IM 12.3.1 Physiology of pain 2024-2025

Pain and Neuronal Plasticity

Prof. Dr. Sandra YounanKasr el Aini Faculty of Medicine, Cairo University (2024-2025)

Aims and Objectives

Aim: Provide a comprehensive understanding of the complex phenomenon of pain and its control mechanisms.Objectives:

• Define pain, emphasizing its affective (emotional) and sensory (physical) dimensions.

• Recognize and analyze various factors that modulate the pain experience, including psychological and physiological influences.

• Differentiate between inflammatory pain and neuropathic pain, including their underlying mechanisms and treatment approaches.

• Understand the neuroanatomy of the pain pathway, detailing both ascending and descending pathways.

• Explain concepts of primary and central sensitization in relation to pain perception.

• Identify characteristics and mechanisms of hyperalgesia (increased pain sensitivity) and allodynia (pain from non-painful stimuli).

Definition of Pain

According to the International Association for the Study of Pain (Mersky, 1979):"Pain is an unpleasant emotional and sensory experience associated with actual or potential tissue damage, or described in terms of such damage." Pain acts as a crucial symptom that signifies issues requiring medical attention.

Importance of Pain

Pain serves a protective role by warning individuals of potential injury or tissue damage, thus prompting avoidance of harmful actions and enabling healing processes. Without the sensation of pain, individuals may not recognize harmful situations, increasing the risk of severe injuries.

Dimensions of Pain

Sensory Dimensions

• Intensity: The perceived strength or severity of the pain.

• Quality: Descriptive attributes (e.g., sharp, dull, throbbing, burning).

• Location: The specific body area where pain is felt.

• Duration: The time frame over which pain is experienced (acute vs. chronic).

Primary Affective Dimension

• Unpleasantness: The inherent distress caused by pain.

• Distress: Associated emotional responses, such as fear or frustration.

Secondary Affective Dimension

• Anxiety: Stressful anticipation of pain or worsened condition.

• Depression: Emotional toll that chronic pain can impose over time.

Factors that Modulate Pain Experience

Pain is influenced by a variety of factors, including psychological and environmental aspects.Factors that can decrease pain:

• Pleasure: Activities generating joy release natural pain-relieving chemicals, such as endorphins.

• Stress: Interestingly, moderate stress can sometimes facilitate analgesia.

• Placebo Effect: Psychological expectation can lead to real physiological changes, alleviating pain perceptions.

• Fear: Can act paradoxically; initial fear can heighten pain awareness, yet fear management (through relaxation, for instance) can reduce pain.

Downregulation of Pain

1. Pleasure: Activities yielding pleasure can induce analgesia, enhancing coping mechanisms. For instance, sucrose ingestion in infants with tissue injury can trigger endogenous opioid release, activating brain pathways associated with pleasure.

2. Stress-induced Analgesia: Historical examples, such as observations made by anesthetic consultant H.K. Beecher during WWII, underscore that soldiers in extreme stress often required no analgesics despite severe injuries, illustrating the complex interaction between stress responses and pain perception.

Somatosensory Cortex

• Located in the postcentral gyrus of the lateral parietal lobe, the somatosensory cortex processes sensory information from the opposite side of the body, demonstrating how each body part corresponds to specific designated areas in the cortex that correspond in size to the density of sensory receptors.

Phantom Limb

Amputees may experience sensations in limbs that are no longer present, categorized as follows:

• Phantom Sensation: Non-painful sensations such as tingling and temperature changes.

• Phantom Pain: Painful sensations characterized by squeezing, throbbing, or burning feelings. Understanding the neural mechanisms behind these experiences reveals continued signal transmission from nerve endings and adaptations in brain function post-amputation.

Treatment of Phantom Limb Pain

Mirror Box Therapy: A therapeutic method that utilizes visual feedback to help reestablish a sense of normalcy for amputees. By reflecting the intact limb’s movement, patients perceive the phantom limb as functioning, aiding perceptual reorganization and pain management.

