Theeffect is powerful enough to be the bane of the (RCT), , and really of modern medicine itself. A dynamic attribute since it can be seemingly manipulated at will, it maybe more accurate to call it the Placebo Response, as proposed by . Their considerable scientific and economic impact is evidence of the shadow placebo responses cast on all of medicine.
- Placebo responses operate even for legitimate drugs and therapies.
- Placebos elicit beneficial responses even when patients take them knowingly.
- Placebo responses are becoming stronger, driving up drug development costs.
- How placebo responses could be leveraged to make medicine more effective, cheaper and safer.
- Examples that illustrate how just about anything to do with a Rx, colors, sizes, numbers, pills versus injections, even diligence in taking placebos, can trigger placebo response and influence its magnitude.
Longer answer for those interested in the details
Scientific Impact Of Placebo Responses
Placebo responses tend to be more pronounced in
- Patient-reported outcomes rather than those independently-assessed ( ).
- Questionnaire- rather than clinical biomarker-based outcomes ( , ).
No surprise since psychology is known to play an outsized role in pain and mental health conditions such as depression, which tend to lack objective diagnostic tests and are instead subjectively diagnosed on the basis of periodically revised, fuzzy questionnaires. Problem is most diseases lack biomarkers with proven therapeutic value.
However, even physiological attributes such as blood glucose levels entail placebo responses. Their concentrations in type II diabetes patients change commensurate to how their awareness of time is experimentally manipulated, lower and higher for those looking at clocks tweaked to run 2X slower or faster, respectively* (). Blood glucose levels! Now that’s an objectively measured response. Already then, we can start to dimly discern the margins of modern biomedicine’s colossal problem. Unsubtly and arbitrarily splitting body (physiology) and mind (psychology) as a matter of course, it may not even be playing with a full deck since almost daily such new pieces of data force us to confront just how intertwined they actually are.
Placebo Responses: Outcome Of Expectation, Conditioning & Rx-Associated Communication/Ritual
Drugs and therapies are supposed to work specifically by targeting specific molecules and pathways involved in different diseases. Placebos, usually sugar pills, are supposed to mimic certain drug attributes. How? Three components working in tandem appear to explain not just how placebos work but also how placebo responses operate even for specific drugs and therapies.
Expectation is the outcome of learning, part of a general conditioning process of knowing one is getting Rx. The myriad components involved in getting Rx can be construed as Rx-associated communication/ritual (the physician, nurses, other care staff; are they warm, caring, supportive; do they explain what’s happening and what they’re doing; how much time they spend with the patient), etc.. Expectations and conditioning can mutually reinforce each other.
Paradigm shift lies in realizing placebo responses are ever-operational, even with legitimate drugs and therapies. Confused? The ‘open-hidden’ experiment design perfected by Benedetti’s team is not only clever but also groundbreaking because it reveals placebo response is an inherent part of response to medications and therapies.
In the original archetype of the ‘open-hidden’ experiment design (5), the powerful opioid painkillerwas more effective when given openly by a doctor compared to being given secretly. Since then, the observation has been replicated in anxiety and Parkinson’s ( , ). Knowingly getting a medication or therapy seems to set up expectations that make the medication or therapy more effective, i.e., by tapping Rx’s latent placebo response ( , See below from 9).
, another leading placebo response researcher, has turned another conventional wisdom about placebos on their head. Giving patients placebos typically entails deception. Naturally this presents an ethical dilemma. If there are indeed bonafide benefits to placebos, how to reap them if doing so violates ethics?
Kaptchuk’s revolutionary idea is to turn this notion of secrecy on its head and to instead give placebos knowingly. Convention dictates knowingly taking placebos should blunt, even eliminate their benefit. Turns out to be not so. First for IBS (n=80,) then for lower back pain (n=97, ), research on small patient groups shows knowingly taking a placebo in the context of an ongoing, supportive, caring, warm patient-physician relationship benefits patients. Rx-associated communication or ritual is a vital part of how placebo responses are triggered and sustained (12).
