Important questions about the placebo response

The placebo response is a wonderful demonstration of the potential of the mind to bring about almost magical healing powers. But though there has been an amazing surge of knowledge about the placebo response over the last several years, there is still much we don’t know, and I think the most exciting times are yet to come. Here are some of the questions I think are particularly interesting, mainly because their answers have important clinical implications.

Not everyone is a “placebo responder”. Why? Perhaps we’ve been looking at this question the wrong way. We’ve been asking, “what makes a placebo responder?” The answer to this question has proven elusive. Perhaps we should be asking, “what prevents someone from being a placebo responder?” We actually already have one answer to this latter question. A fascinating study by Benedetti et al (1995) has shown that Cholecystokinin(CCK) acts to limit placebo responses. When given a CCK antagonist (e.g., proglumide) a considerably larger placebo response occurs. So CCK limits the placebo response and a drug that removes CCK from the picture, removes this limit. For this reason, the CCK antagonist proglumide has been called a “placebo amplifier”.

The CCK discovery is a fascinating one but the question of what limits the placebo is far from fully answered. CCK cannot turn non-placebo responders into responders.

Swearing found to increase pain tolerance

Participants in a recent study at Keele University in the UK were told that the researchers were investigating the degree of stress that various forms of language elicit during stressful experiences and then asked to plunge their hand into a tank of cold water and keep it there for as long as they could while repeating a word of their choice.

They found that swearing people could keep their hand submerged significantly longer than their non-swearing counterparts, perceived the sensation as less painful and exhibited a greater increase in heart rate (see figure below).

The authors suggest that swearing might increase fear-related emotional responses, which have been linked to analgesia responses. They also posit that swearing might elicit aggressive tendencies, which can prompt greater stoicism or machismo. Both of these putative mechanisms are purely speculative and it remains to be seen why exactly swearing helps to reduce pain sensitivity.

PubMed Link: http://www.ncbi.nlm.nih.gov/pubmed/19590391

Nightshirt worn to bed unobtrusively measures stages of sleep

The grand majority of sleep research requires that participants spend at least one night and sometimes many nights in a sleep lab hooked up to equipment capturing a wide array of measures including brain and muscle activity, eye and body movements, and respiration. Getting people to come to a sleep lab has several disadvantages. It's inconvenient for individuals who must disrupt their lives to participate and it necessitates sleeping in a strange environment, away from family.

Recently, a number of interesting products have appeared that claim to be able to measure various objective indices related to sleep.

One of the more interesting I've seen is the Somnus night shirt. The shirt uses thin and flexible respiration sensors that have been directly applied to the shirt's fabric. The shirt's developers claim that respiration data are all that's needed to detect whether someone is awake or asleep and their stage of sleep. For example, during REM sleep, respiration is irregular, whereas in non-REM sleep respiration follows a regular pattern.

I've emailed the company to find out more about the shirt, including what studies have been conducted verifying the validity of their claims and the accuracy of the shirt. If they work, such portable, inexpensive devices that can be used by individuals at home opens up many exciting new research and clinical possibilities.

Link to the company's website.

Link to an article about the device in Technology Review.

TedMed: The TED conference about health and medicine

If you love to watch fascinating people give talks that are cool, thought-provoking, inspiring, then you've got to watch the many wonderful people speak at the TED conference. Every year some of the most

Fantastic blog about science and skepticism

I just discovered a great blog by Dr. Steven Novella, a neurologist at Yale University School of Medicine. He produces a popular podcast called The Skeptics' Guide to the Universe, and also contributes to a number of other blogs that are devoted to the improving an understanding of science among the public.

A recent blog post of his recounts his experience appearing on the Dr. Oz show. Dr. Oz gained fame when he appeared regularly on the Oprah show. So popular was he on Oprah's program that he got his own spinoff. In this episode Oz asks "why are doctors afraid of alternative medicine?" Dr. Novella does an excellent job explaining that doctors are not afraid of anything and that the problem is that either quality scientific evidence is lacking, or that evidence is available and that it has shown that many "alternative" treatments, such as acupuncture, are no better than placebo. In response, Oz claims that Novella is being "dismissive" of the possibilities and then tells the audience that if "alternative treatments work for you, don't let anyone take that away from you."

I highly recommend Novella's blog. And here is the video of Novella's appearance on the Dr. Oz show.

It is natural to think that the world we perceive is a very close facsimile to objective reality, the way things really are. But this is perhaps one of the grandest of illusions. The fact is that our experience is constructed by the human brain. Our experience of our environment and of our body is essentially a simulation. But here's the thing -- the brain does not incorporate all

Observing pain related responses in others can impact our own pain perceptions

Although placebo analgesia is popularly believed to be prompted by taking a "sugar pill" (an inert substance that have no pharmacological effects) while being led to believe that it is an effective painkiller, there are actually many different ways of prompting the placebo response. These include verbal suggestions that induce expectations of efficacy (do these exercises and you'll feel better), conditioning (repeated exposure to a treatment and its effectiveness), etc.

