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The Nocebo Response


pills “The biomedical view is so pervasive that we often fail to see it as such but view it as reality. Questioning this model is like asking whether a goldfish knows it is in water.” – O’Boyle, 1993

The placebo response has become a well-known, though severely misunderstood, phenomenon in popular culture. But many outside of the medical profession have never heard of the “nocebo response” which is often referred to as the “evil twin” of the placebo response.

A nocebo effect is an ill effect caused by the suggestion or belief that something is harmful. The term ‘nocebo’ became popular in the 1990s. Prior to that, both pleasant and harmful effects thought to be due to the power of suggestion were usually referred to as being due to the placebo effect.

But although the general public may not be aware of the term “nocebo response”, the concept behind it is certainly familiar. Many common phrases in our language (“scared to death”, “worried sick”) acknowledge the relationship between the mind and body and the power of thoughts and emotions to cause disease, and even death. In fact, the phenomenon of voodoo death – in which an adept in the voodoo tradition dies from fright after being hexed or cursed – is well-documented in the scientific literature.

The nocebo response is well-known to researchers. In placebo trials for disorders that produce minimal symptoms (e.g. hypertension), nocebo effects are comparable to those seen with an active drug. The most common adverse symptoms include headache in 7%, somnolence in 5%, weakness in 4% and nausea and dizziness in 1% each. In some studies, fatigue and gastrointestinal symptoms both occurred in almost 15% of subjects.

The mere suggestion that a drug can cause side effects can be a self-fulling prophecy for some patients. Studies have shown that the language adopted to describe side effects of drugs can significantly influence patient expectations and outcomes. (Barsky et al. 2002)

In the Framingham Heart Study, the largest and longest running study on heart disease in the world, women who believed they were prone to heart disease were nearly four times as likely to die as women with similar risk factors who didn’t hold such fatalistic views. (Voelker 1996)

A special report called “The Nocebo Effect: Placebo’s Evil Twin” published in The Washington Post in 2002 reported that in studies done of people going into surgery who want to die (to reconnect with a loved one), close to 100% of them die.

In a study of aspirin, patients were warned about possible gastrointestinal problems as a side effect at one location. At another location, no such warning was issued. Those who received the warning were almost three times as likely to experience the side effects. (Reid 2002)

In another experiment, asthmatic patients breathed in a vapor that researchers told them was a chemical irritant or allergen. Nearly half of the patients experienced breathing problems, with a dozen developing full-blown attacks. They were “treated” with a substance they believed to be a bronchodilating medicine, and recovered immediately. In actuality, both the “irritant” and the “medicine” were a nebulized saltwater solution. (Morse 1999)

In perhaps the most phenomenal study, Japanese researchers tested 57 high school boys for their sensitivity to allergens. The boys filled out questionnaires about past experiences with plants, including lacquer trees, which can cause itchy rashes much as poison oak and poison ivy do. Boys who reported having severe reactions to the poisonous trees were blindfolded. Researchers brushed one arm with leaves from a lacquer tree but told the boys they were chestnut tree leaves. The scientists stroked the other arm with chestnut tree leaves but said the foliage came from a lacquer tree. Within minutes the arm the boys believed to have been exposed to the poisonous tree began to react, turning red and developing a bumpy, itchy rash. In most cases the arm that had contact with the actual poison did not react. (Morse 1999)

So what is the significance of the “nocebo effect” in human health? The answer to that question depends on who you ask. The pharmaceutical companies’ primary interest in the nocebo effect is related to drug side effects, which cost the U.S. health system more than $76 billion a year (according to a 1995 University of Arizona study). If even a small percentage of those costs are caused by patient expectations of harm, addressing the nocebo effect could save drug companies a lot of money.

But for providers of health care not primarily motivated by profit, and for the average person, the nocebo response should be a powerful reminder of the capacity of our beliefs, expectations, thoughts and emotions to cause both health and disease. Many people of course know this instinctively. Yet in an era of medicine based increasingly upon technology and a specific type of scientific analysis, it is important to remember that the mind is not separate from the body, and that health and healing depend upon much more than doctors, hospitals, pills and diet.

Recommended links

  • The Nocebo Effect: Placebo’s Evil Twin
  • Meaning, Medicine & the Placebo Effect (book excerpt)
  • The Placebo Response and the Power of Unconscious Healing

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pills on spoon

THS reader Chad sent in this question:

Antidepressants – effective or placebo?

