Are All Placebo Effects Equal? Placebo Pills,Sham Acupuncture,Cue Conditioning and Their Association

Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject''s pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for “placebo responders.” However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia.     

Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia

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.     

Placebo medication use in patient care: a survey of medical interns

The use of placebo medication, long recognized by clinicians, often has serious practical implications, such as patient deception. Past evidence has suggested that resident physicians tend to misuse placebo medication. Interns from two consecutive years of a residency program were surveyed anonymously to assess their knowledge and use of placebos. Of the 74 interns surveyed, 44 (59%) were familiar with placebo use in patient care. Fifty percent of these interns familiar with placebo use had learned about placebos from another physician. All interns who had learned about placebos during their internships had learned from another physician, whereas interns who had gained their knowledge of placebos as medical students were as likely to have learned from the medical literature as they were to have learned from a physician (P = 0.027). Interns aware of placebo use were more likely to consider placebo administration for suspected, factitious pain (P = 0.022). The present study uncovered no relationship between interns' estimations of placebo efficacy and the utility they attributed to placebos in assessing a complaint of pain. This suggests that conceptual inconsistencies underlie their use of placebos. Interns often learn of placebos as medical students and are influenced by physician-mentors. Placebo use in patient care is an area of attention for medical educators.     

Placebo-Induced Somatic Sensations: A Multi-Modal Study of Three Different Placebo Interventions

Somatic sensations induced by placebos are a frequent phenomenon whose etiology and clinical relevance remains unknown. In this study, we have evaluated the quantitative, qualitative, spatial, and temporal characteristics of placebo-induced somatic sensations in response to three different placebo interventions: (1) placebo irritant solution, (2) placebo laser stimulation, and (3) imagined laser stimulation. The quality and intensity of evoked sensations were assessed using the McGill pain questionnaire and visual analogue scales (VAS), while subjects’ sensation drawings processed by a geographic information system (GIS) were used to measure their spatial characteristics. We found that all three interventions are capable of producing robust sensations most frequently described as “tingling” and “warm” that can reach consider-able spatial extent (≤ 205mm^²) and intensity (≤ 80/100 VAS). Sensations from placebo stimulation were often referred to areas remote from the stimulation site and exhibit considerable similarity with referred pain. Interestingly, there was considerable similarity of qualitative features as well as spatial patterns across subjects and placebos. However, placebo laser stimulation elicited significantly stronger and more widespread sensations than placebo irritant solution. Finally, novelty seeking, a character trait assessed by the Temperament and Character Inventory and associated with basal dopaminergic activity, was less pronounced in subjects susceptible to report placebo-induced sensations. Our study has shown that placebo-induced sensations are frequent and can reach considerable intensity and extent. As multiple somatosensory subsystems are involved despite the lack of peripheral stimulus, we propose a central etiology for this phenomenon.     

A guide to the pharmacology of placebos.

The placebo effect is capable of relieving pain in a substantial proportion of patients; affective disorders also respond to the administration of inert medication. Changes in objective measures, such as blood pressure and blood glucose levels, demonstrate the action of placebos. The underlying mechanisms are not yet known, but because the nature and strength of the placebo response are governed by the patient''s perceptions, both positive and negative results may be obtained. The complexity of human perception has made it extremely difficult to characterize the people who react. In clinical situations the placebo may be underused as a therapeutic agent, while in clinical trials the effect may be inadequately evaluated; the power and nature of the placebo effect truly warrant greater recognition.     

The relation of emotions to placebo responses

The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.     

The 1988 Stevenson Memorial lecture. Physiological responses to severe hypoxia in man

Recent measurements at extreme altitude and in low pressure chamber simulations have clarified the human responses to extreme hypoxia. Man can only tolerate the severe oxygen deprivation of great altitudes by an enormous increase in ventilation which has the advantage of defending the alveolar PO2 against the reduced inspired PO2. Nevertheless the arterial PO2 on the Everest summit is less than 30 Torr (1 Torr = 133.3 Pa). An interesting consequence of the hyperventilation is that the respiratory alkalosis greatly increases the oxygen affinity of the hemoglobin and assists in oxygen loading by the pulmonary capillary. The severe hypoxemia impairs the function of many organ systems including the central nervous system, and there is evidence of residual impairment of memory and manipulative skill in climbers returning from great altitudes. At the altitude of Mt. Everest, maximal oxygen uptake is reduced to 20-25% of its sea level value, and it is exquisitely sensitive to barometric pressure. It is likely that the seasonal variation of barometric pressure affects the ability of man to reach the summit without supplementary oxygen.     

