St. Jerome, the patron saint of librarians and language translators lived from 347 to about 420 CE, is regarded as the most learned of the Latin Fathers, reputed to have translated many of the biblical texts from Hebrew, Aramaic and Greek into Latin. Jerome is remembered, perhaps too well, for a single mistake he made, the first use of the term placebo. When he translated the ninth line of Psalm 116, the original Hebrew translated into English should say, “I will walk before the Lord in the lands of the living…” Yet Jerome translated the line into Latin as “Placebo Domino in regione vivorum,” which in English is, “I shall please the Lord in the land of the living.” Whoops

Nobody knows why he chose to use the verb ‘placere,’ which means to please, or why he put it in the first person singular future tense (-bo) to mean, “I will please.” Some suggest that he was only trying to find a word that would fit the pentameter better. Recall how very complicated Latin prose was. Sentences were read in a specific rhythm, the iambic pentameter, and writers are given broad license to alter words to fit into the meter. Whatever the reason, Jerome opted to use a word incongruent with the original meaning. In recent centuries, Jerome’s choice of words has taken on a meaning of its own.

“Pleasing has a central meaning to the notion of placebo: placebo is associated with the pleasing of the patient by the therapist, of the therapist by the patient, or both.”¹

It took more than a thousand years after Jerome until we see the word placebo appear in medicine.

Placebo appeared in the second edition of George Motherby’s New Medical Dictionary in 1785 (but not in his first edition of 1775), where it was defined as “a common place method or medicine.” It appears again in 1811 in Hooper’s Medical Dictionary, but this time defined close to our modern usage, as “any medicine adapted more to please than benefit the patient.”²

The time gap between when these two dictionaries were published and during which the word placebo took on its modern meeting, happens to coincide with Samuel Hahnemann development of homeopathy. According to Robert Jütte in a 2014 article, Hahnemann was “the first physician who administrated placebos to his patient on a systematic and regular basis.” This comes from an analysis of unpublished documents (e.g. patients’ letters) in the Archives of the Institute for the History of Medicine in Stuttgart, Germany, and from Hahnemann’s case journals. Hahnemann clearly differentiated between homeopathic drugs and substances he considered sham medicines. Hahnemann used these placebo medicines often, between 54 to 85% of his prescriptions were for placebo. 

Jütte suggests that Hahnemann’s patients were accustomed to taking medicines daily as was standard for the time. Thus, Hahnemann’s reason for giving placebo was, “to please the impatient patient” who was accustomed to frequent dosing. The long periods of waiting and watching common to homeopathic prescribing were too challenging for patients and the prescriber.³

In our naturopathic training we were taught that we should consider starting patients on placebo prior to actual homeopathic treatments to “clear the case,” that is to see to what extent a patient improved on placebo alone prior to initiating actual homeopathic treatment. This was suggested as a method to differentiate between placebo effect and homeopathic action. For Hahnemann, seeing how a patient reacts to placebo first would make it easier to see when the correct homeopathic remedy had been prescribed.⁴ According to his practice guidelines published between 1810 and 1830, Hahnemann suggests that homeopathic practitioners prescribe “… placebo as a wash-out when discontinuing allopathic medication, and at the beginning of homeopathic treatment, to identify ‘placebo responders.’ It [placebo] was also frequently used in longer-term case management, because the single rarely-repeated doses of active medicines used in homeopathy were believed to produce misleading psychosomatic responses.”⁵ 

This practice of employing placebos carried over to Hahnemann’s students. Homeopaths were among the first to use placebo controls in therapeutic trials and their use was the origin of the single-blind placebo controls used in modern controlled trials.⁶ Homeopathy underwent large placebo-controlled trials in the 1830s. Actually, the first large scale placebo-controlled trials of homeopathy were begun in 1829. Two hospital-based studies were conducted by the Russian military, starting in 1829. The first of these took place in Podolia, Ukraine. Patients in one hospital ward (n-=164) were treated with homeopathy and were compared with patients in a second ward who were treated with standard care. Results of the homeopathic patients were favorable and intriguing enough that a second experiment was set up in St. Petersburg. This second trial was different in that a third arm was added to the study in which one ward’s patients received only placebo and palliative care. Recall that active medical care at the time consisted of bleeding and other nasty heroic interventions. The group receiving palliative care and placebo apparently had the best results.⁷ Other large placebo-controlled trials occurred in the 1830s.⁸ Most references seem to ignore these earlier trials and date the first study as either Haygarth in 1801⁹ or Austin Fint in 1863.¹⁰

