Chronic Pain, Non-Restorative Sleep, and Brain Fog as a Self-Reinforcing Cycle

By Yoon Hang “John” Kim, MD, MPH

Board-Certified Integrative Medicine Physician | Direct Integrative Care

Abstract

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a complex, multi-system illness that remains a diagnosis of exclusion. While its etiology is incompletely understood, emerging evidence supports a compelling pathophysiological model centered on endorphin depletion as a key mediating pathway. This article presents a hypothesis in which chronic pain progressively depletes endogenous opioid reserves, degrades restorative sleep architecture, and ultimately produces the hallmark symptoms of CFS/ME — including profound fatigue, cognitive dysfunction (“brain fog”), and post-exertional malaise. We review the published literature supporting each link in this proposed chain and discuss how, in clinical practice, addressing chronic pain and brain fog represents a critical and often overlooked step in CFS/ME recovery. We further present Low-Dose Naltrexone (LDN) as a cornerstone intervention uniquely positioned to interrupt this cycle by restoring endorphin production, reducing neuroinflammation, and optimizing immune function.

CFS/ME: A Diagnosis of Exclusion

CFS/ME remains one of the most diagnostically challenging conditions in clinical medicine. The terms Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME) are used interchangeably in contemporary practice, referring to the same clinical entity — a chronic, debilitating illness characterized by profound fatigue unrelieved by rest, post-exertional malaise, unrefreshing sleep, cognitive impairment, and widespread pain.

Critically, CFS/ME remains a diagnosis of exclusion. No single biomarker, laboratory test, or imaging study can definitively confirm the diagnosis. Clinicians must systematically rule out hypothyroidism, adrenal insufficiency, anemia, primary sleep disorders, autoimmune diseases, chronic infections, psychiatric conditions, and malignancies before arriving at a CFS/ME diagnosis. The major diagnostic frameworks — the Fukuda Criteria (1994), Canadian Consensus Criteria (2003), and Institute of Medicine Criteria (2015) — all rely fundamentally on symptom patterns after exclusion of other explanatory conditions.

This diagnostic reality, while often frustrating for patients and providers alike, also presents a clinical opportunity. The exclusionary workup itself can identify treatable conditions that contribute to or exacerbate the patient’s illness — which is precisely the philosophy that underpins the integrative approach described below.

The Endorphin Depletion Hypothesis: A Proposed Pathophysiological Pathway

While CFS/ME is undoubtedly multifactorial, we propose that a significant subset of patients may develop or perpetuate their illness through a self-reinforcing cycle of endorphin depletion. The proposed pathway involves three interconnected stages:

Stage 1: Chronic Pain Depletes Endorphin Reserves

The endogenous opioid system — comprising β-endorphins, enkephalins, and dynorphins — serves as the body’s primary internal pain modulation network. These neuropeptides act at multiple levels of the central nervous system, including the spinal cord, midbrain, thalamus, and cortex, to suppress nociceptive signaling and modulate the affective experience of pain.

The critical insight is that chronic pain does not simply co-exist with endorphin dysfunction — it actively depletes it. Sprouse-Blum et al. (2010) described how the endogenous opioid system functions as both a pain-modulating and sensory-filtering system, and that chronic pain states may progressively deplete endorphinergic neurons of their neurotransmitter stores. Almay et al. (1978) demonstrated that patients with chronic organic pain syndromes had significantly lower cerebrospinal fluid (CSF) endorphin levels than those with psychogenic pain or healthy controls. Bäckryd et al. (2014) confirmed this finding using modern Luminex technology, showing that CSF β-endorphin levels were significantly lower in chronic neuropathic pain patients (66 ± 11 pcg/mL) compared to healthy controls (115 ± 14 pcg/mL, p = 0.017), suggesting defective top-down pain inhibition.

Crucially, multiple studies have found that CFS/ME patients specifically have depleted β-endorphin levels. Conti et al. (1998) reported significantly decreased immunoreactive β-endorphin in mononuclear leucocytes from CFS patients compared to healthy controls. Panerai et al. (2002) confirmed that peripheral blood mononuclear cell (PBMC) β-endorphin concentrations were significantly lower in CFS and fibromyalgia patients (p < 0.001) than in healthy subjects, while notably not depleted in patients with depression alone — an important differential finding.

Stage 2: Endorphin Depletion and Chronic Pain Degrade Restorative Sleep

The second stage of the proposed pathway involves the bidirectional relationship between pain, endorphin function, and sleep. The body produces endorphins and other neurochemicals critical for pain management during sleep, and disrupted or insufficient sleep impairs these restorative processes, leading to further pain sensitization.

