In previous postings, we have pushed some giants of placebo research off their column, or rather, jumped off their shoulders (to refer to Robert Merton’s allegory again), namely Henry K Beecher and Stewart Wolf. We have claimed that they cannot be made responsible for the surge of placebo research in the 1990s, as is made visible by the steady increase of the number of studies published every year, from around 50 per year in 1992 to more than 250 nowadays — a delayed response of more than 40 years since these two landmark papers seems implausible.
The rise of neurobiology
The may be more than just one factor, but certainly one driving force is the rise of neurobiological tools and methodologies that have become available (1). The first brain recording after placebo application used conventional EEG technology in 1983 (2, 3), but once brain imaging technology became available, it initiated the first PET study in 1996 (4) and the first functional magnetic resonance (fMRI) study in 1999 (5). After 2000, such neurobiological papers increased constantly, and the predominant research technique became fMRI. The first study recording from single brain cells in Parkinson’s disease was published in 2004 (6).
At nearly the same time, three milestone studies were published from three different groups in 2002. A study by Predrag Petrovic (7) from the Karolinska Institute in Stockholm set the stage with a fMRI study showing that following acute injection of analgesic (remifentanil) or placebo during an acute experimental pain stimulus, both the drug and placebo would activate the orbitofrontal cortex and the anterior cingulate cortex extending into the prefrontal cortex. However, this was more pronounced with the opioid, indicating that in placebo analgesia, the endogenous pain inhibition system is activated. They also described brainstem activation thought to be associated with this.
In the same year (2002), Leuchter et al. (8) from UCLA presented a study showing that depressed patients that had received either an antidepressant or placebo for 4 weeks showed distinctly different activation patterns during a quantitative EEG study, with the placebo responders exhibiting early and predominantly prefrontal cortex activation not seen with the drugs and not seen with placebo non-responders.
And a third study in depressed patients after 6 weeks of double-blinded therapy with an antidepressant, by Mayberg at al. (9) from Toronto using PET, underlined the role of the prefrontal cortex (and other cortical areas) for the placebo response, while subcortical and limbic changes were only seen with the drug. They proposed a top-down mechanism of action in the placebo, while antidepressants operate using a bottom-up mechanism.
The central role of the prefrontal cortex in the generation of the placebo response — clinically as well as experimentally — was invariably demonstrated in many studies afterward but was also shown indirectly by being completely blocked using repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex (10) during experimental placebo analgesia and by the loss of expectation-associated prefrontal cortex mechanisms in Alzheimer’s disease patients, which can make placebo mechanisms (and, in part, also pain medicines) less effective (11).
The neurochemistry of imagination
While the “pharmacology of placebos” of Stewart Wolf (12) assumed but did not investigate biological (endocrine, chemical) mediators of the placebo response, a paper some 20 years later did. Jon D Levine and colleagues showed in a complex experimental approach in patients undergoing third molar extraction that the opiate receptor antagonist naloxone can block placebo analgesia and can increase post-operative pain ratings, but only in placebo responders (13). Ever since then, we have known that placebo analgesia is based on its action to stimulate endogenous endorphin release.
In the rise of neurophysiological investigations, it was later shown that placebo analgesia also includes a non-opioid mediation (14), and it was speculated (though never shown) that other mediators might include nitric oxide (15) and serotonin (16). Instead, oxytocin — proposed by us to be the main mediator of the placebo response (17) — and its regulatory counterpart, vasopressin, were found to boost the placebo response (18), as was dopamine (the central “reward” hormone (19)), endocannabinoids (20), and the CCK-system (for nocebo hyperalgesia) (21). And perhaps there are more to come.
Since many of these studies were done under brain imaging control, the emerging picture did not reveal a specific placebo network operating with specific neurochemical coding, but rather the opposite: applying placebos initiates organ-specific control mechanisms with counter-regulatory properties for the specific functions under investigation. The very same development — hope for a grand unifying theory of the placebo response, followed by fractioning the response into organ-specific subsets — occurred a few years later with the rise of genetics and the deciphering of the human genome, when it was applied to the placebo question.
Losing sight of the patient?
The rise of neurobiology as the driving force behind the increased number of placebo studies published comes at an expense that remained unnoticed until recently (1): While from the early 1950s until 1990 about half of all publications included patients, the percentage dropped to 25% nowadays, while the overall absolute number of papers has increased (Fig. 1 in (1)). Quite obviously, more experimental studies in healthy volunteers than studies in patients have been performed, and while this may have been “normal” when new technologies become available, this trend has not been reversed ever since.
The same paradox — the placebo phenomenon is only of relevance in the context of patient therapy, but is mostly studied in healthy volunteers — can be found when evaluating the 200 submitted abstracts to the first Society of Interdisciplinary Placebo Studies (SIPS) annual meeting in Leiden, The Netherlands, in 2017 (1). While we acknowledge that experimental placebo studies are difficult to perform in patients for many, e.g. ethical reasons — for instance, deception of patients has ethical limitations, and placebo research is to a large extent deceptive — our database is not without a number of examples where findings in healthy humans have been validated in patients, underlining its clinical relevance.
Looking into a doctor’s brain instead
One unique example is the following experimental study performed at Harvard Medical School by Karen B. Jensen under the supervision of Ted Kaptchuk, John Kellow, Irving Kirsch, and others (22); it ranks at the top of our all-time favorite studies in placebo research.
