Dr. Sean Mackie on Understanding and Treating Pain

In this episode of The Drive Podcast, host Dr. Peter Attia welcomes Dr. Sean Mackie, a Professor of Pain Medicine at Stanford University and Director of the Stanford Systems Neuroscience and Pain Lab. The discussion delves into the multifaceted nature of pain, from its fundamental definition and evolutionary purpose to its complex neurobiological mechanisms and diverse treatment approaches. Dr. Mackie shares insights from his extensive research and clinical experience, while Dr. Attia provides personal context through his own challenging history with chronic pain, in which Dr. Mackie played a pivotal role. This episode is highly relevant for anyone seeking a deeper understanding of pain, whether they experience chronic pain themselves, are interested in pain management strategies, or wish to comprehend the science behind this universal human experience.

Key Insights

• Pain is formally defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." Crucially, it's a biopsychosocial phenomenon, where the mind and body are integrated, moving beyond the outdated Cartesian dualistic model.
• Pain perception is highly individual and can vary dramatically even with identical stimuli. This variability is influenced by a multitude of factors, including genetics, psychological state (anxiety, catastrophizing), emotional well-being, sleep quality, and past experiences.
• The nervous system transmits pain signals via specialized nociceptors and distinct nerve fibers: fast A-delta fibers (sharp, localized pain and reflexes) and slow C-fibers (burning, diffuse, emotionally-laden pain). The brain plays an active role in modulating these signals through descending pathways, as described by the Gate Control Theory.
• Pain can be categorized into types such as nociceptive (tissue damage), visceral (internal organs), neuropathic (nerve injury), and the newer category of nociplastic pain (dysfunctional central pain processing, e.g., fibromyalgia), each with different characteristics and treatment considerations.
• Effective pain management often requires a multimodal approach, combining pharmacological interventions (NSAIDs, acetaminophen, anti-neuropathic drugs, judicious use of opioids) with non-pharmacological strategies (neuromodulation like TENS, physical rehabilitation, psychological support, sleep hygiene) tailored to the individual.
• Chronic pain often involves changes in the central nervous system, where the "amplifier" for pain signals can become turned up. Factors like sleep deprivation, chronic stress, and negative emotional states can exacerbate this, highlighting the importance of holistic care.
• Emerging research and treatments, such as Low-Dose Naltrexone (LDN) for conditions like fibromyalgia, show promise by targeting neuroinflammation and central sensitization, offering hope for conditions previously difficult to manage.

Understanding Pain: Beyond a Simple Sensation

Dr. Mackie began by explaining the formal definition of pain: "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." He emphasized that pain is not merely a physical sensation but a complex experience deeply intertwined with emotions. Beyond its unpleasantness, pain serves as a "great motivator," a primitive survival mechanism highly conserved across species, driving organisms away from danger and towards safety or reward. Without pain, Dr. Mackie noted, humans as a species would likely not have survived, citing congenital insensitivity to pain as an example.

He critiqued René Descartes' 17th-century dualistic model of pain, which posited a separation between body (where pain is generated) and mind (a passive receptor). While a foundational mechanistic theory at the time, moving beyond mystical explanations, Dr. Mackie argued this model is "utterly completely wrong" and has had detrimental consequences for pain care, particularly for those with chronic pain, by failing to acknowledge the mind's active role. Modern understanding views pain as an integrated "biopsychosocial phenomenon."

A critical distinction was made between "nociception" – the electrochemical injury signals originating in the periphery – and the subjective "experience of pain." Dr. Mackie stressed that these two "may have nothing to do with each other or very little linkages." This explains why the intensity of tissue damage doesn't always correlate with the level of pain experienced. He also clarified that consciousness is necessary for the *experience* of pain. An unconscious patient undergoing surgery, for instance, does not feel pain but experiences a massive surge of nociceptive signals and the associated physiological stress responses (cortisol, epinephrine, etc.).

The Neurobiology of Pain Transmission

Dr. Mackie detailed the initial stages of pain signaling. Specialized nerve endings called "nociceptors" act as transducers, converting various forms of energy (pressure, heat, cold, chemical changes like pH during infection) into electrochemical impulses or action potentials. These signals are then transmitted by two main types of nerve fibers:

• A-delta fibers: These are relatively thin but myelinated (insulated) fibers that transmit signals quickly, at about 10 meters per second. They are responsible for the initial, sharp, well-localized jolt of pain (e.g., when stepping on a tack). This rapid transmission allows for quick protective reflexes, often initiated at the spinal cord level without conscious thought, and also alerts the brain to initiate escape mechanisms.
• C-fibers: These are thin, unmyelinated, and much slower, transmitting signals at about 1 meter per second. They are responsible for the subsequent, delayed, hot, burning, and more diffuse pain that often has a strong unpleasant emotional quality. Dr. Mackie described this as the "longer-term harm alarm," reminding the individual to protect the injured area and learn from the experience.

