Pharmacological classical conditioning in humans

Flaten, Magne Arve; Simonsen, Terje; Waterloo, Knut; Olsen, Harald

doi:10.1002/(sici)1099-1077(199707/08)12:4<369::aid-hup881>3.0.co;2-d

Cited by 19 publications

(4 citation statements)

References 19 publications

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“…Our study is clearly distinguished from previous studies because it focuses on the nonconscious activation of placebo/nocebo responses and demonstrates that placebo/nocebo can be activated even if the conditioned stimulus is not consciously perceived. In traditional placebo studies, conditioning is often used by pairing the administration of an unconditioned stimulus (e.g., effective analgesic pill, cream, or injection) with a conditioned stimulus (e.g., inert placebo pill, cream, or injection), thus producing placebo responses through "associative learning" (27)(28)(29)(30). Even if associative learning in such studies has been described in terms of a "nonconscious" mechanism (in which cognition may be an epiphenomenon, rather than part of a causal chain), the activation of the conditioned response has always been obtained by a perceptible conditioned stimulus.…”

Section: Discussionmentioning

confidence: 99%

Nonconscious activation of placebo and nocebo pain responses

Jensen

Kaptchuk

Kirsch

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

224

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The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. The first experiment assessed whether a conditioning paradigm, using clearly visible cues for high and low pain, could induce placebo and nocebo responses. The second experiment, in a separate group of subjects, assessed whether conditioned placebo and nocebo responses could be triggered in response to nonconscious (masked) exposures to the same cues. A total of 40 healthy volunteers (24 female, mean age 23 y) were investigated in a laboratory setting. Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses.analgesia | hyperalgesia | consciousness P lacebo and nocebo effects are critical components of medical practice and clinical research. Placebo analgesia and nocebo hyperalgesia are the most robust and well studied of these effects. Learning is known to play an important role in placebo and nocebo effects and the dominant theories invoke classical conditioning and expectancies as explanatory tools (1). Both rely on a notion that the conscious perception of sensory or social stimuli, such as the cue that triggers expectancy or the conditioned stimulus in classical conditioning, are needed to obtain placebo responses. In some circumstances, conditioning may be an automatic nonconscious process, but in most cases, it seems to involve the formation of expectations (2-4). However, it is not known whether conscious perception of a conditioned stimulus is needed to elicit a conditioned response.There is a large literature suggesting that behavior can be motivated by stimuli that are not consciously perceived, because they are presented at low intensities or masked from conscious awareness (5, 6), sometimes referred to as subliminal stimuli. Nonconscious operations are considered a fundamental feature of human cognition, for example in reward processing (7,8), fear learning (9, 10), and social behavior (11,12). Furthermore, evidence suggests that conditioned responses may be acquired outside of conscious awareness (13-15). Neuroimaging studies of the human brain suggest that certain structures, such as the striatum and ...

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Section: Discussionmentioning

confidence: 99%

Nonconscious activation of placebo and nocebo pain responses

Jensen

Kaptchuk

Kirsch

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

224

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“…In one of the few human studies in this field, Flaten et al [62] administered the muscle relaxant carisoprodol once per week for three weeks to healthy volunteers. Carisoprodol reduces blink reflex magnitudes, and tolerance was observed after repeated administration of carisoprodol, i.e.…”

Section: Why Not a Compensatory Response?mentioning

confidence: 99%

“…the drug had less inhibitory effects on blink reflex amplitudes. Flaten et al [62] showed that conditioned stimuli that signalled carisoprodol administration increased blink reflexes, i.e. signals of carisoprodol administration, elicited a conditioned compensatory response.…”

Section: Why Not a Compensatory Response?mentioning

confidence: 99%

The relation of emotions to placebo responses

Flaten

Aslaksen

Lyby

et al. 2011

Phil. Trans. R. Soc. B

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123

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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.

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“…Placebo analgesia is a reduction in pain due to the administration of an inert substance with information that the substance effectively alleviates pain (Flaten et al, 2006;Benedetti, 2008). Moreover, inert factors previously associated with effective treatment, for example, through learning procedures such as classical (e.g., Ader, 1997;Flaten et al, 1997;Flaten, 2013), observational (e.g., Colloca and Benedetti, 2009;Hunter et al, 2014;, and operant conditioning (Adamczyk et al, 2019;Babel, 2020), are also capable of generating placebo effects. Both verbal information and learning procedures can generate expectations about positive outcomes, which are known as one of the mechanisms of placebo effects (Kirsch, 2004;Flaten et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Placebo Analgesia, Nocebo Hyperalgesia, and the Cardiovascular System: A Qualitative Systematic Review

Daniali

Flaten

2020

Front. Physiol.

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Background: Placebo/nocebo effects involve the autonomic nervous system, including cardiac activity, but studies have reported inconsistent findings on how cardiac activity is modulated following a placebo/nocebo effect. However, no systematic review has been conducted to provide a clear picture of cardiac placebo responses. Objective: The main goal of the present study is to review the effects of placebo analgesia and nocebo hyperalgesia on cardiac activity as measured by blood pressure, heart rate, and heart rate variability. Methods: Using several Boolean keyword combinations, the PubMed, EMBASE, PsycINFO, Cochrane Review Library, and ISI Web of Knowledge databases were searched until January 5, 2020, to find studies that analyzed blood pressure, heart rate, or heart rate variability indexes following a placebo analgesic/nocebo hyperalgesic effect. Results: Nineteen studies were found, with some reporting more than one index of cardiac activity; eight studies were on blood pressure, 14 studies on heart rate, and six on heart rate variability. No reliable association between placebo/nocebo effects and blood pressure or heart rate was found. However, placebo effects reduced, and nocebo effects increased low-frequency heart rate variability, and heart rate variability significantly predicted placebo effects in two studies. Conclusion: Placebo/nocebo effects can have reliable effects on heart rate variability, but not on heart rate and blood pressure.

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Pharmacological classical conditioning in humans

Cited by 19 publications

References 19 publications

Nonconscious activation of placebo and nocebo pain responses

Nonconscious activation of placebo and nocebo pain responses

The relation of emotions to placebo responses

Placebo Analgesia, Nocebo Hyperalgesia, and the Cardiovascular System: A Qualitative Systematic Review

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