Understanding Cognitive Decline and Centrally Acting Medications in Athletes

Repetitive head impacts sustained during contact sports carry a well-documented risk for long-term neurological sequelae, including traumatic encephalopathy syndrome and chronic traumatic encephalopathy. However, clinicians often face complex clinical presentations where neurobehavioral dysregulation and cognitive decline cannot be attributed solely to structural brain trauma. Former contact sports competitors routinely endure severe musculoskeletal trauma, leading to debilitating chronic pain, repeated surgical interventions, and subsequent reliance on centrally acting medications. Consequently, differentiating between primary neurodegenerative pathology and secondary iatrogenic or pain-related impairment remains a critical challenge for neurologists, pain physicians, and sports medicine practitioners.

Centrally acting medications, including opioids, gabapentinoids, sedative-hypnotics, muscle relaxants, and psychotropics, directly modulate central nervous system pathways. While these pharmaceutical agents provide necessary relief for intractable musculoskeletal conditions, they frequently alter neurotransmitter dynamics, executive processing, and emotional regulation. Furthermore, persistent pain itself alters central neural processing, often amplifying affective disturbance and cognitive fatigue. Therefore, understanding the independent and combined effects of analgesic polypharmacy, persistent pain, and surgical burden is essential for delivering precise, restorative clinical care to retired elite athletes.

Methodology: Evaluating Chronic Pain and Polypharmacy in the DIAGNOSE CTE Cohort

To address this diagnostic overlap, researchers evaluated data from the multicenter DIAGNOSE CTE research project. Specifically, the investigators examined a well-characterized cohort of 236 male participants. This sample comprised 120 former professional American football players, 60 former collegiate players, and 56 unexposed, asymptomatic controls. The study systematically recorded the total number of prescribed centrally acting medications, average pain severity scores, and lifetime counts of orthopedic surgeries across all three clinical cohorts.

In addition to descriptive comparisons, the authors conducted multivariable logistic regression analyses among the former athletes. These models evaluated the relationship between pharmacological burden, pain scores, and surgical history with consensus diagnoses of cognitive impairment and neurobehavioral dysregulation defined by established traumatic encephalopathy syndrome criteria. Additionally, multivariable linear regression models examined objective cognitive performance on the Montreal Cognitive Assessment alongside validated behavioral, impulsivity, anxiety, and depression rating scales. Importantly, the researchers adjusted all statistical evaluations for key confounding variables, including age, race, educational attainment, and cumulative exposure to contact sports.

Key Findings: Neurobehavioral Dysregulation and MoCA Performance

The study results revealed striking differences in medication utilization, pain exposure, and surgical history across the study groups. Former professional and collegiate athletes exhibited substantially higher average pain scores and used significantly more centrally acting medications than unexposed control subjects. Moreover, statistical modeling demonstrated that both analgesic polypharmacy and elevated pain scores were independently associated with markedly higher odds of receiving a consensus diagnosis of neurobehavioral dysregulation. Specifically, each additional centrally acting medication more than doubled the odds of neurobehavioral dysregulation.

Furthermore, higher pain scores and medication counts correlated directly with increased objective measures of impulsivity, behavioral dysregulation, depression, anxiety, and outward aggression. In contrast, neither pain severity nor medication use showed a statistically significant relationship with consensus-defined syndromic cognitive impairment. However, higher medication counts were significantly associated with lower scores on the Montreal Cognitive Assessment. Consequently, while these pharmacological regimens may not produce catastrophic dementia syndromes, they visibly suppress psychomotor performance, working memory, and attentional capacity in vulnerable athletic populations.

Disentangling Orthopedic Surgical Burden from Neurological Outcomes

Retired professional athletes undergo extensive reconstructive and restorative orthopedic surgeries throughout their athletic careers and post-retirement lives. Indeed, former professional players in this study underwent an average of nearly three orthopedic surgeries, compared to fewer than one surgery among control participants. Clinicians have frequently hypothesized that repeated perioperative neuroinflammation, cumulative general anesthetic exposure, and postoperative systemic stress might directly drive chronic cognitive impairment.

Interestingly, the study findings refuted this hypothesis. The investigators observed no significant association between the cumulative number of orthopedic surgeries and the presence of neurobehavioral dysregulation or cognitive impairment. Similarly, surgical history demonstrated no measurable correlation with Montreal Cognitive Assessment performance or psychometric symptom scales. Therefore, these data strongly indicate that surgical intervention itself does not drive long-term neurobehavioral morbidity. Instead, the persistent chronic pain that necessitates these interventions and the subsequent utilization of centrally acting medications represent the true drivers of affective and cognitive disruption.

