Christian S. Stohler

Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors

Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, we directly examined the activity of the endogenous opioid system on μ-opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of μ-opioid receptor-mediated neurotransmission was observed in both higher-order and sub-cortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of μ-opioid receptor signaling in the human brain.

Neurobiological Mechanisms of the Placebo Effect

Any medical treatment is surrounded by a psychosocial context that affects the therapeutic outcome. If we want to study this psychosocial context, we need to eliminate the specific action of a therapy and to simulate a context that is similar in all respects to that of a real treatment. To do this,

Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses

CONTEXT Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology. OBJECTIVE To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects. DESIGN AND SETTING Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting. PARTICIPANTS Twenty healthy men and women aged 20 to 30 years recruited by advertisement. MAIN OUTCOME MEASURES Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia. RESULTS Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects. CONCLUSIONS Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, impacting perceptions and biological processes. Using healthy human subjects, we examined the role of the nucleus accumbens (NAC), a region centrally involved in the encoding of reward expectation, in the formation of placebo responses. Employing functional molecular imaging, activation of NAC dopamine (DA) release was observed during placebo administration and related to its anticipated effects, perception-anticipation mismatches, and placebo effect development. In additional functional MRI studies, the expectation of monetary gain increased NAC synaptic activity in a manner proportional to placebo-induced DA release, anticipated effects, perception-anticipation differentials, and actual placebo effects. Individual variations in NAC response to reward expectation accounted for 28% of the variance in the formation of placebo analgesia.

Variations in the Human Pain Stress Experience Mediated by Ventral and Dorsal Basal Ganglia Dopamine Activity

In addition to its involvement in motor control and in encoding reward value, increasing evidence also implicates basal ganglia dopaminergic mechanisms in responses to stress and aversive stimuli. Basal ganglia dopamine (DA) neurotransmission may then respond to environmental events depending on their saliency, orienting the subsequent responses of the organism to both positive and negative stimuli. Here we examined the involvement of DA neurotransmission in the human response to pain, a robust physical and emotional stressor across species. Positron emission tomography with the DA D2 receptor antagonist radiotracer [11C]raclopride detected significant activation of DA release in dorsal and ventral regions of the basal ganglia of healthy volunteers. Activation of nigrostriatal (dorsal nucleus caudate and putamen) DA D2 receptor-mediated neurotransmission was positively associated with individual variations in subjective ratings of sensory and affective qualities of the pain. In contrast, mesolimbic (nucleus accumbens) DA activation, which may impact on both D2 and D3 receptors, was exclusively associated with variations in the emotional responses of the individual during the pain challenge (increases in negative affect and fear ratings). These data demonstrate that basal ganglia dopamine D2 receptor-mediated neurotransmission is involved in responses to pain and that it contributes to individual variations in the pain experience at the levels of physical and emotional elements, albeit with different neuroanatomical substrates.

Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women

Prominent interindividual and sex-dependent differences have been described in responses to sustained pain and other stressful stimuli. Variations in μ-opioid receptor-mediated endogenous opioid neurotransmission may underlie some of these processes. We examined both baseline μ-opioid receptor levels and the activation of this neurotransmitter system during sustained pain using positron emission tomography in a sample of young healthy men and women. Women were studied twice, during low and high estrogen states. The high-estrogen state was associated with regional increases in baseline μ-opioid receptor availability in vivo and a greater activation of endogenous opioid neurotransmission during the pain stressor. The latter did not differ from that obtained in males. During the low estrogen condition, however, significant reductions in endogenous opioid tone were observed at the level of thalamus, nucleus accumbens, and amygdala, which were associated with hyperalgesic responses. Estrogen-associated variations in the activity of μ-opioid neurotransmission correlated with individual ratings of the sensory and affective perceptions of the pain and the subsequent recall of that experience. These data demonstrate a significant role of estrogen in modulating endogenous opioid neurotransmission and associated psychophysical responses to a pain stressor in humans.