Economic Impact Of Placebo Responses
Decades-long evidence (, , 15) suggests clinical trial placebo responses are becoming more powerful, especially for painkiller drug candidates (16) and especially in the US ( ).
- Placebo responses in anti-depressant trials were twice as strong in the 2000s compared to those in the 1980s ( ). Even more compelling is the observation that this improvement occurred not for the more subjective patient self-rating but rather for the comparatively more objective observer rating (1).
- Similar placebo response improvement when testing anti-psychotic drugs ( ).
- Placebo response magnitude change may vary by disease since it increased more weakly from 1991 to 2005 in trials for bipolar disorder (20).
Why could placebo responses be strengthening?
- Could be simply because trials now last longer then they used to (21). Longer Rx-associated communication/ritual = Stronger Placebo responses.
- Over the same time period, drug advertisements have undergone a sea change. The US legalized direct-to-consumer prescription drug advertising in 1997, which also exists in New Zealand. One unanticipated consequence? Social conditioning may be strengthening placebo responses.
Consequences of stronger placebo responses
- Clinical trials are the necessary gatekeeper for new drug approvals. More powerful placebo responses increase the bar new drugs have to clear. No surprise new drug approvals have slowed down dramatically in recent years. Clearly some role there for the increasingly more powerful placebo responses.
- Publication bias predicates that ‘real’ placebo response in RCTs remains unknowable. Studies with a significant drug to placebo difference are more likely to get published. Published placebo responses are thus likely lower than in studies that never got/get published. Ergo, actual placebo responses may be even higher than those revealed by clinical trial results that do get published. If this is the case with new drug candidates, no wonder new drug approvals have declined steeply in recent years.
- One consequence of increasingly powerful placebo responses is a move away from the classic RCTs to newer designs such as comparative effectiveness research (CER) trials, which compare novel drugs to approved ones or to standard therapy, i.e., all participants get active Rx. Problem is such trials ‘increase the placebo response without being able to control for it‘ (9). Statistical analyses of such trials are also much challenging since they require showing the test compound is non-inferior to the standard Rx. As Enck et al point out (9, emphasis mine),
‘A non-inferiority trial tests the null hypothesis that the novel drug is inferior by the equivalence margin. If this null hypothesis is rejected, the novel compound can be regarded as clinically equivalent. This, on average, requires a fourfold larger sample size compared to classical RCTs and is one of the reasons why drug companies are increasingly concerned by the growing costs of drug development‘
How Placebo Responses Could Be Leveraged To Make Medicine More Effective, Cheaper & Safer
- Pigeonholing placebos and placebo responses as undesirable or hindrance is problematic. Placebos are supposedly inert substances that should do nothing yet they do. OTOH, even genuine medicines induce placebo responses which increase their effectiveness. A way to reconcile this seeming contradiction would be by viewing placebo responses as an inevitable part of a virtuous feedback loop between psychology and physiology.
- Expectations are outcome of learning, i.e., part of a conditioning process. Benefits of conditioning are well-known for allergies ( , ) and nausea (24). See below from 9 how conditioning works.
- Maybe encouraging placebo responses could make modern biomedicine more effective (9) by
- Reducing healthcare costs since patients could interchangeably take drugs and placebos, and still benefit.
- Minimizing harm from drug side effects since patients would be taking lower doses of drugs.
- Now that would augur a true biomedical revolution. Conundrum is how to do this reproducibly since placebo’s evil twin, , lurks in the wings. Tapping the same pathways could yield harm just as easily as benefit and we simply don’t know enough about the feedback loops between psychology and physiology to manipulate them at will. For example, can block analgesic (anti-pain) placebo response induced by opioid-driven but not non-opioid (NSAID) (25).
Placebo Responses: Research suggests placebo response magnitude depends on just about anything to do with Rx (26).
- Rx Appearance (27). A systematic 1996 review ( ) found red, yellow and orange pills worked better as stimulants while blue and green pills worked better as tranquilizers. Out of 49 nervous system drugs, stimulants were more often red or orange while sedatives were more often green, blue or purple.