Chronic pain contributes significantly to poor sleep quality through pain-related arousals that fragment sleep architecture and prevent the deep, restorative slow-wave sleep essential for tissue repair, immune regulation, and hormonal balance. A comprehensive review by Duo et al. (2023) in Frontiers in Psychiatry detailed the neurochemical mechanisms underlying this relationship, including dysregulation of neurotransmitters (dopamine, serotonin, norepinephrine), HPA axis dysfunction, and increased proinflammatory cytokines (TNF-α, IL-6) that alter sleep architecture and drive insomnia.

Jackson and Bruck (2012) specifically examined sleep abnormalities in CFS/ME in a comprehensive review published in the Journal of Clinical Sleep Medicine. They found that experimental manipulations of pain stimuli during sleep produced decreased delta (slow-wave) activity and increased alpha intrusion — the classic “alpha-delta sleep” pattern characteristic of non-restorative sleep. They noted that CFS/ME patients reported more nocturnal awakenings due to pain compared to both depressed patients and healthy controls, and proposed that physiological arousals during sleep reflect a “vigilant nocturnal state” contributing to daytime fatigue, pain, hypersensitivity, and the subjective experience of non-restorative sleep.

Stage 3: Non-Restorative Sleep Produces the CFS/ME Phenotype

The third and final stage completes the vicious cycle. Chronic non-restorative sleep — now sustained by both ongoing pain and depleted endorphin reserves — produces the full constellation of CFS/ME symptoms. The evidence for this is compelling:

Tang et al. (2017) conducted a systematic review and meta-analysis of longitudinal studies involving over 61,000 participants, finding that a decline in sleep quality was associated with a two- to three-fold increase in the risk of developing a chronic pain condition. Nitter et al. (2012) found that disrupted and non-restorative sleep were significant predictors of chronic pain onset in pain-free individuals over 17 years of follow-up. Perhaps most strikingly, Moldofsky and Scarisbrick demonstrated decades ago that disruption of slow-wave sleep in healthy volunteers induced the pain, fatigue, and cognitive symptoms characteristic of CFS/ME and fibromyalgia.

The cognitive dimension is particularly relevant. Sleep deprivation impairs synaptic plasticity, reduces brain volume in the prefrontal cortex, and alters neurochemical activity — producing the “brain fog” that is one of the most disabling features of CFS/ME. Krause et al. (2017) demonstrated in Nature Reviews Neuroscience that sleep deprivation reduces frontoparietal network connectivity, impairs thalamic gating, and increases neuroinflammation — precisely the pattern seen in CFS/ME. The glymphatic system, responsible for clearing metabolic waste including β-amyloid proteins from the brain, operates primarily during deep sleep; chronic sleep disruption compromises this clearance, contributing to progressive cognitive dysfunction.

The Self-Reinforcing Cycle

The result is a pathological feedback loop: chronic pain depletes endorphins → depleted endorphins impair pain modulation and sleep architecture → non-restorative sleep increases pain sensitivity and neuroinflammation → increased pain further depletes endorphin reserves. Each revolution of this cycle deepens the physiological disruption. Without targeted intervention to break this cycle, the patient becomes progressively more disabled. This model provides a mechanistic explanation for why CFS/ME is so difficult to treat with single-modality approaches and why patients often deteriorate over time when the underlying cycle is not addressed.

Clinical Implications: Addressing Pain and Brain Fog as Critical Recovery Steps

In my integrative medicine practice, I have come to view addressing chronic pain and brain fog as a critical — and often the most important — step in CFS/ME recovery. This is not merely a matter of symptom management; it is about interrupting the pathophysiological cycle at its most vulnerable point.

When patients present with CFS/ME, the instinct of many clinicians is to focus on fatigue as the primary target. However, the endorphin depletion model suggests that fatigue is often a downstream consequence of unresolved pain and the non-restorative sleep it produces. By targeting pain and neuroinflammation directly, we can begin to restore endorphin homeostasis, improve sleep architecture, and create the conditions under which the body’s own restorative processes can function.

Similarly, brain fog is not merely an annoying symptom — it is a clinical marker of neuroinflammation and impaired glymphatic clearance resulting from chronic sleep disruption. Addressing it requires reducing neuroinflammation, restoring restorative sleep, and supporting mitochondrial function in neuronal tissue. In clinical practice, patients who experience improvement in pain and cognitive clarity almost invariably report subsequent improvements in energy, functional capacity, and overall quality of life.

Low-Dose Naltrexone (LDN): Interrupting the Cycle

Low-Dose Naltrexone (LDN) occupies a uniquely favorable position in the treatment of CFS/ME precisely because it addresses the endorphin depletion cycle at multiple points simultaneously.