These signals ascend primarily through the spinal-thalamic pathway to various brain regions, including the thalamus (a sensory relay station), anterior cingulate cortex (associated with emotional aspects and salience detection), insular cortex (integrating bodily awareness with emotional and cognitive input), and amygdala (threat detection and emotional processing). The brain isn't a passive recipient; it actively processes and modulates these signals. This is highlighted by the "Gate Control Theory of Pain" proposed by Melzack and Wall. This theory posits that the spinal cord acts as a gate, capable of amplifying or dampening pain signals before they reach the brain. This gate can be influenced by other sensory inputs, such as touch (via A-beta fibers, which are very fast), and by descending pathways from the brain itself, which are affected by emotions, cognitions, and beliefs.

Types of Pain and Their Characteristics

Dr. Mackie outlined several categories of pain:

• Nociceptive Pain: Caused by the activation of nociceptors due to tissue injury (e.g., a cut, sprain, or post-surgical pain). It's typically well-localized, time-limited, and responds well to standard analgesics like NSAIDs and opioids.
• Visceral Pain: Originates from internal organs. It's often diffuse, poorly localized (e.g., a stomach ache where one gestures vaguely over the abdomen), and can be referred to other body parts (e.g., shoulder pain from diaphragmatic irritation or arm pain during a heart attack). The viscera respond differently to stimuli; for example, cutting bowel tissue may not elicit pain, but stretching or inflammation will.
• Neuropathic Pain: Results from injury or dysfunction of the peripheral or central nervous system itself (e.g., radicular pain from a herniated disc, painful diabetic neuropathy, post-stroke pain). It's often described as burning, sharp, lancinating, stabbing, or shock-like. Standard analgesics are often less effective. Treatments include anti-neuropathic medications originally developed for other conditions, such as anticonvulsants (e.g., gabapentin, pregabalin) and certain antidepressants. Dr. Attia shared his personal experience with severe neuropathic pain and the relief he found with high doses of gabapentin.
• Nociplastic Pain: A newer category characterized by pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence of disease or lesion of the somatosensory system causing the pain. It's thought to represent a dysfunction in central pain processing. Conditions like fibromyalgia, some types of chronic low back pain, irritable bowel syndrome, and temporomandibular disorders are often considered to involve nociplastic mechanisms. Dr. Mackie expressed an opinion that future research might uncover subtle peripheral drivers for some of these conditions currently classified as nociplastic.

Individual Variability and Influencing Factors in Pain Perception

A crucial theme was the vast individual variability in pain perception. Dr. Mackie cited studies, including his own classroom demonstrations with an ice water bath, showing that identical painful stimuli can elicit responses ranging from no pain to excruciating pain across different individuals. "The amount of stimulus or nociception may have little to nothing to do with your experience of pain," he stated. This variability is influenced by:

• Psychological and Emotional State: Anxiety, depression, catastrophizing (a pattern of negative thinking involving rumination, magnification, and helplessness), and overall mental state significantly modulate pain. The prefrontal cortex, involved in cognitive control, plays a key role in these descending modulatory pathways.
• Sleep: Sleep deprivation dramatically increases pain sensitivity. Dr. Mackie explained that poor sleep impairs the prefrontal cortex's ability to modulate pain and changes the "set point" for pain perception in the brain and spinal cord. Chronic pain often leads to a vicious cycle of poor sleep and increased pain.
• Physiological Factors: Glucose control is a major predictor of diabetic neuropathic pain. Diet can influence inflammation, which in turn can sensitize peripheral nociceptors (peripheral sensitization).
• Self-Efficacy and Coping: An individual's belief in their ability to manage their pain (self-efficacy) and their coping strategies are significant predictors of how they experience and manage chronic pain.
• Early Life Events and Trauma: Adverse childhood experiences and a history of trauma can increase vulnerability to persistent pain and affect how opioids are experienced.
• Conditioned Pain Modulation (CPM): This is an endogenous pain inhibitory mechanism where a painful stimulus in one part of the body can reduce pain perception in another. This mechanism is often impaired in conditions like fibromyalgia.

Dr. Mackie also touched on the development of objective biomarkers for pain, particularly using fMRI to identify brain patterns associated with the pain experience. While not intended to replace self-report, these tools could help predict treatment responses and long-term trajectories.

Pharmacological Approaches to Pain Management

The discussion covered several classes of pain medications:

• NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): Examples include ibuprofen and naproxen. They work by inhibiting cyclooxygenase enzymes, reducing inflammation and pain. Dr. Mackie noted an evolving understanding that inflammation is part of the healing process, and suppressing it aggressively with NSAIDs might sometimes delay healing, though the clinical implications are still being debated. He emphasized individual variability in response to different NSAIDs and the importance of balancing benefit with potential side effects (GI, kidney, cardiovascular) especially with long-term use.
• Acetaminophen (Tylenol): Its exact mechanism is not fully understood but involves central effects and possibly some cyclooxygenase inhibition. It can have synergistic effects when combined with NSAIDs, allowing for lower doses of each. Liver toxicity at high doses or with alcohol is a concern.
• Muscle Relaxants: Baclofen was highlighted as a relatively safe option that can be used for muscle spasms, even long-term if beneficial, without the dependency issues of some other muscle relaxants. Dr. Attia shared his positive experience with baclofen for acute musculoskeletal issues.
• Anti-neuropathic Medications:
  • Gabapentinoids (Gabapentin, Pregabalin): Effective for neuropathic pain by modulating calcium channels in the central nervous system. They are generally safe with no lethal dose, but side effects can include drowsiness, dizziness, and with pregabalin, potential weight gain or edema. Dr. Attia's experience with high-dose gabapentin for his severe neuropathic leg pain was discussed.
  • Antidepressants: Tricyclic antidepressants (TCAs) like amitriptyline, nortriptyline, and desipramine, and SNRIs like duloxetine, are used for their analgesic properties, which are distinct from their antidepressant effects. They modulate serotonin and norepinephrine and can have sodium channel-blocking effects. Side effect profiles vary.
• Opioids: Dr. Mackie provided a nuanced perspective, acknowledging the over-prescription crisis and the devastating impact of addiction, while also affirming their essential role in acute pain management (e.g., post-surgery) and end-of-life care. He emphasized being "pro-patient" rather than pro- or anti-opioid. The opioid crisis was described as a "perfect storm" involving pharmaceutical marketing, societal pressures to treat pain (e.g., "pain as the fifth vital sign"), early hospital discharge practices, inadequate physician training in pain management, and patient satisfaction scores. For chronic pain, opioids are not a first-line treatment. Screening for risk factors for persistent opioid use (e.g., depression, catastrophizing, history of trauma) is crucial. The goal for surgical patients is often to use opioids in the hospital and transition to non-opioid analgesics before discharge if possible.

Non-Pharmacological and Novel Approaches

Several other treatment modalities were explored:

• Neuromodulation (TENS - Transcutaneous Electrical Nerve Stimulation): TENS units work by applying electrical stimulation to the skin, activating A-beta (touch) fibers. This is thought to "close the gate" in the spinal cord, reducing the transmission of pain signals from C-fibers and A-delta fibers. It's generally considered safe and can be effective for some types of nociceptive or musculoskeletal pain, though predicting individual response is difficult.
• Acupuncture: Dr. Mackie noted that some patients find relief, particularly for back pain, musculoskeletal pain, and migraines, but predicting responders is challenging. Mechanisms may involve peripheral adenosine release and central brain modulation. He advised it as an option if affordable and safe.
• Cannabis: The evidence for cannabis in chronic pain is mixed, with some limited support for short-term neuropathic pain relief in controlled trials, but less clear benefits in population-level studies. Dr. Mackie noted that Stanford's observational data showed patients using cannabis tended to have worse outcomes, though confounding factors are significant. The Schedule 1 status in the U.S. significantly hinders robust research.
• Fibromyalgia: Characterized by widespread pain, fatigue, morning stiffness, and "fibro fog." It's now understood to involve central nervous system sensitization and impaired conditioned pain modulation. It's often precipitated by a physical or emotional trauma or infection. Management includes brain-modulatory drugs and lifestyle approaches.
• Low-Dose Naltrexone (LDN): Typically used at 4.5 mg (a fraction of the dose used for addiction), LDN is thought to work by blocking toll-like receptor 4 on microglia, thereby reducing neuroinflammation. Dr. Mackie has found it "magical" for some patients with fibromyalgia and Complex Regional Pain Syndrome (CRPS), with minimal side effects (vivid dreams being the most common). Dr. Attia and Dr. Mackie speculated on its potential for other neuroinflammatory conditions.

Throughout the latter part of the podcast, Dr. Attia shared his personal story of developing debilitating back and leg pain during medical school, which ultimately led him to Dr. Mackie. His experience involved multiple failed surgeries, severe neuropathic pain, high-dose opioid use, and significant functional impairment. Dr. Mackie's aggressive, multimodal intervention, starting with a broad series of injections to "put the fire out," followed by more targeted treatments and intensive rehabilitation, was crucial for Dr. Attia's recovery. This story illustrated many concepts discussed, including the severity of neuropathic pain, the role of central sensitization, the importance of breaking the pain cycle to enable rehabilitation, and the psychological impact of chronic pain and the path to regaining self-efficacy.

Conclusion

Dr. Sean Mackie's discussion with Dr. Peter Attia painted a comprehensive picture of pain as a deeply personal and complex biopsychosocial experience. The episode underscored that effective pain management moves far beyond simply masking symptoms, requiring an understanding of the underlying neurobiology, the individual's psychological and social context, and a willingness to employ a tailored, multimodal approach. Key takeaways include the critical difference between nociception and pain, the brain's active role in modulating pain, the diverse nature of pain types, and the profound impact of factors like sleep and emotional state. For listeners, the episode offers not only a scientific understanding of pain but also a message of hope, highlighting the advancements in pain medicine and the importance of proactive, informed, and holistic strategies in addressing this universal human challenge. Dr. Attia's own journey serves as a powerful testament to the potential for recovery when such comprehensive care is applied.