How does the brain mediate placebo analgesia? Evidence for the involvement of the rACC-pontine-cerebellar pathway

We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top-down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience.

The brain is capable of powerfully inhibiting perceived pain intensity. Experimentally, three pain modulating phenomena have been well explored: placebo analgesia (PA), offset analgesia (OA) and conditioned pain modulation (CPM). While all three can reduce pain intensity, these paradigms are not often compared behaviourally, nor are their potentially common psychological or physiological mechanisms considered. Here, we present retrospective behavioural pain rating, psychological and demographic data in 273 pain-free control participants who underwent either PA (n = 100), OA (n = 37) or CPM (n = 136). Significant changes in pain intensities were assessed using permutation testing to derive cohorts where pain was significantly inhibited (inhibitory responders), unchanged (nonresponder) or increased (facilitatory responder) during the expression of each phenomenon. Psychological questionnaire scores, demography and pain perception variability were compared between response cohorts to all three phenomena. We identified largely similar proportions of individuals categorised as either inhibitory responders, nonresponders or facilitatory responders to each of PA, OA and CPM-with no sex differences identified in any phenomena nor response category. Dispositional optimism and calibrated noxious temperature demonstrated a significant effect in PA and CPM responses, respectively-with inhibitory responders recording higher scores than facilitatory responders in PA, and inhibitory responders possessing lower thermal sensitivity to nonresponders in CPM. A shared mechanism was identified between PA and OA, such that perceived pain variability to repeated identical noxious stimuli related to both phenomena's expression. This warrants further investigation given the suggested neural circuit differences between these two phenomena, and only PA is presently linked with Bayesian theorem. Humans are capable of inhibiting their own pain in several ways; however, the brain systems driving these analgesic mechanisms are complex and are known to diverge despite producing similar outcomes. Here we show core behavioural similarities between different forms of endogenous analgesic phenomena, with differences in psychological and physiological correlates.

A prefrontal non-opioid mechanism in placebo analgesia

Two experiments compared placebo and hypnotic analgesia in high and low hypnotizable subjects. Experiment 1 demonstrated that hypnotic and placebo analgesia were equally ineffective in low hypnotizables, but that hypnotic analgesia was much more effective than placebo analgesia in high hypnotizables. Experiment 2 replicated these results, but also included low and high hypnotizables who were given a nonhypnotic suggestion for analgesia. Both the low and high hypnotizables in this group reported greater suggested than placebo analgesia and as much suggested analgesia as high hypnotizable hypnotic subjects. Both experiments found substantial discrepancies between the amount of pain reduction subjects expected from the various treatments and the amount of pain reduction they actually reported following exposure to those treatments. In Experiment 2, subjects in all treatments who reduced reported pain engaged in more cognitive coping and less catastrophizing than those who did not reduce pain. Theoretical implications are discussed.

It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomography, we confirmed that both opioid and placebo analgesia are associated with increased activity in the rACC. We also observed a covariation between the activity in the rACC and the brainstem during both opioid and placebo analgesia, but not during the pain-only condition. These findings indicate a related neural mechanism in placebo and opioid analgesia.

A voxel-based analysis of neurobiological mechanisms in placebo analgesia in rats

The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated.

Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI during placebo analgesia, which is therefore increasingly considered a phenomenon caused by descending inhibition of spinal activity. However, spinal fMRI is technically challenging and prone to false-positive results. Here we recorded laser-evoked potentials (LEPs) during placebo analgesia in humans. LEPs allow neural activity to be measured directly and with high enough temporal resolution to capture the sequence of cortical areas activated by nociceptive stimuli. If placebo analgesia is mediated by inhibition at spinal level, this would result in a general suppression of LEPs rather than in a selective reduction of their late components. LEPs and subjective pain ratings were obtained in two groups of healthy volunteers - one was conditioned for placebo analgesia while the other served as unconditioned control. Laser stimuli at three suprathreshold energies were delivered to the right hand dorsum. Placebo analgesia was associated with a significant reduction of the amplitude of the late P2 component. In contrast, the early N1 component, reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI), was only affected by stimulus energy. This selective suppression of late LEPs indicates that placebo analgesia is mediated by direct intracortical modulation rather than inhibition of the nociceptive input at spinal level. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia.

Emotional modulation of placebo analgesia

Placebo and Active Treatment Additivity in Placebo Analgesia: Research to Date and Future Directions.

Increased levels of Escherichia-Shigella and Klebsiella in the gut contribute to the responsivity of placebo analgesia

Placebo analgesia is one of the most robust and best-studied placebo effects. Recent researches suggest that placebo analgesia activated the μ-opioid receptor signalling in the human brain. However, whether other opioid receptors are involved in the placebo analgesia remains unclear. We have previously evoked placebo responses in mice (Guo et al. 2010, 2011) and these mice may serve as a model for investigating placebo analgesia. In the present study, we tried to explore the site of action and types of opioid receptors involved in placebo response. Male Sprague-Dawley rats were trained with 10 mg/kg morphine for 4 d to establish the placebo analgesia model. This placebo analgesia can be blocked by injection of 5 mg/kg dose naloxone or by microinjection with naloxone (1, 3 or 10 μg/rat) into rostral anterior cingulate cortex (rACC). Then, animals were tested after intra-rACC microinjection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP, a selective μ-opioid receptor antagonist) or naltrindole (NTI, a highly selective δ-opioid receptor antagonist) or nor-binaltorphimine (nor-BNI, a highly selective κ-opioid receptor antagonist). Our results showed that CTOP, but not NTI or nor-BNI, could reduce the pain threshold in placebo analgesia rats. It may be concluded that rACC is the key brain region involved in placebo analgesia and the opioid placebo analgesia is mediated exclusively through μ-opioid receptor in rat.

(139) Mechanisms of Placebo Analgesia: fMRI identifies sustained and transient regional involvement

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

Transcutaneous electrical nerve stimulation and placebo analgesia: Are young and older adults the same?