Physicians and patients should gradually learn that placebo is an integral and inseparable part of medical practice, that it is the basis of its art and raises its scientificity. Jay Katz, 1984 In the beginning was the Word

The history and current understanding of placebo and placebo effect are full of errors and myths. From the very beginning. It is generally known that the word comes from Psalm 116, which priests and the faithful sing when administering the sacrament of the dying, formerly the sacrament of the last anointing. It is the ninth verse and it is the first one everybody repeats after the cantor. Less well known is that Saint Jerome, patron of all translators, although he committed only a small number of errors, translated this verse: אתהלך לפני יהוה בארצות החיים׃ into the Bible incorrectly1. Instead of the proper translation, “Ambulabo coram Domino in regione vivorum,” (I shall walk before the Lord in the land of the living), he established in the Vulgate for many centuries the text: “Placebo Domino in regione vivorum” (I shall please the Lord in the land of the living). That is how the concept placebo came into the world and, despite later correction of the biblical text, it remained there.

The first meaning the term placebo got was a designation for people who took part in funerals as mourners hoping to receive some reward for it, in the worst case food and drink. They were not held in good regard, and such a similarly unsympathetic character was also captured by Geoffrey Chaucer in The Canterbury Tales.

Later, in hospitals, the monks serving there noticed that after a truly ceremonial administration of the sacrament of last anointing, whose effects are healing of the soul, strengthening, peace, and courage to bear suffering together with Christ, healing of the body—if that is beneficial to the soul—and preparation for passage into eternal life, many patients improved “miraculously.” And they were not only those for whom the sacrament was intended. People then cared more about how things stood with God than how today’s international football match would turn out, and after this rite they calmed down, their stress reaction dropped, and both subjective and objective improvement became possible.

Placebo enters the medical lexicon only in the 18th century as a preparation intended more to please the patient than to treat them. Today placebo is something that becomes nothing, or nothing that becomes something. We must give it something, so we give placebo, while in the placebo arm of a pharmacological study, as if we were giving patients “nothing.”

At the same time, the following events can occur in the placebo arm:

  • Spontaneous improvement up to recovery;
  • Fluctuation of the clinical state;
  • Regression to the mean;
  • Effects of other treatment;
  • Consequences of poor patient selection;
  • MAC-type placebo;
  • Placebo through learning and conditioning;
  • A combination of both;
  • The effort to please the physician.

A definition stating that placebo is an inert substance that triggers a physiological response in the organism is logically nonsensical; it is a contradiction in terms, because an inert substance is inert because it triggers no responses.

Outcome control in treatment is not new. The first scientific method using control treatment is attributed to British physician James Lind, who in 1753 published (James Lind: A Treatise of the Scurvy, 1753), how he treated scurvy in twelve sailors in multiple ways and concluded that citrus and orange fruits were more effective2. At the end of the 18th century, Louis XVI had Mesmer’s therapeutic method assessed by an expert commission of physicians from the Royal Academy and recognized specialists from other fields. In the commission there also sat, among others, Antoine Lavoisier, Joseph Guillotin, whose invention ended Lavoisier’s life (without placebo control), senior Academy astronomer Jean Bailly, and the American envoy in Paris, Benjamin Franklin.

After a month’s work, the commission concluded that Mesmer had discovered no real fluid, that the human body contains no previously unknown in- or outflows, and that the effects of his treatment derived exclusively from the “imagination” of his patients. Mesmer did not suspect that he had discovered (or rather rediscovered, opened, and activated) a hypnosis-suggestive area, and the commission did not suspect that the then still unnamed “placebo-like effect3” had a much broader background than mere imagination.

Elisha Perkins fared badly in London too, with his “tractors” (Perkins Tractors), which were two short metal rods shaped like a drop, allegedly from a special alloy, supposedly to draw diseases out of the patient’s body, primarily inflammations and rheumatism. They were available in a small shop on Leicester Square for five guineas, and among this inventor’s patients was President Washington (who now has a city in the USA). A rival and critic, Dr. John Haygarth, made wooden imitations and “cured” four out of five patients with chronic rheumatism using them.