But Luana Colloca and Fabrizio Benedetti, two very prominent researchers in the area placebo effects research recently published an intriguing study investigating social influences on placebo analgesia.

What they did was randomly assign participants to one of 3 groups: social observation, conditioning, and verbal suggestion.

In all groups, participants experience a series of electric shocks preceded by either a red or green light. The placebo part of the study is a sham electrode affixed to the middle finger, which participants are told  delivers a nonpainful stimulation that has an analgesic effect; that is it can reduce the pain of the shocks. The green light is supposed to indicate that this analgesic stimulus has been turned on and that reduced pain should be anticipated.

Now, in the social observation group, participants learn from watching a "demonstrator" go through the series of trials first, that the green light precedes diminished pain relative to red light trials. They can see this because they can see the demonstrator rate the painfulness each pain shock, and they can see that he always rates green trials as less painful than red trials. Subsequent to this "simulation" phase, participants receive a series of red and green-associated pain stimuli in the same way as the demonstrator. In fact green light stimuli were set to be equally painful to red light stimuli.

In the conditioning group, participants are informed that the green and red lights indicate the activation and deactivation, respectively, of the electrode on the middle finger and then are given a series of shocks. To condition the analgesic effect associated with the green light, the shock intensity was surreptitiously lowered. Thus, while participants were led to believe that the electrode affixed to their middle finger was being activated during green light trials and that it was this activation that had an analgesic effect, the electrode was not activated at all and instead, the shock intensity was lowered. After this conditioning phase, a testing period begun whereby the stimulus intensity of green light trials was raised to the same level as red light trials.

In the verbal suggestion group, participants were simply informed that the green light would signal the activation of the analgesic electrode while the red light would indicate its inactivation. In fact, all stimuli were equally painful as in the testing phase of the other conditions.

So what did they find? Well, Colloca and Benedetti were not surprised to find that the conditioning group exhibited a placebo effect as they had shown this effect in a previous study. The unique and truly cool finding here is that participants did not need to experience this conditioning first hand. It was sufficient to merely observe another person undergoing a beneficial effect of a treatment (the "analgesic" electrode). Indeed the magnitude of the placebo responses induced through observational learning was similar to the placebo responses induced through the direct experience of a conditioning procedure.

But that's not all. Another intriguing finding was that the amount of pain reduction exhibited in response to green trials compared to red trials was significantly correlated with how high participants scored on a measure of empathy. So the stronger one's empathic ability, the stronger was the placebo effect following social observation. Why do I find this so fascinating? I'll tell you about it in an upcoming blog post.

In the meantime, do check out this fascinating piece of research for yourself.

Colloca, L & Benedetti, F (2009). Placebo analgesia induced by social observational learning. Pain, 144 (1-2), pp. 28-34.

What is a placebo?

I've seen so many attempts at defining a placebo. The most common is that it is "an inert substance", a "sugar pill". This definition has become popular because historically most discussion surrounding the placebo effect pertained to the use of "placebo" groups in drug trials. In this case, subjects were randomly assigned to receive either an experimental drug with some pharmacological agent(s) being tested or to receive a placebo, a pill that looked, felt, and smelled the same as the active one but which was minus the pharmacological agent(s). This methodology reflected the recognition that people will improve on some outcome for a variety of reasons having nothing to do with the drug being tested.

Say Pfizer is testing a new analgesic for arthritis pain. They set up a clinical trial and assign half to receive their new drug and half to receive an inert counterpart, a "placebo". Participants keep diaries of their pain for a week before taking their pills (so a baseline can be established), then take begin taking their assigned pills. After a month, all the data are collected and analyzed and it is found that indeed those in the active drug group improved, they felt less pain under the influence of the pill compared to their baseline period. But so did the "placebo" group! How can this be? How can people suffering from real pain experience relief from nothing?

The answer is that any or all of several phenomena can occur concomitant with the administration of a "placebo" to cause improvement.

1. Spontaneous remission. This means that any condition can improve on its own, without any intervention. There can be many reasons for this: during the period weather conditions may have become more favorable, lessening pain for all. All chronic medical conditions, including pain, have periods in which symptoms wax and wane.

2. Regression to the mean. Clinical trials of drugs (and other treatments/therapies) tend to seek participants whose pain is especially bad, longstanding, etc. Additionally, people tend to seek out and agree to participating in clinical trials when pain is at its worst. But pain is not always at its worst. Pain varies around some average (i.e., the "mean"). Sometimes it's worse than average; other times it's better than average. Beginning a clinical trial when pain is worse than average, means that it is likely that pain will begin to slide back toward the average (i.e., improve) for no other reason than the natural ups and downs of pain.

