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What Is The Placebo Effect

As any practicing physician worth their salt knows, whether we like it or not, since time immemorial the Placebo effect and its counterpart, Nocebo, are a large component of response to medications and medical procedures. Most important aspect about the placebo effect is it exists even without a placebo, i.e., operates regardless whether the Rx is a highly specialized and well-validated drug with a known mechanism of action or a real procedure on the one hand or placebo or sham procedure on the other. In other words, ipso facto, drug effects include placebo effects.

However, for too long, placebo effect research got bogged down in what placebos are, i.e., placebo pill or sham treatment content took precedence over the context in which treatments, be they real or placebo, are given. Placebo context or placebo ritual encompasses all the disparate elements of any treatment environment including beliefs, expectations, past experiences, not just the patient’s but also the physician’s (see below from 1) and everyone else involved in it.

The focus of cutting-edge placebo research is to uncover and understand the components and processes of this effect. Change in focus from placebo content to context is not only unprecedented but has the potential to truly revolutionize medicine, if it gets the attention it surely deserves like none other but which it unfortunately doesn’t get, given the perennial short-sightedness of biomedicine funders, and biotech and pharma companies. And of course, the medical community also needs to get on board with what the latest in placebo effects research teaches us about how medicines actually work, as in how much a person’s psychological response to being treated plays a major role in a treatment’s effectiveness.

How To Study Placebo Effects

Randomized controlled trial (RCT) which are also Placebo-controlled study don’t help understand the placebo effect since that isn’t really their focus. Rather they merely seek to account for the placebo fait accompli in order to more accurately assess the ‘real’ treatment’s effect. As well, many of them don’t include the key no treatment group necessary to assess the magnitude of the placebo effect separately. However, comparing placebo and no treatment groups doesn’t fully reveal the entirety of placebo effects either.

An early placebo effects RCT (2) found the cholecystokinin antagonist Proglumide to be more effective against post-operative pain compared to placebo. So far so good. However, this study, done by the groundbreaking placebo researcher, Fabrizio Benedetti, included a further group, those who got proglumide but weren’t told about it, i.e., a hidden treatment group. Such patients reported no alleviation of their pain, even though they’d received the same dose of painkiller! How to explain this? When given openly, proglumide presumably interacts with and enhances expectation pathways, i.e., one type of placebo effect. In other words, proglumide doesn’t act on pain pathways itself and thus is only effective when combined with psychosocial mechanisms operating during physician-patient interactions.

A Representative Example Of Experiments That Uncover & Study Placebo Effects Separately From Placebo

A pioneering placebo effect study by the groundbreaking placebo researcher, Ted Kaptchuk, in this RCT on 262 Irritable bowel syndrome (IBS) patients, placebo effects were separated into their 2 main components or combined together and compared to no treatment (3).

  • Placebo ritual alone: a validated placebo acupuncture device which retracts into the needle handle instead of penetrating the skin.
  • Placebo ritual plus patient-clinician relationship. The latter consisted of a prospectively scripted process that entailed attention, warmth, confidence and thoughtful silence.

3 weeks into the trial, using a validated measure for IBS, patients reporting improvement were

  • 28% in the no treatment group.
  • 44% in the placebo ritual group alone.
  • 62% in the placebo ritual plus patient-clinician relationship.

The 62% improvement seen in the placebo ritual plus patient-clinician relationship was similar to that seen in an earlier RCT where patients were treated with Alosetron, a drug used for IBS Rx (4). In other words, this study’s placebo effects were just as effective as active IBS Rx was reported to have been in a previous study.

What kind of experimental design helps uncover, maybe even quantify, placebo effects, which operate regardless of real medication or placebo? The Open-Hidden Study Design.

  • First, to consider that any medical treatment has specific and non-specific effects. The latter could ensue simply from knowledge that a treatment’s being given, i.e., expectation.
  • Second, assess the treatment’s effectiveness by
    • Eliminating its specific effect, i.e., a placebo study: No active Rx, only placebo.
    • Eliminating non-specific effects, i.e., hidden treatment: Active Rx but patient doesn’t know.

Called the Open-Hidden Study Design (see below from 5), this experiment design has thus far best elucidated magnitude and duration of placebo effects, and uncovered their two main drivers, expectations and classic conditioning, i.e., learning.

Open-Hidden Study Design Reveals Placebo Effects Can Ensue From Expectations Of Symptom Improvement

Consider a physician-administered drug.