Respiratory responses to short term hypoxia in the snapping turtle, Chelydra serpentina

Among vertebrates, turtles are able to tolerate exceptionally low oxygen tensions. We have investigated the compensatory mechanisms that regulate respiration and blood oxygen transport in snapping turtles during short exposure to hypoxia. Snapping turtles started to hyperventilate when oxygen levels dropped below 10% O(2). Total ventilation increased 1.75-fold, essentially related to an increase in respiration frequency. During normoxia, respiration occurred in bouts of four to five breaths, whereas at 5% O(2), the ventilation pattern was more regular with breathing bouts consisting of a single breath. The increase in the heart rate between breaths during hypoxia suggests that a high pulmonary blood flow may be maintained during non-ventilatory periods to improve arterial blood oxygenation. After 4 days of hypoxia at 5% O(2), hematocrit, hemoglobin concentration and multiplicity and intraerythrocytic organic phosphate concentration remained unaltered. Accordingly, oxygen binding curves at constant P(CO(2)) showed no changes in oxygen affinity and cooperativity. However, blood pH increased significantly from 7.50+/-0.05 under normoxia to 7.72+/-0.03 under hypoxia. The respiratory alkalosis will produce a pronounced in vivo left-shift of the blood oxygen dissociation curve due to the large Bohr effect and this is shown to be critical for arterial oxygen saturation.     

Possible contribution of quantum-like correlations to the placebo effect: consequences on blind trials

Background

Factors that participate in the biological changes associated with a placebo are not completely understood. Natural evolution, mean regression, concomitant procedures and other non specific effects are well-known factors that contribute to the “placebo effect”. In this article, we suggest that quantum-like correlations predicted by a probabilistic modeling could also play a role.

Results

An elementary experiment in biology or medicine comparing the biological changes associated with two placebos is modeled. The originality of this modeling is that experimenters, biological system and their interactions are described together from the standpoint of a participant who is uninvolved in the measurement process. Moreover, the small random probability fluctuations of a “real” experiment are also taken into account. If both placebos are inert (with only different labels), common sense suggests that the biological changes associated with the two placebos should be comparable. However, the consequence of this modeling is the possibility for two placebos to be associated with different outcomes due to the emergence of quantum-like correlations.

Conclusion

The association of two placebos with different outcomes is counterintuitive and this modeling could give a framework for some unexplained observations where mere placebos are compared (in some alternative medicines for example). This hypothesis can be tested in blind trials by comparing local vs. remote assessment of correlations.

     

A randomized,placebo controlled,trial of preoperative sustained release Betamethasone plus non-controlled intraoperative Ketorolac or Fentanyl on pain after diagnostic laparoscopy or laparoscopic tubal ligation [ISRCTN52633712

