Podcast Summary: The Peter Attia Drive | Episode #345 – Chronic Pain: Pathways, Treatment, and the Path to Physical and Psychological Recovery | Sean Mackey, M.D., Ph.D.

Introduction

In Episode #345 of The Peter Attia Drive, host Dr. Peter Attia engages in an in-depth conversation with Dr. Sean Mackey, a renowned Professor of Pain Medicine at Stanford University and Director of the Stanford Systems Neuroscience and Pain Lab. Released on April 21, 2025, this episode delves into the complex world of chronic pain, exploring its biological pathways, psychological impacts, and innovative treatment modalities.

Personal Connection and Overview

Peter Attia begins by sharing his personal experience with chronic pain during medical school, highlighting the pivotal role Dr. Mackey played in his recovery. This personal narrative sets the stage for a comprehensive discussion on pain's multifaceted nature.

Defining Pain: Beyond Sensation

Dr. Sean Mackey ([03:57]) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage,” emphasizing its dual nature involving both physical sensations and emotional responses. He underscores pain’s evolutionary significance as a fundamental survival mechanism, crucial for avoiding harm and promoting healing.

Historical Perspectives on Pain

Mackey critiques René Descartes' 17th-century dualistic model, which posited a strict separation between body and mind in pain perception. He asserts that this model, although foundational, is outdated and has inadequately influenced modern medical understanding and treatment of pain.

“The idea is the body is where pain is generated, the mind is where it's perceived. But the mind is simply a passive receptacle receiving these signals. That model... it's utterly, completely wrong.” – Dr. Sean Mackey ([03:57])

Types of Pain

The conversation categorizes pain into distinct types, each with unique characteristics and treatment responses:

1. Nociceptive Pain ([24:17]):

   • Caused by activation of primary nociceptors in skin, soft tissues, or viscera.
   • Features include sharp, well-localized pain that responds well to NSAIDs, acetaminophen, and opioids.
   • Example: Acute injuries like a sprained ankle.

2. Visceral Pain ([24:17]):

   • Originates from internal organs.
   • Often diffuse and harder to localize due to converging neural pathways.
   • May require specialized antinociceptive treatments.

3. Neuropathic Pain ([25:44]):

   • Results from injury or dysfunction in the nervous system.
   • Described as burning, sharp, or stabbing sensations.
   • Challenging to treat, often requiring anticonvulsants or antidepressants.

4. Nociplastic Pain ([30:28]):

   • Represents dysfunction in central pain processing without a clear peripheral cause.
   • Associated with conditions like fibromyalgia and irritable bowel syndrome.
   • Emerging category with ongoing research into its mechanisms.

Pain Transmission: Nerve Fibers and Pathways

Mackey explains the roles of different nerve fibers in pain transmission:

• A Delta Fibers ([12:36]):

  • Myelinated and fast (≈10 meters/second).
  • Responsible for sharp, immediate pain and initiating reflexive withdrawal.

• C Fibers ([12:36]):

  • Unmyelinated and slower (≈1 meter/second).
  • Convey dull, burning pain and sustain the pain experience.

• A Beta Fibers ([46:05]):

  • Myelinated and very fast (≈100 meters/second).
  • Primarily involved in touch and proprioception but play a role in pain modulation via the gate control theory.

Gate Control Theory of Pain ([24:17])

Introducing the seminal Gate Control Theory by Melzack and Wall, Mackey describes how the spinal cord acts as a gate, regulating pain signals based on various factors, including the activation of A beta fibers which can inhibit nociceptive signals.

“The A beta fibers are inhibiting the signals coming in from where you hit your thumb with a hammer and preventing them from going to your brain. It's a beautiful example of neuromodulation.” – Dr. Sean Mackey ([46:51])

Pain Perception vs. Nociception ([13:08])

The distinction between nociception (the neural processes of encoding noxious stimuli) and pain perception is highlighted. Even in the absence of conscious pain perception (e.g., under anesthesia), nociceptive signals continue to elicit physiological stress responses.

“There's all sorts of nociception, arguably more.” – Dr. Sean Mackey ([18:51])

Psychological and Emotional Factors

Mackey emphasizes that psychological states—such as anxiety, depression, and catastrophizing—significantly influence pain perception. These factors can amplify pain and impede recovery by affecting the brain's ability to modulate pain signals.

“The psychology is what goes on to impact the physiology.” – Peter Attia ([153:17])

Pharmacological Treatments

The discussion transitions to various pharmacological approaches to pain management, detailing their mechanisms, benefits, and drawbacks:

1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) ([70:12]):

   • Inhibit cyclooxygenase enzymes (COX-1 and COX-2), reducing inflammation and pain.
   • Risks include gastrointestinal bleeding, kidney damage, and cardiovascular issues with long-term use.
   • Mackey notes changing perspectives on NSAIDs, balancing their anti-inflammatory benefits against potential delays in healing ([08:26], [70:12]).