Long before this, however, these approaches were already used by the Church. A case is cited in which in 1565 King Charles IX summoned a woman said to be possessed by a Protestant demon. She was tested with consecrated water poured into red wine and behaved as if bereft of senses. He noticed at the second attempt that they poured plain water into her wine, and she behaved exactly the same, thereby revealing that no demon existed. Evidence of the nonexistence of the devil was very important at that time, because this was not only a matter of faith but often of large assets.

Medicine in the 20th century adopted these experiences and, in attempting to separate the grain from the chaff, introduced randomized, controlled, double-blind studies (RCTs = randomized controlled trials) and statistics4. Placebo is used as a non-existent drug, and what is interesting is that it has a therapeutic effect. A typical reader understands that a drug is more effective if it cured 60% of patients, while placebo only 40%, but in medicine, often chosen by people who did not do well in school mathematics, few realize that the drug’s efficacy is not 60%, but only 36%. Placebo responders worked through different mechanisms. And there are not only 35%, as long incorrectly propagated based on Beecher’s 1950s study5, but under favorable conditions all participants in a study may respond to placebo6. Sometimes active preparations are also used as placebos, most often in situations where patients insist on being prescribed some pharmacotherapy; prescribing an antibiotic during a viral infection is not entirely appropriate7.

However, when medicine stopped treating sick people and began treating diseases, when interest in patients shifted to interest in disease states, more or less clearly defined pathophysiological entities supported by corresponding objective signs and operating within the construct of “evidence based medicine” and finally only laboratory findings (“elevated cholesterol”), such a small thing can easily be lost.

This had already been observed by Renaissance polymath, artist, and thinker Francisco Petrarca8, who wrote in 1346 in a letter to a friend how he specifically envisioned the comparison of different approaches: “I solemnly declare and believe that if a hundred or thousand men of the same age and temper and habits fell ill at the same time with the same disease, and if half were treated according to the recommendations of those doctors who practiced that day, and the other half received no drugs and were left only to Nature’s instincts, I have no doubt as to which of the two would survive (death).”

Placebo response is not a reaction to a substance, but a complex psychobiological and cultural phenomenon that scientific medicine does not want to address.

Placebo response, whether to an inert substance imitating a drug or a “sham” unrealized procedure that is expected to be therapeutic, is not “mere suggestion,” but is triggered by several mechanisms and also points to self-healing capacities of the organism in a certain interpersonal and cultural context. In scientific medicine these facts are an obstacle because of their complexity and ungraspability in a reductionist and positivist-oriented approach, and the provocative character of the emerging links does not answer the questions posed; instead, it asks and opens further ones, which is inconvenient in a commercialized environment.

We have something called the Hawthorne effect, derived from the name of a company focused on selling electrical energy and related matters, located in Cicero near Chicago. Here in the 1930s, scientists proved that the combination of care and attention leads to activity that brings better performance and better results. This fact was repeatedly confirmed in clinical practice9. This is an entirely nonspecific factor that is not taken into account in clinical studies.

When at the end of the 70s we, with Skála and Pirka, in a controlled pharmacological study with amitriptyline10 observed transit through the digestive tract, we found marked differences among patients: from finding barium in the rectal ampule after 90 minutes to an entirely opposite slow course. Another finding was that in two of ten observed patients, after amitriptyline administration, the clinical state improved distinctly, diarrhea ceased, and transit accelerated significantly.

From this study came another clinical insight. Presumably thanks to the involvement of many healthcare workers, a significant nonspecific placebo effect became visible. Of thirty patients, 27 improved significantly. About four years later, colleagues in Plzeň carried out an analogous study with the benzodiazepine anxiolytic clobazam and, instead of placebo, used amitriptyline as the reference drug. That led to improvement in only 60%, which at that time corresponded to its effectiveness under standard conditions in my outpatient practice. Clobazam had 90% therapeutic success. Since then I have read reports of drug effectiveness with great reserve. But I also know how the Hawthorne effect works.

