345 ‒ Chronic pain: pathways, treatment, and the path to physical and psychological recovery

Mackey explains that the 4.5 mg dose was derived from animal studies by Watkins and Hutchinson, converting mg/kg to a 70 kg human. He has seen dramatic results in fibromyalgia and CRPS, and shares an anecdote of a stroke patient with central pain who not only had pain relief but regained speech after years. He acknowledges the controversy with Dan Clauw, who believes the mechanism is opioid receptor antagonism resetting the endogenous opioid system. Mackey finds the neuroinflammation model more compelling given LDN's benefits in MS and ulcerative colitis. He emphasizes the drug's remarkable safety profile, with decades of use at 50 mg for addiction showing no lethal dose. The main side effect is vivid, colorful dreams. He typically starts at 4.5 mg at night, and if patients feel activated, he moves it to morning. He has gone up to 13.5 mg in the stroke case. Cost is about $30/month from compounding pharmacies like Belmar.

Mackey explains that gabapentin is a lousy anti-seizure drug but a good neuropathic pain drug. Its absorption is saturable due to an active transport system in the small intestine; taking more than 900-1000 mg at once results in the excess being excreted. Therefore, he often prescribes 300 mg in the morning and afternoon, and 600 mg at night to aid sleep. If a patient maxes out on gabapentin but still has benefit, he switches to pregabalin, which has linear kinetics and can be dosed higher. He notes the drug's popularity surged after an episode of ER where George Clooney's character used it. He warns about sedation and fall risk, especially in the elderly, and mentions that both drugs can cause weight gain and edema. He shares that Peter Attia took 4 grams/day during his recovery and was very drowsy.

Mackey emphasizes that these drugs are not FDA-approved for pain because they are off-patent, so no company will fund the trials. He uses them extensively, tailoring the choice to the patient. Amitriptyline is his go-to when sedation and sleep improvement are needed, but he avoids it in patients prone to weight gain or urinary issues. He shares a personal embarrassment: he once prescribed amitriptyline to a young woman concerned about weight, and she gained 10-20 pounds. Desipramine and nortriptyline are less sedating and have fewer anticholinergic effects. He notes that the analgesic effect is independent of mood effects, so he counsels patients that they are not being treated for depression. Blood level monitoring is possible for nortriptyline to ensure therapeutic range.

Peter Attia shares his personal use of baclofen 20 mg twice daily for a few days when he gets a kink in his trap or QL flare-up, combined with an NSAID. Mackey agrees that baclofen is one of the safest muscle relaxants, non-habit-forming unlike Soma (carisoprodol) which has barbiturate-like properties. He notes that flexeril (cyclobenzaprine) has tricyclic-like effects and can cause sedation. Baclofen is also used intrathecally via implanted pumps for severe spasticity from spinal cord injury. For oral use, he is comfortable with long-term use if the patient benefits, but typically uses it for acute/subacute episodes and reassesses. He emphasizes that muscle relaxants generally lack strong evidence for chronic pain.

Mackey discusses the synergy, noting that 1+1=3. He mentions the historical concern that NSAIDs might impair healing, referencing orthopedic data on nonunion after joint replacements, but argues that if the pain is limiting function, the benefits of taking NSAIDs to enable movement outweigh the potential risks. He also notes individual variability in response to different NSAIDs; for him, naproxen 500 mg BID works better than ibuprofen, while Peter prefers ibuprofen for its TID dosing alignment with acetaminophen. He advises patients to try different NSAIDs empirically. He also touches on the Vioxx controversy, lamenting its removal despite being a great drug for many, and the need for a black box warning rather than withdrawal.

Mackey shares his personal protocol for managing his own cluster headaches, which occur every 2-3 years in a fall/spring cycle. He describes the prodromal phase with appetite changes, sleep disruption, and a sticky eye sensation. He keeps a tank of oxygen in his car and stockpiles triptans. If he catches the attack early, he can abort it in about 30 minutes instead of enduring hours of agony. He emphasizes that this preparedness and knowledge gave him control, reducing the fear and catastrophizing that previously amplified his suffering. He parallels this with the importance of self-efficacy for all pain patients.

