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Placebo Effect for Pain

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 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).

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.

Posted in: Neuroscience/Mental Health, Pharmaceuticals

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22 thoughts on “Placebo Effect for Pain

  1. windriven says:

    “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.”

    It appears that this study focused on acute pain. Are similar placebo effects expected in chronic pain?

    There are many studies demonstrating the importance of post-operative pain management following major procedures (thoracotomy, CABG, resection of AAA, etc.) Post-operative pain is now often managed with PCA (patient controlled analgesia) systems that allow patients to self administer (carefully controlled and limited) powerful IV or epidural opiates or synthetics. I’ve been away from that technology for a while now but many of the physicians I spoke with 20 years ago found that many patients actually used less narcotics than they would normally have prescribed.

    Some of this effect may be placebo. Typically, these pumps limit the number of doses available per unit time. It would be an interesting study to measure nociception versus “button pushes” and compare the results when a dose was actually delivered versus when no dose was delivered (the patient can’t tell).

  2. daedalus2u says:

    Good article, clearly articulating why the observed effects of placebos on pain is not something extraordinary and why we really need to look to the actual physiological basis by which placebos have their effects.

    Your cautioning to not read too much into this research and to not extrapolate it into other placebo-type effects is well placed. Pain detection, transmission and evaluation is from deep evolutionary time, and is no doubt quite complex. It needs to be complex if it can be modulated by things such as conscious and unconscious motivations.

    You are absolutely correct, they should have used the caveat “for pain”. There is so much CAM that is only placebo, that there is no doubt that some CAM practitioners will latch onto this study and claim that their particular placebo treatment is effective.

  3. Dr.Jon says:

    Placebo effect here is effective because, IMO, in many of these chronic pain patients the noxious stimulus has long since been removed and in essence the only thing that remains is “in their head”, in the quite literal sense.
    It also explains the anti-physiology of the people who say, like one gentlemen did to me not 1 week ago that his dilaudid PCA was not as effective as his PO vicodin in treating his pain. The expectation of Vicodin working overrides the many times stronger narcotic actually being given.

  4. TsuDhoNimh says:

    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

    Observed many times with busted-up skiers and snowboarders, where all we have for pain control is ice and psychology. If you get it properly splinted, iced and slather on the TLC you can usually see some relaxing (which reduces pain), improved color, and patients report feeling “better”.

    The ones who are not readily helped are the ones with their first seriously painful injury, and those with an anxious parent or friend.

  5. Robin says:

    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).

    It probably has to do with fear?

    I recently had scary chest pain that was downgraded to nuisance, when what felt like a heart trouble was diagnosed as costochondritis.

    The knowledge that the nature of the pain isn’t serious has been such a relief. Though the pain is a lot easier to ignore, it hasn’t changed – my chest still hurts like motherf***er and I still want advil and heat. But I’m definitely more annoyed than anxious about it!

  6. For pain that is entirely in the head, one model is depression. The classical effect of hope and expectation on modulating the suffering of depression is when knowledge that suicide is an option is all that makes life bearable. (Cioran’s statement of this phenomenon: “Without the possibility of suicide, I would have killed myself long ago.”)

    I can tolerate a great deal if I know it will eventually end. It’s the neverendingness of the pain that makes it unendurable. Being able to convincingly offer hope of one kind or another — “Try this and we’ll see if it helps. If it doesn’t, I’m still here and I’ll keep working with you to make sure you’re all right” — is what relieves suffering in the short term.

    This is a very basic reason that anything at all will help in the short term, and accounts for the familiar pattern of people trying one thing after another for chronic conditions. The relief provided by hope that an ineffective remedy will work is only short term, but can be re-experienced by switching to a new ineffective remedy and hoping that it will work.

    This should not tempt care providers to offer something that is ineffective in itself; the patient will eventually realize that they don’t feel better and become discouraged again. It just means that caring and empathetic communication will increase the effectiveness of an effective remedy. (In the case of an antidepressant, life may become more tolerable as soon as the antidepressant is prescribed, helping to keep the patient alive until the medication effects kick in some weeks later.)

  7. “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,”

    Thanks for that! I once had a dentist tell me that codeine and vicodin(?) don’t actually stop tooth pain, they only make you not mind the pain so much. I wondered what the heck he was on about.
    It’s a rather fine point when your face/tooth hurts like heck.

  8. Adaptogen says:

    Though pain detection, transmission and evaluation is from deep evolutionary time, it is rather interesting to consider the various ways warriors and athletes dealt with pain. The ability to modulate acute pain based on expectation has been a part of winning wars and sports matches.