  • In open treatment, the physician injects the drug into the patient openly with normal verbal and contextual interactions, i.e., complete representation of routine physician-patient psychosocial interaction.
  • In hidden treatment, patient gets the drug infused via a computer pump in the absence of a physician and the therapeutic context. Hidden treatment patients only know they’re supposed to get a drug injection at some point, not when. Thus they don’t experience the expectation component and other contextual factors associated with their treatment.

With such a design the placebo component is defined as the difference between open and hidden treatments, even though no placebo is given (5, 6).

Several open-hidden studies on painkillers such as Buprenorphine, Ketorolac, Metamizole, Morphine, Tramadol found hidden treatment markedly less effective compared to open treatment.

  • One study had open versus hidden pain treatment groups among both healthy and post-operative patients (7).
    • Healthy volunteers (n=86) subjected to experimental ischemic arm pain (combination of venous blood draw and Esmarch bandage): Hidden treatment group had higher pain ratings.
    • Post-thoracic surgery patients (n=278) with post-operative pain: Hidden treatment group needed much higher doses of pain medication to reduce pain by 50%.
  • One study examined effect of open versus hidden treatment with morphine among 42 patients with post-operative pain, open versus hidden treatment with Diazepam among 30 thoracotomized patients with anxiety, and open versus hidden stimulations of the subthalamic nucleus in 10 Parkinson’s patients (8).
    • In all these cases, pain medications were much less effective in the hidden treatment groups.
    • In all these cases, the open treatment condition differed from the hidden one in three important parameters, namely, patient was aware of the treatment, the therapist was present in the room and thus patient had an expectation of the outcome.

Studies on painful rectal distention balloon in IBS patients given local anesthetic or placebo found subtle manipulation of expectations directly influenced placebo response magnitude.

  • In one study (9), patients were told they ‘may receive an active or placebo agent’.
  • In the other study (10), they were told ‘the agent you have been given is known to significantly reduce pain in some patients’.
  • The second study with the more specific instructions elicited stronger placebo responses.

Implication: Better defined, more specific instructions may improve treatment response.

One study (11) assessed post-operative pain alleviation. Intravenous (iv) saline was the placebo, buprenorphine on request the standard analgesic Rx. Patients were divided into three groups

  • Group One was told iv saline was a rehydrating solution.
  • Group Two that it was a powerful painkiller.
  • Group Three that it may or may not be a powerful painkiller.
  • Group Two took 33% less buprenorphine compared to Group One.
  • Group Three took 20% less buprenorphine compared to Group One.

Implication: Active Rx plus placebo effects could reduce total analgesic usage.

Open-Hidden Study Design Reveals Placebo Effects Can Ensue From Learning To Expect Symptom Improvement, i.e., Pre-Conditioning

For long, the assumption prevailed that in order to work, placebos required deception or concealment. Pioneering placebo effects studies show this isn’t so, that they entail learning processes that allow placebos to work in reducing symptoms even with patients knowing about them.

  • In one study (12), 30 healthy right-handed volunteers were given pain stimulus (electric shock) to their non-dominant hand. At the same time, placebo effect was introduced by surreptitiously reducing pain stimulus to make volunteers believe an analgesic Rx was effective. This subterfuge yielded real 3 to 5-fold pain reductions that lasted as long as 4 to 7 days later, as assessed by repeat experiments when patients knew they were getting placebo, not drug.
  • In one study (13), 54 adult female volunteers were told the study compared analgesia from a topical cream compared to placebo. Patients were randomly assigned to long (4 days) or short (1 day) pre-conditioning, i.e., surreptitious Rx with placebo cream. Placebo effect, i.e., perceived analgesia relief, persisted in the long pre-conditioning group even when they were later openly treated with placebo.

Implication: Reinforcing treatment cues with positive outcomes can create placebo effects independent of expectations, i.e., placebo effects can also be learned.

  • In a study (14) by Benedetti‘s group, 229 adult volunteers were subjected to experimental ischemic arm pain (combination of venous blood draw and Esmarch bandage), and conditioned with either opioid morphine or non-opioid Ketorolac. Placebo effect associated with morphine but not by ketorolac could be reversed by Naloxone. Benedetti interprets this data to suggest that morphine related placebo effect involves Endorphins while ketorolac involves Cannabinoid (15).

Implications: Placebo effects associated with different drugs tap different neurochemical pathways.

