies within a certain class, a homogeneity statistic, Q w, was calculated. Classes of a study also were defined to account for the variability in heterogeneous within-class ds, as well as to explore possible between-group differences. To determine the relationship between these classes and the magnitude of d, categorical models were tested using the between-classes statistic, Q B [21]. To address the bfile-drawerQ problem, a fail-safe N (N fs) was calculated. This value provides an estimate of the number of additional or unpublished studies that would be necessary to reverse the overall probability associated with the observed difference, to a level that is nonsignificant [22,26,27].
Results Description of study features This study meta-analyzed 45 final effect sizes from a total of 1183 participants. Methods of pain induction included ischemia, injection of capsaicin, mild electric shock, or postoperative pain/clinical. The age of the participants ranged from 18 to 59 years. Eight studies reported the number of
male (51%) and female (49%) participants by gender. Race and/or ethnicity were not reported in any study. Studies were analyzed separately for two different outcome variables: (a) self-report of pain response with placebo and (b) self-report of pain response with naloxone treatment. Primary analyses Table 1 shows the summary statistics for the primary analyses. In the first analysis, placebo administration was associated with a reduction in self-report of pain ( P = .001). Effect sizes were heterogeneous for type of pain ( P = .001). Also shown in Table 1 is the analysis illustrating the antianalgesic effects of naloxone on pain perception ( P = .001). Effect sizes in the naloxone studies were also heterogeneous ( P = .016). Exploratory analyses A model was fit for the type of pain. For placebo-induced analgesia studies, there was a significant difference between the mean ds for postoperative/clinical versus experimentally induced pain ( P = .007). Within the category of experimental pain, there was a significant degree of heterogeneity ( P = .003). When breaking experimental pain into discrete categories, it was found that the greatest amount of placebo relief was reported for pain induced by ischemia (d = 1.23; Table 2). Using a similar protocol, a model was fit for naloxoneinduced pain perception. There was no significant difference in the effects of naloxone in experimental versus post-
Table 3 Tests of categorical models for type of experimental pain as a moderator Placebo
Naloxone
Class
k
d+
Type of pain Nonexperimental (Postoperative/clinical) Experimental: ischemia Experimental: capsaicin Experimental: shock Between class
95% CI
8 11 2 2
0.62 0.37–0.87 1.23 1.00 –1.46 0.75 0.34 –1.16 0.53 0.02–1.04 Q B(3) = 15.12, P = .002
Qw
k
d+
11.03 22.87* 0.35 1.74
4 11 2 1
0.37 0.03– 0.70 0.44 0.21– 0.66 1.37 0.94 –1.79 0.30 0.45 –1.06 Q B(3) = 16.70, P = .001
95% CI
Qw 0.37 14.62 0.13 n/a
Note: k = number of effect sizes; d+ = mean weighted effect size; CI = confidence interval; Q w = homogeneity statistic; Q B = between-class effect statistic. * P = 0.01.
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operative/chronic pain; however, within the category of experimental pain, there was a significant between-group difference ( P = .001), with pain induced by capsaicin showing the greatest response to naloxone (d = 1.37; Table 3). Two studies examined the effects of placebo administration on h-endorphin secretion. An effect size of 0.22 was calculated, but was insignificant ( P = .36).
Discussion Overall, the data quantitatively support several decades of literature suggesting that the expectation of analgesia does indeed affect self-report of pain. It was found that a substance administered in full view of the individual, with the suggestion that the substance would alleviate pain, induced a significant reduction in the experience of pain, whether pain was experimentally induced or created by surgical experience. The effect size of 0.89 indicates that the average person treated with placebo for pain was better off than 81% of those who did not receive placebo. More specifically, this means that the distributions of the placebo and nonplacebo groups are separated by 0.89 standard deviations at their means or centers, placing the median of the placebo group curve above 81% of the area under the control-group curve. The data also support the notion that placebo analgesia is mediated, in part, by an endogenous opiate-related mechanism. That is, when naloxone was administered by hidden injection, it was found to augment pain response in those receiving placebo analgesia, but had no effect in those individuals who had no expectation of pain reduction (i.e., were not specifically told that they were receiving a painkiller). Moreover, the type of pain moderated the effects of placebo analgesia. There are several plausible reasons for this. First, it is possible that higher levels of endorphins are released during experimental pain. Second, postoperative pain may be greater in intensity than experimental pain to begin with, such that less relief is reported. In addition, experimental pain is induced under more controlled conditions where the amount of pain delivered is tolerable to most. However, studies examined do suggest that the response can be generalized to a natural setting, where the amount of pain and suffering is not as well controlled. It is also unclear if differences in responses were merely a reflection of differences in the emotional aspect of painsuffering (i.e., the physical sensation plus the emotion and affect evoked by the sensation), as opposed to the physiological sensation only [28]. The placebo response, not surprisingly, can be defined as having opiate and non-opiate-mediated components [13,15,29,30]. It is postulated that while the expectation of analgesia was more suggestive of an opiate-mediated event, drug conditioning may activate other subsystems [29]. Furthermore, placebo analgesia may be mediated by other neurotransmitter/modulator systems, such as cholecystoki-
