Prior research suggests that placebo and remifentanil analgesia share common mechanisms of action. Both target μ-opioid receptors (Levine et al., 1978
; Zubieta et al., 2005
; Wager et al., 2007a
; Eippert et al., 2009
) and they are associated with increases in overlapping brain regions (the periaqueductal gray [PAG] and rostral anterior cingulate [rACC] in particular) during pain (Petrovic et al., 2002
). These common mechanisms could lead to competition for receptor availability or neural synergies, leading to under-additive or over-additive interactions, respectively. Both types of interactions have been found in the past, in treatments as diverse as naproxen for cancer pain (Bergmann et al., 1994
), epinephrine (Penick and Fisher, 1965
), caffeine (Flaten and Blumenthal, 1999
), proglumide (Benedetti et al., 1995
), acupuncture treatment (Kong et al., 2009a
; Kong et al., 2009b
), and several others (Kleijnen et al., 1994
). If drug effects differ as a function of belief, this would undermine the assumptions underlying the standard clinical trial. However, the set of studies we present here indicates that, when combined, opiate drug effects and expectancy effects on brain activity and behavior are in fact additive and dissociable, with effects on different brain regions and at different times.
In this paper, we tested whether drug effects depend on belief by manipulating both remifentanil and expectation and directly testing for interactions. Across two studies, we found support for additive, independent effects of expectancy and remifentanil on pain and pain-related fMRI activity. The Behavioral Experiment used a balanced placebo design, which revealed that expectations (induced by instructions about remifentanil delivery) reduced pain during active opiate administration, consistent with previous findings (Bingel et al., 2011
). Remifentanil also reduced pain. However, testing drug and expectancy in a factorial design revealed effects of belief that were additive
with drug effects, consistent with the assumptions of randomized clinical trials.
In the fMRI Experiment, in place of the balanced placebo design, we used pharmacokinetic model-based estimates of drug concentration across time (Minto et al., 1997b
; Minto et al., 1997a
; Wise et al., 2002
; Wise et al., 2004
) to test interactions between remifentanil and expectancies manipulated by Open vs. Hidden administration context and instructions. Pain reports were affected by both remifentanil and information about drug delivery, but drug-induced pain reduction was the same in both Open and Hidden conditions. Thus, the results replicated the additive effects of the Behavioral Experiment, illustrating that the same conclusions can be made even when the time-course of expectancy versus drug effects is used to isolate effects, rather than the traditional balanced placebo design (though we note that the balanced placebo approach might have more explanatory power in some cases due to the factorial design). Additivity has been used in pain and placebo research (Gracely et al., 1983
; Buhle et al., In press
) and other areas (Sternberg, 1969
) as evidence for separable processing. For example, Gracely et al. (1983)
found that placebo and the opiate antagonist naloxone had additive effects on dental pain, suggesting opioid-independent placebo effects.
fMRI results corroborated the additive effects on pain reports. Remifentanil and expectancy modulated PPN responses during pain and other brain processes in dissociable ways. Remifentanil-induced reductions in PPN regions were widespread, indicating reduced nociceptive/pain-related activity. However, we did not find substantial evidence for differences in drug effects with high vs. low expectations of analgesia, as manipulated by Open vs. Hidden administration context, in either ROI analyses or voxel-wise maps. Rather, expectancy had more limited effects on PPN, with a time course that began when the drug infusion started, before drug concentration in the brain reached peak levels. Thus, expectancy and drug effects on PPN regions were dissociable in that they occurred at different times during the course of the experiment.
Drug and expectancy effects were also dissociable in the sense that they primarily influenced different brain regions. Expectations reduced activity in limbic areas outside of the typical PPN regions—changes that appeared to be shared with drug effects—and increased prefrontal activity, which was not shared with drug effects. Both effects of expectancy have been found in other studies. For example, we recently found that both anticipatory placebo-induced increases in prefrontal cortex and reductions during pain in ventral striatum and other limbic areas predicted the magnitude of placebo analgesia across individuals (Wager et al., 2011
Our results challenge the notion that expectancy effects interact synergistically with opioidergic drugs, in spite of the fact that expectancy effects elicited in similar opiate drug-conditioning paradigms have been shown to be opioid-dependent (Amanzio et al., 2001
). Thus, rather than expectancy “doubling the analgesic benefit of remifentanil” (Bingel et al., 2011
), as has recently been suggested, we offer the alternative interpretation that expectancy operates alongside, but independent of, remifentanil.
