Placebo Effect

The placebo effect occurs when a patient takes an inert substance (sometimes called a "sugar pill") in conjunction with the suggestion from an authority figure or from acquired information that the pill will aid in healing and the patient’s condition improves. This effect has been known since the early 20th century.

Studies published in Proceedings of the National Academy of Sciences using advances in neuroscience (PET scans) have shown that placebos can noticeably reduce pain in humans. Researchers at Columbia and Michigan University have shown that the brains of volunteers who believed that what they were taking was pain medication were shown to be spontaneously releasing opioids, or natural pain relief.^[4] According to that ABC report the Food and Drug Administration contends that as many as 75 percent of patients have had responses to sugar pills. It pointed out that all major clinical trials use placebo groups because the effect is significant and to be expected.

This effect has been known since the early 20th century. Generally, one third of a control group taking a placebo shows improvement, and that the placebo effect yields beneficial clinical results in 60–90% of diseases, including angina pectoris, bronchial asthma, herpes simplex, and duodenal ulcers.^[5]

Whenever a placebo is requested in a medical prescription it may imply a statement by the prescribing doctor that "This patient has come to me pleading for a treatment which does not exist or which I cannot or will not supply; I will please him by giving him something ineffectual and claiming that it is effectual." It could also indicate a belief that the effect was due to a subconscious desire of the patient to please the doctor. Since the placebo effect is in the patient not the doctor this may be more self-consistent. Early usage of the term does not indicate why it was chosen.

Experimenters typically use placebos in the context of a clinical trial, in which a "test group" of patients receives the therapy being tested, and a "control group" receives the placebo. It can then be determined if results from the "test" group exceed those due to the placebo effect. If they do, the therapy or pill given to the "test group" is assumed to have had an effect.

Effect on various symptoms

Pain

Careful studies have shown that the placebo effect can alleviate pain, although the effect is more pronounced with pre-existing pain than with experimentally induced pain. People can be conditioned to expect analgesia in certain situations. When those conditions are provided to the patient, the brain responds by generating a pattern of neural activity that produces objectively quantifiable analgesia. (Benedetti 2003, Wager 2004)

Evans argued that the placebo effect works through a suppression of the acute phase response, and as a result does not work in medical conditions that do not feature this. (Evans 2005) The acute phase response consists of inflammation and sickness behaviour:

Depression

A brain-imaging study found that depressed patients who responded to the placebo effect showed changes in cerebral blood flow, which were similar to the changes in brain function seen in patients who responded to anti-depressant medication. (Leuchter 2002) Other studies argue that up to 75% of the effectiveness of anti-depressant medication is due to the placebo-effect rather than the treatment itself. (Khan 2000)

Withdrawal symptoms on discontinuation

The Women's Health Initiative study of hormone replacement therapy for menopause was discontinued after participants still in the program had been taking either hormones or placebo for an average of 5.7 years. Moderate or severe withdrawal symptoms were reported by 40.5% of those on placebo compared to 63.3% of those on hormone replacement. Pain and stiffness (musculoskeletal symptoms) were the most frequently reported symptoms in both the placebo group (22.2%) and the hormone group (36.8%), exceeding other symptoms by more than 10%. Of those reporting pain and stiffness, 54.7% in the hormone group and 38.3% in the placebo group had these symptoms at the onset of therapy. Tiredness was the second most frequently reported withdrawal symptom (21.3% hormone, 11.6% placebo) and hot flashes/night sweats the third (21.2% hormone, 4.8% placebo).^[26] Only the vasomotor symptoms (hot flashes/night sweats) were acknowledged to be verified effects of menopause by a 2005 National Institutes of Health panel.^[27]

These results may indicate some learned response concerning which withdrawal symptoms appear in a placebo group as well as in the subjects who received therapy, with a greater effect on pain and tiredness than on vasomotor symptoms.

Objective or subjective effects?

