Tools to Reduce & Manage Pain | Dr. Sean Mackey

This batch covers the opening stretch of Huberman's conversation with Dr. Sean Mackey, chief of the Division of Pain Medicine at Stanford, and it is organized around a single reframing: the thing happening in an injured shoulder is not pain. Huberman sets the agenda as a broad survey of 'this thing called pain' and opens with the plainest possible question, 'what is pain?' Mackey's answer is a definition rather than a mechanism: pain is 'this complex and subjective experience' that keeps us away from injury or harm, and it is 'both a sensory and an emotional experience.' He flags the emotional half as the part that 'gets lost on people,' and he adds a claim that recurs throughout the episode, that 'your pain is different from my pain.'

The stakes are stated in epidemiological terms before any neurobiology arrives. Mackey puts the chronic pain population at 'about 100 million Americans' and the cost at 'about a half a trillion dollars a year in medical expenses,' describing it as 'an astounding problem we're facing in society and one that's only getting worse.' He also states his didactic strategy explicitly: to 'break down a little bit of the foundation of pain and kind of build it back up,' because 'in society there's a lot of misunderstanding about what pain is.' That is a fair description of the episode's shape, and it is worth noting that the numbers are offered as background rather than derived from a cited source in this segment.

Huberman's preview names the topics this batch actually reaches and some it does not. He promises the brain-body interactions that 'give rise to this thing that we call pain,' the link between physical and emotional pain, the nervous-system changes underlying chronic pain, and a survey of behavioral, psychological, nutritional, supplemental and prescription approaches. He also advertises heat and cold and a treatment of opioids, including the claim that Mackey makes clear 'which specific clinical circumstances warrant the use of exogenous opioids' alongside 'a warning about their potent addictive potential.' Within these 199 segments the conversation gets through definitions, nociception, over-the-counter drugs, gate control, thresholds, conditioned pain modulation, temperature and attentional strategy; the opioid discussion and most of the chronic-pain material lie beyond it.

Editorially, the batch is interleaved with host-read advertisements for AeroPress, Levels, BetterHelp, AG1 and InsideTracker. They are clearly demarcated by Huberman's transitions and contain no clinical claims bearing on the pain argument, so they are noted here only to explain the gaps in segment numbering.

Huberman supplies the lived motivation for the mechanistic discussion. A kinked neck or a pulled back muscle, he says, resolves quickly for him, but while it lasts he becomes 'slightly more irritable, perhaps much more irritable depending on who you ask,' and 'thinking is harder. Sleeping is harder. Concentrating on anything besides the pain.' His description of something 'nagging from the inside' sets up the question of whether pain lives in the brain, the body, or both. Mackey's answer is unhedged on the location and then immediately complicated: 'It's clearly in our brain,' followed by a request to 'lay a little foundation' because what happens in the body 'is not pain.'

The foundation is a three-stage chain. First, sensors in skin, soft tissue and deep tissue called nociceptors detect temperature, pressure and pH changes such as those produced by inflammation. Second, the signal travels on two fiber classes: fast A delta fibers, responsible for 'that sharp jolt of pain' when you step on a tack or touch a hot stove, and slower C fibers, responsible for 'that dull, achy pain.' Third, the signals reach the spinal cord, where they are 'shaped' and 'changed a little bit,' and only on arrival in the brain, where they 'converge with this magical mystery set of nerves,' does the experience of pain arise. The phrase 'magical mystery set of nerves' is doing rhetorical work rather than mechanistic work, and it is the one place in this passage where the explanation thins out.

And if there's one key message I'd like to get to the audience is that what goes on out here, what goes on in your shoulder, in your neck is not pain. That's nociception. Those are electrical signals, electrochemical impulses being transmitted. And that is to be distinguished from what becomes the subjective experience of pain that you have.

From that distinction Mackey draws a historical and a clinical conclusion. He attributes to Descartes, 'that French philosopher, I think 17th century,' the idea of 'this direct linkage between the body and our actions and the stimulus and the response,' and then rejects it outright: 'And it's wrong.' The target is not only a philosophical error but a surviving clinical one, since 'even in medical care, we have this biomedical model that still is perpetuating this idea of a one to one relationship.' The practical consequence is projective: because we 'project onto others our own experiences of pain,' an observer substitutes their own expected pain for the patient's report. Mackey ties this to chronic pain's reputation as 'the invisible disease,' and in a follow-up exchange sharpens the point with fibromyalgia, where 'outwardly, visibly, you don't see anything wrong,' in contrast to 'a fractured bone' or 'a swollen ankle' that visibly license belief.

Huberman's question is carefully posed. Color perception differs between people by some unknown mechanism, he notes, but that is a different claim from saying there is a place in the brain we can point to and call the pain area. He asks whether the thalamus, the neocortex, or some distributed arrangement is responsible, and the framing matters because it separates 'pain is subjective' from 'pain is localizable.'

