Evidence from rats that morphine tolerance is a learned response.

It is proposed that the direct analgesic effect of morphine becomes attenuated over the course of successive administrations of the narcotic by a conditioned, compensatory, hyperalgesic response elicited by the administration procedure, the net result being analgesic tolerance. Using the "hot plate" analgesia assessment situation with rats, this conditioning view of tolerance is supported by several findings: (a) It is necessary to have reliable environmental cues predicting the systemic effects of morphine if tolerance is to be observed, (b) a hyperalgesic conditioned response may be observed in morphine-tolerant subjects when drug administration cues are followed by a placebo, and (c) merely by repeatedly presenting environmental cues previously associated with morphine (but now presented with a placebo), morphine tolerance can be extinguished.     

The Neural Bases of Placebo Effects in Pain

Abstract— Placebo effects are beneficial effects of treatment caused not by the biological action of the treatment but by one's response to the treatment process itself. One possible mechanism of placebo treatments is that they create positive expectations, which change one's appraisal of the situation and may thereby shape sensory and emotional processing. Recent brain-imaging evidence suggests that placebo-induced expectations of analgesia increase activity in the prefrontal cortex in anticipation of pain and decrease the brain's response to painful stimulation. These findings suggest that placebo treatments can alter experience, not just alter what participants are willing to report about pain. To the extent that they involve neural systems mediating expectancy and appraisal, placebo effects in pain may share common circuitry with placebo effects in depression, Parkinson's disease, and other disorders.     

Placebo Effects and Informed Consent

The concepts of placebos and placebo effects refer to extremely diverse phenomena. I recommend dissolving the concepts of placebos and placebo effects into loosely related groups of specific mechanisms, including (potentially among others) expectation-fulfillment, classical conditioning, and attentional-somatic feedback loops. If this approach is on the right track, it has three main implications for the ethics of informed consent. First, because of the expectation-fulfillment mechanism, the process of informing cannot be considered independently from the potential effects of treatment. Obtaining informed consent influences the effects of treatment. This provides support for the authorized concealment and authorized deception paradigms, and perhaps even for outright deceptive placebo use. Second, doctors may easily fail to consider the potential benefits of conditioning, leading them to misjudge the trade-off between beneficence and autonomy. Third, how attentional-somatic feedback loops play out depends not only on the content of the informing process but also on its framing. This suggests a role for libertarian paternalism in clinical practice.     

The role of predrug signals in morphine analgesic tolerance: support for a Pavlovian conditioning model of tolerance

According to a model of morphine tolerance, which emphasizes Pavlovian conditioning principles, tolerance results from an association between predrug environmental cues and the systemic effects of the drug. To assess this model, groups of rats were administered morphine on either three or nine occasions, with a complex environmental stimulus either paired or not paired with each injection. Control groups had equivalent experience with the environmental cue and injection procedure, but the injected substance was physiological saline. Subsequently, the analgesic effect of the opiate was tested in all subjects following administration of the drug in conjunction with the environmental cue. As expected on the basis of the conditioning model of tolerance, subjects with a pretest history of paired morphine administrations displayed analgesic tolerance, but subjects with a pretest history of unpaired administration displayed no evidence of such tolerance. The results suggest that prior demonstrations that the display of morphine tolerance is specific to the drug administration environment may be readily interpreted by a conditioning analysis of tolerance.     

Context‐induced placebo effects—An investigation of contrast effects in response expectations and actual product efficacy

Recent research on the placebo effect of marketing actions has demonstrated that characteristics that are not inherent to a product's physical properties per se, such as its price, brand, or packaging can considerably shape consumers' expectations about and actual efficacy of a marketed product. However, potential contextual effects that other products may have on the construction of consumers' efficacy beliefs and objective consumption outcomes remain unexplored. Across two experimental studies, we show that people's response expectations regarding a focal product are inversely related to the alleged superiority of context options and that such context‐induced expectations can carry over to behavioural performance metrics; a phenomenon we refer to as context‐induced placebo effects.     

The placebo puzzle: putting together the pieces.

This article outlines and assesses the main theories of the placebo effect and suggests how they might sit together in a larger model of placebo etiology. Among the approaches considered are expectancy theory, emotional change theory, classical conditioning, and the biological approach. Although these are sometimes assumed to be competing models, in many cases they shed light on different pans of the placebo puzzle. Expectancies are the core of most placebo effects in human beings. The effects of expectancies are sometimes unmediated but in other cases are mediated by changes in emotional state, immune system function, perception, or behavior. Although expectancies are implicated in most placebo effects, a small number of placebo effects may be solely attributable to nonconscious contingency learning.     

Adherence,expectations and the placebo response: Why is good adherence to an inert treatment beneficial?

