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Placebo and nocebo
Published in Harald Breivik, William I Campbell, Michael K Nicholas, Clinical Pain Management, 2008
Luana Colloca, Damien G Finniss, Fabrizio Benedetti
The open-hidden paradigm has been discussed as an interesting paradigm for studying placebo effects.139 Overall, at least three important clinical and methodological implications derive from this paradigm.17 First, the lesser effectiveness of hidden treatments indicates the crucial role of the patient–provider interaction. Second, by using the hidden paradigm, the efficacy of some treatments can be assessed without the need for placebo administration, thus overcoming the ethical problem of placebo administration and deception. Third, the hidden paradigm can change the conception of how clinical trials must be viewed and conducted. In fact, it is possible to isolate the specific action of a treatment (such as the pharmacological properties of a drug) from the overall effect of the treatment (the specific action plus the context-driven placebo mechanisms). One important implication of this paradigm is that it can demonstrate that even though a drug may show strong analgesic efficacy in a normal RCT design, it may in fact have little or no specific analgesic properties. This was demonstrated in a study by Benedetti and coworkers,95 whereby the CCK antagonist proglumide was tested in both a standard RCT design and a hidden fashion. When administered in full view of the patient, proglumide was shown to be an effective analgesic. However, when the patients did not know they were receiving the drug, it had no effect on pain, demonstrating that the drug had no specific analgesic properties (Figure 41.4). The action of the CCK antagonist proglumide consists in the potentiation of top-down placebo mechanisms and it does not act directly on pain pathways. This valuable information would not be obtained using a standard RCT design and therefore the open-hidden paradigm may represent an excellent alternative for studying certain treatments. It also underscores the power of the expectation component of an active treatment on the overall effectiveness of the treatment. In other words, proglumide induces a reduction of pain if, and only if, associated with a placebo procedure. Today we know that proglumide is not a painkiller, but it acts on placebo-activated opioid mechanisms.
Cholecystokinin and Neuroendocrine Secretion
Published in Craig A. Johnston, Charles D. Barnes, Brain-Gut Peptides and Reproductive Function, 2020
Joseph G. Verbalis, Edward M. Stricker
Fortunately, more sensitive and specific compounds than proglumide have recently become available. The most promising among these is MK 329 (initially named L-364,718), which displays marked selectivity for CCK A receptors (IC50 of 0.08 ± 0.02 nM for rat pancreatic tissue versus 245 ± 97 nM for guinea pig brain tissue; Chang and Lotti, 1986). Although not all studies using peripheral injection of MK 329 have shown increases in food intake (e.g., Khosla and Crawley, 1988; Schneider et al., 1988), several now have (Hewson et al., 1988; Reidelberger and O'Rourke, 1989). However, several qualifying points should be considered concerning such studies: (1) increments in food intake have generally been modest, ranging from 5 to 20% in most positive studies; (2) protocols employing highly palatable diets generally have been more successful in showing larger increments in food intake (Hewson et al., 1988); (3) effects have not been sustained in chronic studies, suggesting some degree of tolerance to the effects of the antagonist (Watson et al., 1988); (4) because MK 329 can cross the blood-brain barrier, effects on food intake cannot be definitely assigned to peripheral CCK receptor blockade because of significant binding of this compound to CCK B receptors; moreover, the fact that much larger doses of MK 329 are required to increase food intake than to block the effects of peripherally administered CCK (see review, Schneider et al., 1988) can be viewed as consistent with the possibility of a central rather than a peripheral effect of the antagonist; and (5) CCK antagonists have been shown to have significant antinociceptive properties (Dourish et al., 1988), suggesting that at high doses such agents could increase food intake by eliminating or reducing the discomfort associated with gastric distention rather than by blocking peripheral CCK effects. Despite these and other uncertainties, further studies using MK 329 and similar compounds hold out the best promise of understanding the function of endogenously secreted CCK. Future development of a more selective CCK B receptor antagonist will allow even better evaluation of central CCK actions, and specifically of its effects on neuroendocrine secretion.
What is the role of placebo in neurotherapeutics?
Published in Expert Review of Neurotherapeutics, 2022
Elisa Frisaldi, Aziz Shaibani, Marco Trucco, Edoardo Milano, Fabrizio Benedetti
The last three decades have witnessed the beginning of clarification of neurochemical and pharmacological details of placebo analgesia [1]. In 1978, a pioneering study by Levine et al. [28] showed that the opiate antagonist naloxone was able to reduce the placebo response in dental postoperative pain. That was the first indication that endogenous opioids were involved in placebo analgesia. Subsequent experiments provided even more compelling evidence that the secretion of endogenous opioids in the brain was the key event in placebo pain modulation. Placebo responders had levels of β-endorphin in the cerebrospinal fluid that were more than double those of non-responders; opioids released by a placebo procedure displayed the same side effects as exogenous opiates; naloxone-sensitive cardiac effects could be observed during placebo-induced expectation of analgesia. Indirect support also came from the placebo-potentiating role of the cholecystokinin (CCK) antagonist proglumide. In fact, the CCK system effects counteracted those of opioids, delineating a picture where the placebo effect seems to be under the opposing influence of facilitating opioids and inhibiting CCK. In some situations, however, a placebo effect can still occur after blockade of opioid mechanisms by naloxone, indicating that systems other than opioids are also implicated. For example, with a morphine conditioning and/or expectation-inducing protocol, naloxone was able to completely reverse placebo analgesia induced in experimental ischemic arm pain. Conversely, with the use of ketorolac (a non-opioid analgesic) in the same protocol, the cannabinoid antagonist rimonabant was capable of reversing placebo analgesia, thus suggesting that at least two different biochemical pathways could be involved: endogenous opioids and endocannabinoids [1].