Neurobiology of placebo effects in analgesia Flashcards
What is the origin of the word “placebo,” and how was it initially viewed in the context of medicine?
- “Placebo” is derived from Latin, meaning “I shall please.”
What is the modern definition of the placebo effect?
- 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
How does descending inhibition relate to the placebo effect in pain modulation?
- 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
What are the key components of the descending pain modulation system within the CNS?
- Descending pathway.
- Midbrain PAG and RVM.
- Inhibition of ascending nociceptive transmission.
- Stress-induced analgesia.
- Mediated by opioid and cannabinoid systems.
- GABA disinhibition for analgesia.
How do opioids and cannabinoids affect descending analgesia at the cellular level?
- Opioids inhibit GABA release
- Activation of output neurons
- Cannabinoids act pre-synaptically
- Excitation of output neurons.
How has the placebo effect been regarded historically in clinical trials and why is it now a subject of scientific inquiry?
- Historically seen as problematic.
- Led to double-blind placebo trials.
- Now a focus of scientific research.
What are the mechanisms behind placebo effects?
- Conscious and unconscious mechanisms.
- Conscious: patient’s awareness of expectations and beliefs.
- Unconscious: conditioned responses.
Which brain regions are involved in the placebo response, and what roles do they play?
- 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
What are the key components of the descending pain modulation system within the CNS?
- Descending pathway
- Midbrain PAG & RVM
- Inhibition of ascending nociceptive transmission
- Stress-induced analgesia
- Mediated by opioid & cannabinoid systems
- GABA disinhibition for analgesia
How do opioids and cannabinoids affect descending analgesia at the cellular level?
- Opioids inhibit GABA release.
- Activation of output neurons.
- Cannabinoids act pre-synaptically.
- Excitation of output neurons.
How has the placebo effect been regarded historically in clinical trials and why is it now a subject of scientific inquiry?
-Historically seen as problematic.
- Led to double-blind placebo trials.
- Now a focus of scientific research.
What are the mechanisms behind placebo effects?
-Conscious and unconscious mechanisms.
- Conscious: patient’s awareness of expectations and beliefs.
- Unconscious: conditioned responses.
Which brain regions are involved in the placebo response, and what roles do they play?
- 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
How do expectation and conditioning play different roles in placebo analgesia?
- Expectation triggers endogenous opioids.
- Conditioning activates specific subsystems.
- Conditioning can involve opioids or non-opioid systems
What role do cannabinoid receptors play in non-opioid placebo analgesia?
- Non-opioid placebo analgesia is mediated by cannabinoid receptors.
- Rimonabant blocks non-opioid analgesia.
How was the placebo analgesia experiment conducted by Benedetti in 2011, and what were the key findings?
- 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.
What are common misconceptions in placebo studies, and how can they be addressed?
- 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.
What are the key characteristics and principles of a double-blind placebo-controlled study?
- 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.
What is the difference between open and hidden treatments in placebo effects, and what does research suggest about their efficacy?
- 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.
How does brain imaging support the opioid hypothesis in placebo analgesia?
- 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.
How do expectations and the psychosocial context affect drug responses and receptor pathways?
- Expectations & conditioning mechanisms activate receptor pathways.
- Psychosocial context can perturb the system & change drug responses
- Implications for understanding drug action.
What complicates the relationship between nociceptive input, pain experience, and reporting pain or relief?
- Nociception is often not linearly related to pain experience.
- Factors include peripheral & central sensitization, genetics, cognition, and emotions.
Which brain regions are involved in the descending pain and cognitive modulatory networks?
- dlPFC, vlPFC, PAG, thalamus, amygdala, RVM, ACC.
- Hippocampus plays a role in amplifying pain experiences during nocebo or increasing anxiety.
How do an individual’s expectations influence a drug’s therapeutic efficacy, and what should be considered in drug treatment regimes to optimize outcomes?
- 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.