Restoring Endorphin Production

Through its transient blockade of mu-opioid receptors, LDN triggers a compensatory upregulation of endogenous opioid production — the “rebound effect.” This directly addresses the core deficit proposed in the endorphin depletion model. Cabanas et al. (2021) demonstrated that LDN treatment in ME/CFS patients restored TRPM3 ion channel function in natural killer (NK) cells, and that enhancement of delta-opioid receptor activity promoted NK cell cytotoxicity in response to β-endorphins, suggesting that LDN directly supports the endogenous opioid-immune axis that is compromised in CFS/ME.

Reducing Neuroinflammation and Clearing Brain Fog

LDN modulates microglial activation by blocking Toll-like receptor 4 (TLR4), a critical pathway in innate immune activation within the central nervous system. Overactivated microglia produce proinflammatory cytokines that drive neuroinflammation — the direct biological substrate of brain fog. As Dr. Lucinda Bateman of the Bateman Horne Center has noted, LDN reduces the production of cytokines causing neuroinflammation, and “neuroinflammation is associated with brain fog.” Younger et al.’s fibromyalgia studies confirmed that LDN reduced erythrocyte sedimentation rate and a wide array of proinflammatory cytokines, demonstrating measurable anti-inflammatory effects.

Clinical Evidence in CFS/ME

The largest clinical study of LDN in ME/CFS to date, Polo et al. (2019), retrospectively analyzed 218 patients treated with LDN (3.0–4.5 mg/day) over an average follow-up of 1.7 years. A positive treatment response was reported by 73.9% of patients, with improvements in alertness (51.4%), physical function (23.9%), and cognitive function (21.1%). The authors concluded that the mechanism likely involves “rebound of endorphins following short-term suppression” or “direct action suppressing inflammation induced by microglia” — both consistent with the endorphin depletion model. Side effects were mild (primarily transient insomnia and nausea) with no serious adverse events reported.

Optimizing Immune Function

Beyond pain and neuroinflammation, LDN also optimizes immune function — a critical consideration given the well-documented NK cell dysfunction in CFS/ME. Rather than broadly suppressing immune activity like conventional immunosuppressants, LDN modulates the immune response toward balanced function, reducing the chronic immune activation that perpetuates the inflammatory milieu of CFS/ME while restoring appropriate cytotoxic activity against pathogens and abnormal cells.

Integrating LDN into Clinical Practice

In my practice at Direct Integrative Care, LDN has become a cornerstone of my approach to CFS/ME precisely because it simultaneously addresses the key elements of the endorphin depletion cycle. However, LDN works best as part of a comprehensive treatment strategy:

• Start low, go slow: Initiate at 0.5–1.5 mg at bedtime, titrating to 1.5–4.5 mg over several weeks. Sensitive patients — particularly those with MCAS — may need ultra-low doses (0.1 mg) initially.
• Address sleep concurrently: Optimizing sleep architecture while LDN rebuilds endorphin reserves accelerates recovery. This may involve low-dose sleep support, magnesium, melatonin, and addressing primary sleep disorders.
• Target neuroinflammation: Combine LDN with anti-inflammatory nutritional strategies (omega-3 fatty acids, curcumin, CoQ10) and mitochondrial support (D-ribose, L-carnitine) to address brain fog from multiple angles.
• Evaluate hidden drivers: Use the SHINE framework (Sleep, Hormones, Hidden Infections, Nutrition, Endocrine/Autoimmune) to systematically identify and treat contributing factors.
• Set realistic expectations: Counsel patients that full therapeutic effects may take 2–3 months to manifest. Vivid dreams, a common initial effect, typically resolve within weeks.

Conclusion

The endorphin depletion hypothesis offers a coherent, evidence-supported pathophysiological model for understanding a significant subset of CFS/ME patients. By recognizing chronic pain as a driver of endorphin depletion, and endorphin depletion as a driver of non-restorative sleep and neuroinflammation, we gain a mechanistic framework that explains the interconnected symptoms of this devastating illness and identifies clear therapeutic targets.

In clinical practice, prioritizing the treatment of chronic pain and brain fog — rather than treating them as secondary symptoms — represents a paradigm shift in CFS/ME management. Low-Dose Naltrexone, with its unique ability to restore endorphin production, reduce neuroinflammation, and optimize immune function, emerges as a cornerstone treatment uniquely suited to interrupt the pathological cycle at its core.

As our understanding of the neuroimmune pathophysiology of CFS/ME continues to evolve, the endorphin depletion model provides both a testable hypothesis for researchers and an actionable clinical framework for practitioners seeking to offer their patients genuine, mechanistically informed hope.

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Dr. Yoon Hang “John” Kim, MD, MPH is a board-certified integrative medicine physician and the founder of Direct Integrative Care. He leads the LDN Support Group with over 7,000 members and is the author of three books on Low-Dose Naltrexone therapy. For more information, visit www.directintegrativecare.com

Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting any new treatment.