As for placebo, we may have a placebo response based on expectation and in the case of analgesia can be canceled by naloxone; we may have a placebo response that cannot be canceled by naloxone because it is based on classical conditioning11, and we may have a combination of both12. The fact that pain subsided after placebo in any case does not mean that the pain was not “real.”

In the first case above, the difference between the effects of two placebo NaCl infusions was eight words in total. Benedetti and Amanzio administered physiological saline as an analgesic for laser-induced forearm pain. In one case without any specification, in the second with assurance that it was an effective analgesic. In the second case pain receded through presumed action on opioid and cholecystokinin receptors. After naloxone, however, it returned13. These naloxone-related findings had been methodologically verified less precisely only from the 1970s14

Pain is always subjective, as WHO has bindingly defined, and similarly we can look at the subjective sense of comfort or discomfort in a defined somatic illness, which may differ greatly with exactly the same objective findings15. A study performed by Kaptchuk’s team and published in NEJM in 2011 in 39 patients with asthma is considered one of the most strictly methodologically conducted studies16. Albuterol delivered by spray improved objective FEV1 (Forced Expiratory Volume – time) by 20%, whereas both placebo procedures—sham acupuncture and placebo spray—by only 7%. Meanwhile, subjective improvement in the three procedures did not differ significantly (albuterol 50%, sham acupuncture 46% and placebo inhaler 45%), while it was significantly better than receiving no treatment, where it was only 21%.

More recent imaging studies suggest that aside from the opioid system, other mechanisms are involved in anticipatory analgesia as well, originating from orbitofrontal and ventrolateral prefrontal cortex17,18. The placebo effect on improvement in mobility among patients with Parkinson’s disease has so far not been plausibly explained19, yet it can be objectively demonstrated and therapeutically used successfully despite small sample sizes in published studies, just like good results for acupuncture20.

The MAC Effect of a Drug and Its Placebo

It would be a deep error to assume that the drug molecule itself is responsible for its whole effect. Under certain conditions even the active molecule does not have to act at all, as shown by Colloca with Benedetti in their 2005 study21. An analgesic acting on the cholecystokinin system had no analgesic effect if patients did not know they were receiving pain medication and the substance was administered without explanation. The same author pair later expanded placebo analgesic mechanisms to include a social learning pathway22. Into this set of facts fits somewhat awkwardly the finding that placebo is effective even when patients are not deceived and know they are receiving an inactive substance, as shown by Kaptchuk with colleagues in the treatment of patients with irritable colon syndrome23. In addition to the above factors, many other more and less specific social and culturally conditioned influences must be taken into account, described as the MAC effect24,25,26: meaning and context. Therefore, it can easily happen that a much more effective drug shows lower clinical effectiveness than another, much less effective one that carries a larger MAC.

The MAC effect consists of all information circulating about a given preparation, from halo effect, through route of administration—injectable is more effective than oral27, 28, 29—and tablet appearance30 to reports of objective outcomes in clinical use. Brand significance plays a role, as shown by Branthwaite and Cooper31 already in 1981. A placebo fitted with a top-tier corporate logo had very good analgesic effects and appeared as weaker against active agents only in the last, highest quartile of patients (very significant improvement). Let us not dismiss the idea that a similar benefit is represented by a “good name of a healthcare institution,” or specific persons. Verbal suggestion32 can considerably strengthen effects. It has only a small effect on its own according to the authors’ findings. In the age of worshiping consumerism (likely always, but especially now), the declared price33 contributes to placebo effect in a strikingly inverse way: an expensive injection (ten times more expensive) of alleged antiparkinsonian medicine improved mobility more than a “cheap” one. But only if the expensive one was used first. In the reverse order this model did not work. According to prevailing views of both authors and many commentators, perhaps that is because even the “cheap” $100 injection seemed very expensive to patients, and further increase in effect with rising price did not occur.

