Accurate Education – Central Sensitization and Untreated Sleep Apnea

Central Sensitization (CS) and Untreated Sleep Apnea

Recognizing that even when patients can be tested and diagnosed with sleep apnea, proper treatment is often beyond reach for financial and other reasons. For this reason, this section is devoted to exploring the mechanisms by which untreated sleep apnea contributes to central sensitization and how the use of nutraceuticals may offset some of the impact sleep apnea has on CS. Furthermore, based on the 4-Domain (4-D) approach to the management of chronic pain, personalized protocols may be engaged for those with untreated sleep apnea that may succeed in greater success in reducing CS and it’s impact on general health, especially chronic pain then simply targeting the condition with nutraceuticals.

[1] https://aasm.org/new-national-indicator-report-details-importance-prompt-sleep-apnea-diagnosis-treatment/

[2] https://academic.oup.com/sleep/article/48/Supplement_1/A278/8135407

[3] https://investor.resmed.com/news-events/press-releases/detail/65/people-with-sleep-apnea-live-longer-on-cpap-in-large-late-breaking-resmed-supported-alaska-study-presented-at-ers

See:

• Nutraceuticals for Central Sensitization (CS)
• Central Sensitization – Untreated Sleep Apnea
• A Guide to the 4 Domain Approach

Key to Links:

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• Red text – another page on this website
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Definitions and Terms Related to Pain

Untreated Sleep Apnea and Central Sensitization

Scope of Untreated Sleep Apnea

Types of Sleep Apnea

1. Obstructive Sleep Apnea (OSA): The most frequent type, caused by a physical blockage when throat muscles relax and collapse the airway. This type is the most commonly found in obese individuals in those with short thick necks.
2. Central Sleep Apnea (CSA): A less common type where the brain fails to send proper signals to breathing muscles. This type is most common when induced by brain injury or stroke..
3. Complex Sleep Apnea Syndrome: A mix of both, often emerging when treating OSA.

How Untreated Sleep Apnea can Contribute to Central Sensitization (CS)

Evidence — predominantly from OSA research — supports several converging mechanisms. The literature on central sleep apnea (CSA) and pain sensitization is notably sparse compared to OSA. Below is a synthesis distinguishing the two.

Obstructive Sleep Apnea (OSA) and Central Sensitization

OSA is the far better-studied entity in relation to pain processing. The two primary pathophysiologic drivers are chronic intermittent hypoxia (CIH) and Sleep Fragmentation, each contributing to central sensitization through overlapping but distinct pathways:[1][2] intermittent hypoxia refers to the drop in oxygen levels during the episodes in which breathing is paused during sleep apnea, also contributed by the build-up of carbon dioxide which impairs the drive to breathe. The severity of the drop in oxygen correlates with the severity of problems related to untreated sleep apnea. Sleep Fragmentation (SF) refers to the breakdown of the normal stages of sleep, which must be maintained for brain health and general physiological functioning.

1. Glial cell activation and neuroinflammation. Chronic intermittent hypoxia (CIH) activates astrocytes and microglia in the spinal cord dorsal horn and periaqueductal grey (PAG), producing a low-grade neuroinflammatory state with elevated IL-1β, TNF-α, and prostaglandin E2. This neuroinflammation increases excitability of central nociceptive neurons.[3][4][5][6]
2. NMDA receptor upregulation. IH drives increased expression of the GluN2B subunit of NMDA receptors in the spinal cord, enhancing synaptic plasticity in pro-nociceptive pathways — a hallmark mechanism of central sensitization.[3]
3. –CGRP-mediated peripheral and central sensitization. Chronic IH increases calcitonin gene-related peptide (CGRP) expression in trigeminal ganglia and enhances CGRP-positive afferent terminals in laminae I-II of the trigeminal subnucleus caudalis, driving mechanical allodynia.[7]
4. Oxidative stress. IH enhances NADPH oxidase activity and reactive oxygen species (ROS) production, contributing to oxidative neuronal injury and further inflammatory cascading.[6][5]
5. Sleep fragmentation effects. Independent of hypoxia, sleep disruption itself enhances central sensitization markers — secondary hyperalgesia in males and temporal summation in females — through IL-6 elevation and precuneus hyperexcitability. Nocturnal desaturation is independently associated with pain even after controlling for sleep fragmentation.[8][9][10]
6. Descending modulation impairment. Astrocyte activation in the PAG may impair descending inhibitory pain pathways, reducing endogenous pain control.[3][4]

