Antonella Pollo

Response expectancies in placebo analgesia and their clinical relevance.

&NA; Response expectancies have been proposed as the major determinant of placebo effects. Here we report that different expectations produce different analgesic effects which in turn can be harnessed in clinical practice. Thoracotomized patients were treated with buprenorphine on request for 3 consecutive days, together with a basal intravenous infusion of saline solution. However, the symbolic meaning of this basal infusion was changed in three different groups of patients. The first group was told nothing about any analgesic effect (natural history). The second group was told that the basal infusion was either a powerful painkiller or a placebo (classic double‐blind administration). The third group was told that the basal infusion was a potent painkiller (deceptive administration). Therefore, whereas the analgesic treatment was exactly the same in the three groups, the verbal instructions about the basal infusion differed. The placebo effect of the saline basal infusion was measured by recording the doses of buprenorphine requested over the three‐days treatment. We found that the double‐blind group showed a reduction of buprenorphine requests compared to the natural history group. However, this reduction was even larger in the deceptive administration group. Overall, after 3 days of placebo infusion, the first group received 11.55 mg of buprenorphine, the second group 9.15 mg, and the third group 7.65 mg. Despite these dose differences, analgesia was the same in the three groups. These results indicate that different verbal instructions about certain and uncertain expectations of analgesia produce different placebo analgesic effects, which in turn trigger a dramatic change of behaviour leading to a significant reduction of opioid intake.

Response variability to analgesics: a role for non-specific activation of endogenous opioids.

&NA; Individual differences in pharmacokinetics and pharmacodynamics, the type of pain and the method of drug administration can account for the response variability to analgesics. By integrating a clinical and an experimental approach, we report here that another important source of variability is represented by individual differences in non‐specific (placebo) activation of endogenous opioid systems. In the first part of this study, we analyzed the effectiveness of buprenorphine, tramadol, ketorolac and metamizol in the clinical setting, where the placebo effect was completely eliminated by means of hidden infusions. We found that the hidden injections were significantly less effective and less variable compared with open injections (in full view of the subject), suggesting that part of the response variability was due to non‐specific factors (placebo). Since we could not administer the opioid antagonist, naloxone, to these patients, in the second part of this study, we induced experimental ischemic arm pain in healthy volunteers and found that, as occurred in clinical pain, the analgesic response to a hidden injection of the non‐opioid ketorolac was less effective and less variable than an open injection. Most importantly, we obtained the same effects by adding naloxone to an open injection of ketorolac, thus blocking the opioid‐mediated placebo component of analgesia. These findings indicate that both the psychological (hidden injection) and pharmacological (naloxone) blockade of the placebo response reduce the effectiveness of, and the response variability to, analgesic drugs. Therefore, an important source of response variability to analgesics appears to be due to differences in non‐specific activation of endogenous opioid systems.

How placebos change the patient's brain.

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinsons disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic–cholecystokinergic–dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinsons disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patients brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimers type.

Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients.

Expectations about future events are known to trigger neural mechanisms that affect both perception and action. Here we report that different and opposite expectations of bad and good motor performance modulate the therapeutic effects of subthalamic nucleus stimulation in Parkinsonian patients who had undergone chronic implantation of electrodes for deep brain stimulation. By analyzing the effects of subthalamic stimulation on the velocity of movement of the right hand, we found hand movement to be faster when the patients expected a good motor performance. The expectation of good performance was induced through a placebo-like procedure, thus indicating that placebo-induced expectations have influence on the treatment outcome. All these effects occurred within minutes, suggesting that expectations induce neural changes very quickly.

Placebo analgesia and the heart.

&NA; Placebo‐activated endogenous opioids act on pain mechanisms inducing analgesia, as well as on the respiratory centers inducing respiratory depression. Here, we show that placebo analgesia is accompanied by a reduced &bgr;‐adrenergic activity of the heart. We measured heart rate during placebo‐induced expectation of analgesia, both in the clinical and the laboratory setting. In the clinical setting, we found that the placebo analgesic response to an electrical noxious stimulus was accompanied by a reduced heart rate response. In order to investigate this effect from a pharmacological viewpoint, we reproduced the same effect in the laboratory setting by using experimental ischemic arm pain. We found that the opioid antagonist naloxone completely antagonized both placebo analgesia and the concomitant reduced heart rate response, whereas the &bgr;‐blocker propranolol antagonized the placebo heart rate reduction, but not placebo analgesia. By contrast, both placebo responses were present during muscarinic blockade with atropine, indicating no involvement of the parasympathetic system. In order to better understand the effects of naloxone and propranolol, we performed a spectral analysis of the heart rate variability for the identification of the sympathetic and parasympathetic components, and found that the &bgr;‐adrenergic low frequency (0.15 Hz) spectral component was reduced during placebo analgesia, an effect that was reversed by naloxone. These findings indicate that placebo analgesia is accompanied by a complex cascade of events which affect the cardiovascular system.

Opioid-Mediated Placebo Responses Boost Pain Endurance and Physical Performance: Is It Doping in Sport Competitions?

The neurobiological investigation of the placebo effect has shown that placebos can activate the endogenous opioid systems in some conditions. So far, the impact of this finding has been within the context of the clinical setting. Here we present an experiment that simulates a sport competition, a situation in which opioids are considered to be illegal drugs. After repeated administrations of morphine in the precompetition training phase, its replacement with a placebo on the day of competition induced an opioid-mediated increase of pain endurance and physical performance, although no illegal drug was administered. The placebo analgesic responses were obtained after two morphine administrations that were separated as long as 1 week from each other. These long time intervals indicate that the pharmacological conditioning procedure has long-lasting effects and that opioid-mediated placebo responses may have practical implications and applications. For example, in the context of the present sport simulation, athletes can be preconditioned with morphine and then a placebo can be given just before competition, thus avoiding administration of the illegal drug on the competition day. However, these morphine-like effects of placebos raise the important question whether opioid-mediated placebo responses are ethically acceptable in sport competitions or whether they have to be considered a doping procedure in all respects.

