Placebo vs. 'doing nothing' — which wins?
Giving a suffering patient a placebo while telling them that they are genuinely being treated is widely viewed as unethical, even though “everyone knows” that placebos do have a positive effect on most people. But what if you tell the patient, “I’m giving you a placebo. Physically, it has no effect, but studies have shown that people do get better if they think they’re being treated.”
Safe and ineffective
Last week, a study published in the Journal of the American Medical Association (JAMA) described just such a scenario. A group of scientists set out to test placebos without deception, comparing them with “treatment as usual.” Their aim was to assess just how helpful placebos can be, examining both the experiences of the study’s participants and the ways in which their brains responded to the 2 types of “treatment.”
101 people with chronic back pain were recruited for the study and randomized into two groups. The study’s participants knew which group they were assigned to, but the researchers did not have access to this information until after the study’s conclusion.
The “open-label placebo” group were told that they would be treated with a substance that had no known effect on back pain. They were shown 2 videos about placebos and then had a structured conversation with the study’s doctor, during which it was explained to them that placebos can have powerful effects despite their inert nature, that they can cause the body to release opioids (which might be expected to relieve pain), that they can somehow trigger a healing response in the body that is not understood, and that “thinking positive thoughts” can in general be beneficial.
Members of the placebo group changed into medical gowns before the procedure and were then given a single injection of saline (saltwater) into the back, at the place where they were experiencing the most pain.
Throughout the yearlong study, they also continued with their usual regimen to deal with back pain, including medications, exercises, and so forth. They were not to start doing or taking anything new.
The “usual care” group were given no extra treatments at any point during the study. All they had to do was agree to continue doing whatever they had been doing before to deal with their pain, and not to start anything new.
Study participants were tracked periodically over the next year. Their first check-in was immediately after the treatment (or lack of), followed by a month later, two months later, three months later, half a year later, and a year later.
At each check-in, they were asked to rate their level of pain on a scale of 0 to 10, where 0 is no pain and 10 is extremely intense pain. Participants were also asked to gauge their levels of depression, anxiety, anger, and sleep quality.
In order to assess any changes in their brains, they also underwent MRI assessments.
Saltwater in first place
The results, when they came in, were found to be statistically significant in several areas. Directly following the injection (or lack of one), the researchers found that 31 out of 44 people in the placebo group and 25 out of 47 people in the “usual care” group reported that their level of pain had gone down by between 30 and 50 percent:
Of 44 patients randomized to OLP [open-label placebo] followed up at post-treatment, 20 (45.4%) reported 30% pain reduction and 11 (24.4%) reported 50% pain reduction.
Of 47 patients randomized to usual care followed up at post-treatment, 18 (38.3%) reported 30% pain reduction and 7 (14.9%) had a 50% pain reduction.
Comparing placebo to usual care, this was a win for the placebo group of more than 0.61 points on the 11-point pain scale. The placebo group also won in the areas of sleep and mood with statistically significant differences between them and the usual care group.
Placebo won at the one-month mark as well and the difference between the two groups was described as statistically significant.
The researchers concluded that,
An open-label subcutaneous placebo (saline) injection led to significant improvements in pain intensity, mood, and sleep at 1 month post-treatment compared with usual care.
Assessing the results of MRI scans also led the researchers to conclude that placebo treatment produced significant brain changes in areas that they judged to be linked to pain:
The findings of this trial suggest that open-label placebo treatments can confer meaningful clinical benefits to patients with chronic back pain by engaging prefrontal-brainstem pathways linked to pain regulation and opioidergic function.
They also noted that the brain changes observed following an open placebo seemed very similar to the results observed when people were “deceptively” given placebos in other clinical trials.
By the one-year mark, there was no longer any significant difference between the two groups in terms of pain intensity. However, trial participants in the placebo group did have significantly better scores in depression, anger, anxiety, sleep, and their perception of change.
The researchers also noted that people who tended to “catastrophize” their pain had a better response to placebo than others.
However, having greater expectations of improvement did not seem to improve outcomes for people on placebo treatment.
Saltwater defeats steroids too
Treating chronic back pain is notoriously difficult. The researchers noted in their study that placebo is often just as helpful as “genuine” treatment:
Placebo treatments often provide as much pain relief as bona fide treatments, such as steroid injections.