Factors Increasing Pain Experience

• Nocebo Effect: Negative expectations can exacerbate pain experiences, highlighting the psychological component of pain perception.

• Stress-Induced Hyperalgesia: Such as experiences in settings of anxiety, like dental offices, can elevate perceived pain levels.

• Inflammation: Inflammatory responses can intensify pain experiences through biochemical mediators.

• Neuropathic Pain: Resulting from lesions or diseases impacting the somatosensory system, often resistant to conventional treatments.

Inflammatory Pain

Associated with conditions that follow tissue injuries, it is typically managed through nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and newer pharmacological treatments that target specific growth factors involved in the inflammatory process.

Neuropathic Pain

Arises from damage to the nervous system, presenting challenges in management, often requiring alternative approaches like tricyclic antidepressants, which can modify pain pathways.Example: Trigeminal neuralgia, characterized by unilateral facial pain, exemplifies the complexities of neuropathic pain.

Pain Pathways Overview

Pain Processing Pathway:

• Pain receptors stimulate peripheral sensory nerves, such as C fibers and A delta fibers, transmitting signals to the nervous system.

• First-order neurons carry these signals to the ipsilateral dorsal root ganglia (DRG), where second-order neurons relay information to the ipsilateral dorsal horn of the spinal cord.

• Signals are then conveyed to third-order neurons in the contralateral thalamus before ascending to the contralateral cortex, which ultimately enables pain perception.

Primary and Central Sensitization

Definitions:

• Allodynia: A condition where normally non-painful stimuli provoke pain.

• Hyperalgesia: Heightened sensitivity to painful stimuli.

Primary Sensitization arises primarily through C fibers in response to mechanical stimuli, whereas Central Sensitization relates to responses from thermal stimuli processed by C fibers in the DRG.

Chronic Pain and Central Sensitization

Chronic pain is often linked with sustained central sensitization. For example, individuals with chronic low back pain may show more intense and widespread pain responses even to normal stimuli when compared to healthy individuals.

Brain Communication with Dorsal Horn

The brain communicates with the dorsal horn to modulate pain via descending pathways, notably through the Rostromedial Ventral Medulla (RVM). This communication can either inhibit or amplify pain experiences based on various neurotransmitters (e.g., noradrenalin, GABA, serotonin, glutamate).

Descending Pain Modulation

Inhibitory pathways are established from the anterior cingulate cortex to the periaqueductal gray (PAG), down to the RVM and dorsal horn neurons, whereas facilitatory pathways mediated by ON neurons can contribute to the persistence of chronic pain conditions.

Opioids and Chronic Pain

The administration of opioids in chronic pain patients is sometimes pursued to alleviate pain, with lower addiction risks owing to the nature of chronic pain minimizing the rewarding effects typically associated with opioid use.Opioids exert their effects by binding to specific opioid receptors, generating morphine-like outcomes that can effectively reduce pain perception in suitable patients.

Risk of Addiction

While addiction risk is generally low for cases of non-terminal chronic pain, particularly without prior substance use disorders, it is essential to remain vigilant against the potential for relapse and compulsive drug-seeking behaviors associated with opioid use. Addiction is characterized by compulsive use despite adverse consequences, highlighting the need for careful monitoring and management.

References

• Fields, H. L. (2009). The Psychology of Pain. Sci Am Mind, 42-49.

• Fields, H. (2004). State-dependent opioid control of pain. Nature Reviews Neuroscience, 5(7), 565-575.

• Eippert et al. (2009). Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia. Neuron, 63(4), 533-543.

• Ramachandran, V. S., & Altschuler, E. L. (2009). Visual feedback's role in restoring brain function. Brain, 132(7), 1693-1710.

• Marinus et al. (2011). Complex regional pain syndrome Clinical features. Lancet Neurology, 10: 637-48.

• Todd, A. J. (2010). Neuronal circuitry for pain processing in the dorsal horn. Nature Reviews Neuroscience, 11(12), 823-836.