I have been yattering about placebo history but avoiding digging in and writing about the specific study I want to, the recent trial by Ashar et al., published in September 2024 that reported success employing open label placebos to successfully treat chronic back pain.¹¹

Before I do, we should make another short detour to explain this new concept of “open label placebo,” perhaps better described as “non-deceptive placebo.”

There is a longstanding problem with using placebos that has only gotten worse in recent years. The problem is that doctors are supposed to be honest and not deceive their patients. Over the last half-century, greater emphasis has been put on the concept of patient autonomy and this goes hand-in-hand with the idea that physicians should be forthcoming and provide patients adequate and truthful information about their diagnoses, prognoses, and treatment. Put simply, doctors are now expected to tell the truth. Placebos, because they require deception, violate this ethical standard and threaten a patient’s autonomy and ability to make informed decisions. Papers in the medical journals argue the difference between deception and lying, but no matter how one frames it, giving a placebo is inherently a dishonest act, and for doctors to deceive patients is frowned upon.¹² The only honorable solution found is for doctors to tell their patients exactly what they are getting, in the case of a placebo, not getting. As absurd as this sounds at first glance, this is exactly what Ted Kaptchuk tried in 2010. He conducted a clinical trial with “open label placebos.” Both the doctors prescribing, and the patients receiving the placebo, knew and were well-aware that they were being administered and receiving a placebo. There was no deceit involved. Patients with irritable bowel syndrome (IBS) (n=80) were divided into two groups, half received sugar pills and the other half nothing. Those who received the sugar pill experienced global symptom improvement by day 11 and by the end of the trial at day 21, had experienced significant reductions in symptom severity and relief of symptoms. Even their quality of life was trending toward improvement.¹³ In 2022, in a similar study, improvements were seen in children with IBS symptoms (n=30).¹⁴

I should point out even if Kaptchuk and other academic researchers worry about the ethics of using placebos, this doesn’t seem to inhibit clinicians from using them. In 2008 more than half of internists and rheumatologists in the US admitted to using placebos, that is “a medication such as vitamins or analgesics that would have no effect on the illness but were prescribed for their psychological value.”¹⁵ In the UK placebo use may be even higher: In a 2013 survey, 97% of primary care doctors admitted to using a placebo at least once in their career and 77% say they prescribed a placebo at least once a week.¹⁶

Kaptchuk summarized his ongoing research on OLPs in the New York Times in October 2023, “Currently, more than a dozen randomized trials demonstrate that open-placebo treatment can reduce symptoms in many illnesses with primarily self-reported symptoms such as chronic low back pain, migraine, knee pain, and more. These findings suggest that patients do not have to believe, expect or have faith in placebos to elicit placebo effects.”¹⁷

If Kaptchuk’s name seems familiar, it is because he wrote a well-known book on acupuncture, The Web that has No Weaver, first published in 1983, that has been a common textbook in naturopathic schools.

The effect of open label placebos (OLPs) has now been confirmed by multiple meta-analyses including Charlesworth et al. (2017, n=260),¹⁸ von Wernsdorff et al. (2021),¹⁹ and Albazee et al. (2024).²⁰ [In a fascinating study from May 2024, Schienle and Kogler report that taking an imaginary pill was superior in reducing anxiety compared to taking an actual OLP pill.²¹ ]

So, in effect, this recent study by Ashar et al. simply adds to the existing data. 