Objective: The current study sought to better understand why good adherence to a placebo treatment has been reliably associated with health benefits. We proposed a model where initial expectations shape adherence, which then influences subsequent expectations that affect placebo response. Design: Seventy-two participants were told that they were enrolling in a study of physical activity and memory, and were asked to increase their physical activity by 35% for two weeks (placebo treatment). Main outcome measures: Adherence to this physical activity target was measured by pedometer. Expectations and short-term memory (free recall) were assessed before and after physical activity. Results: Initial expectations predicted adherence to physical activity (r = .27, p < .03), but adherence did not predict subsequent expectations (r = .06, p = .60). Testing a multi-step meditational model revealed that initial expectations predicted better memory even after controlling for adherence, subsequent expectations, baseline memory and gender (c’ = 1.10, 95% CI = .46–1.74). Stronger expectations for memory improvement predicted better memory performance, but adherence and later expectations did not mediate this association. Conclusions: Good adherence to a placebo may reflect strong treatment expectations which may convey benefits by enhancing the non-specific effects of treatment.     

Drug-onset cues as signals: intraadministration associations and tolerance.

On the basis of a conditioning analysis of drug tolerance, drug-associated cues become associated with the drug effect. These cues elicit conditional compensatory responses and modulate the expression of tolerance. Although there are many findings consistent with the conditioning analysis of tolerance, there also are contrary findings. The results of these experiments suggest that some of the apparently contradictory findings result because interoceptive pharmacological cues, as well as exteroceptive environmental cues, are paired with a drug effect. That is, within each administration, early drug-onset cues may become associated with the later, larger drug effect, and these pharmacological cues may overshadow simultaneously present environmental cues. We demonstrate the contribution of such intraadministration associations to tolerance to the analgesic effect of morphine and to the expression of conditional compensatory hyperalgesia.     

The Power of Expectation – Understanding the Placebo and Nocebo Phenomenon

Although placebo pills are supposed to have no pharmacological activity, people taking placebo pills describe a variety of positive (i.e., placebo phenomenon) and negative (i.e., nocebo phenomenon) reactions. This has major clinical implications. Placebo reactions account for a substantial part of improvement when treating patients with hypertension, mental disorders, and even after surgical procedures. The nocebo phenomenon on the other hand is responsible for non‐compliance and discontinuation of many pharmaceutical interventions. Mechanisms that underlie the placebo and nocebo effects may be related to expectation and/or classical conditioning, but some methodological issues should also be considered. Most experimental studies investigating the placebo effect have used paradigms to induce ‘placebo analgesia’, the reduction of pain perception after receiving an inert substance and an instruction that this medication would relieve pain. This paradigm allows investigators to examine the neurobiological circuitry of the placebo response using neuroimaging techniques.     

The placebo effect: dissolving the expectancy versus conditioning debate

The authors review the literature on the 2 main models of the placebo effect: expectancy theory and classical conditioning. A path is suggested to dissolving the theoretical impasse that has long plagued this issue. The key is to make a clear distinction between 2 questions: What factors shape placebo effects? and What learning mediates the placebo effect? The reviewed literature suggests that classical conditioning procedures are one shaping factor but that verbal information can also shape placebo effects. The literature also suggests that conditioning procedures and other sources of information sometimes shape conscious expectancies and that these expectancies mediate some placebo effects; however, in other cases conditioning procedures appear to shape placebo effects that are not mediated by conscious cognition.     

The biochemical bases of the placebo effect

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson’s disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral striatum of patients with Parkinson’s disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson’s disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson’s disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

新药临床试验中的反安慰剂效应

新药在临床试验中设立安慰剂对照需要患者知情同意,有违安慰剂暗示治疗的本意。在一种新药Ⅱ期临床试验中,发现告知与隐瞒设立安慰剂对照的事实,疗效差异明显。表明告知患者可能使用到安慰剂,会产生反安慰剂效应,影响疗效判定。提出疗效判定尽量使用客观指标、采用叠加设计、采用暂时隐瞒法、心理医生介入等4项对策。     

The concept of placebo

This paper attempts to define the concept of placebo as it is used in the clinical context The author claims that X is a placebo if and only if X has such a property d_p, that whenever in a therapeutic situation T a stimulus S appears, then in attending conditions A, it will cause a beneficial reaction R in the patient. Formally, the same structure may be used to define any pharmacologically active drug. The main difference between the drug and a placebo is in the range of possible substitutions for X and the property d. For the active drug there is only one possible substitution for X and property d and it can be scientifically explained why, and how the drug works. In the case of a placebo a set of possible substitutions for X and d is open, and so far it is impossible to offer any scientifically valid explanation of the action mechanism of placebo.     

