Placebo Effect

Psychological Mechanisms: Expectations

"Mentalistic theory": your expectations about the treatment are what make it successful or unsuccessful. Your perceptions of the doctor and treatment. You don't typically see the placebo effect in the absence of expectations ***Conditioning and expectations are likely working together... Conditioning → expectations → placebo effect

History of Placebo

1799: John Haygarth - no difference between expensive perconstracters (sticks that wave over patient to get over disease) and wooden sticks. 1903: Richard Cabot - 1920: Lancet Paper - first time placebo effect mentioned in a study. 1945: Henry K. Beecher - randomized controlled placebo trial in a study.

Placebo Effect

A beneficial effect produced by a treatment, which cannot be attributed to the physiological properties of the placebo itself, rather to its therapeutic intent. "There are men on whom the mere sight of medicine is operative." - Michel de Montaigne. Treatment for migraines: 26-32% of patients respond to placebos. Women are less likely to experience the placebo effect than men. Women are more responsive to the nocebo effect than men.

Ethical Dilemma

As a doctor, you want to inform patients of the medical side effects, but also want them to have the least amount of negative side effects as possible.

Biological Mechanisms: Immune Mediators

Behavioral conditioning of immunosuppression is possible in humans. Flavoured drink + immunosuppressive drug --> immunosuppression. Flavoured drink + placebo--> immunosuppression. Therefore, the placebo pill provided the same type of response as the immunosuppressive drug.

Health care provider's behaviour and interactions: Histamine Skin Prick Study

Doctor administers placebo cream for the rash and either gives patients good news that it will make the rash better or tells them it would make the rash worse. - When she said it would make it worse = rash became worse shortly after. - When she said it would make it better = rash became better. The physiological responses to the histamine was affected by their beliefs. Warmth and competence of doctor predicted if the placebo cream would improve or worsen the rash. - Warm and competent doctor who connected with patient = what she said about the cream made the affect even stronger. - When doctor was cold and incompetent = what she said about the cream made no difference at all.

Evaluation of Classical Conditioning

Evidence for conditioning: - Placebos are more effective if the patient has already had active treatment. Evidence against conditioning: - Patients who have never had treatment before. - Extinction.

Where does the placebo effect work and not work? Not all types of pain respond the same

Experimental pain is the least sensitive to the placebo effect (shock or a pinch). Pain-related to anxiety (i.e. patients with CVD) is the most sensitive (up to 90% response). Ailments placebo effect has shown effects on: - Parkinsons' Disease - IBS - Immune function - Pain (related to anxiety) - Depression - Anxiety - Knee surgery

Danger of expectations: The "Nocebo Effect" Lactose Intolerance, Finasteride study, Woman Giving Birth

Patients can experience adverse side effects from a treatment even if it is a placebo. Lactose Intolerance Study: Lactose pill was a placebo pill (should have no effect). - 44% of participants with lactose intolerance reported GI symptoms. - 26% of participants without lactose intolerance reported symptoms. Nocebo effect can also occur with non-placebo medications. Finasteride Drug Study: Nocebo and erectile dysfunction. - 44% of those informed about side effects reported ED. - 15% of those not informed about side effects reported ED. Women about to give birth: - "We are going to give you a local anesthetic that will numb the area so that you will be comfortable during the procedure." OR "You are going to feel a big bee sting; this is the worst part of the procedure." - The perceived pain was significantly greater after the second statement, which emphasized the downside of the injection.

Biological mechanisms: Hormones

Placebo --> Endogenous Opioid Release (body releases natural pain killers) --> Pain Relief. How to test --> block the receptors that opioids bind to and see if you get same response in patients. Participants who were particulary responsive to placebos in pain relief - when receptors were blocked they did not get the same placebo effect anymore.

The "Honest Placebo" Harvard IBS study Back pain study

Placebos work even if the patient is told that the treatment is a placebo. Harvard IBS study: - Placebo group had 2x the symptom relief. - Improvement was comparable to actual IBS medications. Chronic low back pain study: - Patients taking pain pills --> 16% reduction in max pain --> 0% reduction in disability. - Patients taking placebo --> 30% reduction in max pain --> 29% reduction in disability. - Did not tell the patients they thought it would work - not the power of suggestion! "Magic Feel Good" pills distributed online, targeted for children.

What makes a placebo effective?

Setting: - Medical > non-medical. Cost of medication: - More effective if costs $$$. Route of administration - Injections > pills. Color: - Blue pills = sedatives - White pills = pain Culture: - Americans tend to prefer injections, whereas Europeans tend to prefer pills. The health care provider's behavior and interactions with the patient can have a pronounced effect on whether a placebo treatment works.

Arthroscopic knee surgery Study

Study done by Bruce Moseley (2002) on the efficiency of arthroscopy for osteoarthritis of the knee. Double-blind, randomized placebo-controlled trial. Intervention groups: - Arthroscopic surgery - Saline flush of the knee - Placebo group - knee opened and no surgery done. The intervention groups were not any more effective than a placebo surgery at reducing pain and improving function in patients.

Placebos in Public Health

Substitution programs for drug addiction: - Overlapping mechanisms of action. - Potential for more gradual weaning off of active drugs Promising avenue of research : --> Reports of successful saline substitution for morphine. --> Subjects unable to distinguish between methadone and placebo.

Biological Mechanisms: Neurotransmitters

The placebo effect in Parkinson's Disease caused by a lack of dopamine in the brain (substantia nigra). **PD is very responsive to placebo effect. Treatment = administer L-Dopa, the precursor for dopamine. Placebo can have the same effect as administering L-Dopa. - Endogenous dopamine (DA) release and receptor binding. - Endogenous dopamine (DA) receptor agonist vs. placebo --> no significant difference in symptom relief. Placebo and administration of dopamine agonists had the same effect.

Takeaways

The placebo effect is powerful and occurs in many different contexts. Both psychological and biological mechanisms are at play. Placebo characteristics matter. There is a gap between mechanistic research and clinical practice.

Psychological Mechanisms: Classical Conditioning

The process of associated learning where two stimuli are linked together to produce a new learned response. A neutral stimulus (bell/alarm) is paired with a stimulus that naturally provokes a response (unconditioned stimulus - i.e. food & salivation). Eventually, the conditioned stimulus alone will elicit the conditioned response (ringing the bell whenever food is present --> salivation). Pills of a certain color, taste, etc. that become associated with the body's natural healing processes. Example: Needle + Morphine = Relief (happen over enough times). Present patients with needle alone becomes a conditioned stimulus that elicits conditioned response of pain relief.

Placebos in Medicine

Two parallel questions: - Can placebo treatments produce clinically significant benefit? - Can nocebo effects produce clinically significant worsening? *Hard to incentive the effect and time that goes into cultivating strong patient-provider relationships.