Clinical Implications for Pain Management and Medication Deprescribing

These findings provide clear guidance for clinicians managing former contact sport athletes presenting with memory complaints, behavioral lability, or depressive symptoms. Instead of prematurely attributing all cognitive or mood symptoms to irreversible neurodegenerative processes such as chronic traumatic encephalopathy, physicians must conduct rigorous pharmacological audits. Polypharmacy involving centrally acting medications must be scrutinized, as cumulative sedative burdens frequently mimic or exacerbate organic neurobehavioral syndromes.

Consequently, multidisciplinary care teams should prioritize comprehensive medication reconciliation and structured deprescribing protocols whenever clinically feasible. Integrating non-pharmacological interventions—such as targeted physical therapy, interventional pain procedures, cognitive behavioral therapy for chronic pain, and sleep hygiene optimization—can substantially mitigate pain while reducing reliance on centrally acting pharmaceuticals. Furthermore, treating sleep fragmentation, which frequently co-occurs with musculoskeletal pain, can markedly improve mood regulation, executive control, and daytime alertness without requiring high-dose sedative medications.

Future Directions in Contact Sports Medicine and Athlete Healthcare

As sports medicine and neurology continue to refine diagnostic biomarkers for neurodegenerative diseases, distinguishing reversible functional symptoms from irreversible tauopathies remains paramount. Longitudinal prospective studies are needed to evaluate whether targeted deprescribing protocols and comprehensive multidisciplinary pain rehabilitation can reverse neurobehavioral dysregulation and restore Montreal Cognitive Assessment scores in retired athletes.

Additionally, medical teams working with active athletes must establish proactive pain management strategies that minimize long-term dependence on neuroactive agents. Educating players, trainers, and sports physicians regarding the cognitive and emotional costs of long-term analgesic therapy is vital. By addressing the interconnected triad of head impacts, chronic pain, and central nervous system medications, healthcare professionals can deliver balanced, personalized care that protects both musculoskeletal functionality and long-term neurocognitive health.

What are the primary risks associated with centrally acting medications in former contact sport athletes?

Centrally acting medications, including opioids, muscle relaxants, gabapentinoids, and sedative-hypnotics, significantly elevate the risk of neurobehavioral dysregulation. Furthermore, these pharmacological agents impair cognitive processing, psychomotor speed, and attention, leading to measurable score reductions on standardized cognitive assessments such as the Montreal Cognitive Assessment. Consequently, polypharmacy can closely mimic or exacerbate symptoms commonly attributed to chronic traumatic encephalopathy.

How does chronic pain contribute to neurobehavioral dysregulation?

Persistent chronic pain alters central neural processing, leading to heightened neuroinflammation, emotional distress, and executive exhaustion. Moreover, chronic pain disrupts restorative sleep architecture, which further compromises prefrontal cortex function. As a result, patients experiencing severe chronic pain exhibit substantially higher rates of impulsivity, depression, anxiety, aggression, and behavioral dysregulation compared to individuals without persistent musculoskeletal discomfort.

Does multiple orthopedic surgeries correlate with long-term cognitive impairment?

According to current evidence from the DIAGNOSE CTE cohort, cumulative lifetime orthopedic surgical history is not significantly associated with neurobehavioral dysregulation or cognitive decline. Although former contact sport athletes undergo significantly more surgeries than unexposed individuals, long-term cognitive and mood symptoms stem primarily from persistent post-injury chronic pain and subsequent centrally acting medication use rather than surgical or anesthetic exposure.

Disclaimer: This content is for informational and educational purposes only and should not be considered medical advice. Always consult a qualified healthcare professional regarding any medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

Puleio A et al. Centrally Acting Medications, Chronic Pain, and Orthopedic Surgical History Among Former American Football Players. Neurology. 2026 Sep 22. doi: 10.1212/WNL.0000000000218475. PMID: 42664488.

Katz DI, et al. National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome. Neurology. 2021;96(18):848-863. doi: 10.1212/WNL.0000000000011863.

Alosco ML, et al. Repetitive head impacts and chronic traumatic encephalopathy: a review of the current literature. Lancet Neurol. 2020;19(1):15-17. doi: 10.1016/S1474-4422(19)30424-6.