nin [13] and dopamine [15] or by the inhibition of prostaglandin-related pathways [29]. Data support the notion that the bplacebo responseQ is more than just that of an inert, nonspecific factor, but instead, the result of discrete, although multiple, physiological events [4]. Others have proposed that it is personal expectances and a desire for an attenuation of pain that is important [31]. These expectancies are important for the delivery of medical, as well as psychological, treatments. Brody [32] suggests a broader definition of placebo response from inert, nonspecific factors to physiological changes attributable to the symbolism of treatment. More recent evidence, using functional magnetic resonance imaging (fMRI), showed that placebo analgesia was related to decreased brain activity in parts of the brain mediating pain, suggesting that placebos actually alter the experience of pain [33]. Critique and future directions Most studies included in our review adhered to stringent methodology, with several criteria, as outlined by Grevert et al. [14]. These criteria included [1] a no-treatment control group [2], a hidden injection of naloxone to ensure that it is not the awareness of the injection influencing pain rating [3], a between-group design [4], and an appropriate dose of naloxone. Additionally, as previously mentioned, placebo administration should be in full view of the participant, with (or without an additional control condition) the suggestion that pain medication is being administered. While the studies examined showed extremely well-planned methodologies, a glaring omission in the literature is the direct measurement of endogenous opiate levels (e.g., h-endorphin). Only two studies, to our knowledge, utilized this methodology [34,35]. Inasmuch as there were only two studies, we did not include these as part of a formal analysis, but an effect size of 0.22 was calculated. Although this was not significant ( P = .36), most likely due to the lack of statistical power, it calls attention to the need for further studies with similar measurements. These findings also highlight the importance of context, words, and attitudes of medical and mental health providers. Studies show that, while a good therapeutic relationship plays an important role in outcome (e.g., better communication may enhance compliance), the symbolic impact of health care and mental health providers’ words and context can affect the course of illness [4]. Within the field of mental health, for example, it has been shown that many antidepressants are, at best, only marginally more effective than placebo is [7,8,36] and that between 25% and 60% of those treated with placebo report a decrease in depressive symptoms [1,2]. Others have found that placebo administration in depressed individuals who report an improvement in depressive symptoms show concurrent changes in brain function similar to those on antidepressant medication [9,11]. Perceptions are influenced by general beliefs about the environment and world [37]. A thorough understanding of
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the power of the spoken word and the resulting psychoneuroendocrine mechanisms involved in placebo responding will hopefully lead to better communication and improved interactions between psychologists/physicians and clients and significantly improve treatment outcome.
Appendix. Studies Included in the Meta-analysis Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: Expectation-activated opioid systems versus conditioning-activated subsystems. J Neurosci 1999; 19:484 –494. Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: A role for non-specific activation of endogenous opioids. Pain 2001; 90:205 –215. Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996; 64:535 –543. Benedetti F, Arduino C, Amanzio M. Somatotopic activation of opioid systems by target-directed expectations of analgesia. J Neurosci 1999; 19:3639–3648. Gracely RH, Dubner R, Wolskee PJ, Deeter WR. Placebo and naloxone can alter post-surgical pain by separate mechanisms. Nature 1983; 306:264 –265. Grevert P, Albert LH, Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain 1983; 16:129 –143. Hersh EV, Ochs H, Quinn P, MacAfee K, Cooper SA. Narcotic receptor blockade and its effects on the analgesic response to placebo and ibuprofen after oral surgery. Oral Surg Oral Med Oral Pathol 1993; 75:539 –546. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978:654 –657. Levine JD, Gordon NC. Influence of the method of drug administration on analgesic response. Nature 1984; 312: 755 –756. Pollo A, Vighetti S, Rainero I, Benedetti F. Placebo analgesia and the heart. Pain 2003; 102:125 –133. Posner J, Burke CA. The effects of naloxone on opiate and placebo analgesia in healthy volunteers. Psychopharmacol 1985; 87:468 – 472. Roelofs J, ter Riet G, Peters ML, Kessels AGH, Ruelen JPH, Menheere PPCA. Expectations of analgesia do not affect nociceptive R-III reflex activity: An experimental study into the mechanism of placebo-induced analgesia. Pain 2000; 89:75 –80.
References [1] Shapiro AK, Shapiro E. The powerful placebo: from ancient priest to modern physician. Baltimore7 Johns Hopkins Univ Press, 1997. [2] Quitkin FM. Placebos, drug effects, and study design: a clinician’s guide. Am J Psychiatry 1999;156:829 – 36. [3] Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344(21):1594 – 602.
