#345 ‒ Chronic pain: pathways, treatment, and the path to physical and psychological recovery | Sean Mackey, M.D., Ph.D.
Dr. Sean Mackey, Professor of Pain Medicine at Stanford, discusses pain as a biopsychosocial phenomenon, its evolutionary role, and how it's transmitted. He covers various pain types, individual perception differences, and management strategies including medications, neuromodulation, and the psychological impact of chronic pain.
Deep Dive Analysis
18 Topic Outline
Introduction to Dr. Sean Mackey and Peter's Personal Story
Defining Pain: Formal Definition and Evolutionary Purpose
Historical Models of Pain and the Biopsychosocial Shift
Biological Mechanisms of Pain: Nociceptors and Nerve Fibers
Consciousness and Pain Perception During Anesthesia
Categorizing Pain: Nociceptive, Visceral, Neuropathic, Nociplastic
Objective Measurement of Pain Using fMRI
Brain's Role in Pain Modulation and Individual Variability
Impact of Psychological Factors and Sleep on Pain
Peter's Chronic Back Pain Journey and Opioid Experience
Pharmacology of NSAIDs, COX-2 Inhibitors, and Acetaminophen
Muscle Relaxants: Benefits and Use Cases
Defining Chronic Pain and Antidepressants in Management
Opioids: Nuanced Role and Responsible Prescribing
Alternative Therapies: Acupuncture and Cannabis
Fibromyalgia: Definition, Mechanisms, and Low-Dose Naltrexone
Peter's Recovery and the Role of Rehabilitation
Sean's Personal Experience with Cluster Headaches
11 Key Concepts
Pain (Formal Definition)
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. It also serves as a primitive, essential motivator for survival, driving organisms away from danger.
Descartes' Dualistic Model of Pain
A 17th-century framework proposing a complete separation between the body, where pain is generated, and the mind, which passively perceives these signals. This model, though foundational, is now considered fundamentally incorrect as it fails to account for the integrated nature of pain.
Biopsychosocial Model of Pain
A modern, integrated understanding that pain is a complex phenomenon influenced by biological (e.g., nociception), psychological (e.g., emotions, beliefs), and social (e.g., environment, support) factors. It emphasizes that pain is not merely a physical sensation but a holistic experience.
Nociceptors
Specialized transducers located in skin, soft tissues, deep tissues, and viscera that convert different forms of energy (pressure, heat, cold, or chemical changes) into electrochemical impulses, which are then transmitted up nerves.
C-fibers
Thin, slow nerve fibers that transmit electrochemical impulses at about one meter per second. They are responsible for the delayed, hot, burning, and unpleasant sensation of pain, acting as a 'longer-term harm alarm' to promote healing and prevent re-injury.
A-delta Fibers
Faster nerve fibers with some insulation that transmit electrochemical impulses at about 10 meters per second. They are responsible for the sharp, well-localized jolt of pain, initiating rapid withdrawal reflexes and protective actions.
Neuropathic Pain
Pain caused by injury or dysfunction to either the peripheral or the central nervous system. It is often described with qualities like burning, sharp, lancinating, stabbing, or shock-like, and can be challenging to treat with common analgesics.
Nociplastic Pain
A newly introduced category of pain thought to represent dysfunction in the central pain processing system, causing, perpetuating, and amplifying pain even in the absence of identifiable peripheral causes. It is associated with conditions like fibromyalgia, temporomandibular disorders, and irritable bowel syndrome.
Gate Control Theory of Pain
A theory positing that the spinal cord acts like a 'gate,' opening or closing to turn up or down pain signals heading to the brain. This gate is influenced by other nerve fibers, such as fast-conducting A-beta touch fibers, and descending systems from the brain, allowing for neuromodulation.
Catastrophizing
A concept describing an individual's response to pain characterized by amplification of pain, rumination (repetitive thoughts) about pain, and a sense of helplessness or loss of control over their pain. It has neurobiological consequences, negatively impacting prefrontal cortical circuits that modulate pain.
Low-Dose Naltrexone (LDN)
Naltrexone at a very low dose (e.g., 4.5 mg) that is thought to block toll-like 4 receptors on microglia, which are neural immune modulators. By blocking these receptors, LDN may reduce neuroinflammation and pain perception, distinct from its use as an opioid blocker at higher doses.
14 Questions Answered
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage, serving as a primitive and essential survival mechanism.
Historically, pain was viewed through René Descartes' dualistic model, separating body and mind. Modern understanding has shifted to an integrated biopsychosocial model, recognizing pain as a complex phenomenon influenced by biological, psychological, and social factors.
While there isn't a single 'pain receptor,' specialized transducers called nociceptors convert various forms of energy (pressure, heat, cold, chemical changes) into electrochemical impulses that are transmitted up nerves.
Yes, a conscious brain is required for the *experience* of pain. During unconscious states like anesthesia, nociceptive signals (injury signals) still reach the spinal cord and brain, causing stress responses, but the patient does not perceive pain.