2. Acetaminophen ([75:29]):

   • Mechanism not fully understood but thought to act centrally.
   • Safe at recommended doses but can cause severe liver damage in overdose ([31:32]).
   • Often combined with NSAIDs for synergistic effects ([76:29]).

3. Opioids ([93:53]):

   • Powerful analgesics effective for acute and certain chronic pain conditions.
   • Controversial due to risks of addiction, abuse, and societal impact.
   • Mackey advocates for responsible use, emphasizing patient-specific strategies and avoiding overprescription ([94:58]).

4. Anticonvulsants and Antidepressants for Neuropathic Pain ([28:20], [86:19]):

   • Gabapentin and Pregabalin: Modulate calcium channels to reduce nerve pain.
     • Effective but can cause drowsiness and dizziness.
   • Tricyclic Antidepressants (TCAs): Enhance serotonin and norepinephrine levels, also blocking sodium channels.
     • Examples: Desipramine, Nortriptyline, Amitriptyline.
     • Benefits in pain modulation but come with side effects like sedation and weight gain ([91:38]).

5. Muscle Relaxants ([78:49]):

   • Baclofen: GABA-B agonist used for muscle spasticity and acute pain flare-ups.
     • Non-habit forming but can cause sedation and dizziness.
   • Benzodiazepines and Flexeril: Generally avoided due to dependency risks and side effects ([82:34]).

6. Low Dose Naltrexone (LDN) ([86:06]):

   • Initially used for addiction treatment, LDN is emerging as a treatment for chronic pain by modulating microglial activity and reducing neuroinflammation.
   • Safe with minimal side effects, including vivid dreams ([86:17], [87:12]).
   • Mackey shares anecdotal success stories, advocating for broader research and acceptance ([86:06]).

Neuromodulation Techniques

Mackey discusses non-pharmacological neuromodulation methods that leverage the body’s own pain modulation systems:

• Transcutaneous Electrical Nerve Stimulation (TENS) ([47:45]):
  • Uses electrical currents to activate A beta fibers, inhibiting nociceptive signaling.
  • Effective primarily for nociceptive pain, though responses vary among individuals ([50:05]).

Objective Measurement of Pain

Highlighting advancements in pain research, Mackey describes the use of functional Magnetic Resonance Imaging (fMRI) to identify brain patterns associated with pain. While recognizing the subjective nature of pain, these biomarkers aim to predict pain trajectories and personalize treatment strategies ([30:28], [33:10]).

Chronic Pain: Prevalence and Impact

Chronic pain affects 50 to 100 million Americans, with significant societal costs exceeding half a trillion dollars annually. Conditions like low back pain, neck pain, and headaches are prevalent, and syndromes such as fibromyalgia present substantial challenges due to their unclear mechanisms and widespread impact.

Fibromyalgia

Fibromyalgia is characterized by widespread pain, fatigue, cognitive fog, and sleep disturbances. Mackey explains it as a syndrome with possible small fiber neuropathy and ongoing central sensitization, requiring multifaceted management approaches combining pharmacological and behavioral strategies.

Psychosocial and Functional Aspects

Emphasizing the biopsychosocial model, Mackey and Attia discuss how social isolation and impaired social functioning exacerbate chronic pain. Addressing psychological factors and enhancing social support are crucial components of effective pain management.

Cluster Headaches

Dr. Mackey shares his personal experience with cluster headaches, a rare but debilitating condition. Effective management includes abortive treatments like triptans and oxygen therapy, and preventive strategies using medications like calcium channel blockers and low dose naltrexone.

Conclusion and Key Takeaways

The episode underscores the complexity of chronic pain, integrating biological, psychological, and social dimensions. Dr. Sean Mackey advocates for personalized, multifaceted treatment approaches, leveraging both pharmacological and non-pharmacological strategies to enhance pain management and improve quality of life. Through advancements in research and a holistic understanding of pain, the medical community can better address the pervasive challenges posed by chronic pain.

Notable Quotes

• “Pain is the great motivator. Pain is so wonderful because it's so terrible. It keeps us alive without pain.” – Dr. Sean Mackey ([03:57])

• “The amount of stimulus or nociception may have little to nothing to do with your experience of pain.” – Peter Attia ([52:38])

• “The psychology is what goes on to impact the physiology.” – Peter Attia ([153:17])

• “The only way you can be hurt taking [gabapentin] is if you're struck by a truck that's carrying it.” – Dr. Sean Mackey ([86:06])

• “This is one tool I use more and more because of its safety profile and its potential for getting me a home run.” – Dr. Sean Mackey ([86:35])

Final Thoughts

For those seeking to understand chronic pain's intricate pathways and effective management strategies, this episode offers valuable insights from one of the leading experts in the field. Dr. Sean Mackey’s expertise combined with Dr. Peter Attia’s personal narrative provides a comprehensive exploration of chronic pain, its challenges, and the evolving landscape of its treatment.