Clinical Research: July 2019

What is placebo effect ??

Placebo effects are beneficial effects that are attributable to the brain-mind response to the context in which a treatment is delivered rather than to specific action of the drug. mediated by the diverse process including learning, expectation and social cognition and can influence various clinical and physiological outcomes related to health. commonly used terms for placebo are "sugar pills", "dummy drugs", "fake drugs", "sham treatment".

Though placebo was introduced in 18^thwas century, has been featured in medical treatment since 1995, when Henry k. Beecher published an influential paper entitled powerful placebo by enlightening the clinically important aspects of placebo treatment.

modern medicines in spite of its overwhelming success over disease by altering physiology and pathological mechanism, couldn't succeed over pain and psychological distress that are integral to many diseases and to treat disorders like depression, chronic pain, anxiety and fatigue. In such spectrum placebo is dragging more attentions.

Where is placebo being Used ?

A placebo is used in clinical trials to test the effectiveness of treatments and is most often used in drug studies. For instance, people in one group get the tested drug, while the others receive a fake drug, or placebo, that they think is the real thing. This way, the researchers can measure if the drug works by comparing how both groups react. If they both have the same reaction — improvement or not — the drug is deemed not to work.
Actual potency of drug can be determined by eliminating psychological factors by using appropriate statistical methods of analysis
Placebo as an anonymous therapy during any intervention of established treatment which includes emotional, cognitive and social aspects of clinical practice.

Psycho-physiology behind placebo effect !!!

Placebo works through a complicated and holistic psycho-physiological system. psychological and physiological components of the placebo phenomenon are connected in a way which is analogous to the connection between thermal imagery and skin blood flow and skin temperature. By analogy, the physiological effects of placebo treatment depends on content of patients treatment related imagery

The long term effect of placebo in a specific disease depends on duration and repetition of single placebo effects. Therefore, its effects is more long-lasting than the effects of more specific agents
Unlike disease pathology, pain and distress are rooted in complex brain functions and influenced by internal thought, brain pathology, brain states and conception of social and environmental context. Moreover visual perception, memory, decision making , athletic and cognitive performances also share context effects.
Emerging neuroscience implicates multiple brain systems and neurochemical mediators including opioids, cannabinoids and dopamine . Certain relevant brain areas involved are: prefrontal cortex, anterior insula, rostral anterior singulate cortex and amygdala in analgesia)

Humans are endowed with uniquely powerful system for representing context, which help to tailor our response to the needs of given situations. clinical context particularly denotes certain psychological element like learned associations between cues and positiveness/Negative experiences, conceptual knowledge based on verbal suggestion, expectation about treatment outcome and social interactions, patient-care provider relationship, emotional and cognitive interaction with clinicians etc.

Moreover, recent clinical research into placebo effects has provided compelling evidence that these effects are genuine biopsychosocial phenomena that represent more than simply spontaneous remission, normal symptom fluctuations, and regression to the mean.

Potential and Identified benefits of placebo treatment:

potency and magnitude of placebo effect is under appreciate in terms of clinical practice. Both psychology and physiology are affected equally sometimes effects of placebo have been found to be stronger than the effects of medication itself.

Improves the quality of life
Mitigates burdens of disability and decrease mortality. in ones study, patients with congestive heart failure who adhere to taking placebo regularly were 50% less likely to die than medication group.
Similar results on stroke and heart attack
Placebo have been found to influence the activity of the autonomic nervous system such as heart rate , GI activity and respiration
Endocrine secretions, specially level of cortisol is found to be decreased based on expectation only.
Immune system activities were found to be greatly affected by placebo mechanism. Immunosupression was seen by placebo-induced response and in another study, watching advertisement of the antihistamine drug "claritin" led to the drug being more effective than others who didn't receive any pro-drug messages.

Sometimes, clinicians and pharmaceutical products are being appreciated beyond scientifically proven efficacy, which might have been associated with placebo effects.

How Neurobilogy is linked to ???

Despite numerous experiments, neurobiological system are yet to learn. As of now, it might be different according to type of stimulus or expectation.
For neuroscientist, placebo studies provides a way to investigate how the brain system that process contextual information influence physiological and clinically relevant outcomes
Neuroimaging studies on pain modules shows decrease in activity of thalamus, somatosensory cortex (processing center), insula (mediates emotional response) and anterior cingulate cortex (emotional response).
larger the placebo effects greater the reduction of activity on these areas.
Other than pain centers, placebo also activates pathways between brain stem to spinal cord to inhibit pain response.

In mid-brain, an area called periaqueductal grey gets activated, which inhibits variety of cortical areas, and leads to increased secretions of natural painkillers (endogenous opioids).

Some studies shows activity in periaqueductal grey is associated with degree of placebo in analgesia. Same mechanism works in anti-anxiety placebo medications
Higher brain regions like prefrontal cortex, amygdala and striatums also affected by placebo.
Other than mitigating pain, placebo has also been found to affect experiences ranging from emotions to movements in Parkinson's diseases. Studies in PD has shown to increase the level of dopamine in striatum, which is associated with improved movements /mobility.

The full neural circuitry of brain might be more complex than collection of particular regions as outlined above, which might includes more intricate neurological basis than just endogenous opioids and dopamines. recent examples: cholecystokinin and oxytocin.

Same brain regions ( lets say prefrontal cortex) can be acting differently in different diseases (pain and anxiety). thus it's uncertain if this shareds neurall circuitary is actually working in the same manner in different placebo situations.

Why one can't rely on placebo as treatment strategy?

First, though placebos may provide relief, they rarely cure. The evidence to date suggests that the therapeutic benefits associated with placebo effects do not alter the Pathophysiology of diseases beyond their symptomatic manifestations. Several experiments demonstrated that common symptoms of cancer and side effects of treatment (nausea, vomiting, fatigue, hot flashes etc.) are greatly improved with placebo but there is no evidence that placebos can shrink tumors.

Similarly, in patients with asthma, symptoms like breathlessness, chest tightness have been greatly improved without affecting FEV1 (forced expiratory volume in 1 second ).

The psycho social factors that promote therapeutic placebo effects also have the potential to cause adverse consequences, known as nocebo effects. generally anticipation of the negative symptoms of drug therapy leads to presentation of actual symptoms. Such nocebo effect has been demonstrated in Benign Prostatic Hyperplasia with "finsteride". Those patients informed of sexual side effects reported such effects three times more than those uninformed. similar finding with anti-migraine therapy on cognitive effects.

Although relief of symptoms is one aspects of treatment, on which placebo has been succeeded, core truth of medicine lies in cure and control disease. there are paucity of evidence where placebo actually cured disease by changing the pathophysiology.