Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia

Abstract

Recent advances in placebo research have demonstrated the mind's power to alter physiology. In this study, we combined an expectancy manipulation model with both verum and sham acupuncture treatments to address: 1) how and to what extent treatment and expectancy effects — including both subjective pain intensity levels (pain sensory ratings) and objective physiological activations (fMRI) — interact; and 2) if the underlying mechanism of expectancy remains the same whether placebo treatment is given alone or in conjunction with active treatment. The results indicate that although verum acupuncture + high expectation and sham acupuncture + high expectation induced subjective reports of analgesia of equal magnitude, fMRI analysis showed that verum acupuncture produced greater fMRI signal decrease in pain related brain regions during application of calibrated heat pain stimuli on the right arm. We believe our study provides brain imaging evidence for the existence of different mechanisms underlying acupuncture analgesia and expectancy evoked placebo analgesia. Our results also suggest that the brain network involved in expectancy may vary under different treatment situations (verum and sham acupuncture treatment).

Introduction

Embedded in biomedical science are many sets of related dichotomies: body or mind, objective or subjective, biology or belief, specific or non-specific, and pharmacology or placebo (Kirmayer, 1988). In treatment, these effects are generally considered additive (Kirsch, 2000, Kleijnen et al., 1994). In fact, the fundamental assumption of the randomized controlled trial is that a medication or procedure demonstrates efficacy by producing a statistically significant additive value above a placebo effect (Kaptchuk, 1998). Taking pain relief as an example, it is believed that analgesic treatments consist of two components: the treatment specific effect from the physical or pharmacological interventions, and the non-specific, or placebo, component. The latter is believed to be induced by the psychosocial context in which the treatment is given including expectations of therapeutic benefit (Colloca and Benedetti, 2005, Kleijnen et al., 1994).

Acupuncture has been studied in almost one thousand different randomized controlled trials (RCTs) (Ernst, 2006, Kaptchuk, 2000, Linde et al., 2001). The results of these trials have been contradictory or equivocal. In these trials, it is not uncommon for “placebo/sham acupuncture/minimal acupuncture” controls to induce positive therapeutic effects on the same order of magnitude as verum (genuine) acupuncture. In other studies, verum and sham groups often demonstrate superiority and clinical benefits over waiting list of conventional therapies controls (Brinkhaus et al., 2006, Haake et al., 2007, Kaptchuk, 2000, Kaptchuk, 2002a, Leibing et al., 2002, Linde et al., 2005, Melchart et al., 2005).

Acupuncture RCTs also suggest that expectancy, a crucial component of placebo (Benedetti, 2008, Kirsch, 1985, Montgomery and Kirsch, 1997), plays an important role in acupuncture treatment efficacy (Kaptchuk, 2002b, Kaptchuk et al., 2006, Linde et al., 2007). Importantly, basic science research investigating acupuncture analgesia on experimental pain, (which has produced more consistently positive results for acupuncture than clinical trials), has implicated overlapping mechanisms involving endogenous opioids and CCK for example, in both acupuncture (Han, 2003, Mayer et al., 1977) and placebo analgesia (Benedetti et al., 1999, Levine et al., 1978). This information suggests that the clinical practice of acupuncture may utilize some of the same endogenous analgesic mechanisms elicited by placebo treatments. Taken together, these findings beg the question — do the same mechanisms underlie acupuncture and placebo analgesia?

In parallel, advances in brain imaging provide scientists with new tools for investigating the neurobiological mechanisms underlying both placebo/nocebo and acupuncture treatment. Studies in placebo and nocebo research have shown the dramatic power of the mind to alter physiology and underlying brain circuitry (Bingel et al., 2006, Colloca et al., 2008b, Craggs et al., 2007, Kong et al., 2008, Kong et al., 2006a, Lieberman et al., 2004, Petrovic et al., 2002, Price et al., 2007, Scott et al., 2007, Scott et al., 2008, Wager et al., 2004, Wager et al., 2007, Zubieta et al., 2005). Investigations of acupuncture also demonstrate complicated brain networks involved in acupuncture stimulation (Dougherty et al., 2008, Fang et al., in press, Fang et al., 2004, Hui et al., 2000, Hui et al., 2005, Kong et al., 2007b, Kong et al., 2009, Kong et al., 2002, Li et al., 2004, Li et al., 2006, Napadow et al., 2007, Napadow et al., 2006, Napadow et al., 2004, Pariente et al., 2005, Wu et al., 1999, Wu et al., 2002, Yoo et al., 2004) and acupuncture analgesia (Zhang et al., 2003a,b). In contrast, little empirical work has directly examined the interactions between the physiological components of interventions and such non-specific factors as expectancy. For example, do acupuncture analgesia and placebo analgesia work through the same brain networks? Is the underlying mechanism of expectancy the same whether placebo treatment is given alone or in conjunction with active treatment?

One difficulty in studying placebo analgesia using healthy volunteers and experimentally-induced pain is that the placebo effects are fewer and smaller than those in genuine clinical pain studies (Beecher, 1959, Charron et al., 2006, Shapiro and Shapiro, 1997). In a previous study (Kong et al., 2006a), using a well-established expectancy/conditioning manipulation to increase expectation of analgesia, we found that placebo analgesia evoked by sham acupuncture, as indicated by subjective pain rating reductions, was significantly greater on placebo sites than on the control sites on the same right arm where subjects were not expecting an analgesic effect. The magnitude of this analgesia effect is comparable with the magnitude of the verum acupuncture analgesia effect observed in another study from our group (Kong et al., 2005).

In this current study, we combined the same expectancy/conditioning manipulation model to investigate whether the patterns of neural activation underlying the modulation of pain perception by verum acupuncture analgesia and expectancy evoked placebo analgesia can be distinguished using fMRI. In this experiment, subjects were randomized into four groups, receiving verum or sham acupuncture paired with either high or low expectancy/conditioning manipulation. Then analgesic response to experimental heat pain applied on the right forearm was tested. In each group, we also included a within-subject control. Subjects were told that if they responded to the acupuncture treatment they would experience analgesia only on the treated side of their arm, but not on the untreated side of their arm (Fig. 1). Forty-eight subjects (12 in each group) completed the experiment. In this manuscript, we present the data from two high expectancy groups (real and sham acupuncture) to investigate the underlying mechanisms of verum acupuncture and expectancy/conditioning induced placebo analgesia. Data from the low expectancy groups will be presented in a separate manuscript.