The following reviews the interconnected mechanisms by which chronic intermittent hypoxia induces neuronal damage through glial activation, oxidative stress, and vascular dysfunction. The underlying mechanism of CIH‐induced neuronal damage:

(A) CIH can exert an impact on the structure and function of neuron synapses and thereby cause damage to neurons by inhibiting the synthesis of synaptophysin; It can activate astrocytes to release inflammatory factors that affect the formation and stability of neuronal synapses, thereby damaging neurons.

(B) CIH can activate microglia to release inflammatory factors, trigger inflammatory reactions and oxidative stress, and then damage neurons.

(C) CIH can enhance NADPH enzyme activity, promote the production of ROS, trigger inflammatory reactions and oxidative stress, and then damage neurons.

(D) CIH induces NOS activation via multiple signaling pathways, resulting in vascular endothelial dysfunction, compromised blood flow, and subsequent neuronal injury.

Central Sleep Apnea (CSA) and Central Sensitization

The literature does not directly address CSA’s relationship to central sensitization as a distinct entity from OSA. However, mechanistic reasoning supports that CSA could contribute through:

(A) Intermittent hypoxia — CSA also produces cyclical desaturation, though typically with a different pattern (crescendo-decrescendo in Cheyne-Stokes) and often less severe than OSA. The IH-driven mechanisms (glial activation, neuroinflammation, NMDA upregulation) would apply proportionally to the degree of hypoxic burden.

(B) Sleep fragmentation — CSA causes frequent arousals that disrupt sleep architecture, which independently promotes central sensitization.[8][9]

(C) Key differences from OSA: CSA lacks the mechanical upper airway obstruction, meaning there is no contribution from intrathoracic pressure swings, sympathetic surges from obstructive efforts, or OSA-associated obesity-driven systemic inflammation. CSA also often occurs in the context of heart failure or opioid use, which themselves modulate pain processing. Opioid-induced CSA is particularly relevant in pain patients, as it creates a vicious cycle: opioids cause CSA, CSA worsens central sensitization, and worsening pain may lead to increased opioid use.

Treatment Options Beyond Treating the Sleep Apnea

As a key player in the driving forces behind chronic pain, central sensitization (CS) should be a target in the management of any chronic pain syndrome likely to be associated with CS. At this time, there is no specific conventional prescription management for CS. Rather, treatment of CS is generally directed at individual drivers of CS including system systemic inflammation, oxidative stress, and mitochondrial dysfunction. This section explores nutraceutical compounds, potentially be beneficial for the management of Central sensitization.

A multimodal approach targeting central sensitization mechanisms is recommended:[12][13][4]

   Pharmacologic options:

1. SNRIs (duloxetine, milnacipran) and tricyclics (amitriptyline, nortriptyline) — target descending inhibitory pathways[12][13]
2. Alpha-2-delta ligands (pregabalin, gabapentin) — reduce excitatory neurotransmission[12][13]
3. Low-dose naltrexone — reduces neuroinflammation via glial modulation[13][4]
4. CGRP antagoists: (1) monoclonal antibodies (injections taken monthly); (2) Nurtec (rimegepant) – a pill that dissolves under the tongue); (3) Ubrelvy (ubrogepant( (a pill you take by mouth);  Zavspret (zavegepant (a nasal spray you put in your nose) — medications particularly relevant given the CGRP-mediated sensitization demonstrated in CIH research models; currently indicated for migraine but mechanistically applicable[7][13]
5. Minocycline  — directly inhibit microglial activation, though clinical translation remains limited[4]
6. Cannabidiol (CBD) — preclinical evidence suggests it may reduce glial activation[4]