Here are 10 case-based single best answer (SBA) questions related to pain and neuronal plasticity:

1. Case 1: Inflammatory Pain

A 45-year-old man presents to the emergency department with severe lower back pain after lifting a heavy box. He describes the pain as sharp and localized to the lower back. What is the most likely underlying mechanism for his pain?

• A) Neuropathic pain

• B) Inflammatory pain

• C) Central sensitization

• D) Allodynia Correct Answer: B) Inflammatory pain

2. Case 2: Neuropathic Pain

A 30-year-old woman reports intermittent, extremely painful shocks in her left cheek triggered by light touch. What condition does she most likely have?

• A) Inflammatory pain

• B) Neuropathic pain

• C) Hyperalgesia

• D) Phantom limb painCorrect Answer: B) Neuropathic pain

3. Case 3: Phantom Limb Pain

An amputee reports experiencing a painful sensation in his right leg, which was removed three months ago. This sensation includes feelings of burning and squeezing. What type of pain is he experiencing?

• A) Allodynia

• B) Neuropathic pain

• C) Phantom pain

• D) Acute painCorrect Answer: C) Phantom pain

4. Case 4: Chronic Pain Management

A 50-year-old female with chronic low back pain is being considered for opioid therapy. Which of the following statements is true regarding opioid use for chronic pain?

• A) Opioids have no potential for addiction in chronic pain patients.

• B) Opioids are the first-line treatment for all chronic pain conditions.

• C) The risk of addiction is low without a history of substance use disorders.

• D) Opioids always eliminate pain completely.Correct Answer: C) The risk of addiction is low without a history of substance use disorders.

5. Case 5: Stress-Induced Analgesia

An army soldier sustains a severe injury but reports lower levels of pain than anticipated due to the high-stress situation. What physiological phenomenon does this illustrate?

• A) Stress-induced hyperalgesia

• B) The nocebo effect

• C) Stress-induced analgesia

• D) Central sensitizationCorrect Answer: C) Stress-induced analgesia

6. Case 6: Pain Pathway Review

A 28-year-old man has chronic pain due to nerve damage from diabetes. In his case, which structure is primarily affected when transmitting signals from the periphery to the central nervous system?

• A) Periaqueductal Gray (PAG)

• B) Dorsal root ganglia (DRG)

• C) Medulla oblongata

• D) Somatosensory cortexCorrect Answer: B) Dorsal root ganglia (DRG)

7. Case 7: Pain Perception

A patient expresses that his pain feels worse on some days due to heightened stress. What psychological effect best explains this phenomenon?

• A) Allodynia

• B) Nocebo effect

• C) Hyperalgesia

• D) Central sensitizationCorrect Answer: C) Hyperalgesia

8. Case 8: Treatment of Inflammatory Pain

A patient with post-operative pain is given ibuprofen for pain relief. What is the primary mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen?

• A) Inhibit opioid receptors

• B) Block the synthesis of prostaglandins

• C) Enhance GABAergic transmission

• D) Stimulate the release of endorphinsCorrect Answer: B) Block the synthesis of prostaglandins

9. Case 9: The Role of the Placebo Effect

A study demonstrated that patients who expected pain relief experienced significantly less pain when given a placebo treatment. What is the underlying explanation for this phenomenon?

• A) Direct pharmacological effects of the placebo

• B) Psychological expectation leading to physiological changes

• C) Increased pain threshold from ancient practices

• D) Reduced exercise levels and subsequent pain reliefCorrect Answer: B) Psychological expectation leading to physiological changes

10. Case 10: Mechanisms of Central Sensitization

A researcher is studying how chronic pain conditions lead to central sensitization in patients. Which of the following changes is characteristic of central sensitization?

• A) Decreased pain perception to non-painful stimuli

• B) Increased responsiveness of central pain pathways

• C) Direct damage to peripheral sensory nerves

• D) Activation of nociceptive specific pathways onlyCorrect Answer: B) Increased responsiveness of central pain pathways