- Rx Frequency/number. A meta-analysis ( ) of anti-duodenal ulcer RCTs found a difference in whether participants took 4 (51 trials) or 2 (28 trials) pills a day. After 4 weeks, 44% (805 of 1821) of those who took 4 placebo pills per day had healed duodenal ulcers compared to 36% (545 of 1504) of those who took 2, statistically a highly significant difference.
- Rx Form. A meta-analysis (30) of 22 trials found placebo injections (32%, 279 of 862 patients) to be more effective against migraine (feeling better one hour later) compared to placebo pills (26%, 222 of 865 patients), statistically a highly significant difference.
- Placebo-Taking Compliance Reduces Mortality Rates. BEST (Beta Blocker Evaluation of Survival Trial) participants ( ) who took >75% of their prescribed placebos had significantly better outcomes (291 of 1038, 28%, died) compared to less compliant placebo-takers (55 of 136, 40%, died). A meta-analysis (32) of 21 RCT or cohort studies on conditions ranging from cancer-associated infections to heart attack to HIV found similar differences, lower mortality rates (4.3%, 581 of 13429 participants) for compliant placebo-takers compared to those less compliant (6.2%, 415 of 6204 participants).
- Influence of Doctors ( , 9, 12, See below from 33 using data from 34).
Placebo Responses: Age, Culture, Ethnicity, Gender, etc. Also Matter
However, hastily generalizing such results could also be in error.
- Different colors seem to matter differently in different countries, i.e., cultural differences are also at play (35).
- An Italian study found women responded more strongly to blue sleeping pills compared to men who preferred orange ones (36).
- Placebo injections may be more effective than pills at treating migraines in the US (33.6%, 151 of 449 patients for injections versus 22.3%, 25 of 112 patients for pills), not in Europe (25.1%, 80 of 318 patients for injections versus 27.1%, 182 of 670 patients for pills) (37).
- Meta-analysis of 100 old RCTs of on found placebo effects that ranged from 6% in Brazil, ~20% in Denmark and the Netherlands to >60% in Germany (38).
- Again, would be wrong to conclude Germans are inherently more predisposed to strong placebo effects since the same analysis found them with among the lowest placebo effect for anti-hypertensive Rx.
- Rotation-induced nausea is a condition with well-established ethnic differences (24).
Even Surgeries Aren’t Immune To Placebo Responses
Unlike medications, especially for subjective symptoms such as pain, surgery is usually done for tangible reasons yet even it isn’t immune to placebo responses, some attributable to bonafide placebo response power and some attesting to the futility of certain prevalent and expensive surgical procedures.
- Back in the 1950s, ligating the internal mammary artery became a popular procedure to alleviate , the idea being restricting blood flow to a nearby region would improve supply going to the coronary arteries. Small placebo-controlled studies (39, 40) of this procedure found similar improvement (significantly less pain, lower nitroglycerine use) regardless whether patients got the ligation or just a skin incision.
- Highly cited placebo-controlled studies ( , ) on surgical Rx for osteoporosis found no difference in improvement magnitude (modest pain score improvement, physical function) between patients who got either (n=38, 68) or sham Rx (n=40, 63).
- Highly cited placebo-controlled US-based studies (43, ) on found no difference in improvement magnitude between patients who got either arthroscopic debridement/ ( ), or simulated debridement (placebo, 3 small stab wounds in the knee). Even two years later, all patients had similar 6 point improvement on a 100 point scale that measured walking and bending. At the time these studies were done (1996-2002), 650,000 such arthroscopies were performed in the US each year, for an average cost of ~US $5000 each, obviously a colossal waste. An example of not the power of placebos but rather of uselessness of certain prevalent medical procedures.
* A preliminary study with few participants (n=47) that desperately needs replication. Also poor form to show data as Mean + Standard Error of the Mean (46). What that means is that actual variation within each group was much higher than what the authors chose to show, i.e., much more actual overlap between groups.
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