Placebo and the new physiology of the doctor-patient relationship

Abstract

Modern medicine has progressed in parallel with the advancement of biochemistry, anatomy, and physiology. By using the tools of modern medicine, the physician today can treat and prevent a number of diseases through pharmacology, genetics, and physical interventions. Besides this materia medica, the patient's mind, cognitions, and emotions play a central part as well in any therapeutic outcome, as investigated by disciplines such as psychoneuroendocrinoimmunology. This review describes recent findings that give scientific evidence to the old tenet that patients must be both cured and cared for. In fact, we are today in a good position to investigate complex psychological factors, like placebo effects and the doctor-patient relationship, by using a physiological and neuroscientific approach. These intricate psychological factors can be approached through biochemistry, anatomy, and physiology, thus eliminating the old dichotomy between biology and psychology. This is both a biomedical and a philosophical enterprise that is changing the way we approach and interpret medicine and human biology. In the first case, curing the disease only is not sufficient, and care of the patient is of tantamount importance. In the second case, the philosophical debate about the mind-body interaction can find some important answers in the study of placebo effects. Therefore, maybe paradoxically, the placebo effect and the doctor-patient relationship can be approached by using the same biochemical, cellular and physiological tools of the materia medica, which represents an epochal transition from general concepts such as suggestibility and power of mind to a true physiology of the doctor-patient interaction.

Figure 1.

The psychosocial context around the patient and the therapy. When a medical treatment is administered, several sensory and social stimuli, as well as personal beliefs and memories, tell the patient that a therapy is being performed. The whole context constitutes the ritual of the therapeutic act, which is at the very heart of placebo and nocebo responses.

Figure 2.

The clinical improvement that may be observed after placebo administration is due to many factors. The real placebo response is attributable only to the psychobiological factors, namely, to psychological and physiological changes in the patient's brain.

Figure 3.

The four steps of the doctor-patient relationship. The interaction between the healer/therapist and his patient can be envisaged as a homeostatic system in which the variable to be controlled is represented by the feeling of sickness (symptoms). The very act of administering a treatment is a psychological and social event that is sometimes capable of inhibiting a symptom such as pain, even though the treatment is fake.

Figure 4.

Brain regions that are involved in empathy, compassion, and admiration. During the doctor-patient relationship, several complex brain functions are involved, such as the doctor's empathic and compassionate behavior and the patient's admiration/trust towards the figure of the doctor. iFG, inferior frontal gyrus; AI, anterior insula; SII, secondary somatosensory area; TP, temporal pole; STS, superior temporal sulcus; TPJ, temporal parietal junction; MFC, medial frontal cortex; vmPF, ventromedial prefrontal cortex; ACC, anterior cingulate cortex; asPMC, anterosuperior posteromedial cortex; piPMC, posteroinferior posteromedial cortex.

Figure 5.

One of the key elements during the doctor-patient relationship is represented by the patient's trust. The amygdala (Amy) is responsible for untrustworthiness: the higher the amygdala activity, the more untrustworthy the judgments about a person. Oxytocin increases trust by binding to its own receptors (Oxtr) on the amygdala and by inhibiting its activity.

Figure 6.

This figure includes only the psychobiological factors of FIGURE 2. It can be seen that several psychological and biological factors may be involved in the clinical improvement following administration of a placebo. Therefore, there is not a single placebo response but many, with different mechanisms across different medical conditions and therapeutic interventions.

Figure 7.

The mechanism of the placebo analgesic response depends on the previous exposure to different pharmacological agents, thus suggesting a memory for drug action. The previous exposure to opioids leads to opioid-mediated placebo responses, whereas the prior exposure to nonsteroid anti-inflammatory drugs (NSAIDs) leads to cannabinoid-mediated placebo responses. Cholecystokinin (CCK) antagonizes the opioid-mediated placebo responses. All these effects can be blocked by means of the appropriate antagonistic drugs, such as the opioid antagonist naloxone, the cannabinoid antagonist rimonabant, and the CCK antagonist proglumide.

Figure 8.

Activation likelihood estimation meta-analysis of different brain imaging studies of placebo analgesia in experimental pain. Red means activation areas, whereas green means deactivation areas. The sequence of events from placebo administration to inhibition of regions involved in pain processing can be subdivided into at least three stages: expectation of analgesia (top panel), activation in the early phase of pain stimulation (middle panel), and deactivation of some areas involved in pain processing (bottom panel).

Figure 9.

Neuronal changes in placebo responders and nonresponders in Parkinson's disease. Top panel: the intraoperative recording sites (VA, ventral anterior thalamus; VLa, anterior ventral lateral thalamus; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata). Bottom panel: a placebo responder with a decrease of −2 on the UPDRS scale (Unified Parkinson's Disease Rating Scale), along with the neuronal activity changes, expressed as the percentage increase/decrease relative to baseline. The bottom panel also shows two placebo nonresponders. Whereas the first nonresponder shows no change in neuron activity, the second nonresponder shows a decrease in the STN which, however, is not enough to induce SNr and VA-VLa changes.

Figure 10.

Conditioned immune and hormonal placebo responses. The association between the immunosuppressor cyclosporine A (US, unconditioned stimulus) and strawberry milk (CS, conditioned stimulus) for n times leads to conditioned immunosuppression of both interleukin 2 (IL-2) and interferon-γ (IFN-γ) when the CS alone is presented (top panel). Likewise, the association between the serotonin agonist sumatriptan and contextual cues for n times leads to conditioned growth hormone (GH) and cortisol responses when the contextual cues alone are presented (bottom panel).

Figure 11.

Comparison between an open and a hidden administration of metamizol in postoperative pain. Whereas the arrow in the top panel indicates the timing of metamizol administration by the doctor, the arrow in the bottom panel indicates metamizol administration (same dose and same infusion rate) by a computer unbeknownst to the patient. Note the analgesic effect following the open administration but no effect at all following the hidden administration. Therefore, the pain reduction in the top panel is not attributable to the pharmacodynamic effect of metamizol but merely to a psychological effect.

Figure 12.

If there is no prefrontal control, there is no placebo response. There are at least three evidences for this assertion. First, placebo analgesic responses are reduced or completely absent in Alzheimer's patients with functional disconnection of the prefrontal lobes with the rest of the brain. Second, reduced integrity of the prefrontal white matter is related to reduced placebo analgesic responses. Third, the inactivation of the dorsolateral prefrontal cortex with transcranial magnetic stimulation leads to the blockade of placebo analgesia.