Pain perception varies widely due to individual differences in brain processing, emotional state, cognitive factors, beliefs, early life experiences, and the brain's capacity to modulate (turn up or down) pain signals through descending control systems.
Pain is categorized into nociceptive pain (from primary nociceptor activation), visceral pain (from internal organs), neuropathic pain (from nervous system injury/dysfunction), and nociplastic pain (from central pain processing dysfunction, e.g., fibromyalgia).
While traditionally subjective, research using functional magnetic resonance imaging (fMRI) has identified core patterns in the brain that represent the experience of pain, allowing for objective biomarkers to predict pain states, treatment responses, and future vulnerability.
NSAIDs work by inhibiting cyclooxygenase, reducing inflammation and the 'inflammatory soup' that sensitizes nociceptors. While effective for acute pain, there's debate on whether they might delay natural healing, and long-term use carries risks to blood pressure, heart, and kidneys.
Muscle relaxants like Baclofen help reduce muscle spasms and associated pain. Baclofen is considered relatively safe and non-habit-forming, often used for acute muscle kinks or spasms, but long-term use data for chronic conditions is limited.
Chronic pain is defined as pain that persists beyond the expected time of tissue healing, making it context-specific rather than solely based on an arbitrary timeframe like three or six months.
Antidepressants, particularly tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine, are effective pain agents not primarily for their mood-changing properties, but because they modulate neurotransmitters (serotonin, norepinephrine) and block sodium channels in pain pathways in the brain and spinal cord.
Opioids are a powerful tool for pain relief, especially in acute and end-of-life care, but their use requires careful consideration due to risks of dependence and abuse. Responsible prescribing involves assessing patient vulnerabilities (e.g., depression, anxiety, trauma history) and integrating them into a broader, team-based pain management plan focused on functional rehabilitation.
Fibromyalgia is a syndrome of widespread bodily pain, fatigue, mental fog, and sleep disturbances, now understood to involve abnormal brain processing of pain and potentially small fiber neuropathy. Management often involves brain modulatory drugs like duloxetine and low-dose naltrexone, alongside physical and psychological therapies.
At low doses (e.g., 4.5 mg), naltrexone is thought to block toll-like 4 receptors on microglia, which are neural immune modulators that, when activated by stress or injury, release inflammatory mediators that sensitize central nerves. By blocking this, LDN may reduce neuroinflammation and pain perception.
30 Actionable Insights
1. Reject Dualistic Pain Model
Discard the outdated dualistic model of pain that separates body and mind, and instead understand pain as an integrated biopsychosocial phenomenon.
2. Acknowledge Individual Pain Variability
Understand that the intensity of a physical stimulus (nociception) may have little correlation with an individual’s actual experience of pain, as perception varies widely from person to person.
3. Acknowledge Psychological Pain Influence
Recognize that psychological and emotional factors, including early life experiences, significantly influence pain perception, even in the face of identical physical stimuli.
4. Manage Mental State for Pain
Be aware that your mental state, including anxiety, apprehension, and sleep quality, significantly influences your experience and perception of pain.
5. Prioritize Sleep to Reduce Pain
Ensure adequate sleep, as sleep deprivation significantly alters the brain and spinal cord’s set point for pain perception, amplifying pain and impairing its modulation.
6. Adopt Anti-Inflammatory Diet
Consider your diet’s role in pain, as consuming foods that cause inflammation can lead to peripheral sensitization, amplifying nociceptor activity and increasing pain perception.
7. Control Glucose for Neuropathic Pain
For individuals with diabetic neuropathic pain, strict glucose control is a major predictor of pain management, as high blood sugar damages nerve fibers involved in pain.
8. Educate Yourself on Pain Condition
Learn as much as possible about your specific pain condition to become informed, which can reduce fear, prevent amplification of pain, and build self-efficacy, significantly improving your quality of life.
9. View Pain Setbacks as Temporary
When experiencing pain setbacks, adopt the mindset that they are not permanent; this builds confidence, reduces catastrophizing, and helps you make necessary adjustments, knowing the discomfort will eventually pass.
10. Prioritize Social Connection for Pain
Actively combat social isolation and prioritize social functioning, as it plays a key role in managing overall pain and improving quality of life.
11. Request Pre-Surgical Pain Plan
Before elective surgery, proactively ask your surgeon about pain management, requesting an interface with an acute pain service to develop a pre-surgical plan, including regional anesthetics, to optimize recovery and minimize opioid use.
12. Address Pre-Surgical Psychological Vulnerabilities
Be aware that preoperative psychological factors like depression, anxiety, catastrophizing, and trauma history are strong predictors of persistent pain and opioid use after surgery, and addressing these can improve outcomes.
13. Trial Low-Dose Naltrexone for Chronic Pain
Consider a trial of Low-Dose Naltrexone (LDN) at 4.5mg for chronic pain conditions like fibromyalgia, as it may reduce neuroinflammation with minimal side effects (vivid dreams) and low cost.