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[4] Benedetti F. How the doctor’s words affect the patient’s brain. Eval Health Prof 2002;25(4):369 – 86. [5] Starfield B, Wray C, Hess K, Gross R, Birk PS, D’Lugoff BC. The influence of patient–practitioner agreement on outcome of care. Am J Publ Health 1981;71:127 – 32. [6] Shetty N, Friedman JH, Keiburtz K, Marshall FJ, Oakes D. The placebo response in Parkinson’s disease. Parkinson study group. Clin Neuropharmacol 1999;22:207 – 12. [7] Greenberg RP, Bornstein RF, Greenberg MD, Fisher S. A meta-analysis of antidepressant outcome under bblinderQ conditions. J Consult Clin Psychol 1992;60(5):664 – 9. [8] Greenberg RP, Fisher S. Mood-mending medicines: probing drug, psychotherapy, and placebo solutions. In: Fisher S, Greenberg RP, editors. From placebo to panacea: putting psychiatric drugs to the test. New York7 Wiley, 1997. pp. 115 – 72. [9] Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA. The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002;159(5):728 – 37. [10] Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia—imaging a shared neural network. Science 2002;295: 1737 – 40. [11] Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002;159:122 – 9. [12] Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978:654 – 7. [13] Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996;64:535 – 43. [14] Grevert P, Albert LH, Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain 1983;16:129 – 43. [15] de la Fuente-Fernandez R, Stoessl AJ. The biochemical bases for reward: implications for the placebo effect. Eval Health Prof 2002;25: 387 – 98. [16] Benedetti F, Amanzio M. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 1997; 51:109 – 25. [17] ter Riet G, de Craen AJM, de Boer A, Kessels AGH. Is placebo analgesia mediated by endogenous opioids? A systematic review. Pain 1998;76:273 – 5. [18] Cohen J. Statistical power analysis for the behavioral sciences. New York7 Academic Press, 1969. [19] Johnson BT. DSTAT: software for the meta-analytic review of research literatures. Hillsdale (NJ)7 Erlbaum, 1989. [20] Rosenthal R, Rubin D. Meta-analytic procedures for combining studies with multiple effect sizes. Psychol Bull 1986;99:400 – 6. [21] Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando7 Academic Press, 1985. [22] Wolf FM. Meta-analysis: quantitative methods of research synthesis. Newbury Park7 Sage Publications, 1986. [23] Benschop RJ, Geenen R, Mills PJ, Naliboff BD, Kiecolt-Glaser JK, Herbert TB, van der Pompe G, Miller GE, Matthews KA, Godaert GLR, Gilmore SL, Glaser R, Heijnen CJ, Dopp JM, Bijlsma JM, Solomon GF, Cacioppo JT. Cardiovascular and immune responses to acute psychological stress in young and old women: a meta-analysis. Psychosom Med 1998;60:290 – 6. [24] Jorgensen RS, Johnson BT, Kolodzeij ME, Schreer GE. Elevated blood pressure and personality: a meta-analytic review. Psychol Bull 1996; 120:293 – 320. [25] Rossy LA, Buckelew SP, Dorr N, Haggland KJ, Thayer JF, McIntosh MJ, Hewett JE, Johnson JC. A meta-analysis of fibromyalgia treatment interventions. Ann Behav Med 1999;21:180 – 91. [26] Rosenthal R. The bfile-drawerQ problem and tolerance for null results. Psychol Bull 1979;86:638 – 41. [27] Orwin RG. A fail-safe N for effect size. J Educ Stat 1983;8:157 – 9. [28] Beecher HK. Relationship of significance of wound to pain experienced. J Am Med Assoc 1956;161:1609 – 13.
120
M.D. Sauro, R.P. Greenberg / Journal of Psychosomatic Research 58 (2005) 115 – 120
[29] Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioningactivated subsystems. J Neurosci 1999;19:484 – 94. [30] Price DD, Soerensen LV. Endogenous opioid and non-opioid pathways as mediators of placebo analgesia. In: Guess HA, Kleinman A, Kusek JW, Engel LW, editors. The science of the placebo. London7 BMJ Books, 2002. pp. 183 – 206. [31] Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 1999;83:147 – 56. [32] Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract 2000;49(7):649 – 54. [33] Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in
[34]
[35]
[36] [37]
fMRI in the anticipation and experience of pain. Science 2004;303: 1162 – 7. Lipman JJ, Miller BE, Mays KS, Miller MN, North WC, Byrne WL. Peak beta endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response. Psychopharmacology 1990;102:112 – 6. Roelofs J, ter Riet G, Peters ML, Kessels AGH, Ruelen JPH, Menheere PPCA. Expectations of analgesia do not affect nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia. Pain 2000;89:75 – 80. Kirsch I, 1999. The placebo effect: an interdisciplinary exploration. Cambridge (MA)7 Harvard Univ Press, 1999. Houston BK, 1986. Personality dimensions in reactivity and cardiovascular disease. New York7 Wiley, 1986.