   Non-pharmacologic options:

1. Pain neuroscience education — reframes the pain experience and reduces catastrophizing[12]
2. Cognition-targeted exercise therapy — graded exercise reduces central sensitization markers[12]
3. Sleep hygiene and cognitive behavioral therapy for insomnia (CBT-I) — addresses the sleep fragmentation component independent of apnea treatment[12][4]
4. Stress management — severe stress is an independent glial activator and should be addressed as a sensitization driver[4]

Nutraceuticals for Central Sensitization

See: Nutraceuticals for Central Sensitization (CS)

  Compounds that have gained interest in treating central sensitization include

1. Curcumin
2. palmitoylethanamide (PEA)
3. acetyl L-carnitine (ALC)
4. alpha lipoid acid (ALA)
5. cannabidiol (CBD)
6. delta-9 THC
7. acetyl cysteine (NAC)
8. Omega-3
9. Resveratrol
10. EGCG (catechins found in green tea, coffee and cocoa)
11. Low dose naltrexone (LDN)

Practical considerations: Comorbid OSA and insomnia produces significantly higher pain intensity than either condition alone, suggesting that addressing both sleep-disordered breathing and sleep quality is essential.[14] CPAP therapy has demonstrated reduced pain intensity and decreased opioid requirements, particularly for headache-related pain.[15][16]

References

1. The Association of Obstructive Sleep Apnea and Pain Outcomes in Adults: A Systematic Review. Charokopos A, Card ME, Gunderson C, Steffens C, Bastian LA. Pain Medicine (Malden, Mass.). 2018;19(suppl_1):S69-S75. doi:10.1093/pm/pny140.
2. Obstructive Sleep Apnea’s Association With the Cervical Spine Abnormalities, Posture, and Pain: A Systematic Review. Pham T, Lin CK, Leek D, Chandrashekhar R, Annaswamy TM. Sleep Medicine. 2020;75:468-476. doi:10.1016/j.sleep.2020.09.008.
3. Intermittent Hypoxia Triggers Glial Cell Activation, GluN2B Receptor Upregulation and Hyperalgesia in a Mouse Model of Sleep Apnea. Liu YC, Chiu BY, Tu KY, Liu IC, Chen SL. European Journal of Pain (London, England). 2025;29(6):e70039. doi:10.1002/ejp.70039.
4. Sleep Disturbances and Severe Stress as Glial Activators: Key Targets for Treating Central Sensitization in Chronic Pain Patients?. Nijs J, Loggia ML, Polli A, et al. Expert Opinion on Therapeutic Targets. 2017;21(8):817-826. doi:10.1080/14728222.2017.1353603.
5. Mechanisms of Microglial Activation in Models of Inflammation and Hypoxia: Implications for Chronic Intermittent Hypoxia. Kiernan EA, Smith SM, Mitchell GS, Watters JJ. The Journal of Physiology. 2016;594(6):1563-77. doi:10.1113/JP271502.
6. Sleep Apnoea and the Brain: A Complex Relationship. Rosenzweig I, Glasser M, Polsek D, et al. The Lancet. Respiratory Medicine. 2015;3(5):404-14. doi:10.1016/S2213-2600(15)00090-9.
7. Effect of Chronic Intermittent Hypoxia on Ocular and Intraoral Mechanical Allodynia Mediated via the Calcitonin Gene-Related Peptide in a Rat. Katagiri A, Kishimoto S, Okamoto Y, et al. Sleep. 2024;47(3):zsad332. doi:10.1093/sleep/zsad332.
8. Sex Differences in Measures of Central Sensitization and Pain Sensitivity to Experimental Sleep Disruption: Implications for Sex Differences in Chronic Pain. Smith MT, Remeniuk B, Finan PH, et al. Sleep. 2019;42(2). doi:10.1093/sleep/zsy209.
9. Precuneus Hyperexcitability Mediates Inflammatory-Driven Pain Hypersensitivity Following Sleep Disruption: A Multimodal Neuroimaging Study. Li C, Wang Y, Zhou K, et al. Frontiers in Immunology. 2026;17:1744480. doi:10.3389/fimmu.2026.1744480.
10. Nocturnal Intermittent Hypoxia Is Independently Associated With Pain in Subjects Suffering From Sleep-Disordered Breathing. Doufas AG, Tian L, Davies MF, Warby SC. Anesthesiology. 2013;119(5):1149-62. doi:10.1097/ALN.0b013e3182a951fc.
11. Chronic Intermittent Hypoxia‐Induced Neural Injury: Pathophysiology, Neurodegenerative Implications, and Therapeutic Insights. Jia NN, Yao MF, Zhu CX, et al. CNS Neuroscience & Therapeutics. 2025;31(4):e70384. doi:10.1111/cns.70384.
12. Treatment of Central Sensitization in Patients With Chronic Pain: Time for Change?. Nijs J, Leysen L, Vanlauwe J, et al. Expert Opinion on Pharmacotherapy. 2019;20(16):1961-1970. doi:10.1080/14656566.2019.1647166.
13. Central Sensitization: When It Is Not “All in Your Head”. Mohabbat AB, Wilkinson JM. American Family Physician. 2023;107(1):92-96.
14. An Examination of Pain’s Relationship to Sleep Fragmentation and Disordered Breathing Across Common Sleep Disorders. Mundt JM, Eisenschenk S, Robinson ME. Pain Medicine (Malden, Mass.). 2018;19(8):1516-1524. doi:10.1093/pm/pnx211.
15. Positive Airway Pressure Therapy for Chronic Pain in Patients With Obstructive Sleep Apnea-a Systematic Review. McCarthy K, Saripella A, Selvanathan J, et al. Sleep & Breathing = Schlaf & Atmung. 2022;26(1):47-55. doi:10.1007/s11325-021-02363-7.
16. Prevalence and Characteristics of Pain in Moderate-to-Severe Obstructive Sleep Apnea Patients and Effect of CPAP Treatment. Shen C, Ou Y, Ouyang R, Zong D. Scientific Reports. 2023;13(1):15758. doi:10.1038/s41598-023-42967-5.

