Whether one takes an ibuprofen to relieve a headache or an antidepressant to boost serotonin levels, the body is responding to more than just the active drug. The mere act of taking a pill may elicit a placebo effect, which is understood as an improvement (or worsening in the case of the nocebo effect) of symptoms independent of chance and the drug’s activity.


Much insight into this process has been gained in recent years by studying inert treatments called placebos, which may take on different forms – most famously a sugar pill – depending on the therapeutic intervention. Medical dictionaries of the late 18th and early 19th centuries first described placebos as substances prescribed not for their known medical benefits, but rather for appeasing seemingly gullible patients. Over time, they have been prescribed to many healthy but self-proclaimed ailing patients. As such, they are appropriately named, for placebo translates from Latin to “I shall please.” The use of placebos in efficacy testing of new treatments was first described in the 1700s, but has only been part of standardized guidelines for the last sixty years. More recently, abundant evidence has been gathered that suggests that a placebo is more than just an inert sugar pill; rather, it may be key to understanding the neuropsychology of responses to treatment and how these responses may be modulated.

What is currently understood about the placebo effect and how is it defined? Fabrizio Benedetti, a leading neurologist studying the placebo response at the University of Turin Medical School in Italy, gives a more holistic definition of the placebo than as a sham or necessary study control, describing it as “… the entire ritual of the therapeutic act”. In essence, this means that both the sugar pill and the context of its administration make up the placebo. It follows that the simple details of a placebo’s appearance are chosen to match the drug being tested, as elements like shape, colour, and text can influence the response to a placebo. However, the doctor-patient relationship may also take the spotlight, as verbal and non-verbal communication contributes considerably to the magnitude and direction of the placebo response. Moreover, the patient’s expectations and learning behaviour, both grounded in prior experience, are fundamental for the response. If one takes an analgesic to relieve a headache (prior experience), one may take an analgesic again with the expectation of pain relief. At the same time, the brain is thought to be learning (or becoming conditioned) that taking a pill is associated with pain relief. Finally, there is not one single form of the placebo response. Different personal elements and acute environmental circumstances lead to variability among people, and a change in context can lead to a different response even within the same person.

 

Illustrated by Catherine Schrankel & Kieran Manion.

 

Increasing investigation of the underlying neurological effects counters the outdated explanation of the placebo effect being based on the patient’s imagination and perceived intelligence. Insight into why the placebo response occurs has been gained by studying the neural mechanisms mediating expectation and learning tied in with the reward system. Early on, a striking study by Levine et al. in 1978 showed how the response may take place in pain management. Here, signalling of endogenous opioids (endorphins) leads to pain relief, while administration of naloxone, an inhibitor of the opioid system, abrogates the placebo response. Since then, placebo research has been able to pinpoint specific neural pathways and regions of the brain involved in producing the physiological response. These findings attribute considerable credibility to the research into the placebo effect and underline the validity of its contribution to the therapeutic regimen.

Benedetti’s definition highlights how labelling the placebo as an inert substance leads to problematic implications in clinical use and research. In medicine, it may be possible to harness the body’s own healing mechanisms to improve the efficacy of a drug in practice. However, this relies on a supportive environment, in particular regarding the patient’s interaction with the administering health practitioner, which is ideally highly empathetic. Considering the variability of these interactions and the resulting response, is it entirely feasible to rely on only the placebo effect? Would it be safe and ethical to use placebos as a treatment in and of themselves? Or should we simply try to harness the placebo effect to maximize the benefits from drug treatments?

Illustrated by Catherine Schrankel & Kieran Manion.
Illustrated by Catherine Schrankel & Kieran Manion.

In research, on the other hand, it is of the utmost importance to decrease the placebo effect along with its variability in order to reliably test the effectiveness of new drugs. Issues that require tackling are the temporally-based shrinking efficacy gap between active drugs and placebo, as well as factors regarding geographical location and study design. The performance of analgesics over placebo has been decreasing, particularly in the United States, with studies indicating either only marginal or no benefit at all over placebos in relieving pain. However, this may not directly lead to the conclusion that analgesics aren’t working; rather, it is possible that the magnitude of placebo responses has been increasing in study participants in the United States. Possible reasons for this may be the nature of the therapeutic intervention or study design; for example, increased patient and practitioner interactions in studies may strengthen the placebo response. Removing the health care practitioner’s influence may be possible in certain cases, but it is practically impossible to remove the patient’s experience and learned behaviours. The problem of testing drug activity and administration is further exemplified in a recent study by Kam-Hansen et al. (2014) of Ted Kaptchuk’s group at Harvard Medical School, in which they looked at the placebo effect in migraine relief. Patients receiving the active drug mislabelled as a placebo did not experience improved symptom relief compared to the actual placebo itself. Strikingly, patients receiving the same drug with the correct label experienced improved treatment by 50%. Clearly, pharmaceutical research needs to address these difficulties when determining whether a drug’s active components are acting as hypothesized.

Compiling the evidence for the effectiveness of placebos in symptom alleviation does not immediately translate into a justification for their use in clinical practice. A debate arises for medical bioethicists toying with the most obvious problem of placebo-based treatment: deception. While some argue that it is not truly deception, as the expected outcome of treatment is an improvement of the pre-treatment state as promised, Asai and Kadooka (2013) counter that being deceived is largely undesired and such dishonesty may even undermine the patient and health care provider relationship. Work by Ted Kaptchuk’s group and others provides evidence for effective placebo responses induced by open-label placebo treatments, which may eliminate this controversy. However, Asai and Kadooka still express scepticism: “… [open-label placebos’] future use may be relatively limited and the clinical use of placebo without deception may not constitute the mainstream of the placebo use.” Even placebo researchers such as Benedetti do not recommend the clinical use of placebos, largely due to their variable efficacy. Adding to the debate, Kaptchuk and the bioethicist Franklin G. Miller stress in a recently published perspective piece (2015) that “[although] placebos may provide relief, they rarely cure.” Nevertheless, the role placebos play in biomedical research and our understanding of the therapeutic act is continuously gaining in importance. Whether the clinical use of placebos will become a licensed and mainstream practice is still up for discussion.


References:

  1. Barton A. The placebo effect: a new study underscores its remarkable powerThe Globe and Mail. Jan. 12, 2014.
  2. DiSalvo D. Why is the placebo effect exploding in the U.S. but nowhere else? Forbes. Oct. 7, 2015.
  3. Haake M et al. German acupuncture trials (GERAC) for chronic low back painArchives of Internal Medicine. 2007; 167(17): 1892-1898.
  4. He W et al. Review of controlled clinical trials on acupuncture versus sham-acupuncture in GermanyJournal of Traditional Chinese Medicine. 2013; 33(3): 403-407.
  5. Madrigal AC. The dark side of the placebo effect: when intense belief killsThe Atlantic. Sep. 14, 2011.
  6. Marchant J. Strong placebo response thwarts painkiller trialsNature Newsdoi:10.1038/nature.2015.18511
  7. Niemi M. Placebo effect: a cure in the mindScientific American. Feb. 1, 2009.
  8. Ossola A. In painkiller trials, placebo effect is becoming more powerful. Popular Science. Oct.7, 2015.
  9. Rheims S et al. Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsyPLoS Medicine. 2008; 5(8): e166.
  10. Specter M. The power of nothingThe New Yorker. Dec. 12, 2011. 
  11. Tuttle AH et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic painPain. 2015; 156(12): 2616-2626.

 

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