Neurobiological Mechanisms of Placebo Responses

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, potentially impacting perceptions and biological processes. We used sustained pain as a model to determine the neural mechanisms underlying placebo‐induced analgesia and affective changes in healthy humans. Subjects were informed that they could receive either an active agent or an inactive compound, similar to routine clinical trials. Using PET and the μ‐opioid selective radiotracer [11C]carfentanil we demonstrate placebo‐induced activation of opioid neurotransmission in a number of brain regions. These include the rostral anterior cingulate, orbitofrontal and dorsolateral prefrontal cortex, anterior and posterior insula, nucleus accumbens, amygdala, thalamus, hypothalamus, and periaqueductal grey. Some of these regions overlap with those involved in pain and affective regulation but also motivated behavior. The activation of endogenous opioid neurotransmission was further associated with reductions in pain report and negative affective state. Additional studies with the radiotracer [11C]raclopride, studies labeling dopamine D2/3 receptors, also demonstrate the activation of nucleus accumbens dopamine during placebo administration under expectation of analgesia. Both dopamine and opioid neurotransmission were related to expectations of analgesia and deviations from those initial expectations. When the activity of the nucleus accumbens was probed with fMRI using a monetary reward expectation paradigm, its activation was correlated with both dopamine, opioid responses to placebo in this region and the formation of placebo analgesia. These data confirm that specific neural circuits and neurotransmitter systems respond to the expectation of benefit during placebo administration, inducing measurable physiological changes.

Pain maps from facial pain patients indicate a broad pain geography.

Two hundred consecutive female patients, who were referred to a university-based facial pain clinic, were asked to mark all painful sites on sketches showing the contours of a human body in the frontal and rear views. The drawings were analyzed with transparent templates containing 1875 (frontal view) and 1929 (rear view) square cells of equal size. The average patient scored 71.8 cells in the frontal and 99.7 cells in the rear view (corresponding to 3.8% and 5.2% of the maximum possible scores). In individual patient drawings, however, up to 42.7% and 44.9% of all cells were marked. Only 37 cases (18.5%) exhibited pain that was limited to the trigeminal system. An analysis of the pain distribution according to the arrangements of dermatomes revealed three distinct clusters of patients: (1) pain restricted to the region innervated by the trigeminal nerves (n = 37); (2) pain in the trigeminal dermatomes and any combination involving the spinal dermatomes C2, C3, and C4, but no other dermatomes (n = 32); and (3) pain sites involving dermatomes in addition to the ones listed above (n = 131). Mean ages in the three clusters were 38.7, 35.5, and 37.5 years, respectively (p = 0.62, n.s.). Widespread pain existed for longer durations (median, 48 months) than conditions involving local and regional pain (median, 24 months) (p = 0.02, s.). Our findings showed that among a great percentage of persistent facial pain patients the pain distribution is more widespread than commonly assumed, and that the persistence of pain in the regional and widespread pain presentations is significantly greater than in cases with pain limited to the trigeminal system.

The effect of experimental jaw muscle pain on postural muscle activity

&NA; The purpose of this study was to examine whether tonic muscle pain of an intensity at least as great as that reported by the majority of chronic muscle pain patients causes an increase in postural electromyographic activity of the affected musculature. Twenty young adults volunteered for experiments, knowing that they involved experimental pain. We chose a controlled, two‐period crossover and repeated measures design involving four experimental conditions: (1) baseline 1, (2) tonic experimental muscle pain, (3) sham pain, and (4) baseline 2. Subjects were randomly assigned to one of two sequential orders that differed with respect to whether tonic pain preceded sham pain or vice versa. At the within‐subject level, the condition (baseline 1, sham pain, tonic pain, baseline 2) had a statistically significant effect on mean rms electromyographic activity at all four recording sites. We found that postural activities at all four recording sites, left/right masseter and left/right anterior temporalis were statistically different from baseline 1 and 2 during tonic pain (P < 0.004, s.; P < 0.024, s.). However, postural activities during tonic pain and sham pain were not significantly different from each other (P < 0.493, n.s.). We concluded that our data do not support the hyperactivity model which assumes a re‐enforcing link between pain and muscle hyperactivity.

A closed-loop system for maintaining constant experimental muscle pain in man

A microprocessor-based control system for maintaining a constant level of experimental muscle pain was developed. Pain was induced in the relaxed right masseter of healthy young adults by using an infusion pump to inject an algesic 0.15 mL bolus of 5% hypertonic saline over 15 s. Subjects supplied feedback on their present pain intensity (PPI) via a 10-cm-long electronic visual-analog scale (VAS) and a 0.07-Hz zero-order hold. The adaptive controller identified the system dynamic response and proportional-integral-derivative (PID) controller parameters from the subjects initial response to the bolus (pain rise and fall time constants and peak amplitude) as well as his/her response to a 90-s constant infusion. Using the pain feedback, the adaptive PID controller was successfully used to adjust the infusion rate to maintain PPI in five out of seven healthy adults at a mean (SD) 4.8