Placebos and placebo effects II

PublicationNr. 2 - 2 maart 2017
Authormw J. Zaal en mw L. Bogaard

II. The use of placebo in medical practice

The second GEBU article on placebos and placebo effects deals with the use of placebos in medical practice. It first examines the magnitude of and differences in the placebo response for two commonly used drugs, which clearly shows that there is no standard placebo effect or response. The physiological mechanisms found so far to be involved in the placebo response differ for the various disorders. Mapping these mechanisms will require more research. The article goes on to explain how the placebo response can be used in practice, and the associated consequences in terms of medical ethics. There is no such thing as a typical placebo responder. Although genotyping might in the future be able to help optimise treatments, its application in medical practice is still a distant prospect. Until such time, a care provider cannot determine at a glance whether a patient will respond better to treatment because he or she has a stronger placebo response. Possible factors that can be used to enhance the effects of treatment include personal characteristics of patients that affect compliance and their confidence in the treatment. In more general terms, the relation between care provider and patient has proved to be an instrument that can be used to influence the patient’s expectations and hence the placebo response. The form in which a drug is administered can also influence the placebo response, as it may strengthen or undermine the patient’s confidence in the treatment and hence their expectations. The current trend among care insurers to regularly change the brand they are willing to reimburse, resulting in changes in the drug’s external appearance, could thus have an unfavourable effect. A less easily modifiable way to increase the placebo response would seem to be that of conditioning patients, where negative expectations can undo the effect of positive conditioning. Non-drug treatments, such as psychotherapy or surgical interventions, are not discussed in the article, but they too may offer opportunities for optimising the placebo response.

In any drug therapy, part of the effect is due to the placebo response, regardless of the magnitude of the drug effect. Care providers often subconsciously influence this response, but the response can also be deliberately used to optimise a patient’s treatment. Using this option efficiently requires an understanding of the magnitude of the placebo response and the characteristics of typical placebo responders. If a patient is a placebo responder, this will make the treatment more effective than among non-responders, which is advantageous for both patient and care provider.

The Dutch Medical Treatment Contracts Act (WGBO) makes it difficult, though not impossible, for care providers to use placebos in their practice. The compulsory ‘informed consent’, which means the patient has to be informed about the nature of the treatment, affects the magnitude of the placebo response and can increase the nocebo response. Optimising drug therapy by increasing the placebo response, for instance by influencing the patient’s expectations, is not regarded as unethical. In addition, research has shown that the placebo response remains even if the patient is aware that he or she is receiving a placebo.

Research into the placebo effect is hampered by the fact that not all study designs are suitable to determine its existence and magnitude. Whereas the placebo response can be measured in two-armed studies, investigating the placebo effect requires three-armed studies. Furthermore, it is often impossible to use blinding, making the findings less reliable. Nearly all studies have concluded that more research into the placebo effect and placebo response is warranted. Well-designed studies have been scarce, which means that convincing conclusions can hardly ever be drawn. This implies that care providers currently have few concrete options for optimising treatment by enhancing the placebo response. The most feasible option is that of influencing the patient’s expectations about their treatment, an important precondition being the nature of the relationship between a care provider and their patients.


  1. Beecher HK. The powerful placebo. JAMA 1955; 159: 1602-1606.
  2. Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 2008; 48: 33-60.
  3. Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996; 64: 535-543.
  4. Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev 2013; 93: 1207-1246.
  5. Roelofs PDDM, Deyo RA, Koes BW, Scholten RJPM, van Tulder MW. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev 2008: CD000396.
  6. Bons SCS, Borg MAJP, Donk M van den, Koes BW, Kuijpers T, Ostelo RWJG, et al. NHG-standaard ’Aspecifieke lagerugpijn’ (tweede herziening). Huisarts Wet 2017; 60: 78-84.
  7. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2013 : CD008783.
  8. Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.
  9. Cremonini F, Ziogas DC, Chang HY, Kokkotou E, Kelley JM, Conboy L, et al. Meta-analysis: the effects of placebo treatment on gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2010; 32: 29-42.
  10. Howick J, Friedemann C, Tsakok M, Watson R, Tsakok T, Thomas J, et al. Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One 2013; 8: e62599.
  11. Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev 2010: CD003974.
  12. Hróbjartsson A, Norup M. The use of placebo interventions in medical practice–a national questionnaire survey of Danish clinicians. Eval Health Prof 2003; 26: 153-165.
  13. Tilburt JC, Emanuel EJ, Kaptchuk TJ, Curlin FA, Miller FG. Prescribing ’placebo treatments’: results of national survey of US internists and rheumatologists. BMJ 2008; 337: a1938.
  14. Hall KT, Loscalzo J, Kaptchuk TJ. Genetics and the placebo effect: the placebome. Trends Mol Med 2015; 21: 285-294.
  15. Tiwari AK, Zai CC, Sajeev G, Arenovich T, Müller DJ, Kennedy JL. Analysis of 34 candidate genes in bupropion and placebo remission. Int J Neuropsychopharmacol 2013; 16: 771-781.
  16. Yue Z, Cai C, Ai-Fang Y, Feng-Min T, Li C, Bin W. The effect of placebo adherence on reducing cardiovascular mortality: a meta-analysis. Clin Res Cardiol 2014; 103: 229-235.
  17. Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, Asteggiano G. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 2006; 121: 133-144.
  18. Macedo A, Baños JE, Farré M. Placebo response in the prophylaxis of migraine: a meta-analysis. Eur J Pain 2008; 12: 68-75.
  19. Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov 2013; 12: 191-204.
  20. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects on health outcomes: a systematic review. Lancet 2001; 357: 757-762.
  21. Faasse K, Cundy T, Gamble G, Petrie KJ. The effect of an apparent change to a branded or generic medication on drug effectiveness and side effects. Psychosom Med 2013; 75: 90-96.
  22. Schwartz NA, Turturro MA, Istvan DJ, Larkin GL. Patients’ perceptions of route of nonsteroidal anti-inflammatory drug administration and its effect on analgesia. Acad Emerg Med 2000; 7: 857-861.
  23. Buckalew LW, Coffield KE. An investigation of drug expectancy as a function of capsule colour and size and preparation form. J Clin Psychopharmacol 1982; 2: 245-248.
  24. Blackwell B, Bloomfield SS, Buncher CR. Demonstration to medical students of placebo responses and non-drug factors. Lancet 1972; 1: 1279-1282.
  25. Craen AJM de, Tijssen JGP, Gans J de, Kleijnen J. Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol 2000; 247: 183-188.
  26. Saradeth T, Resch KL, Ernst E. Placebo treatment for varicosity: don’t eat it, rub it! Phlebology 1994; 9: 63-66.
  27. Lasagna L, Laties VG, Dohan JL. Further studies on the ’pharmacology’ of placebo administration. J Clin Invest 1958; 37: 533-537.
  28. Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain 2006; 124: 126-133.
  29. Colloca L, Sigaudo M, Benedetti F. The role of learning in nocebo and placebo effects. Pain 2008; 136: 211-218.
  30. Miller FG, Colloca L. The legitimacy of placebo treatments in clinical practice: evidence and ethics. Am J Bioeth 2009; 9: 39-47.
  31. Wet op de Geneeskundige Behandelingsovereenkomst. Via:
  32. Doering BK, Rief W. Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends Pharmacol Sci 2012; 33: 165-172.
  33. Sandler AD, Glesne CE, Bodfish JW. Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J Dev Behav Pediatr 2010; 31: 369-375.
  34. Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One 2010; 5: e15591.

*The literature refers to the Dutch text