Pavlovian inhibitory conditioning and tolerance to pentobarbital-induced hypothermia in rats

In this experiment we investigated inhibitory Pavlovian conditioning in the development of tolerance to pentobarbital-induced hypothermia. During an initial phase, one group of rats (discrimination group) received training in which, on alternate days, one conditional stimulus (CS+) was associated with administration of 30 mg/kg pentobarbital, and a different conditional stimulus (CS-) was associated with administration of physiological saline. During the phase, control groups received either exposure to both CSs but not the drug or to the drug but no CSs or to neither the CSs nor the drug. Subsequently, half the rats in each group received injections of pentobarbital in the presence of one of the CSs and the remaining half in the presence of the other CS. Rats from the discrimination group injected with pentobarbital in the presence of CS+ displayed the most tolerance (i.e., smallest drug effect), whereas rats from the discrimination group injected with pentobarbital in the presence of CS- displayed the least tolerance (i.e., greatest drug effect). The attenuation of tolerance seen in rats of the discrimination group injected in the presence of CS- provides evidence of inhibitory Pavlovian conditioning. Additional evidence of inhibitory conditioning was provided by the fact that CS2 enhanced the hypothermic effects of pentobarbital in the discrimination group, whereas CS1 attenuated these effects. Implications of the results for the nature of inhibitory conditioning are discussed.     

Perceived Retail Crowding and Shopping Satisfaction: What Modifies This Relationship?

Research has shown that an increase in perceived crowding in a retail store (created from either human or spatial density) can decrease the level of satisfaction that shoppers have with the store. The three studies reported here examine the retail crowding‐satisfaction relationship to determine the extent to which it is a simple, direct relationship. Specifically, we consider the possibility that the crowding–satisfaction relationship is mediated by emotional reactions that are experienced while shopping. In addition, moderating variables such as prior expectations of crowding, tolerance for crowding, and store type are examined for their influence on the crowding–satisfaction relationship. The results of two field studies indicate that whereas emotions only partially mediate the relationship, the decrease in shopping satisfaction due to crowding is moderated by expectations of crowding and personal tolerance for crowding. A laboratory experiment replicated the field studies and shows, in addition, that although ceiling and floor effects may be present, the relationship between perceived crowding and shopping satisfaction appears to vary by store type.     

Evaluation of drug toxicity in clinical trials

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding preapproval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected “unimportant” number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease — and treatment — specific. The modification of clinical trials according to the proposed changes may increase the trials’ sensitivity at detecting adverse effects of drugs. A lecture on the subject of this paper was presented at the 6th International Bioethics Conference on the subject of ‘The Responsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3–4 June 2005.     

Psychological effects of deep-breathing: the impact of expectancy-priming

Outcome expectancy could mediate the psychological effects of exercise-related interventions, which implies that part of the psychological benefits of physical activity could be ascribed to placebo effects. In this framed field-experiment, 89 healthy participants were studied in three groups, (1) breathing-primed (deep-breathing with an exercise-related expectancy), (2) breathing-unprimed (deep-breathing with no exercise-related expectancy), and (3) control (no intervention). Deep-breathing lasted for three minutes. Before and after deep-breathing, or sitting quietly in the control group, participants completed two questionnaires assessing their positive- and negative affect (NA) and subjective well-being (WB). In contrast to the control group, both the breathing-primed and breathing-unprimed groups showed decreased NA and increased subjective WB. The breathing-primed group reported larger changes in WB than the breathing-unprimed group, in addition to also exhibiting significant increases in positive affect. These findings support the hypothesis of the work that expectations mediate the psychological effects of deep-breathing beyond the intervention’s specific effects. Therefore, future research should control for expectations related to an intervention when gauging psychological changes.     

Occasion setting and drug tolerance

There is considerable evidence that drug-paired cues become associated with drug effects. It has been hypothesized that these cues act as Pavlovian conditional stimuli (CSs), and elicit conditional compensatory responses that contribute to tolerance. On the basis of a conditioning analysis of tolerance, we would expect that is should be possible to establish drug-paired cues as occasion setters, as well as conditional stimuli. Using feature-positive discrimination training, we evaluated the contribution of occasion-setting stimuli (as well as CSs) to tolerance to the hypothermic effect of ethanol in rats. The results indicated that a complete associative analysis of drug tolerance should incorporate not only the CS properties of predrug cues, but also the occasion-setting properties of such cues. The findings have implications for interpreting conflicting findings concerning extinction of tolerance and for cue-exposure treatments of addiction.     

Occasion Setting and Drug Tolerance

There is considerable evidence that drug-paired cues become associated with drug effects. It has been hypothesized that these cues act as Pavlovian conditional stimuli (CSs), and elicit conditional compensatory responses that contribute to tolerance. On the basis of a conditioning analysis of tolerance, we would expect that it should be possible to establish drug-paired cues as occasion setters, as well as conditional stimuli. Using feature-positive discrimination training, we evaluated the contribution of occasion-setting stimuli (as well as CSs) to tolerance to the hypothermic effect of ethanol in rats. The results indicated that a complete associative analysis of drug tolerance should incorporate not only the CS properties of predrug cues, but also the occasion-setting properties of such cues. The findings have implications for interpreting conflicting findings concerning extinction of tolerance and for cue-exposure treatments of addiction.