Yes, adding modifier points for untreated OSA is well-supported by the evidence, and the mechanistic case is arguably stronger than for some of the existing lifestyle modifiers. OSA drives pathology across three of the four 4D domains — oxidative stress, neuroinflammation, and mitochondrial dysfunction — through intermittent hypoxia (IH) as a distinct, continuous pathogenic load that operates independently of (and additively with) the sleep quality already captured in the lifestyle assessment.

Domain-by-Domain Evidence for OSA Modifiers

Oxidative stress (+2 points recommended). The evidence here is robust and directly maps to the 4D protocol’s biomarkers. OSA patients demonstrate elevated 8-isoprostane (the same F2-isoprostane family the protocol measures), with AHI independently predicting 8-isoprostane levels after adjustment for confounders including BMI.[1] Increased 8-OHdG (DNA oxidation marker), lipid peroxidation products (TBARS, oxidized LDL), and protein carbonylation are all documented in OSA.[2][3][4] The mechanism — NADPH oxidase activation in leukocytes producing excess ROS with concurrent reduction in antioxidant capacity (decreased SOD, vitamins A and E, paraoxonase-1) — creates a dual oxidative burden.[5][3] Critically, these oxidative stress markers correlate with AHI and oxygen desaturation indices and decrease with CPAP therapy, confirming a direct causal link.[2] A +2 modifier is justified because the oxidative stress from IH is continuous and self-perpetuating as long as OSA remains untreated, directly counteracting antioxidant nutraceuticals (NAC, alpha-lipoic acid, CoQ10).

The following figure illustrates the mechanistic pathways from IH to oxidative stress:

Figure 2 Oxidative stress as an intermediary pathway of OSA‐associated CV disease. The intermittent hypoxia characteristic of OSA leads to increased oxidative burst of leukocytes via activation of NOX. Excessively produced ROS enhance lipid peroxidation and isoprostane formation. NO bioavailability is reduced by diminished expression of eNOS and its inhibition by ADMA. Finally, antioxidant capacity is impaired in affected patients. ADMA: asymmetric dimethylarginine; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; NOX: NADPH oxidase; ROS: reactive oxygen species; SOD: superoxide dismutase.