An additional benefit of the present study is that we used an ecological method of eliciting expectancies. Previous studies of expectancy effects during drug administration (Bingel et al., 2011
) and placebo analgesia used conditioning manipulations, in which drug/placebo administration was paired with reductions in actual stimulus intensity. The type of expectancies that are induced through procedures that lower stimulation are quite different from the effects of prior exposure to drug treatment (Kirsch et al., 2004
), and participants’ learning history strongly influences placebo analgesia (Colloca and Benedetti, 2009
). Here, participants in the Behavioral Experiment had no prior experience with remifentanil, and fMRI Experiment participants received various doses paired with high intensity stimulation during a fully Open label dosing procedure prior to the experimental session (see Materials and Methods). These approaches are likely to elicit the type of expectations observed in the clinic more closely than surreptitious procedures, as patient expectations generally stem from previous experiences with drug treatment or beliefs without prior experience.
Our findings have implications for clinical trials, for treatment, and for future research. They support the validity of the assumptions underlying RCTs for opiate drugs, while also illustrating that expectations and beliefs do influence patients’ subjective experience and associated neural responses. Thus, optimal patient outcomes can be achieved by pairing medication with high expectation of relief. Naturally, interactions between psychological states and drugs may depend heavily on both the psychological state (e.g., anxiety might interact with opiate treatment) and the drug (e.g., other opiates, non-steroidal anti inflammatory analgesics, or cannabinoids may interact with expectations). Thus, this study represents an initial step in an important research program that tests for drug x
expectancy interactions with different combinations of drug treatment and psychological contexts or interventions. Efforts towards testing drug x
expectancy interactions have been made in several areas, including alcohol and drug research (Rohsenow and Marlatt, 1981
; Volkow et al., 2003
; Gundersen et al., 2008
) and pain (Levine and Gordon, 1984
; Kleijnen et al., 1994
; Martin et al., 1994
; Kong et al., 2009a
; Kong et al., 2009b
). Incorporation of brain activity measures into this experimental framework has the potential to elucidate how drug effects may vary as a function of the endogenous state of the drug recipient, and thus to advance the goals of enhancing treatment effects in general and personalized medicine in particular. These efforts are all the more important when considering the brain mechanisms underlying clinically relevant phenomena, as pharmacological treatments often work on the same neural and neurochemical mechanisms as endogenous self-regulatory processes. Thus, we hope that this study will help serve as a launching point for testing for interactions between pharmacological and psychological processes in other domains.
As with any study, several considerations must be evaluated in adopting this approach for future studies or clinical trials. First, we used a low dose (.04 μg/kg/min) of remifentanil in order to avoid unblinding (awareness of whether the true drug was given or not based on side effects) in the Hidden condition. This dose was essentially identical to the dose applied in previous work (Bingel et al., 2011
). It is possible that conclusions about additivity might be valid only for low doses. At higher doses, unblinding could reduce placebo effects and/or make the balanced placebo design impractical.
Partial unblinding is also a possibility in this study, though we do not believe it substantively affected our results. We selected doses for each person to produce analgesia while minimizing subjective awareness of side effects in the fMRI Experiment, and participants’ guesses about the true drug blocks were not better than chance in the Behavioral Experiment. If partial unblinding did occur, it would create an over-additive interaction (apparent synergy), while in fact we observed a non-significant trend towards under-additive interactions in both studies.
It remains unknown whether similar brain mechanisms of placebo effects and potential placebo-drug interactions would be observed if a different drug were employed. As mentioned, placebo analgesia and remifentanil analgesia share many mechanisms; future research should examine whether and how expectancies interact with other drugs. Finally, testing the balanced placebo design necessarily involves some deception, and therefore may not be suitable for every type of clinical study.