For their study, the group used only two female confederates playing a patient role they had rehearsed, but a total of 18 young male and female physicians that had agreed to volunteer for a study investigating what happened in the doctor’s a brain when he/she is able — or not able — to relieve the patient’s pain. For this, the study team had developed a complex cover-story: the doctors had to interview one of the presumed pain patients before being placed in a brain scanner. Here, they were instructed to apply electrical pain stimulus to the patient’s forearm using a (sham) device while observing the patient’s face through a mirror. They could either apply the pain stimulus by pressing one (dummy) button or prevent the pain from occurring by pressing another (dummy) button, according to a pre-determined script, while brain scans were taken. And the “patient” acted accordingly, showing either a painful face during the pain stimulation or a face indicating relief in the no-pain condition.
As is turns out, applying pain to a patient activates the same brain pain matrix in the doctor’s brain that would light up when the patient was scanned, e.g. the prefrontal cortex, the parietal cortex, the cerebellum, and the insula, and relieving (preventing) pain activated the ventral striatum, the area with predominant dopamine release, the subcortical brain reward center. Doctors’ rating of satisfaction (being able to relief pain) correlated high with striatum (reward) as well as prefrontal cortex (placebo) activation, indicating its relevance for our understanding of empathy (we will discuss this at another time) and confirming the role of the prefrontal cortex, also for the provider of (placebo) treatment and not only for the patient placebo responder.
No giants needed anymore
As we have pointed out before, the progression of placebo research is not as much a consequence of a few individuals that proposed the relevance of the topic — often prematurely without much of an empirical base — but rather the collective effort of a few hundred researchers from different disciplines and subspecialties that collectively push a topic into public awareness that has been known forever but remained in the “smud corner” of medicine for its negative connotation — such as being associated with deceiving patients — and the bad conscience doctors may have when using placebos in their daily practice. For this situation, the pharmaceutical industry cannot claim innocence, as we will show another time.
This is part 13 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.
- Enck P, Horing B, Broelz E, Weimer K. Knowledge Gaps in Placebo Research: With Special Reference to Neurobiology. International review of neurobiology. 2018;139:85-106.
- Irwin P, Fink M. Familiarization session and placebo control in EEG studies of drug effects. Neuropsychobiology. 1983;10(2-3):173-7.
- Levy RS, Jankovic J. Placebo-induced conversion reaction: a neurobehavioral and EEG study of hysterical aphasia, seizure, and coma. Journal of abnormal psychology. 1983;92(2):243-9.
- Schmidt ME, Ernst M, Matochik JA, Maisog JM, Pan BS, Zametkin AJ, et al. Cerebral glucose metabolism during pharmacologic studies: test-retest under placebo conditions. J Nucl Med. 1996;37(7):1142-9.
- Kleinschmidt A, Bruhn H, Kruger G, Merboldt KD, Stoppe G, Frahm J. Effects of sedation, stimulation, and placebo on cerebral blood oxygenation: a magnetic resonance neuroimaging study of psychotropic drug action. NMR in biomedicine. 1999;12(5):286-92.
- Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, et al. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nature neuroscience. 2004;7(6):587-8.
- Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia– imaging a shared neuronal network. Science. 2002;295(5560):1737-40.
- Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. The American journal of psychiatry. 2002;159(1):122-9.
- Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, et al. The functional neuroanatomy of the placebo effect. The American journal of psychiatry. 2002;159(5):728-37.
- Krummenacher P, Candia V, Folkers G, Schedlowski M, Schonbachler G. Prefrontal cortex modulates placebo analgesia. Pain. 2010;148(3):368-74.
- Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, et al. Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain. 2006;121(1-2):133-44.
- Wolf S. The pharmacology of placebos. Pharmacological reviews. 1959;11:689-704.
- Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. The Lancet. 1978;2(8091):654-7.
- Petrovic P, Kalso E, Petersson KM, Andersson J, Fransson P, Ingvar M. A prefrontal non-opioid mechanism in placebo analgesia. Pain. 2010;150(1):59-65.
- Stefano GB, Fricchione GL, Slingsby BT, Benson H. The placebo effect and relaxation response: neural processes and their coupling to constitutive nitric oxide. Brain research Brain research reviews. 2001;35(1):1-19.
- Clayton AH, West SG, McGarvey E, Leslie C, Keller A. Biochemical evidence of the placebo effect during the treatment of menstrual migraines. Journal of clinical psychopharmacology. 2005;25(4):400-1.
- Enck P, Klosterhalfen S. The story of O–is oxytocin the mediator of the placebo response? Neurogastroenterology and motility. 2009;21(4):347-50.
- Colloca L, Pine DS, Ernst M, Miller FG, Grillon C. Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized Trial. Biological psychiatry. 2015;79(10):794-802.
- de la Fuente-Fernandez R, Stoessl AJ. The placebo effect in Parkinson’s disease. Trends in neurosciences. 2002;25(6):302-6.
- Benedetti F, Amanzio M, Rosato R, Blanchard C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature medicine. 2011;17(10):1228-30.
- Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. The Journal of neuroscience. 2006;26(46):12014-22.
- Jensen KB, Petrovic P, Kerr CE, Kirsch I, Raicek J, Cheetham A, et al. Sharing pain and relief: neural correlates of physicians during treatment of patients. Molecular psychiatry. 2014;19(3):392-8.