Ashar’s study was conducted from November 2017 to August 2018, with one-year follow-up and completed in November 2019. This study was part of a larger trial designed to facilitate two comparisons of interest: a test of a psychotherapy intervention, known as Pain Reprocessing Therapy with OLP serving as the control condition. The Ashar article compares just OLP vs. usual care and focuses on mechanistic and clinical outcomes of OLP.²² Participants were 21 to 70 years-old and had chronic back pain. They were recruited from Boulder, Colorado, and had back pain for at least half the days of the past six months with a one-week average pain intensity of four or greater on a 10-point scale. Applicants with leg pain worse than back pain or self-reported diagnoses of inflammatory disorders or metastasizing cancers were excluded. So were people self-reporting psychosis, personality disorders, pain-related compensation or recent litigation, 

One hundred and one participants began the trial, 51 of whom were treated with OLP and the remaining 50 received ‘usual care.’ Forty-three of those receiving OLP and 36 receiving usual care completed the 12-month followup and their data were used in the analysis.

Active participants received a single subcutaneous lumbar injection of saline solution containing no active medication at the site of their greatest back pain. Prior to the injection they received information about the power of placebo to relieve pain. Study participants were followed for a full 12 months.

Pain intensity (on a scale of 1-10) at 1-month post-treatment was the primary outcome tracked. Secondary outcomes included pain interference, depression, anxiety, anger, and sleep quality. 

Open label placebo (OLP) reduced chronic back pain (CBP) intensity posttreatment (relative reduction, 0.61; Hedges g = 0.45; 95% CI, -0.89 to 0.04; P = .02). 

Forty-five percent of patients who received OLP reported a 30% reduction in pain and 24% reported a 50% reduction.

Pain relief was also noted in those who only received usual care: 38% reported a 30% reduction and 15% reported a 50% reduction

In the OLP group significant benefits were also observed for depression, anger, anxiety, and sleep disruption (Hedges g = 0.3-0.5; all P < .03). It appears that the response to the single lumbar subdermal saline placebo injection was associated with improvements that persisted for the full year.

Ashar’s research team used sophisticated fMRIs to identify brain changes in patients who responded to these “non-treatments” and this suggests similar functional shifts occurred as seen when traditional deceptive placebos are used. These functional MRIs were performed before and after “treatment” during evoked and spontaneous back pain. Brain responses to evoked back pain for OLP increased in rostral anterior cingulate and ventromedial prefrontal cortex and decreased in somatomotor cortices and thalamus. During spontaneous pain, functional connectivity analyses identified OLP increases in ventromedial prefrontal cortex connectivity to the rostral ventral medulla, a pain-modulatory brainstem nucleus. 

“The placebo treatment also led to reduced somatic motor activity and increased medial prefrontal activity during evoked back pain and to increased medial prefrontal-brainstem functional connectivity during spontaneous pain.”

Fabizio Benedetti in a series of papers over the past dozen or so years has been able to identify some of the chemical pathways elicited by placebo use. Pain relief appears to be mediated by opioid, cannabinoid, and cholecystokinin pathways while in Parkinson’s disease, patients’ symptom reduction depends on shifts in dopaminergic activation in the striatum and neuronal changes in basal ganglia. Benedetti directs our attention away from our now disproven assumption that the patient has to believe in the placebo’s potential for benefit to a new concept that the basis of placebo effect is “… the therapeutic ritual around the patient, [and it] plays a crucial role in the therapeutic outcome…”²³ Placebo effect doesn’t depend on words, belief or logic but rather ritual, and social hierarchies, to be triggered. Listening to the empathetic practitioner wearing the white coat appears more crucial than any active ingredients in the pill.

While we are aware that placebo can have measurable effects on patient outcomes, yet, it’s still easy to forget such treatments can have clinical impact that competes with standard therapies for effectiveness. For example, in a 2017 systematic review of the literature, Louw et al. examined randomized controlled trials that compared surgery versus sham surgery in orthopedics. They identified six randomized RCTS (n=277) of good methodological quality. Their evaluation suggests that the sham surgeries were as effective as actual surgery in reducing pain and improving disability.²⁴

Those old fashioned deceptive, placebos can be quite effective. In a 2020 review paper published in the British Medical Journal, Kaptchuk et al., wrote that in 140,000 patients suffering from various chronic pain conditions, placebo responses provided 50 to 75% of the benefits of drug treatments for pain. Similar percentages were seen for relief of cancer related fatigue and menopausal hot flashes.²⁵

Another example, while we are at it, is a 2017 systematic review of the literature by Louw et al. that examined randomized controlled trials that compared surgery versus sham surgery in orthopedics (n=277). Their evaluation suggests that the sham surgeries were as effective as actual surgery in reducing pain and improving disability.²⁶

Even if poorly understood, the placebo effect is well documented and there is little doubt that well administered placebos relieve pain and discomfort. 

