Clinical Briefs: Placebo Effect: The Brain and Pain
With Comments from Russell H. Greenfield, MD Dr. Greenfield is Medical Director, Carolinas Integrative Health, Carolinas HealthCare System, Charlotte, NC, and Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC.
Source: Zubieta J-K, et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25: 7754-7762.
Goal: To determine whether introduction of placebo with expectation of analgesia activates endogenous opioid neurotransmission within the human brain.
Design: Randomized, single-blind, counterbalanced trial.
Subjects: Male volunteers (n = 14), 20-30 years of age.
Methods: Each volunteer underwent PET scanning three times with radiolabeled carfentanil. The first scan was performed at baseline, the latter scans associated with either a sustained pain challenge (infusion of 5% hypertonic saline into the left masseter muscle) or sustained pain with placebo with implied analgesic properties. Following initiation of hypertonic saline infusion, subjects were asked to report pain intensity every 15 seconds using an electronic visual analog scale (VAS). Researchers used these data to maintain pain intensity scores throughout the duration of the experiment. The placebo condition utilized intravenous normal saline administered every 4 minutes for 15 seconds following a computer-generated warning and subsequent second-by-second count of the 15-second infusion. Participants, who had been advised they were receiving an agent "that may or may not relieve pain," were asked to estimate the expected analgesic response before and after normal saline administration. Upon completion of the study individual participants completed a battery of questionnaires addressing pain and affect.
Results: The sustained pain stimulus was associated with activation of endo-genous opioid transmission and mu-opioid receptors. Data revealed that expectation of analgesia was achieved in participants, and that placebo administration resulted in an increase in the average rate of analgesic stimulus required to maintain pain. The degree of placebo-induced mu-opioid system activation was relatively regionally specific for individual subjects, but directly involved the associative, higher-order brain regions. Significant effects of placebo were noted for ratings of pain intensity and unpleasantness, as well as for affective measures.
Conclusion: Expectation of pain relief, a cognitive factor, is capable of modulating physical and emotional states through site-specific activation of mu-opioid brain receptor signaling in young men.
Study strengths: Use of adaptive system of pain stimulus provision to override systemic antinociceptive responses; compensating for small anatomic variations among subjects.
Study weaknesses: Limited generalizability.
Of note: The study employed a mu-opioid receptor-selective radiotracer, such that activation of the neurotransmitter system was evidenced by reductions in in vivo availability of synaptic mu-opioid receptors to bind the radio-labeled tracer; mu-opioid receptors are thought to primarily mediate the observed effects of placebo and naloxone; researchers often categorize subjects into high or low placebo responders, and this may be the result of individualized blood-flow responses in areas like the rostral anterior cingulate; studies employing functional MRI have shown reductions in activity of pain-specific regions of the brain after placebo administration with expectation of analgesia; both gender- and age-specific effects have been described for mu-opioid receptor concentrations, as well as capacity for their activation, which explains why the authors studied such a restricted sample; at trial's end, nine subjects were classified as high placebo responders, five as low.
We knew that: The authors define the placebo effect as positive physiological or psychological changes associated with administration of inert substances or procedures and positive expectations (in contrast, a nocebo creates negative health expectations); prior studies addressing both clinical and experimentally induced pain have reported reductions in pain ratings after placebo administration with expectation of analgesia that were reversed by administration of naloxone (changes thus mediated through activation of pain-suppressive endogenous opioid neurotransmission); sustained pain induces systemic antinociceptive responses that lower pain ratings over time, thus potentially interfering with studies of the placebo effect.
Clinical import: In this trial, placebo-induced activation of brain neurotransmission correlated strongly with decreased pain intensity and sensory pain qualities. The authors state theirs is the first report to document direct evidence that a placebo with implied analgesic properties regionally activates a specific pain and stress inhibitory neurotransmitter system through direct effects on mu-opioid receptors, and that this activation is associated with real reductions in suffering. The data also suggest that placebo-induced changes in neurochemical signaling represent a graded effect, not an on-off phenomenon. This well-done study lends credence to the existence of the mind/body continuum. Though subjects were healthy volunteers, most practitioners intuit that appropriately engaging a patient's belief in treatment may enhance the therapeutic effect of any clinical intervention. Results of this high-tech trial support that notion.
What to do with this article: Make copies to hand out to your peers.
Greenfield RH. Placebo effect: The brain and pain. Altern Med Alert 2006;9(1):12.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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