Neuroinflammation (+2 points recommended). As established in the prior discussion, IH activates microglia toward a pro-inflammatory phenotype with upregulation of TLR4, NF-κB, and NLRP3 inflammasome pathways.[6][7][8] An important nuance: IH produces microglial priming — microglia exposed to IH cycles show increased NF-κB expression and, when subsequently stimulated with IL-1β, mount an exaggerated inflammatory response compared to non-primed cells.[9] This priming effect means OSA does not merely add neuroinflammation — it amplifies the neuroinflammatory response to other triggers (stress, poor sleep quality, peripheral inflammation), making it a multiplicative rather than additive risk factor. HIF-1α activation and NLRP3 inflammasome engagement further drive the neuroinflammatory cascade.[7] A +2 modifier is appropriate, consistent with the existing stress modifier (+2 to Neuroinflammation), given that both operate through microglial activation but via distinct pathways (HPA axis for stress vs. IH/TLR4 for OSA).

Mitochondrial dysfunction (+1 point recommended). Severe OSA is associated with significantly reduced mitochondrial DNA copy number (mtDNA-CN) — 675 ± 487 vs. 1136 ± 955 in non-severe OSA (p = 0.007 after adjustment for confounders) — a direct biomarker of mitochondrial health.[10] IH promotes ceramide-mediated mitochondrial fragmentation, impaired oxidative phosphorylation, and disrupted mitochondrial dynamics.[11] OSA patients also show increased mitochondrial DNA damage correlating with reactive oxygen metabolite levels (R = 0.5, p < 0.01).[12] A +1 modifier (rather than +2) is appropriate because: (a) the mitochondrial effects are partially downstream of the oxidative stress already captured by the oxidative stress modifier, and (b) the existing sleep quality modifier already assigns +1 to Mitochondrial Dysfunction for poor sleep, and OSA-specific mitochondrial damage adds to but does not dwarf this effect.

Systemic inflammation (+1 point recommended). Though not the primary question, OSA also drives NF-κB–mediated upregulation of TNF-α, IL-8, and ICAM-1, which decrease with CPAP.[5] This warrants a modest +1 modifier to the Systemic Inflammation domain, particularly for patients with moderate-to-severe OSA (AHI ≥15).

Proposed OSA Modifier Summary

Implementation Considerations

Severity stratification. The modifiers above apply to moderate-to-severe untreated OSA (AHI ≥15). For mild OSA (AHI 5–14), halving the modifiers (+1 oxidative stress, +1 neuroinflammation, +0 for mitochondrial/systemic inflammation) would be reasonable, as oxidative stress markers and mtDNA damage correlate with AHI severity.[2][1][10]

Distinguishing from existing sleep modifier. The current protocol assigns +2 to Neuroinflammation and +1 to Mitochondrial Dysfunction for poor sleep quality (Sleep Quality Score ≥6). The OSA modifier should be additive to this, because OSA’s IH-driven pathology is mechanistically distinct from sleep fragmentation alone. A patient with untreated moderate-severe OSA AND poor sleep quality would receive both modifiers (capped at 10 per the existing formula). This is analogous to how the protocol currently allows both exercise and diet modifiers to stack on the Systemic Inflammation domain.

Screening integration. Adding a single screening question to the Simplified Lifestyle Vital Signs — “Have you been diagnosed with sleep apnea? If yes, are you currently using CPAP/BiPAP?” — would be sufficient to trigger the modifier. The existing sleep assessment already prompts sleep apnea evaluation for high-scoring patients; the modifier formalizes what happens when untreated OSA is confirmed.