3. Detection ambiguity. On a scale of 0 (no pain at all) to 10 (worst pain imaginable), please rate your pain. Sound simple and straightforward, right? Well, not necessarily. Pain is highly subjective. Diabetes, cardiovascular disease, and cancer all have established objective indices that can objectively quantify their state. For example, a simple pin-prick blood test can produce a index of blood glucose, which is a reliable indicator of the presence of diabetes and of how well it is being managed. But pain has no such measure; it is inherently a subjective phenomenon and so we must rely mainly on people's reports of their pain. This is all well and fine but there is ambiguity in how we feel.

Now, imagine that you are led to believe that you have been given a powerful painkiller and then asked to rate your pain on that 0 to 10 scale. Believing you received an analgesic may prime your attention toward the detection of evidence of reduced pain. Pain naturally waxes and wanes. Before participation in the drug trial, you might have interpreted the waning of pain for what it is -- a valley in an unending series of hills and valleys. But because you are concomitantly taking what what you believe is an analgesic there is a greater likelihood that you will interpret the waning of pain as evidence that that the drug is working.

Also, detecting pain in the body is a bit like detecting the temperature outside. Numerous factors can influence your perception of temperature: humidity, wind, how sunny it is, your own mood and anxiety level, etc. We might say that the influence of all these factors leads to ambiguity in detecting the temperature. An implication of this ambiguity is that your estimate of temperature can be manipulated by getting you to focus on some of these factors more than others, which is essentially what drug trials can do.

4. Placebo response. The placebo response is that










So clinical trials of drugs must show that a drug produces improvements that are over and above

Objectively measuring pain

Pain is an inherently private, subjective phenomenon. There is, at the present time, simply no blood test, or even brain scan that can objectively quantify pain. This fact makes it tough on both pain patients as well as pain clinicians.

The subjective nature of pain is tough for patients because it means that their pain is often dismissed. The patient cannot point to a test result proving that the severity of the pain that they claim is "real". One chronic pain patient I met told me that she was regularly "punished" for her extraordinary coping efforts because the more effectively she coped, the less she appeared to be in pain, the less concern, attention, and patience she received from others around her who interpreted her coping as an indication that she was in less pain. This really is a terrible problem for people with chronic pain and can add to their suffering considerably.

The subjective nature of pain is tough for clinicians because it is difficult to determine the efficacy of their treatments. First, two individuals may rate their pain as 7 on a 0 to 10 scale, but that doesn't mean they their pain experience is equal. This may be because of differences in past experience; that is ratings are relative to each individual's extreme experiences. Patient A may be in excruciating pain that patient B would rate as a 9 or 10, but because Patient A has experienced even worse pain, to her, the pain is perceived at about 7 out of 10. Second, there may be differences in patient motivations. Some individuals may use opportunities to rate their pain as a means of expressing their suffering. They might really feel more like a 5 or 6 but boost it a notch as a means of communicating that they're feeling a great deal of hurt.

There exist several subjective pain scales. The most popular are...

Numeric Rating Scale

Visual Analog Scale

Category Intensity Scale

Faces Scale

Wong et al (1995)

Wong-Baker FACES Pain Rating Scale. Note: From Wong, D.: Whaley and Wong's Nursing Care of Infants and Children, ed 5, 1995, p. 1085. Copyrighted by Mosby-Year Book, Inc.

Observing someone modeling pain tolerant behavior can influence one's own perception of pain

Social factors have been shown in dozens if not hundreds of studies to have widespread and profound effects on numerous health outcomes. For example, people who are isolated tend to live shorter and less happy lives, and knowing others are available for social support can buffer us against the ravages of everyday stresses in life and decrease the risk of cardiovascular disease, diabetes and other conditions. Given this immense influence of social relationships on so many aspects of health, it has been surprising to me that there has been relatively little research exploring the impact of social factors on pain!

Indeed, I think this topic is so important that I chose to make it the topic of my Ph.D. dissertation.

In the process of becoming familiar with the scientific literature, it occurred to me that one way in which one's social environment might influence pain is through social modeling. That is, the degree to which people would find some experience painful would depend on the responses of others in their social environment. In other words, after watching someone stoically absorb painful shocks you would feel less pain from those shocks than if you had just observed someone responding more weakly to the pain stimuli.

In the 1970s, psychologist Albert Bandura, developed what has become known as social learning theory. The essence of social learning theory is that people can learn new responses through observing others in lieu of direct experience. Bandura, in his 1977 book said, "Learning would be exceedingly laborious, not to mention hazardous, if people had to rely solely on the effects of their own actions to inform them what to do. Fortunately, most human behavior is learned observationally through modeling"

I thought this was pretty straightforward stuff so when I hit the literature I expected to find lots of studies looking at social modeling and pain. I was surprised to learn that I would have to go all the way back to 1976 and a paper written by Kenneth Craig and presented at an American Psychological Association meeting.

Here's how it went...