The use of antidepressant medication has become so widespread and commonly accepted that it seems almost sacrilegious to question it. But alas, questioning is the name of the game here at The Healthy Skeptic!

And what do you know? Antidepressants aren’t all they’re cracked up to be. In fact, a recent meta-review of published studies on the efficacy of antidepressant drugs revealed that selective serotonin reuptake inhibitors (SSRIs), which are the most commonly prescribed drugs to treat depression, have no clinically meaningful advantage over placebo.

What that means is that in most of the trials reviewed, patients who took a sugar pill recovered from depression just as often as those who took the active drug. This study may come as some surprise to both physicians and the general public, whose faith in the efficacy of these drugs has led to over 118 million prescriptions in 2007 and over $16 billion in sales.

But should this really come as a surprise? Antidepressant drugs are thought to act by altering levels of brain neurotransmitters; however, it takes several weeks before these changes can be measured. Yet patients often report symptomatic relief within hours or days of receiving an antidepressant.

Available data suggests, in fact, that SSRIs are no more effective than placebos and have considerable adverse effects and risks, including increased suicidality amongst both children and adults. Sapirstein and Kirsch conducted a meta-analysis of 3,000 patients who received either antidepressants, psychotherapy, placebo or no treatment at all. They found that 27% of therapeutic responses were attributable to drug activities, 50% to psychological factors, and 23% to “non-specific” factors. In other words, 73% of the response to the drug was unrelated to its pharmacological activities – and antidepressants may be no better or more specific than placebos.

This of course raises grave questions about why the National Institute for Health and Clinical Excellence (NICE) still recommends that antidepressants should the be first line treatment for moderate or severe depression. Their message is identical to that of the Defeat Depression Campaign in the early 90s, which contributed to the 253% rise in antidepressant prescribing in 10 years.

In a review published in the British Medical Journal in February of 2006, researchers Joanna Moncrieff and Irving Kirsch point out that the NICE recommendations ignore even their own study data. Although the NICE meta-analysis of placebo controlled trials of SSRIs found statistically significant differences in levels of symptoms, these were so small that the effects were deemed “unlikely to be clinically important.”

After analyzing several published studies and reviews, Moncrieff and Kirsch reached the following conclusions:

Summary points

  1. SSRIs have no clinically meaningful advantage over placebo
  2. Claims that antidepressants are more effective in more severe conditions have little evidence to support them
  3. Methodological artifacts may account for the small degree of superiority shown over placebo
  4. Antidepressants have not been convincingly shown to affect the long-term outcome of depression or suicide rates

The response to a drug or placebo in a clinical trial for depression is often measured using the Hamilton rating scale, a multiple choice questionnaire which doctors use to rate the severity of a patient’s condition. The questionnaire rates the severity of symptoms observed in depression such as low mood, insomnia, agitation, anxiety and weight-loss; it is considered to be a highly reliable physician-rated scale and has been reported to be more sensitive than patient-rated scales to drug/placebo differences. (Murray, 1989)

In the NICE meta-analysis, the difference between drug and placebo groups was one point. The most commonly used 17 item version of the Hamilton scale has a maximum score of 52. It is highly unlikely that a difference of one point on a 52-point scale is clinically significant, a fact that the FDA has admitted in memoranda (Laughren, 1998; Leber, 1998) reviewed by Moncrieff and Kirsch.

Other studies have yielded similar results. A study by Khan et al. found a 10% difference in levels of symptoms between placebo and active drugs in two different meta-analyses. In a more recent review, Kirsch et al. invoked the Freedom of Information (FOA) act to obtain access to previously unpublished studies (the drug companies are under no requirement to publish a study they have sponsored if the results don’t suit them). The overall difference between drugs and placebos in that analyses was 1.7 points on the Hamilton scale.

Moncrieff and Kirsch also point out that the Hamilton scale contains seven items concerning sleep and anxiety, with each item on sleep scoring up to six points. Therefore any drug with some sedative properties, including many antidepressants, could produce a difference of two points or more without exerting any specific antidepressant effect.

Follow-up studies that track patients for a significant length of time have also shown very poor outcomes for people treated for depression both in the hospital and in outpatient settings, and the overall prevalence of depression is rising despite increased use of antidepressants. Suicide rates have increased in some groups and some countries, despite increased prescribing of antidepressant, and there are continuing concerns that SSRIs may increase the risk of suicidal behavior in obht cildren and adults.