The top‐down influence of ergogenic placebos on muscle work and fatigue

Placebos have been shown to induce powerful effects in a variety of medical conditions, such as pain and movement disorders, as well as to increase physical performance and endurance in healthy subjects. Here we investigated the effects of an ergogenic placebo on the performance of the quadriceps muscle, which is responsible for the extension of the leg relative to the thigh. In a first experiment, a placebo was administered along with the suggestion that it was caffeine at high dose. This resulted in a significant increase in mean muscle work across subjects, which, however, was not accompanied by a decrease of perceived muscle fatigue. In a second experiment, the placebo caffeine was administered twice in two different sessions. Each time, the weight to be lifted with the quadriceps was reduced surreptitiously so as to make the subjects believe that the ‘ergogenic agent’ was effective. After this conditioning procedure, the load was restored to the original weight, and both muscle work and perceived fatigue assessed after placebo administration. Compared with the first experiment, the placebo effect was larger, with a significant increase in muscle work and decrease in perceived muscle fatigue. Within the context of the role of peripheral and/or central mechanisms in muscle performance, the present findings suggest a central mechanism of top‐down modulation of muscle fatigue. In addition, the difference between the first and second experiment underscores the role of learning in increasing muscle performance with placebos.

Placebo mechanisms across different conditions: from the clinical setting to physical performance

Although the great increase in interest in the placebo phenomenon was spurred by the clinical implications of its use, the progressive elucidation of the neurobiological and pharmacological mechanisms underlying the placebo effect also helps cast new light on the relationship between mind (and brain) and body, a topic of foremost philosophical importance but also a major medical issue in light of the complex interactions between the brain on the one hand and body functions on the other. While the concept of placebo can be a general one, with a broad definition generally applicable to many different contexts, the description of the cerebral processes called into action in specific situations can vary widely. In this paper, examples will be given where physiological or pathological conditions are altered following the administration of an inert substance or verbal instructions tailored to induce expectation of a change, and explanations will be offered with details on neurotransmitter changes and neural pathways activated. As an instance of how placebo effects can extend beyond the clinical setting, data in the physical performance domain and implications for sport competitions will also be presented and discussed.

Sensitivity to dihydropyridines, omega-conotoxin and noradrenaline reveals multiple high-voltage-activated Ca2+ channels in rat insulinoma and human pancreatic beta-cells

High-voltage-activated (HVA) Ba2+ currents of rat insulinoma (RINm5F) and human pancreatic β-cells were tested for their sensitivity to dihydropyridines (DHPs), ω-conotoxin (ω-CgTx) and noradrenaline. In RINm5F cells, block of HVA currents by nimodipine, nitrendipine and nifedipine was voltage- and dose-dependent (apparent KD<37 nM) and largely incomplete even at saturating doses of DHPs (mean 53%, at 10 μM and 0 mV). Analysis of slow tail currents in Bay K 8644-treated cells indicated the existence of Bay K 8644-insensitive channels that turned on at slightly more positive voltages and deactivated more quickly than Bay K 8644-modified channels. DHP Ca2+ agonists and antagonists in human β-cells had similar features to RINm5F cells except that DHP block was more pronounced (76%, at 10 μM and 0 mV) and Bay K 8644 action was more effective, suggesting a higher density of L-type Ca2+ channels in these cells. In RINm5F cells, but not in human β-cells, DHP-resistant currents were sensitive to ω-CgTx. The toxin depressed 10–20% of the DHP-resistant currents sparing a “residual” current (25–35%) with similar voltage-dependent characteristics and Ca2+/Ba2+ permeability. Noradrenaline (10 μM) exhibited different actions on the various HVA current components: (1) it prolonged the activation kinetics of ω-CgTx-sensitive currents, (2) it depressed by about 20% the size of DHP-sensitive currents, and (3) it had little or no effects on the residual DHP- and ω-CgTx-resistant current although intracellularly applied guanosine 5′-O-(3-thiotriphosphate) (GTP-γ-S) prolonged its activation time course. The first action was clearly voltage-dependent and most evident in RINm5F cells that displayed neuronal-like processes. The second was observed more frequently, was voltage-independent and fully blocked by saturating doses of nifedipine (10 μM). Both actions were prevented by intracellular perfusion with guanosine 5′-O-(2-thiodiphosphate) (GDP-β-S). Our data suggest that beside a majority of L-type channels, RINm5F and human pancreatic β-cells may express a variable fraction of DHP-insensitive channels that may be involved in the control of insulin secretion during β-cell activity.

Hidden Administration of Drugs

In placebo‐controlled trials, the placebo component of treatments is usually assessed by simulating a therapy through the administration of a dummy treatment (placebo) in order to eliminate the specific effects of the therapy. Recently, a radically different approach to the analysis of placebo responses has been implemented in which placebo responses are assessed without placebo groups. To do this, the placebo (psychological) component is eliminated by conducting hidden (unexpected) administrations of the active treatment. Compelling experimental evidence now shows that when the psychological component is eliminated through the administration of therapies unbeknownst to the patient, the effects of a variety of treatments are significantly reduced. Overall, the experimental data show that the action of different pharmacological agents can be modulated by cognitive and affective factors that can increase or decrease the effects of drugs. This experimental approach is thus a window into the complex interactions between psychology and pharmacodynamics.