It has long been recognized that there are substantial multifactorial placebo effects that create real and illusory improvements in response to even an inactive treatment. There is a tendency, however (especially in popular discussion), to oversimplify placebo effects – to treat them as one mind-over-matter effect for all outcomes. Meanwhile researchers are elucidating the many mechanisms that go into measured placebo effects, and the differing magnitude of placebo effects for different outcomes.

For example, placebo effects for pain appear to be maximal, while placebo effects for outcomes like cancer survival appear to be minimal.

A recent study sheds additional light on the expectation placebo effect for pain. The effect is, not surprisingly, substantial. However it does not extrapolate to placebo effects for outcomes other than pain, and the results of this very study give some indication why. From the abstract:

The effect of a fixed concentration of the ?-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).

What they found was that the positive expectation group reported twice the analgesic effect as the no expectation group, and the negative expectation group reported no analgesic effect. This is a dramatic effect, but not surprising.

There are systems in the brain that specifically alter the perception of pain. Mood, expectation, and attention all affect the perception of pain. This makes evolutionary sense, since pain is meant to be a warning system for tissue damage or disease, and so needs to have an acute grip on our attention. At the same time, there are circumstances when we may need to function despite our pain, or when it would be adaptive to habituate to chronic pain. There are therefore mechanisms in the brain that function to enhance and draw our emotional attention to pain, and others that  function to inhibit pain.

It also needs to be noted that, broadly speaking, there are two components to pain. There is the origin and transmission of the pain signal, which is perceived as any tactile sensation. But then there is a specific emotional component to pain which occurs in the brain – that processing which makes pain hurt, that makes it into an emotionally negative experience. These two components can be separated. Narcotics, for example, are especially good at blocking the emotional component of pain, so that at times patients on opiates may report that they feel the pain but it does not bother them. Additionally, while withdrawing from narcotics the emotional component of pain in enhanced – patients may have what appears to be an exaggerated emotional response to even minor pain.

Therefore – since there is a built in system for modulating pain in response to both the physical and emotional environment, it makes sense that this system can be manipulated with physical and emotional inputs. If you make a patient feel better emotionally or decrease their stress or anxiety, their perception of pain will decrease, or at least it will not bother them as much (or, more precisely, their reporting of pain will decrease). This is why multi-disciplinary pain clinics often include psychological therapy as part of the overall approach.

This study demonstrates that expectation itself can have a dramatic effect on pain perception. They further elucidate, with fMRI analysis, the neuroanatomy that underlies this effect.

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.

This finding support prior research:

Further PET studies with dopamine D2/D3 receptor-labeling radiotracer demonstrate that basal ganglia including NAC are related to placebo analgesic responses. NAC dopamine release induced by placebo analgesia is related to expectation of analgesia. These data indicate that the aforementioned brain regions and neurotransmitters such as endogenous opioid and dopamine systems contribute to placebo analgesia.

The fMRI shows us where the effect is, and the PET scanning additionally shows us that dopamine is the important neurotransmitter involved in this effect.

What I would have loved to have seen in this study (perhaps this will be part of a follow up) is the same three treatment arms with a placebo treatment. This would enable us to directly compare the relative size of the expectation effect to the opiate effect. There are other questions as well. How much variation is there in the magnitude of this effect from person to person? Does the expectation effect habituate over time? Is the magnitude the same for different kinds of pain?

Conclusion

This study reinforces prior research indicating that there are built-in neurological mechanisms that modulate the perception and emotional content of pain. The study gives us further information about the exact brain structures involved in this effect. The authors conclude:

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.

They should have added “for pain.” This study says nothing about other treatment effects for which there does not exist a target system for symptom modulation. This error is distressingly common, especially in the translation of such research to the public. Pain is uniquely amenable to manipulation through mood and expectation. This does not predict that any other symptom or disease state can be so manipulated.

This situation is analogous to stress and heart disease. The heart is specifically susceptible to the physiological effects of emotional stress. Stress reduction, therefore, decreases, for example, the risk of heart attack. This does not mean, however, that stress reduction will therefore decrease the risks of any disease or adverse outcome.

All too often, however, people speak of “the placebo effect” as if it is one effect, equal for all outcomes. This notion is then supported with hand-waving explanations about self-healing. But the research is actually quite clear. There are many placebo effects. Expectation is only one effect among many,  and many of these effects are illusory – they create the false appearance of improvement where none exists (like regression to the mean or observational bias). Further, when speaking of the expectation effect we must be careful not to falsely extrapolate this effect from one outcome (like pain) to others.

This and other studies show that the brain is hardwired to modulate pain based upon expectation. There is no reason to think that this effect translates to other subjective symptoms, let alone objective outcomes like survival.

But I do agree with the authors to the extent that this and other studies do suggest that practitioners should seek to ethically maximize the benefits of positive expectation when treating pain. This should not, of course, violate the principles of honesty or informed consent. But putting a positive spin on the potential of a pain intervention is therapeutic. This does not justify, in my opinion, using a known placebo intervention (unless the patient was informed that it was a placebo or a treatment without any biological activity), because otherwise this would involve unethical deception (and could also create and reinforce unscientific beliefs in patients that could result in harm downstream). Further, as this study shows, you can get a sizable placebo effect from physiologically effective treatments.