Implications Of Placebo-Associated Learning Effects: Placebos As Drugs Have Potential To Reduce Drug Costs, Dependency, Dose, Side-effects, Tolerance

  • In a pioneering randomized, two group, open-label placebo study (16) on 80 IBS patients, Kaptchuk et al openly gave sugar pills to one of the groups as ‘placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes‘. Both groups involved similar patient-provider interactions, the only difference between them being that one got sugar pills. Those who took sugar pills (22/37, 59%) reported significantly higher improvement in symptom relief compared to the no treatment group (15/43, 35%).
  • In a 2016 study on 42 Parkinson’s disease patients (17), Benedetti et al showed that timing of pre-conditioning with placebo during treatment with apomorphine could
    • Produce both clinical and neuronal responses.
    • Convert even placebo non-responders to responders.
    • Clearest sign that active learning was involved was evident in the fact that greater the number of prior exposures to apomorphine, greater magnitude and longer duration of clinical and neuronal placebo responses.
  • A 2016 review (18) of 22 placebo effects studies on conditions as varied as Attention deficit hyperactivity disorder (ADHD), experimental immunosuppression, insomnia and pain concluded placebos have the potential to be used openly to reduce drug costs, dependency, dose, side-effects and tolerance. Such usage could be especially propitious and timely in the case of opioid use whose per capita use in US is double that in the UK, 3X that in the Netherlands and 26X that in Japan (18), stoking an unprecedented public health crisis that even appears to have truncated life expectencies among white, non-Hispanic Americans (19).


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2. Benedetti, Fabrizio, Martina Amanzio, and Giuliano Maggi. “Potentiation of placebo analgesia by proglumide.” The Lancet 346.8984 (1995): 1231.

3. Kaptchuk, Ted J., et al. “Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome.” Bmj 336.7651 (2008): 999-1003. http://www.bmj.com/content/bmj/3…

4. Camilleri, Michael, et al. “Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.” The Lancet 355.9209 (2000): 1035-1040. https://www.researchgate.net/pro…

5. Colloca, Luana, et al. “Overt versus covert treatment for pain, anxiety, and Parkinson’s disease.” The Lancet Neurology 3.11 (2004): 679-684. https://www.researchgate.net/pro…

6. Price, Donald D. “Assessing placebo effects without placebo groups: an untapped possibility?.” Pain 90.3 (2001): 201-203.

7. Amanzio, Martina, et al. “Response variability to analgesics: a role for non-specific activation of endogenous opioids.” Pain 90.3 (2001): 205-215. https://www.researchgate.net/pro…

8. Benedetti, Fabrizio, et al. “Open versus hidden medical treatments: The patient’s knowledge about a therapy affects the therapy outcome.” Prevention & Treatment 6.1 (2003): 1a.

9. Verne, G. Nicholas, et al. “Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients.” Pain 105.1 (2003): 223-230.

10. Vase, Lene, et al. “The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients: An empirical investigation.” Pain 105.1 (2003): 17-25. http://citeseerx.ist.psu.edu/vie…

11. Pollo, Antonella, et al. “Response expectancies in placebo analgesia and their clinical relevance.” Pain 93.1 (2001): 77-84. https://www.researchgate.net/pro…

12. Colloca, Luana, and Fabrizio Benedetti. “How prior experience shapes placebo analgesia.” Pain 124.1 (2006): 126-133. https://www.researchgate.net/pro…

13. Schafer, Scott M., Luana Colloca, and Tor D. Wager. “Conditioned placebo analgesia persists when subjects know they are receiving a placebo.” The Journal of Pain 16.5 (2015): 412-420. https://www.ncbi.nlm.nih.gov/pmc…

14. Amanzio, Martina, and Fabrizio Benedetti. “Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.” The Journal of Neuroscience 19.1 (1999): 484-494. https://www.researchgate.net/pro…

15. Marchant, Jo. “Placebos: Honest fakery.” Nature 535.7611 (2016): S14-S15. http://www.nature.com/nature/jou…

16. Kaptchuk, Ted J., et al. “Placebos without deception: a randomized controlled trial in irritable bowel syndrome.” PloS one 5.12 (2010): e15591. http://journals.plos.org/plosone…

17. Benedetti, Fabrizio, et al. “Teaching neurons to respond to placebos.” The Journal of physiology (2016). http://onlinelibrary.wiley.com/d…

18. Colloca, Luana, Paul Enck, and David DeGrazia. “Relieving pain using dose-extending placebos: a scoping review.” Pain (2016).

19. Case, Anne, and Angus Deaton. “Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century.” Proceedings of the National Academy of Sciences 112.49 (2015): 15078-15083. http://www.pnas.org/content/112/…