Mackey concedes the wish and denies the fact: 'we'd all love if there was a pain center in the brain that we could just go knock out. But it's not that simple.' His explanation is evolutionary redundancy. Pain is 'such a conserved phenomenon,' and 'when you knock out one pathway going to the brain, there's others there that will carry that system forward.' The formulation is memorable and slightly paradoxical: pain is 'so wonderful because it is so terrible unless it goes wrong.' The answer to the localizability question is then flat: 'no, there's not one pain brain area.'

The intermediate concept was the 'pain matrix,' comprising the insular cortex, the cingulate cortex, the amygdala and other regions 'that all subserve different functions.' Mackey reports that the field is 'moving away from that' because 'every year or so we pick up another region of the brain that's contributing to this network.' What replaces it is not a single locus but a search for 'common signatures, common brain networks' and 'brain based biomarkers,' a line of work he dates to 'well over a dozen years ago' and describes as continuing to accumulate. Listeners should register the evidential status of this claim: it is presented as an established finding of conserved distributed regions, but no effect sizes, sample sizes or validation results are given in these segments, so the strength of the biomarker program cannot be assessed from the episode alone.

The pharmacology section begins with a terminological correction that is more than pedantry. Huberman asks where a drug like ibuprofen or acetaminophen acts, and Mackey replies that 'technically NSAIDs, nonsteroidal anti-inflammatory drugs like ibuprofen, like Naprosyn' are 'actually not analgesics. They're not technically pain killers.' The true analgesic category, in his usage, includes opioids; NSAIDs belong to a different class, 'anti-hyperalgesic drugs.' The distinction predicts the experiment he then describes.

Injury produces sensitization of the damaged area, which Mackey calls 'a beautiful thing, because it sends a message to us to protect it.' NSAIDs reduce 'some of that sensitization out in the periphery and then back in the spinal cord and in the brain,' but they do not raise the painfulness of a fresh, uninjured stimulus. Hence the demonstration: 'You can in a normal situation hit your hand with a fork. Measure the amount of pain. Now go take an NSAID like ibuprofen. If you hit your hand with that same fork, there'll be no difference.' Both hosts then disclaim the demonstration, Huberman with 'Folks, please don't do that' and Mackey with 'Don't do that at home, please.' The exchange is a useful stress test of the class claim: the drug blunts inflammatory sensitization, not nociception as such.

The mechanism is cyclooxygenase. Aspirin and other NSAIDs are described as 'basically a cox, cyclooxygenase inhibitor,' and COX products 'wind up or amplify the nociceptors so that after an injury, you note that you're more sensitive there.' Sunburn is the illustrative case: 'After a sunburn, you end up having more sensitization. That is what we refer to as peripheral sensitization.' When Huberman presses on prostaglandins, Mackey confirms the family and the conversation links back to the podcast's recurring point that inflammation and cortisol are not simply villains. The sympathetically framed conclusion is that NSAIDs are 'anti-hyperalgesic,' with Mackey apologizing for 'the jargony terms that we use.'

The threshold question, when should pain be treated at all, gets a functional answer rather than a numerical one. Mackey sets it at the point where pain is 'impacting your quality of life and your ability to take care of the activities of daily living, engage with family, friends, go to work.' He also warns against the extreme case: 'You don't want to be reaching for a very potent opioid just so that you can continue walking on a fractured ankle that you haven't gotten evaluated by a clinician and perhaps casted.' The same logic is extended to professional sports, where he hopes injections that return an athlete to the field with a broken bone 'doesn't go on anymore,' and Huberman, drawing on his own experience of being contacted by teams, doubts that it has stopped.

The most substantive tension in the episode surfaces here. Mackey notes that NSAIDs were once handed out routinely for acute injury, but that research now suggests 'by blocking inflammation, by blocking that, we may be blocking the normal healing process,' with observed 'delays in fracture repair' and 'delays in tissue repair.' That creates a genuine conflict between symptomatic benefit and recovery cost, and his resolution is pragmatic: 'if you're not sleeping at night, you're not going to heal,' so 'take it at the lowest dose that you can get away with.'

Huberman then proposes an asymmetry that would settle the question in favor of abstaining: if the person can sleep 'reasonably well' and only movement is uncomfortable, should they take nothing? Mackey declines to endorse that. His reply is an explicit statement about the evidence base rather than about biology: 'we've got a lot more data on the benefits of NSAIDs, this class of medication reducing pain, than we have data showing the bad consequences of it. And so we're still needing more data on the whole healing message.' He carves out orthopedic surgery, where he says many surgeons 'prefer people not to be on NSAIDs' after total hip or knee replacement and where he considers the point 'pretty clear,' but distinguishes that from the acute-injury case under discussion. This is the cleanest statement of uncertainty in the batch, and it cuts against the more confident framing of the healing-delay concern a few segments earlier.