Furthermore, while standard treatments tend to have unpleasant and even dangerous side effects, placebo treatment is generally accepted as being harmless:
Many standard CBP treatments (e.g., nonsteroidal anti-inflammatory drugs, epidural steroid injections) yield comparable effect sizes but with more adverse events.
The researchers also pointed out that while a placebo’s effect no longer seemed significant by a year after the sham injection, any benefit provided by steroids has also usually disappeared by that point:
Open-label placebo vs usual care pain intensity reductions were not significant through 1 year follow-up. This parallels the effects of epidural steroid injections, whose benefits also typically fade with time. Patients thus often return for repeat steroid injections, although these must be limited due to safety concerns.
Therefore, they recommended researching regular placebo injections as a recognized form of treatment for chronic back pain, as well as to examine the effect of “withdrawing” from sham treatment:
As there are no safety concerns with repeated OLP injections, future studies could investigate repeated OLP injections as a maintenance treatment aiming to provide sustained pain reductions, with randomized withdrawal studies to estimate the effects of OLP discontinuation.
If chronic pain is 'all in the mind' then that would explain it...
The researchers started from the position of knowing that placebos work.
Placebo or sham treatments for chronic pain are powerful: in many cases, they provide as much or nearly as much pain relief as bona fide pills, injections, and surgeries.
Open-label placebo treatments have demonstrated benefits for several conditions, including migraine, cancer-related fatigue, irritable bowel syndrome, and chronic back pain (CBP).
What intrigued them was why this should be even when people knew that they were getting the equivalent of a sugar-pill.
They hypothesized (without spelling it out explicitly) that people with chronic back pain don’t really have genuine pain, and that therefore a placebo, whose effects are limited to the “brain and behavioral processes,” may be uniquely suited to treating them.
Open-label placebo treatments, which primarily engage brain and behavioral processes, may thus target core mechanisms of CBP.
... but how to explain why 'doing nothing' helps too?
However, there was one question that the researchers didn’t address.
People who got a placebo injection experienced benefit, for whatever reason.
But why did people who got nothing at all do better as well? As one can see from the graph, their improvement was almost as considerable as that of the people in the placebo group.
What if pain leads to gain?
One possible explanation is that they were paid to participate in the study. Each person recruited was paid $50 for an eligibility session with an EEG (a test recording electrical brain activity) or $24 for an eligibility session without EEG. Each MRI session was compensated to the tune of $75, and each of the first three monthly follow-up sessions earned participants another $5, while the final two follow-up sessions were compensated at $20 apiece.
Participants would thus earn up to $225 for completing this study with EEG, or $230 without EEG.
Perhaps, when experiencing pain pays off, people take a perverse pleasure in their status and feel better about their situation?
What if being validated leads to a cure?
Another possible explanation is very simple. While those in the “usual care” group received no extra treatment, what they did receive was attention. Participating in a research study by definition involves people taking an interest in you, talking to you, listening to you describe your symptoms, and to an extent having them validate your experience.
People with chronic pain tend also to have chronic experience with invalidation (as the implicit bias of the researchers revealed, as noted above) and to be taken seriously for once may have been very beneficial for them.
From the despair of chronic pain to belief in recovery
Both of these factors would probably apply most strongly in the immediate aftermath of the injection/lack-of treatment, and the results bear this out. But what would explain the degree of sustained benefit over the rest of the year?
Perhaps, people who experience themselves differently, even for a day or two, or a week or more, suddenly realize that change is possible, after having been resigned to their chronic pain for months or even years. Perhaps this gives them optimism that improvement is possible, and also encourages them to take up new behaviors (such as exercise, going on trips or vacations, or socializing) that they had given up prior to the study.
In fact, the researchers seem to suggest something of this kind (although they only link it to the placebo group):
Sustained benefits of OLP vs usual care through 1-year of follow-up were observed on depression, anxiety, sleep, and anger. These effects were not significant at 1 month post-treatment but emerged later.
The delayed emergence of these effects could potentially be explained by mutually reinforcing improvements across these multiple processes (sleep, mood) creating positive feedback loops providing increasing benefits over time, following an initial incubation period.
To sum up: There is really no such thing as doing nothing, because everything has an effect. If a person can be drawn out of chronic pain just by being listened to for an hour, seven times a year, just think how much we can do for one another even with the smallest exertion.
