Neurobiology of placebo effects in analgesia

Question 1

What is the origin of the word “placebo,” and how was it initially viewed in the context of medicine?

Answer 1

• “Placebo” is derived from Latin, meaning “I shall please.”

Question 2

What is the modern definition of the placebo effect?

Answer 2

• it encompasses a psycho-socio-biological phenomenon
• occurs when patients believe in the effectiveness of a therapy and expect a reduction in symptoms
• placebo effects can result from either a dummy treatment or administration of an inert medical treatment, which may/may not be pharmacological

Question 3

How does descending inhibition relate to the placebo effect in pain modulation?

Answer 3

• descending inhibition involves disinhibition of PAG-RVM pathway through GABAergic interneurons
• opioids & cannabinoids suppress inhibitory GABAergic interneurons, indirectly exciting output neurons in antinociceptive pathway, which inhibits nociceptive transmission at the spinal cord level
• Opioids & cannabinoids act on inhibitory & excitatory neurons to mediate pronociception & antinociception, playing a role in placebo effect related to pain relief

Question 4

What are the key components of the descending pain modulation system within the CNS?

Answer 4

• Descending pathway.
• Midbrain PAG and RVM.
• Inhibition of ascending nociceptive transmission.
• Stress-induced analgesia.
• Mediated by opioid and cannabinoid systems.
• GABA disinhibition for analgesia.

Question 5

How do opioids and cannabinoids affect descending analgesia at the cellular level?

Answer 5

• Opioids inhibit GABA release
• Activation of output neurons
• Cannabinoids act pre-synaptically
• Excitation of output neurons.

Question 6

How has the placebo effect been regarded historically in clinical trials and why is it now a subject of scientific inquiry?

Answer 6

• Historically seen as problematic.
• Led to double-blind placebo trials.
• Now a focus of scientific research.

Question 7

What are the mechanisms behind placebo effects?

Answer 7

• Conscious and unconscious mechanisms.
• Conscious: patient’s awareness of expectations and beliefs.
• Unconscious: conditioned responses.

Question 8

Which brain regions are involved in the placebo response, and what roles do they play?

Answer 8

• Dorsolateral prefrontal cortex.
• Nucleus accumbens (reward system).
• Orbitofrontal cortex (cognitive processes).
• Balance of cognitive factors and conditioning mechanisms.
• Crucial for opioid or non-opioid system activation

Question 9

What are the key components of the descending pain modulation system within the CNS?

Answer 9

• Descending pathway
• Midbrain PAG & RVM
• Inhibition of ascending nociceptive transmission
• Stress-induced analgesia
• Mediated by opioid & cannabinoid systems
• GABA disinhibition for analgesia

Question 10

How do opioids and cannabinoids affect descending analgesia at the cellular level?

Answer 10

• Opioids inhibit GABA release.
• Activation of output neurons.
• Cannabinoids act pre-synaptically.
• Excitation of output neurons.

Question 11

How has the placebo effect been regarded historically in clinical trials and why is it now a subject of scientific inquiry?

Answer 11

-Historically seen as problematic.
- Led to double-blind placebo trials.
- Now a focus of scientific research.

Question 12

What are the mechanisms behind placebo effects?

Answer 12

-Conscious and unconscious mechanisms.
- Conscious: patient’s awareness of expectations and beliefs.
- Unconscious: conditioned responses.

Question 13

Which brain regions are involved in the placebo response, and what roles do they play?

Answer 13

• Dorsolateral prefrontal cortex
• Nucleus accumbens (reward system)
• Orbitofrontal cortex (cognitive processes)
• Balance of cognitive factors & conditioning mechanisms
• Crucial for opioid or non-opioid system activation

Question 14

How do expectation and conditioning play different roles in placebo analgesia?

Answer 14

• Expectation triggers endogenous opioids.
• Conditioning activates specific subsystems.
• Conditioning can involve opioids or non-opioid systems

Question 15

What role do cannabinoid receptors play in non-opioid placebo analgesia?

Answer 15

• Non-opioid placebo analgesia is mediated by cannabinoid receptors.
• Rimonabant blocks non-opioid analgesia.

Question 16

How was the placebo analgesia experiment conducted by Benedetti in 2011, and what were the key findings?

Answer 16

• Six groups: no-treatment, rimonabant (control), opioid conditioning, morphine, non-opioid conditioning, non-opioid conditioning with rimonabant.
• Rimonabant had no effect on relationship between morphine and placebo.
• Rimonabant disrupted correlation between analgesic response to ketorolac and placebo.

Question 17

What are common misconceptions in placebo studies, and how can they be addressed?

Answer 17

• Misattributing placebo effects to spontaneous remission/regression to the mean.
• Real placebos are due to expectation & conditioning
• Addressed through double-blind randomized placebo-controlled studies with two arms.

Question 18

What are the key characteristics and principles of a double-blind placebo-controlled study?

Answer 18

• Two arms: one with active treatment, one with a placebo.
• Neither doctor nor patient knows which treatment is administered.
• Patients informed of the 50% probability of receiving placebo.
• To conclude drug effectiveness, it must outperform the placebo.

Question 19

What is the difference between open and hidden treatments in placebo effects, and what does research suggest about their efficacy?

Answer 19

• Hidden treatment (telling patient a painkiller is given but only saline) can be as potent as morphine
• Open treatment initially provides benefits mainly due to placebo effect
• Making expectation pathways silent decreases the effectiveness of hidden therapy, inhibiting the top-down pathway that interferes with pain perception.

Question 20

How does brain imaging support the opioid hypothesis in placebo analgesia?

Answer 20

• Same brain areas activated by placebo & opioid drugs
• Involvement of descending rACC-PAG-pons-medulla pain-modulating circuit in placebo analgesia
• fMRI studies show decreased activity in pain pathways after placebo treatment &activation of a cognitive-evaluative network before placebo response.

Question 21

How do expectations and the psychosocial context affect drug responses and receptor pathways?

Answer 21

• Expectations & conditioning mechanisms activate receptor pathways.
• Psychosocial context can perturb the system & change drug responses
• Implications for understanding drug action.

Question 22

What complicates the relationship between nociceptive input, pain experience, and reporting pain or relief?

Answer 22

• Nociception is often not linearly related to pain experience.
• Factors include peripheral & central sensitization, genetics, cognition, and emotions.

Question 23

Which brain regions are involved in the descending pain and cognitive modulatory networks?

Answer 23

• dlPFC, vlPFC, PAG, thalamus, amygdala, RVM, ACC.
• Hippocampus plays a role in amplifying pain experiences during nocebo or increasing anxiety.

Question 24

How do an individual’s expectations influence a drug’s therapeutic efficacy, and what should be considered in drug treatment regimes to optimize outcomes?

Answer 24

• Individual expectations critically influence drug efficacy.
• Brain mechanisms vary depending on expectancy
• Integrating patients’ beliefs & expectations into treatment, alongside traditional considerations, may be necessary to optimize outcomes.