BACKGROUND: Gynecological laparoscopic surgery procedures are often complicated by postoperative pain resulting in an unpleasant experience for the patient, delayed discharge, and increased cost. Glucocorticosteroids have been suggested to reduce the severity and incidence of postoperative pain. METHODS: This study examines the efficacy of a sustained release betamethasone preparation to reduce postoperative pain and the requirement for pain relief drugs after either diagnostic laparoscopy or tubal ligation. Patients were recruited, as presenting, after obtaining informed consent. Prior to surgery, patients were randomly selected by a computer generated table to receive either pharmacy-coded betamethasone (12 mg IM Celestone trade mark ) or an optically identical placebo injection of Intralipid trade mark and isotonic saline mixture. The effect of non-controlled prophylactic intraoperative treatment with either fentanyl or ketorolac per surgeon's orders was also noted in this study. Blood samples taken at recovery and at discharge times were extracted and analyzed for circulating betamethasone. Visual analog scale data on pain was gathered at six post-recovery time points in a triple blind fashion and statistically compared. The postoperative requirement for pain relief drugs was also examined. RESULTS: Although the injection achieved a sustained therapeutic concentration, no beneficial effect of IM betamethasone on postoperative pain or reduction in pain relief drugs was observed during the postoperative period. Indeed, the mean combined pain scores during the 2 hour postoperative period, adjusted for postoperative opioids as the major confounding factor, were higher approaching statistical significance (P = 0.056) in the treatment group. Higher pain scores were also observed for the tubal ligation patients relative to diagnostic laparoscopy. Intraoperative fentanyl treatment did not significantly lower the average pain score during the 2 hour postoperative period. Intraoperative ketorolac treatment significantly lowered (P = 0.027) pain scores and reduced the postoperative requirement for additional pain relief drugs. CONCLUSIONS: There was a lack of efficacy of preoperative sustained release betamethasone in reducing postoperative pain despite maintaining a therapeutic concentration during the postoperative period. Intraoperative Ketorolac did afford some short-term pain relief in the postoperative period and reduced the need for additional pain relief drugs.     

A comparison of chronic aspartame exposure to aspirin on inflammation, hyperalgesia and open field activity following carrageenan-induced monoarthritis.

The purpose of the present study was to investigate whether chronic aspartame exposure possesses analgesic and anti-inflammatory actions in the carrageenan-induced monoarthritis model similar to those properties of aspirin. Prior research demonstrated that aspartame can reduce second phase formalin pain and increase motor activity in arthritic patients. Fifty-eight male Sprague-Dawly rats were treated with aspartame (25, 50, 100 mg/kg) or saline for six days. An additional group of animals received daily injections of saline and on the sixth treatment day, received a 150-mg/kg dose of aspirin 30-minutes prior to behavioral testing. On Day 6, animals received an intra-articular (i.a.) injection of 2% lambda carrageenan (CARR) or an equal volume of saline and were tested four hours later on threshold to mechanical and thermal stimuli, open field activity, and knee joint diameter. Aspirin-treated arthritic animals exhibited significantly less mechanical hyperalgesia and knee joint inflammation compared with vehicle treated arthritic animals. However, aspirin did not reverse thermal hyperalgesia or increase motor activity to control levels. Aspartame did not reduce inflammation, increase motor activity, or attenuate thermal allodynia, but at 50 mg/kg did attenuate mechanical allodynia compared with vehicle treated arthritic animals. The anti-hyperalgesic effect on mechanical hyperalgesia was not seen at 25 mg/kg or 100 mg/kg aspartame. These results suggest that a certain amount of aspartame may provide relief of arthritic pain to a similar degree as aspirin in some individuals. The specific effect of aspartame and aspirin on mechanical hyperalgesia should be considered when these agents are used for the therapeutic treatment of arthritic conditions.     

Metabolic and ventilatory responses to hypoxia in two altitudinal populations of the toad, Bufo bankorensis

Effects of hypoxia on resting oxygen consumption (MO2), lung ventilation, and heart rate at different ambient PO2 were compared between lowland and high altitude populations of the toad, Bufo bankorensis. Resting MO2 decreased significantly in mild hypoxia (PO2 = 120 mm Hg) at 10 degrees C and in moderate hypoxia (PO2 = 80 mm Hg) at 25 degrees C in both altitudinal populations; however, resting MO2 did not differ significantly between the two populations. Numbers of lung ventilation periods (VP) and total inspired volume (VL) did not change with PO2 at 10 degrees C, but did increase at moderate and severe hypoxia (40 mm Hg), respectively, at 25 degrees C. Resting heart rates did not change during hypoxia and did not differ between altitude populations. The results suggest (1) the effect of PO2 change on MO2 should be considered in future studies involving transfer of anurans to a different altitude; and (2) the metabolic and ventilatory physiology in B. bankorensis does not compensate for the low temperature and PO2 at high altitude.     

External respiration, gas exchange and blood acid-base status in dogs with hyperthermia

Experiments on dogs have shown that hyperthermia intensifies respiration, increases oxygen consumption, induces pronounced discrepancy of the alveolar ventilation to carbon dioxide elimination, severe hypocapnia and decompensated respiratory alkalosis.     

