W11: Intro to pain and placebo +nocebo effects

What is pain, and why do we need it?

An unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage. Pain directs attention to danger and prevents further harm. People with congenital insensitivity to pain suffer severe injuries, infections, and have reduced lifespan because they lack protective feedback. Acute pain is adaptive, promoting withdrawal and avoidance learning—but pain becomes problematic when chronic.

Describe the four stages of the pain mechanism.

Transduction: Nociceptors detect thermal, mechanical, or chemical damage.
Transmission: Primary afferents release glutamate and substance P in the dorsal horn.
Perception: Ascending pathways reach thalamus, insula, ACC, and somatosensory cortex.
Modulation: Descending pathways, especially PAG, can amplify or suppress pain.

What are nociceptors and what stimuli activate them?

Nociceptors are free-ending sensory neurons that detect noxious mechanical, thermal (extremes), chemical (capsaicin), or electrical stimuli. Different subtypes respond to different modalities. They initiate transduction—the first step in converting harmful stimuli into neural signals interpreted as pain.

How do thermoreceptors differ from nociceptors?

Thermoreceptors detect non-noxious temperature changes, while nociceptors activate only at damaging extremes around 45c. Normal thermal detection and pain thresholds are distinct, explaining why warmth is perceptible long before heat becomes painful.

What are pain sensitivity and pain tolerance?

Pain sensitivity reflects how strongly a person perceives painful stimuli; pain tolerance is the maximum intensity they are willing to endure. These vary across individuals and are influenced by genetics, sex, and psychological context.W

What is the difference between a delta fibers and c fiber?

Both are important for different types of pain. A delta are myelinated, these are the A fibers and fire quickly. C fibers are not; it's more of a dull ache and slow firing.

What is the Gate Control Theory of pain?

Melzack & Wall (1965) proposed that non-painful sensory input can compete and modulate in the spinal cord dorsal horn, reducing transmission of nociceptive signals. Like if you rubbed your finger when hit by a hammer. This theory explains why rubbing an injury or applying pressure can reduce pain and highlights top-down modulation.

What is the PAG important for?

Dampening or heightening response to a stimuli. Its in the descending pathway, important for modulation.

What are the important cortices for the ascending pathway?

Somatasory, insular and anterior Cingualte cortices

What brain regions process sensory, cognitive, and affective components of pain?

S1, S2, and posterior insula encode sensory-discriminative aspects. ACC, anterior insula, PFC, and parietal areas handle cognitive–evaluative components. Limbic structures—temporal pole, amygdala, perigenual cortex—encode affective unpleasantness. Pain is multidimensional, not purely sensory. The affective areas may not say where the pain is but are important in chronic pain.

Describe an example of extreme top-down modulation of pain.

Aron Ralston amputated his own arm while trapped in a canyon. Excitement at surviving suppressed the emotional unpleasantness of the pain. This illustrates powerful modulation: descending pathways from cortex through PAG can drastically reduce perceived pain despite severe nociception.

what are the two dimension of pain modulation and do they go together/

The dimensions are the sensory and emotional dimensions. these two dont always go together. For example pain is more intense when attended to and unpleasentness changes based on bad or good mood.

What is the biopsychosocial model of pain?

Pain is influenced by biological factors (genetics, sex), psychological factors (attention, anxiety, depression, prior stress), and social context. Hair colour affects thermal pain sensitivity; sleep, mood, and attention modulate pain intensity. Pain cannot be explained by nociception alone.

What evidence shows social pain overlaps with physical pain?

Exclusion in a virtual ball-toss game activates anterior cingulate and insula—the same regions responding to heat pain. Kross et al. (2011) showed heartbreak activates somatosensory cortex too. Social rejection literally “hurts,” sharing neural substrates with physical pain.

Can physical painkillers reduce social pain? Describe a study.

DeWall et al. (2010) showed Tylenol taken daily for 3 weeks reduced “hurt feelings.” In fMRI, Tylenol lowered ACC and insula responses during cyber-ostracism compared with placebo, suggesting overlapping neural mechanisms for social and physical pain.

How does partner support influence pain?

Viewing a romantic partner’s photo reduced pain by 44% in women experiencing painful stimuli (Master et al., 2009). Partner contact or imagery engages emotional and reward circuits that downregulate pain networks, demonstrating social modulation of pain perception.

A placebo is a beneficial effect driven by positive expectations and or treatments without any therapeutic benefits. (e.g., sugar pill). A nocebo is a harmful effect driven by negative expectations. Both reflect psychological influences on physiological outcomes.

Covert vs Overt placebo":

If you see receiving any medicine, you immediately think its better.

What did the Kam-Hansen (2014) migraine study show about labelling?

Properly labelled Maxalt worked best. Surprisingly, Maxalt labelled as “placebo” was equally effective as placebo labelled “Maxalt.”, there was no difference. Even open-label placebo reduced symptoms compared to no treatment. Expectation from the label significantly shaped drug response magnitude.

How do treatment provider expectations influence placebo effects?

Gracely et al. (1985) showed patients reported more pain relief when clinicians believed they were administering strong analgesics. Provider expectations shape patient expectations, which alter descending pain modulation and perceived relief.

What are the 3 different wat placebo effects can be ellicited?

Parallel group design where there are parallel groups either getting active drug or placebo drug. Open vs hidden drug design and response conditionaing design.

How do classical conditioning and social learning produce placebo/nocebo effects?

Pairing cues with relief or pain creates conditioned placebo/nocebo responses (Egorova et al., 2020). Social observation—seeing someone else experience relief—also produces placebo effects (Colloca & Benedetti, 2009). Both operate through expectation learning.

What neural mechanisms underlie placebo analgesia?

Placebo reduces pain through DLPFC–PAG pathways, activating endogenous opioid and dopamine systems. Expectation of benefits releases endorphins and dopamine, which may cause pain relief. Imaging shows increased PAG activity and connectivity during placebo. The response engages sensory, cognitive, and emotional networks (Wager & Atlas, 2015; Colloca, 2019).

How does placebo reduce social/emotional pain and is there a difference from physical pain?

a Koban et al. (2017) showed placebo of an effecive pain killer which reduces distress on social pain but not the heat pain. Placebo still works in the DLPFC-PAG system but social pain can be distinguished from physical pain in the DLPFC. 

Why are RCTs essential in medicine?

Placebo effects can match or exceed drug effects. Randomised, double-blind placebo-controlled trials isolate true drug efficacy from expectation effects. Without RCTs, perceived benefits might reflect placebo rather than pharmacological action.

What communication strategies reduce nocebo effects?

Positive framing reduces nocebo:
“You’ll feel numb and comfortable” produces less pain than “big bee sting.”
Varelmann et al. (2010) showed negative wording increases perceived pain. Clinicians should minimise alarming language, provide reassurance, and build trust.

What are open-label placebos (OLPs), and do they work?

OLPs are placebos given with full disclosure. Meta-analyses (Fendel et al., 2025) show small but reliable improvements across 60 RCTs—larger in clinical populations and self-report outcomes. Mechanisms may include positive expectations, supportive relationships, and medical ritual.