    Consider even the various phrases in our society: work through the pain period, no pain – no game, pain is part of the process, etc.

    To comment on WINDRIVEN’s remark about chronic pain: It seems that similar placebo effects are not likely generalizable to modulating chronic pain or perhaps may not yield as robust of an effect. The experiment you describe does seem interesting and I hope some variation of it takes place. This placebo research is really fascinating.

    SBM viewers may enjoy this short video about the placebo effect:

    http://www.youtube.com/watch?v=yfRVCaA5o18

    Dr. Ben Goldacre also does a great job in comically descibring the placebo and nocebo effect:

    http://www.youtube.com/watch?v=O1Q3jZw4FGs

  9. windriven says:

    @Dr. Jon

    “The expectation of Vicodin working overrides the many times stronger narcotic actually being given.”

    An alternative explanation is that Vicodin has a relatively high street value whereas PCA dilaudid is hard to peddle.

  10. pmoran says:

    Steven, do you think we understand the meaning of these MRI and PET changes well enough to be now sure that the placebo “effects” are real, and not merely a manifestation of biased reporting i.e. patients giving what they think are the expected answers?

    It is extremely difficult to sure in most studies of expectancy effects.

  11. My beloved former GP (who left his practice for more lucrative/less overtime work directing the state’s penitentiary system’s medical delivery) was a master of the MD Jedi Mind Trick. He would always close an appointment with some version of “I fully expect this treatment to work in X days, and here’s why….”

    Even though it felt like a version of “These aren’t the droids you’re looking for,” he was nearly always right.

  12. Anthropologist Underground – LOL! I want a Jedi Doctor.

  13. Jann Bellamy says:

    “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).”

    Are you saying that regression to the mean and observational bias are types of placebo effect, or just using them as examples of false appearance of improvement?

    Has anyone done a post discussing the many ways a “CAM” treatment might seem effective when it’s not? It would be great to have that topic summarized as it is so important in discussing “CAM” with others.

  14. Harriet Hall says:

    Jann,

    Barry Beyerstein’s classic article on Quackwatch, “Why Bogus Therapies Often Seem to Work” says it all. It would be hard to improve on his summary.
    http://www.quackwatch.com/01QuackeryRelatedTopics/altbelief.html

  15. Harriet Hall,

    I followed your link to Barry Beyerstein’s article and found a related article by you back in 2004, with this:

    “To rely on testimonials and to not wonder how things work or what science says about them is like having a set of the Encyclopedia Britannica and using it only to press flowers. Our brains are capable of much more and I think it is far more satisfying to use them to look at information that challenges our preconceptions and increases our knowledge.”

    That’s a lovely image.

  16. Jann Bellamy says:

    That’s just what I needed. Thanks, Harriet.

  17. Dr.Jon says:

    @windriven Haha. He was admitted ;)

  18. JMB says:

    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.

    I think integrating beliefs and expectations of the patient into a treatment plan has been a long tradition, not something new.

  19. pmoran says:

    I asked this a few days ago of Steven. Anyone can answer.

    Steven, do you think we understand the meaning of these MRI and PET changes well enough to be now sure that the placebo “effects” are real, and not merely a manifestation of biased reporting i.e. patients giving what they think are the expected answers?

  20. pmoran says:

    Also, Steven seems to want to be emphasize that his post is only relevant to pain management e.g. “– practitioners should seek to ethically maximize the benefits of positive expectation when treating pain“.

    Would not any subjective symptom behave much the same, even if not necessarily engaging the same pathways?

  21. zimney3pt says:

    @pmoran

    There have been some priliminary study done with pain education (improved understanding of the neuroscience of pain and the various components, thus helping create an improved expectation of what the brain is doing within the neuromatrix) and seeing changes in fMRI before and after (Moseley, 2005).

    The work of Melzack and Wall (and others) is instrumental for practitioners to understand pain better and what is happening within the neuromatrix to create the output of pain. Melzack points to the inputs of cognitive-evaluative, sensory-discriminative, and motivational-effective that lead to the output patterns to produce the multidimensions of pain experience as well as concurrent homeostatic and behavioral responses. A deeper understanding of these helps us explain placebo or nocebo.

    I like Ramachandran’s quote in “Phantoms of the Brain” – “Pain is an opinion…”, this opinion can change by expectations of the neuromatrix, creating placebo.

    ‘It is not “mind over matter”, but the brain is made up of matter and it does matter.’

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