14. Utilize Gabapentinoids for Neuropathic Pain
For neuropathic pain, consider gabapentin or pregabalin, which turn down pain signals in the spinal cord and brain and can aid sleep, though elderly patients should be cautious of falls.
15. Use Antidepressants for Pain Modulation
Consider specific antidepressants, particularly tricyclics (e.g., desipramine, nortriptyline) and SNRIs (e.g., duloxetine), for pain management, as they modulate neurotransmitter systems involved in pain regardless of mood.
16. Opioids as Last-Resort Tool
Consider opioids as a specific tool for severe pain, such as end-of-life or cancer pain, but avoid them as a first-line agent due to their risks and the availability of many other pain management options.
17. Combine Acetaminophen and Ibuprofen
For enhanced pain relief, combine acetaminophen and ibuprofen due to their different mechanisms of action, which allows for lower doses of each while achieving synergistic effects.
18. Judicious NSAID Use for Function
Use NSAIDs like ibuprofen or naproxen to reduce inflammation and improve function if pain is significant, but be mindful that for minor pain, avoiding them might support natural healing processes.
19. Experiment with NSAID Types
Due to individual variability in response and how different NSAIDs permeate tissues, experiment with various types (e.g., naproxen, ibuprofen) to find which is most effective for your pain.
20. Limit Acetaminophen with Alcohol/Liver Issues
Limit acetaminophen intake, especially if you have liver dysfunction or consume large amounts of alcohol, with a recent push to reduce the maximum daily dose to two grams.
21. Consult Doctor for NSAID Use
Before prolonged use of NSAIDs (e.g., 800mg ibuprofen three times daily for 1-2 weeks), consult your doctor, especially if you are older or have kidney or GI issues.
22. Consider Baclofen for Muscle Pain
For acute muscle pain, consider Baclofen as a safe, non-habit-forming muscle relaxant, but continuously evaluate its long-term benefit and consider weaning if no longer effective.
23. Utilize TENS for Musculoskeletal Pain
For nociceptive musculoskeletal pain, consider using a TENS (Transcutaneous Electrical Neural Stimulation) unit, placing pads over the painful area to activate A-beta fibers and achieve neuromodulatory pain relief.
24. Rub Injured Area for Pain Relief
When experiencing pain from an injury, rub the affected area to activate A-beta touch fibers, which can inhibit pain signals in the spinal cord and reduce pain perception.
25. Differentiate Pain Signals’ Purpose
Understand that sharp, localized pain (A-delta fibers) prompts immediate withdrawal, while delayed, burning pain (C-fibers) serves as a long-term harm alarm to encourage healing and prevent re-injury.
26. Understand Pain’s Survival Role
Recognize pain as a fundamental, primitive survival mechanism that keeps us alive, rather than solely an unpleasant experience.
27. Understand Fibromyalgia’s Central Nature
Recognize fibromyalgia as a complex syndrome of widespread pain, fatigue, and cognitive issues, linked to abnormal central pain processing in the brain and often triggered by traumatic events.
28. Consider Acupuncture for Pain
If affordable and performed in a hygienic facility, consider trying acupuncture for pain, as some individuals find it effective for conditions like back pain, musculoskeletal pain, and migraines.
29. Approach Cannabis for Pain with Caution
Approach cannabis for pain relief with caution, as evidence is mixed; while some short-term benefits for neuropathic pain exist, current forms are not well-studied or standardized, and observational data suggests worse outcomes for chronic users.
30. Embrace Discomfort in Workouts
Actively engage in hard workouts and embrace the experience of physical discomfort, distinguishing it from chronic pain to build resilience and promote overall well-being.
6 Key Quotes
Pain is so wonderful because it's so terrible. It keeps us alive.
Sean Mackey
The amount of stimulus or nociception may have little to nothing to do with your experience of pain.
Sean Mackey
The surgeon, I got enough to worry about. I got to make sure you didn't leak, that that anastomosis is fine, that you're not getting a wound infection. Your pain is literally like third or fourth on the list of my concerns for you to have the best outcome.
Peter Attia
I am not pro-opioid. I am not anti-opioid. I am pro-patient. I view them as a tool.
Sean Mackey
Breaking the cycle isn't the cure. It sets you up to go after the cure.
Peter Attia
This guy is either going to crash and burn or he's going to do something really awesome.
Sean Mackey
1 Protocols
Acute Pain Management for Elective Surgery
Sean Mackey- Seek a pre-surgical consultation with a pain service to develop a comprehensive pain management plan.
- Implement a regional anesthetic approach (e.g., peripheral nerve catheters or epidural catheters) during surgery.
- Consider intravenous ketamine to augment pain relief during the perioperative period.
- Ensure a good handoff of the pain plan to post-operative care providers.
- Follow the patient outside the hospital for medication and pain management, focusing on optimal functional rehabilitation.