Mackey recounts the case of Peter Attia, who was bedridden with severe testicular/groin pain after multiple back surgeries. After a lidocaine infusion failed, Mackey performed an extensive series of injections from top to bottom of the spine late at night without sedation because Peter was desperate. The procedure provided immediate, complete pain relief for two weeks, allowing Peter to start walking and eventually engage in months of rehabilitation. Over subsequent months, Mackey repeated more targeted injections to isolate the pain generator (T12-L1 facet arthropathy). This approach exemplifies using interventional procedures not as a cure but as a bridge to functional recovery. Mackey notes that normally he would not do such a non-specific procedure, but the extreme situation warranted it.

Mackey explains the gate control theory and how TENS exploits it. He notes that it's a form of neuromodulation patients can do at home. He cannot predict who will respond, but it's safe and worth trying for nociceptive pain. He mentions that acupuncture may work similarly by stimulating peripheral nerves. He uses TENS as part of a multimodal approach, not as a standalone cure.

Sean Mackey argues that Descartes' 17th-century dualistic model, while the first mechanistic framework, was completely wrong and has persisted for hundreds of years, influencing medical care, policy, and societal attitudes. He explains that only in recent decades have we appreciated that pain is a complex integration of biological, psychological, and social factors. This new understanding explains why two people with identical injuries can have vastly different pain experiences, and why factors like early life trauma, depression, and social isolation profoundly affect pain. He notes that even today, many surgeons still implicitly hold the dualistic view, but there is growing acceptance of the biopsychosocial model, which is crucial for validating patients with conditions like fibromyalgia.

Mackey describes how animal studies by Linda Watkins and Mark Hutchinson showed LDN blocks toll-like receptor 4 on microglia, the immune cells of the central nervous system. In chronic pain states, microglia become activated and release inflammatory mediators that sensitize pain pathways; LDN may turn off this neuroinflammatory switch. He has used it successfully in fibromyalgia, complex regional pain syndrome, and shares a remarkable case of a stroke patient with central pain who not only had pain relief but regained speech after years. He acknowledges controversy: some researchers believe LDN works by resetting the endogenous opioid system rather than via microglia. Regardless, he emphasizes its safety—decades of data at 10x the dose show no lethal dose, and side effects are limited to vivid dreams in 20-30% of patients. It costs about $30/month from compounding pharmacies. He now uses it more and more as a first-line adjunct.

Mackey explains that nociplastic pain is thought to represent dysfunction in the central pain processing system, leading to amplified pain without identifiable peripheral pathology. However, he personally believes that medical science hasn't caught up to identify specific peripheral drivers. He points to controversy over whether fibromyalgia is actually a small fiber neuropathy, as some skin biopsies show C-fiber abnormalities. He suggests that as diagnostic tools improve, many 'nociplastic' conditions will be reclassified. This matters because it influences treatment strategies—if a peripheral driver exists, targeting it could be more effective than purely central approaches.

Mackey describes a study led by Jennifer Hah and Ian Carroll that used the Beck Depression Inventory in preoperative patients. Factor analysis revealed that the self-loathing component—feeling bad about oneself—was the primary driver of persistent opioid use, not other aspects like anhedonia or cognitive symptoms. He cautions that this is from an observational study and ideally would be tested in a randomized trial, but such trials are unlikely to be funded given the current focus on non-opioid alternatives. He uses this insight to have informed conversations with patients about their individual risk, rather than denying opioids outright. The broader message is that psychological factors are neurobiological—they reflect specific brain circuits that modulate pain and reward.

Mackey recounts his journey from undiagnosed agony to becoming an expert on his condition. Once he understood the diagnosis, the typical cycle, and had abortive treatments (high-flow oxygen, triptans), the fear dissipated. He still experienced the same sensory pain and agitation, but knowing it would end and having a plan gave him a sense of control. This self-efficacy broke the catastrophizing loop—rumination, helplessness, amplification—that worsens pain via prefrontal cortex dysfunction and HPA axis dysregulation. He parallels this with Peter Attia's back pain recovery, where understanding the waxing/waning nature and having rehab tools allowed Peter to avoid spiraling after setbacks. Mackey emphasizes that this is a teachable skill: patients can learn about their condition and develop coping strategies to regain control.