I have personal experience with color and placebo34. In September 1968, when representatives of Western pharmaceutical companies who were visiting us during the Prague Spring for raw materials, literature, and also cognac were leaving after a short stay, they left me several boxes of then totally new and until then unknown two-colored capsules (medications were fundamentally only in tablet form; magistral compounds of powders and their blends were placed “ad neb” into capsules pressed from edible paper). A woman physician, in her free time, filled hundreds to thousands of these capsules with milk sugar and we launched research on modification of placebo effect by drug color. She helped us brainstorm names, and with her assistance we baptized the most nauseating placebo (dark cement-gray plus terracotta), after which several patients vomited, some collapsed, and two women developed hives, as Estebin® in honor of the StB. Otherwise, I can confirm, in agreement with literary data35, that green color “calmed” spasms, while yellow and red had the strongest sympathomimetic side effects.

Soothing blue in placebo anxiolytics and hypnotics seems to work worldwide except for Italian men. Their cultural background cancels universal symbolism. For them blue is stimulating, since their national football team that keeps them awake is called Forza Azzurri36!

And then there is a pleasant story for those who think all the human mind lies between the ears and no further. That study was carried out thirty years ago at a dental polyclinic in Germany, then western and capitalist37. Investigators decided to test the effects of fentanyl analgesic, placebo, and naloxone after wisdom tooth extraction and that in a strictly blinded design (literally nobody knew what was in which tablet), patients would receive one of three preparations: fentanyl, placebo, or naloxone, and were informed only that they had received either placebo that may or may not reduce their pain, or naloxone that may or may not worsen it, and after the procedure they filled out a questionnaire on a scale of how the preparation worked and affected pain.

Fentanyl is a very potent analgesic and was then considered king of all. It belongs to the opioid family, and that is where a snag emerged. At the start of the study, its coordinator came to the physicians and sadly told them fentanyl could not be included in the study because of restrictions applying to opioids, so only two remaining pills stayed. This is how the study started without fentanyl.

After several weeks, the coordinator returned with good news that fentanyl had been managed to include in the study and that from that day on it was among the administered drugs. This fact did not reach the patient information, yet analgesic treatment results started to become much more favorable. This is visible on the attached study graph. In the first part of the study depicted by the upper curve (PN), pain after the procedure increased, while in the second part (PNF) a strong analgesic effect was clearly apparent. The only difference between the two groups was that in the second group the doctors knew that fentanyl—the king of analgesics—was among the administered drugs. Patients were not told this.

I love studies put together by a “gotcha” design and this one belongs to that category. In both parts, patients received nothing but placebo, that is by definition an inert substance that does not trigger any reaction in the organism. The study is named: Physicians’ Expectations Affect Placebo Analgesia and was published in The Lancet. It has still not been answered reliably how and through what mechanism information about what doctors were expecting from the administered drug reached the patient group. The practical clinical application of this scientific truth is that if I administer a drug in which I myself believe, I add (how many percent?) to its clinical effect.

Once a pharmaceutical company had as its tagline a slogan justifying discomfort during pharmacotherapy: if it has no adverse effects, then it is not a drug. In this respect, placebo does very well, as shown by a study published in 2006 in BMJ38. In a fully placebo study (sham acupuncture versus tablets) 133 patients with painful shoulder arthritis were included twice. In addition to symptom relief, adverse signs were also monitored. There were many. In the tablet group, sleepiness occurred in 20% of patients, xerostomia in 19%, restlessness in 7%, and dizziness in 5%. Anxiety, nausea, and nightmares appeared in 3% of patients. The needle that was never inserted because it retracted into its sheath after touching the target point caused pain in 15%, pain after its “withdrawal” in 10%, and redness or swelling in 3%.

If conservative treatment approaches are a good inspiration strengthening placebo efficacy, how much more strongly surgical approaches should act, when we recall the greater efficacy of placebo administered parenterally compared with oral administration; disruption of bodily integrity unquestionably has a much greater dramatic impact. And it also truly works; from the first experiments with ligation and mammaria conducted in good faith believing “this really works,” where patients with stable angina pectoris improved in 30–80% and patients with heart failure in about a quarter of cases39.

