The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil, 2011, Bingel et al.

[Chandelier]

https://www.science.org/doi/10.1126/scitranslmed.3001244

Spoiler: Authors

ULRIKE BINGEL, VISHVARANI WANIGASEKERA, KATJA WIECH, ROISIN NI MHUIRCHEARTAIGH, MICHAEL C. LEE, MARKUS PLONER, AND IRENE TRACEY

Abstract​

Evidence from behavioral and self-reported data suggests that the patients’ beliefs and expectations can shape both therapeutic and adverse effects of any given drug.

We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging.

The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain).

We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms.

Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia.

These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus.

On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy.

We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

Gloomy Forecasts Prove True​

A pessimist walks into a hospital. His grim prediction that doctors will be unable to alleviate his back pain proved correct—after several days of various treatments, his pain persisted. According to new results from Bingel and colleagues, the gloomy outlook this patient brought with him into his pain treatment may have ensured that his prediction was a self-fulfilling prophesy. Using sophisticated brain imaging techniques, the authors show that one’s expectation of the success of a pain treatment can markedly influence its effectiveness.
In this new study, healthy people were exposed to pain-provoking heat and also given the painkilling opioid drug remifentanil. In advance of each instance of drug administration, the authors informed the subjects that the drug would have no effect, that it would diminish the sensation of pain, or that it would make the pain worse. When subjects expected the drug to be effective, they were not disappointed—they experienced twice as much pain relief as they did when they expected to obtain no benefit from the drug (but did, in fact, get some relief). In contrast, when they expected remifentanil to make the heat pain worse they found that their pain was unchanged. But these subjective reports could be influenced by a host of variables. What was actually happening within the brains of these individuals to shift their pain perceptions so dramatically?
With functional magnetic resonance imaging (fMRI), the authors of Bingel et al. examined brain activity during the experiment. Thermal pain itself causes activation of a so-called pain circuit, which encompasses numerous brain regions including the somatosensory cortex, the cingulate cortex, insula, thalamus, and brainstem. Expectation of increased pain was accompanied by more neural activity in the hippocampus, midcingulate cortex, and medial prefrontal cortex—brain areas that mediate mood and anxiety—than was observed in these regions during expectation of analgesia. Conversely, individuals who expected the drug to mitigate their pain showed increases in the anterior cingulate cortex and the striatum, signs that descending mechanisms of pain inhibition were engaged.
These clues about how our beliefs can affect the way we experience medical treatment for pain can improve the practice of medicine. A drug with a true biological effect may appear to be ineffective to a patient conditioned to expect failure, whether the patient is enrolled in a clinical trial or treated in a physician’s office. Patient education about treatments can help counteract this problem by shaping beliefs to maximize drug effectiveness. If appropriate treatments are accompanied by encouraging words, a pessimist could become an optimist about his future robust health, and thereby make it so.

 

[Chandelier]

Professor Bingel speaks about this study in a recent interview with the german magazine Der Spiegel.
AI Summary:

In a study using the potent, short-acting opioid Remifentanil, Bingel's team investigated how expectations affect pain perception. All participants received the same dose of the drug, but were divided into three groups with different expectation settings: one was unaware treatment had begun (neutral), one was told they were receiving a powerful analgesic (positive), and one was falsely informed the medication was being stopped (negative). B.

The results were striking: Positive expectation nearly doubled pain relief, while negative expectation almost completely neutralized the drug’s effect — despite identical pharmacological dosing. This demonstrates that negative expectations and emotions can entirely undermine even highly effective treatments. These findings are not limited to experimental opioids but extend to everyday situations, like taking over-the-counter painkillers such as ibuprofen.

A post about the interview has been created here: https://www.s4me.info/threads/news-from-germany.11006/post-640577

 

[Utsikt]

They did something weird in the first conditioning run (edit: they did a conditioning run before the main experiments to «induce positive and negative treatment expectations»).

In all of the experiments, pain was induced by a thermal pad attached to their leg, and the temperature was set to what corresponded to 70 of 100 on a VAS pain scale. During the positive expectation conditioning run and without telling them, they lowered the temperature by 1 degree C, and increased it by 1 degree C during the negative expectation conditioning run.

This means that the participants were taught through real experiences that positive expectations caused less pain, even if that wouldn’t otherwise be true, and the opposite for the negative. If this learning is key to achieve a change in the reported VAS, it would be impossible to reliably recreate outside of an experimental setting, because the patient wouldn’t have the ability to learn through real experience that positive expectations actually result in lower pain.




If we compare figure 1 no expectations (getting the drug when you’re told you get saline) with figure S5 (getting the drug when you’re told you get the drug), you can see that the VAS scores are similar at around 55. Which means that simply telling someone «you’re now getting a drug that reduces pain», does not in itself result in less pain than being given the drug when you think you’re getting saline. So an un-manipulated positive expectation doesn’t influence the reported pain.

Therefore, I think it’s reasonable to infer that the difference in VAS scores in figure 1 for positive and negative expectations, are most likely due to the participants being taught through actual real experiences that there is a difference between the two scenarios.

Which to my mind makes the study pretty much irrelevant for clinical practice, for the reasons mentioned above.

They also hid another observation in the supplements: that neither optimism or depressiveness influenced the actual pain ratings in the positive and negative expectancy tests, even though both scores correlated with their expectations of pain. Further substantiating the interpretation that expectations alone does not influence reported pain levels.

 

[rvallee]

It's easy to get the exact same effect with the appearance of luxury. Lots of experiments have been run, and all they do is point out how it's easy to get false answers from people if you try hard enough to get them. Which of course is exactly what those experiments do. Every professional involved has expectations about the *cebos, and they act on it, influence the participants, the experiment and its interpretation with it.

Examples of this phenomenon removed from a clinical setting are usually based on presenting cheap things as expensive, and getting people to marvel at how luxurious they are. Fake luxury stores showing cheap items will have gullible people, even rich people who do pay exorbitant prices as a thing they barely think about, falling over themselves noting the superiority of those products compared to cheap items at cheap stores bought by cheap people.

Similar experiments exist with food. Create an elaborate fake dining experience, and serve, well-presented, some of the cheapest items, cooked about as well as a school cafeteria. As long as it's presented like a fine dining experience, including wine the participants wouldn't even accept to drink if they knew which brand and quality, and they'd all gush about how this fine diner was obviously worth a $200 price tag.

When you want to influence people's responses, and work to influence them, you usually will. As long as you make your outcomes easy to manipulate, and interpret them in the way you want them to be.

And that's all this fake-ass *cebo is all about: pissing on people's legs and getting them to tell you how pleasant the rainfall feels like. I've never seen something so obviously fake being taken seriously by people who absolutely should know better, who in fact do know better, but choose to exempt this particular belief from their normal reasoning. Which is exactly what every single person who adopts pseudoscientific beliefs does. For the exact same reason: it must be true if I believe in it, because I'm not a gullible person who believes in false things.

 

[Utsikt]

During the positive expectation conditioning run and without telling them, they lowered the temperature by 1 degree C, and increased it by 1 degree C during the negative expectation conditioning run.

I looked a bit more into this because I wondered if 1 C would actually make a difference.

The heating pad took 1.5 seconds to ramp up, maintained the temperature for 6 seconds and took 1.5 seconds to ramp down.

The threshold for starting to feel pain from heat to the skin is about 44 C (which is also the point at which permanent damage can start to occur). The pad goes to 55 C. If they aimed for 70/100 on a VAS scale where 100 is unbearable pain, I can imagine a world where going from e.g. 52 C to 53 C would make a noticeable difference. The same with going from 52 C to 51 C.