Human responses to extreme altitudes

It is a strange coincidence that the highest point on Earthis very close to the limit of human tolerance to hypoxia. Thephysiological changes that allow humans to reach these extremealtitudes involve enormous alterations of their normal state.It is useful to contrast this response with two others to highaltitude. One is acclimatization that allows lowlanders to ascendto altitudes of up to 5000 m and remain there for an indefiniteperiod. The other is evolutionary adaptation which allows highlandersto live continuously over generations at altitudes up to 5000m. These two responses enable humans to survive for an indefiniteperiod at high altitude. By contrast, the changes that allowascent to extreme altitudes are not compatible with an extendedstay because of a poorly-understood process called high-altitudedeterioration. The most important physiological response toextreme altitude is extreme hyperventilation which, on the summitof Mt. Everest, drives the alveolar P_CO2 down to 7–8 mmHg.This is associated with a marked respiratory alkalosis withan arterial pH exceeding 7.7. Interestingly this alkalosis increasesthe oxygen affinity of hemoglobin, a response which the successfulclimber shares with many other animals in oxygen-deprived environments.The arterial P_O2 on the Everest summit is only about 30 mmHgand falls on exercise because of diffusion limitation of oxygenacross the blood-gas barrier. Maximal oxygen consumption onthe summit is just over 1 liter.min^–1. Anaerobic metabolismas measured by blood lactate levels is paradoxically reducedat extreme altitudes.     

Placebo in the treatment of pain

Placebo is the use of the substance or procedure without specific activity for the condition that is trying to be healed. In medicine, benefits of placebo effect are used since 1985 and 1978 placebo effect was first scientifically confirmed. It was found that placebo induced analgesia depends on the release of endogenous opiates in the brain and that the placebo effect can be undone using the opiates antagonist naloxone. Functional magnetic resonance imaging of the brain showed that placebo analgesia was obtained regarding the activation and increased functional relationship between ant. cingulate, prefrontal, orbitofrontal, and insular cortex, nucleus accumlens, amygdala, periaqueduktalne gray matter and spinal cord. Placebo also facilitates descending inhibition of nociceptive reflexes through periacvaeductal gray substance. Placebo effect can be achieved in several ways: by using pharmacological preparations or simulation of operating or other procedures. This phenomenon is associated with perception and expectation of the patient. To achieve the effect of placebo it is essential degree of the suggestions of the person who prescribe a placebo, and the degree of belief of the person receiving the placebo. Expected effect of placebo is to achieve the same effect as the right remedy. Achieved placebo effect depends on the way of presentation. If a substance is presented as harmful, it may cause harmful effects, called 'nocebo" effect. Placebo effect is not equal in all patients, same as the real effect of the drug is not always equal in all patients. Application of placebo in terms of analgesia will cause a positive response in 35% of patients. Almost the same percentage (36%) of patients will respond to treatment with morphine in medium doses (6-8 mg). Therefore, one should remember that response to placebo does not mean that a person simulates the pain and then it is unethical to withhold the correct treatment especially in light of findings that the prefrontal cortex is activated expecting liberation of pain and how this action reduce activities in brain regions responsible for sensation of pain (thalamus, somatosensory cortex and other parts of the cortex). However, the use of placebos is ethically, legally and morally very dubious. The basis for the placebo effect is deception. It undermines honest relationship and trust between doctor and patient which is extremely important for successful treatment. Consciously giving placebos to patients for a condition that can be adequately treated, with prejudice the right of patients to the best care possible, opens up many bioethical issues. Despite all the current knowledge level, placebo effect remains still a scientific mystery.     

Effect of intranasal arginine vasopressin on human headache

Arginine vasopressin (AVP), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood–brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of AVP to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that AVP in the brain rather than the spinal cord and blood circulation plays an important role in rat pain modulation. For understanding the role of AVP on pain modulation in human, the communication tried to investigate the effect of intranasal AVP on human headache. The results showed that (1) AVP concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients, who related with the headache level; (2) there was a positive relationship between plasma and CSF AVP concentration in headache patients; and (3) intranasal AVP could relieve the human headache in a dose-dependent manner. The data suggested that intranasal AVP, which was delivered to the brain through olfactory region, could treat human headache and AVP might be a potential drug of pain relief by intranasal administration.     