Treatment response tracking. When patients initiate CPAP, the OSA modifier should be reassessed at 8–12 weeks. CPAP adherence ≥4 hours/night reduces oxidative stress markers and inflammatory biomarkers, and the modifier could be reduced or removed with documented adherence, mirroring how lifestyle modifiers change when behaviors improve.[2][5]

Central sleep apnea. As discussed previously, CSA produces IH (typically less severe) without the mechanical/sympathetic surge components of OSA. A conservative approach would be to apply half the OSA modifiers (+1 oxidative stress, +1 neuroinflammation) for documented untreated CSA, acknowledging the weaker direct evidence while recognizing the shared IH mechanism. The additional consideration of opioid-induced CSA in pain patients warrants a clinical flag similar to the existing Inactive + Poor Sleep interaction alert.

Would you like to explore how opioid-induced central sleep apnea could be specifically flagged within the 4D protocol as an interaction alert?

References

1. Obstructive Sleep Apnea and Circulating Biomarkers of Oxidative Stress: A Cross-Sectional Study. Peres BU, Allen AJH, Shah A, et al. Antioxidants (Basel, Switzerland). 2020;9(6):E476. doi:10.3390/antiox9060476.
2. Oxidative Stress Markers among Obstructive Sleep Apnea Patients. Stanek A, Brożyna-Tkaczyk K, Myśliński W. Oxidative Medicine and Cellular Longevity. 2021;2021:9681595. doi:10.1155/2021/9681595.
3. Obstructive Sleep Apnea, Oxidative Stress, and Cardiovascular Disease: Evidence from Human Studies. Eisele HJ, Markart P, Schulz R. Oxidative Medicine and Cellular Longevity. 2015;2015:608438. doi:10.1155/2015/608438.
4. Cardiovascular Complications of Sleep Apnea: Role of Oxidative Stress. Badran M, Ayas N, Laher I. Oxidative Medicine and Cellular Longevity. 2014;2014:985258. doi:10.1155/2014/985258.
5. Interactions of Obstructive Sleep Apnea With the Pathophysiology of Cardiovascular Disease, Part 1: JACC State-of-the-Art Review. Javaheri S, Javaheri S, Somers VK, et al. Journal of the American College of Cardiology. 2024;84(13):1208-1223. doi:10.1016/j.jacc.2024.02.059.
6. Mechanisms of Microglial Activation in Models of Inflammation and Hypoxia: Implications for Chronic Intermittent Hypoxia. Kiernan EA, Smith SM, Mitchell GS, Watters JJ. The Journal of Physiology. 2016;594(6):1563-77. doi:10.1113/JP271502.
7. Advances in Immunology of Obstructive Sleep Apnea: Mechanistic Insights, Clinical Impact, and Therapeutic Perspectives. Dong N, Yue H. Frontiers in Immunology. 2025;16:1654450. doi:10.3389/fimmu.2025.1654450.
8. Sleep Apnoea and the Brain: A Complex Relationship. Rosenzweig I, Glasser M, Polsek D, et al. The Lancet. Respiratory Medicine. 2015;3(5):404-14. doi:10.1016/S2213-2600(15)00090-9.
9. Intermittent Hypoxia Treatments Cause Cellular Priming in Human Microglia. De Felice M, Germelli L, Piccarducci R, et al. Journal of Cellular and Molecular Medicine. 2023;27(6):819-830. doi:10.1111/jcmm.17682.
10. Mitochondrial Dysfunction in Patients With Severe Obstructive Sleep Apnea. Huang TN, Chung YP, Lin RJ, Wang JY, Chung WS. Sleep Medicine. 2026;146:109071. doi:10.1016/j.sleep.2026.109071.
11. Cyclic Altitude Training, Mitochondrial Health, and the Oral-Airway Axis: Intermittent Hypoxia Between Adaptation and Disease. Cannon M, Peldyak J, Reynolds PR, Bikman B. Journal of Clinical Medicine. 2026;15(14):5402. doi:10.3390/jcm15145402.
12. Mitochondrial DNA Alteration in Obstructive Sleep Apnea. Lacedonia D, Carpagnano GE, Crisetti E, et al. Respiratory Research. 2015;16:47. doi:10.1186/s12931-015-0205-7.

Emphasis on Education

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

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