A recent meta-analysis of work on surgical procedures performed by Jonas’ group40 does not confirm the efficacy of surgical solutions for many chronic painful conditions. It rates the effectiveness of bariatric surgery for obesity as borderline; the only diagnostically defined group indicated for surgery, in its view, are patients with gastroesophageal reflux disease (GERD). For comparison, a graph summarizing their data:

Placebo Effect Based on Conditioning

If in all cases of clinical success of placebo its opponents could argue “suggestion,” this would hardly pass in animals. One of the proven cases of placebo effect arising from classical conditioning is today’s legendary work by the founders of the field known as neuropsychoneuroimmunology, Robert Ader and Nicholas Cohen41,42, in which mice with systemic lupus were used and a highly flavorful saccharin used as conditioned stimulus paired (or not in a control group) with administration of effective cyclosporine. Survival of mice “treated” with saccharin after stopping cyclosporine was significantly longer where the two stimuli were paired, that is, where a classic conditioned response had been established.

Conditioned analgesia in humans can also be induced by a different path than via opioid receptors, as shown by Amanzio with Benedetti43 in their study, when they administered non-opioid ketorolac tromethamine as an analgesic and therefore showed that both expectation factors and factors of classical conditioning reinforced by repeated administration of effective analgesic can contribute to placebo analgesia, and that this analgesia can be blocked by naloxone completely, partly, or resistant to this blockade. Through this route comes a path to analgesia via various relaxation, concentration, and meditation techniques44.

In summary, placebo effect is essentially an effect arising from a psychosocial context and available data indicate that various social stimuli such as words, rituals, or therapeutic acts can alter both chemical and neurophysiological processes in the brain. Mechanisms activated by placebo are the same as those activated by drugs (or drugs), which suggests that the final effect of a drug is also the result of cognitive/affective interference. At the same time, when prefrontal functions are significantly disrupted, placebo response is reduced, or absent altogether, as is the case in Alzheimer’s-type dementia45.

A recently reported finding from Canadian authors is worthy of note: they performed a meta-analysis of the latest studies on drugs for neuropathic pain from the USA46 and found that increasing the follow-up interval resulted in reduced differences between active drugs and placebo, reaching the border of significance. At the same time, baseline pain intensities of included patients did not decrease, the effectiveness of administered analgesics did not decrease, but placebo “effectiveness” increased. Comments from reviewers and additional experts agree that it is not excluded that if studies in previous years had been performed over equally long periods, there would not have been a demonstrated significant effectiveness not only for many analgesics but also many psychopharmacological agents introduced then.

Among many other issues tied to this subject matter, one crucial point cannot be avoided: how far is the use of placebo ethical at a time when emphasis is placed on patient autonomy, consent to treatment, and full informedness? The latest revision of the Helsinki Declaration in 201347 states that in therapeutic studies placebo may be used if no therapy is available, or if required by research aims. There is general consensus that it should be used as minimally as possible in psychiatric patients, where relapse is a threat48. As for its use in therapy, ethicists agree that despite the above-mentioned requirements, placebo does not conflict with ethics where a physician is convinced that it is for the patient’s good49. But surveys among patients also show that most are favorable to use of placebo50 in indicated cases.

Some Practical Advice:

  • Prescribe a more frequent daily dose
  • Apply treatment in a therapeutic setting
  • Pay attention to route of administration (s.c. > p.o.)
  • Record the effects of the applied procedure
  • The atmosphere during administration should be warm and caring
  • During administration, you should radiate certainty
  • Recognize what the patient believes in
  • Make sure the patient believes in your treatment
  • Compare your belief with the patient’s belief and culture
  • Add a safe and clear conditioned stimulus (needle, touch, scent)
  • Emphasize that treatment is new and prominent
  • Use well-known and proven company brands
  • If it is significant for the patient, do not hesitate—while observing all safeguards—to induce microtrauma (needle, scarification)
  • Inform the patient what they can expect
  • Use light, laser, electronic devices that “deliver” the drug into the body
  • Include repeated reassurances with a suggestive intonation in your verbal expression
  • Use methods that reduce patient anxiety
  • Create a ritual when applying any therapy
  • Recommended prices for treatment should be neither too low nor excessively high
  • Touch the patient!

Author: MUDr. Radkin Honzák, CSc.

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