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

Background  

Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.     

Can an Educational Handout Enhance Placebo Analgesia for Experimentally-Induced Pain?

The placebo effect is an interesting phenomenon whereby a dummy treatment can produce therapeutic benefit, such as, pain relief. While evidence for the placebo effect is growing, relatively few studies have explored ways of enhancing placebo effects. To address this, the current study tested whether placebo-induced analgesia could be enhanced by providing an educational handout about the efficacy of analgesics. Fifty university students were allocated to receive placebo treatment under the guise of a new analgesic formula, either with or without an educational handout, or to a no treatment control group before undergoing electrical and cold pressor pain tests. There was a placebo effect for electrically-induced pain with those receiving placebo treatment reporting significantly less pain compared with those who received no treatment. There was also some evidence of enhancement of this placebo-induced analgesia for electrically-induced pain as a result of the educational handout. No differences were found on cold pressor-induced pain. These findings suggest that providing educational information about a treatment could enhance its efficacy via the placebo effect. Future studies should test different methods of providing educational information in order to determine which elicit the strongest effects.     

Metabolic Adaptations May Counteract Ventilatory Adaptations of Intermittent Hypoxic Exposure during Submaximal Exercise at Altitudes up to 4000 m

Intermittent hypoxic exposure (IHE) has been shown to induce aspects of altitude acclimatization which affect ventilatory, cardiovascular and metabolic responses during exercise in normoxia and hypoxia. However, knowledge on altitude-dependent effects and possible interactions remains scarce. Therefore, we determined the effects of IHE on cardiorespiratory and metabolic responses at different simulated altitudes in the same healthy subjects. Eight healthy male volunteers participated in the study and were tested before and 1 to 2 days after IHE (7×1 hour at 4500 m). The participants cycled at 2 submaximal workloads (corresponding to 40% and 60% of peak oxygen uptake at low altitude) at simulated altitudes of 2000 m, 3000 m, and 4000 m in a randomized order. Gas analysis was performed and arterial oxygen saturation, blood lactate concentrations, and blood gases were determined during exercise. Additionally baroreflex sensitivity, hypoxic and hypercapnic ventilatory response were determined before and after IHE. Hypoxic ventilatory response was increased after IHE (p<0.05). There were no altitude-dependent changes by IHE in any of the determined parameters. However, blood lactate concentrations and carbon dioxide output were reduced; minute ventilation and arterial oxygen saturation were unchanged, and ventilatory equivalent for carbon dioxide was increased after IHE irrespective of altitude. Changes in hypoxic ventilatory response were associated with changes in blood lactate (r = −0.72, p<0.05). Changes in blood lactate correlated with changes in carbon dioxide output (r = 0.61, p<0.01) and minute ventilation (r = 0.54, p<0.01). Based on the present results it seems that the reductions in blood lactate and carbon dioxide output have counteracted the increased hypoxic ventilatory response. As a result minute ventilation and arterial oxygen saturation did not increase during submaximal exercise at simulated altitudes between 2000 m and 4000 m.     

Influence of stimulus frequency and probe size on vibration-induced alleviation of acute orofacial pain

The pain-relieving effect of vibratory stimulation, using different stimulus parameters, and placebo stimulation in acute orofacial pain is reported. The influence of 10-, 100-, and 200-Hz vibrations on pain reduction was studied in 96 patients; two different probe sizes were used. 54 out of 76 patients, receiving vibrations at any of the above frequencies, reported relief of pain to some extent, while only 6 out of 20 patients receiving placebo treatment experienced pain alleviation. No significant differences were found between the different frequencies and probe sizes used regarding the pain-relieving effect. However, placebo stimulation was significantly less effective than any kind of vibratory stimulation. Induction time for pain relief was significantly shorter using the larger probe as compared to using the smaller probe, regardless of frequency. The results indicate that the vibratory frequency (10-200 Hz) for activation of pain-inhibitory mechanisms is not critical in acute orofacial pain. Also, spatial summation from vibration-sensitive afferents seems to be of importance for a fast activation of the inhibitory systems.