The advantage to OLPs is they do not require deception to work and can be used to provide benefit without any fear of crossing ethical lines by the prescriber.^27,28 The other thing is that they hint to us quite strongly that our concept of how placebos work, that is by fooling the patient into a false belief, is inaccurate.

The benefits seen in Ashar et al.’s current trial are nearly identical to those reported in another chronic back pain study. Published in 2019, Kleine-Borgmann reported modest pain reductions using OLP for CBP (pain reduction of 0.61 of an 11-point scale), modest but significant. Common CBP treatments, such as nonsteroidal anti-inflammatory drugs, epidural steroid injections, have about the same impact but come with the risk of adverse events. In 2016, Carvalho et al., in a similar study of OLP for CBP, had reported larger pain reductions, suggesting that OLP effects may be magnified in certain contexts.”²⁹ 

One quite notable aspect to the results reported in this Ashar back pain study is the persistence of the improvement. Reductions in depression, anxiety, anger, and improvements in sleep persisted through a full one-year of followup. These improvements in mood had not reached significance at the one-month followup but accrued gradually over time. Such gradual changes might be explained by saying improvements in any one of these traits might spill over and create improvements in these other parameters.³⁰ Considering that the OLP saline injection was given just one time, one must either doubt the reported results, or simply marvel at the phenomenon that was triggered.

It is as if some switch was thrown somewhere in the brain that turns on a homeostatic system designed to restore a healthy equilibrium, kind of like when a popup screen appears on your computer offering to restore the computer’s original system setting if you click on it. Yet if belief is not required for placebo to work, we need to find a new way to think about this reaction. The process must be triggered in some area of the brain that does not use words or logic to calculate. 

In this study Ashar goes on to attempt to explain a rationale for what seem like global changes in neuropsychological processes. This reader found some of the data garnered from fMRI studies to be over my head (pun sort of intended). Especially the conceptual frameworks that explain the mind-brain processes. Analogies and metaphors that come to mind may or may not reflect the reality or complexity of what is happening. It does seem that if we might understand these neuropsychological processes, we might mediate placebo effects and enhance a broad range of therapeutic interventions.³¹

See charts below:

Link to request permission to reuse these charts:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391328/figure/zoi240976f2

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At this point how might this information inform our patient interactions? I suspect some practitioners purposefully express greater confidence in their suggested interventions than justified by current research in the hope it will bolster placebo action. Ashar’s and other OLP studies would suggest this is unnecessary. It may be that being truthful and saying, “We are not certain that this will work, it may only be a placebo” when describing a proposed intervention may not lessen its power to trigger benefit. Nor do we need to be negligent in omitting mention of negative studies. We might say, “Research on whether this is effective varies. Some studies suggest it does while others are unable to confirm the benefit.” Being truthful and trustworthy, whenever possible, would seem to be a superior policy.

References

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4. Placebo – The Second Best Remedy: A Modern Perspective. https://www.homeopathy360.com/2020/01/31/placebo-the-second-best-remedy-a-modern-perspective/
5. Peschier G. Sur le saccharum lactis. Bibliothèque Homoeopathique 1835; 4: 273-80
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17. Kaptchuk TJ. NY Times. Oct 10, 2023. Assessed 10/28.2023.
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24. Louw A, Diener I, Fernández-de-Las-Peñas C, Puentedura EJ. Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Med. 2017 Apr 1;18(4):736-750. 
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26. Louw A, Diener I, Fernández-de-Las-Peñas C, Puentedura EJ. Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Med. 2017 Apr 1;18(4):736-750. 
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31. Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015 Jul;16(7):403-18.