Hrobjartsson and Götzsche published a study in 2001 and a follow-up study in 2004 questioning the nature of the placebo effect. (Hrobjartsson 2001, Hrobjartsson 2004) They performed two meta-analyses involving 156 clinical trials in which an experimental drug or treatment protocol was compared to a placebo group and an untreated group, and specifically asked whether the placebo group improved compared to the untreated group. Hrobjartsson and Götzsche found that in studies with a binary outcome, meaning patients were classified as improved or not improved, the placebo group had no statistically significant improvement over the no-treatment group. Similarly, there was no significant placebo effect in studies in which objective outcomes (such as blood pressure) were measured by an independent observer. The placebo effect could only be documented in studies in which the outcomes (improvement or failure to improve) were reported by the subjects themselves. The authors concluded that the placebo effect does not have "powerful clinical effects," (objective effects) and that patient-reported improvements (subjective effects) in pain were small and could not be clearly distinguished from bias.

These results suggest that the placebo effect is largely subjective. This would help explain why the placebo effect is easiest to demonstrate in conditions where subjective factors are very prominent or significant parts of the problem. Some of these conditions are headache, stomachache, asthma, allergy, tension, and the experience of pain, which is often a significant part of many mild and serious illnesses.

Mechanism for the effect

It is universally accepted that, for a placebo response to occur, the subject must believe an effective medication (or other treatment) has been administered to them, but must not know it is an ineffective placebo. This is quite different from the case of an "active drug", where the drug response is generated even in the case of covert administration, in other words regardless of whether the patient knows or doesn't know they have received any medication.

The question of just how and why placebo responses are generated is not an abstract theoretical issue; it has wide implications for both clinical practice and the experimental evaluation of therapeutic interventions.

In recent times, three different hypotheses have been offered to account for these placebo responses — i.e., "expectancy theory" and 'classical conditioning" and motivation — which, whilst emphasizing different factors, are not mutually exclusive and, in fact, overlap to a certain extent.

Expectancy effect

The subject-expectancy effect attributes the placebo effect to conscious or unconscious manipulation by patients in reporting improvement. Hrobjartsson and Götzsche argued in their article, "Most patients are polite and prone to please the investigators by reporting improvement, even when no improvement was felt." Subjective bias can also be unconscious, where the patient believes he is improving as a result of the attention and care he has received.

Conditioning

Classical conditioning is a type of associative learning where the subject learns to associate a particular stimulus with a particular response. In this case the stimulant is the substance perceived as medicine but is the placebo, and the response is the relief of symptoms. It is difficult to tell the difference between conditioning and the expectancy effect when the outcome is subjective and reported by the patient. However, conditioning can result in measurable biological changes similar to the changes seen with the real treatment or drug. For example, studies showing that placebo treatments result in changes in brain function similar to the real drug are probably examples of conditioning resulting in objectively measurable results. (Sauro 2005, Wager 2004, Arnaldo 2002)

Motivation

Motivational explanations of the placebo effect have typically considered the placebo effect to be an outcome of one’s desire to feel better, reduce anxiety, or cooperate with an experimenter or health care professional (Price et al. 1999, Margo 1999). The motivational perspective is supported by recent research showing that nonconscious goals for cooperation can be satisfied by confirming expectations about a treatment (Geers et al. 2005).

Role of endogenous opiates

The discovery in 1975 of Endogenous opiates alias endorphins (substances like opiates but naturally produced in the body) have changed matters in investing placebo effect. When patients who claimed to experience pain relief after receiving a placebo were injected with naloxone (a drug that blocks the effects of opiates), their pain returned, suggesting that the placebo effect may be partly due to psychological reaction causing release of natural opiates. (Sauro 2005)

Ethical challenges and concerns

Bioethicists have raised diverse concerns on the use of placebos in modern medicine and research. These have been largely incorporated into modern rules for the use of placebos in research but some issues remain subject to debate. The ethics of prescribing placebos in medical practice is highly debated. Some practitioners argue that the use of placebos is sometimes justified because it will do no harm and may do some good. With the publication of studies by Hróbjartsson and Götzsche and others, the proposition that placebos may do some good is under fire.

Most of these concerns have been addressed in the modern conventions for the use of placebos in research; however, some issues remain subject to debate.

A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year. The most frequently prescribed placebos were antibiotics for viral infections, and vitamins for fatigue. Specialists and hospital-based physicians reported much lower rates of placebo use. (Hrobjartsson 2003) A 2004 study in the British Medical Journal of physicians in Israel found that 60% used placebos in their medical practice, most commonly to "fend off" requests for unjustified medications or to calm a patient. Of the physicians who reported using placebos, only 15% told their patients they were receiving placebos or non-specific medications.