In children, the balance of benefits to risks in antidepressant treatment is already recognized as “unfavorable”. The analyses performed by Moncrieff and Kirsch strongly suggests that the same is the case for adults, and that the ongoing uncertainty about the possible risk of increased suicidality as well as the adverse effects of antidepressant drugs warrant a “thorough re-evaluation of our current approach” to treating depression.

I couldn’t agree more. One question the authors failed to pose, which I believe to be at the root of the matter, is why are so many more children and adults depressed now than before? You might not be surprised to learn that I have some thoughts about this. But I’ll save them for another post.

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Pleasure is good for you


gramophoneThere’s no doubt that optimal nutrition plays a significant role in supporting our health and well-being. But nutrition, as important as it is, obviously isn’t the only factor that influences our physiology.

Over the past several years, an increasing amount of research has focused on the role of emotions, behavior and beliefs in contributing to both health and disease. In fact, an entirely new discipline called “psychoneuroimmunology” (say that three times fast!) has emerged to study the connection between the mind and the body. In short, what has been revealed is that the separation we make between “the mind” and “the body” is largely an illusion. Mind and body exist in a continuous and interrelated web of connections that is only now beginning to be discovered by western science.

But though the idea that our thoughts and emotions can directly influence our physiology is new to modern biomedicine (just ten years ago it was dismissed by most physicians and researchers as so much “New Age” fluff), it has been deeply ingrained in our cultural paradigm for centuries. It is embedded in our language; consider the phrases “worried sick” or “scared to death”, and you’ll know what I mean. I’m sure all of you have had the experience of becoming ill after a particularly stressful period at work, or feeling moody and perhaps depressed while you are physically ill. These are both prime examples of how interconnected our mental and emotional health is.

In their book Feeling Good Is Good For You, researchers Carl J. Charnetski and Francis X Brennan set out to review the emerging evidence that pleasure can boost our immune systems and lengthen our lives. According to the authors,:

“In every way, stress is the antithesis of pleasure. It jangles your nerves, juggles a whole host of your body’s hormones, elevates your blood pressure, and makes your pulse race… It also weakens your immune system’s ability to resist illness and disease.”

If stress is the antithesis of pleasure, then it follows that pleasure is the antithesis of stress. And the best way to fight stress, say Charnetski and Brennan, is with pleasure. Our bodies secrete chemicals called endorphins when we experience pleasure. Animal research has revealed, for example, that endorphin levels are up to 86 times higher after animals experience multiple orgasms! But endorphins are also released, albeit at lower levels, in more mundane daily activities such as playing with a pet, watching a funny movie, listening to our favorite music, visiting a favorite place or connecting with loved ones.

The chemicals released when we experience pleasure do more than counteract stress hormones and improve mood. Consider these additional effects:

  • They improve immune function by producing an antibacterial peptide
  • They enhance the killer instincts and abilities of various immune components, including B cells, T cells, NK cells, and immunoglobulins.
  • They enable certain immune cells to secrete their own endorphins as a way of improving their disease-fighting capacity

Charnetski and Brennan examine several “pleasure inducing” experiences that have been scientifically proven to promote health and well-being.

  • Music
  • Touch
  • Pets
  • Humor
  • Positive attitude and insight

Most of us are already aware of the healing power of those things listed above – at least on some level. But in this culture, there is also an overwhelming reliance on medicine, surgery, diet and other physiological interventions to treat disease. Though we may pay lip service to the idea that stress causes illness and pleasure can prevent it, how many of us actually attribute the same importance to listening to music or watching a funny movie as we do to taking a pill? The lesson in this book is that our thoughts, beliefs, emotions and behavior are all capable of inducing the same physiological changes in our bodies as foods, supplements, pills and even surgery are.

If you doubt that this is true, consider the placebo effect. It has been proven over and over again that pharmacologically inert substances like sugar pills can have identical or even greater therapeutic effects than drugs in certain cases. Even more impressive are the trials that have shown that sham surgery (when small incisions are made to convince the patient they have had the operation, but no surgery is performed) is at times as effective as the actual surgery.

Clearly this points to the power we all have to heal ourselves. If only the suggestion or belief that we will heal is enough to induce the physiological changes that lead to healing, without the presence of any “active” pharmacological substance or surgical intervention, then clearly our thoughts, beliefs and emotions have the potential to be powerful medicine.

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