Postsurgical Pain and Opioid Use in Older Adults: Effects of Mild Cognitive Impairment

Older adults account for a growing proportion of patients undergoing major orthopedic and complex spine procedures. As the population ages, increasing numbers of surgical patients present with preexisting cognitive impairment that falls short of dementia but may nevertheless influence recovery after surgery. Mild cognitive impairment (MCI) represents an intermediate stage between normal cognitive aging and dementia and is characterized by measurable cognitive deficits with relative preservation of functional independence. Despite the high prevalence of MCI among older surgical patients, limited information is available regarding how underlying cognitive status may influence the biological and physiological mechanisms associated with postoperative recovery.

Pain processing is a complex phenomenon involving peripheral sensory pathways, central nervous system modulation, autonomic nervous system regulation, and behavioral responses. Emerging evidence suggests that neurodegenerative processes associated with cognitive impairment may alter pain perception and pain regulation. Structural and functional changes within brain regions involved in pain processing, including areas responsible for sensory discrimination, emotional appraisal, and descending inhibitory control, may affect responses to acute surgical injury. Consequently, individuals with MCI may experience postoperative pain differently than cognitively intact older adults, potentially influencing recovery trajectories and patterns of analgesic utilization.

The relationship between cognitive impairment and postoperative recovery has important public health implications. Persistent postsurgical pain remains a significant cause of morbidity following orthopedic and spine surgery, contributing to impaired physical function, reduced quality of life, healthcare utilization, and prolonged exposure to opioid medications. Understanding mechanisms that contribute to variability in pain experiences among older adults may facilitate development of individualized perioperative pain management strategies and improve recovery outcomes in this vulnerable population.

This prospective observational study is designed to characterize biological, physiological, and behavioral factors that may underlie differences in postoperative recovery among older adults with and without MCI. The study incorporates multidimensional assessments of pain-related mechanisms before surgery and during postoperative recovery. These assessments evaluate sensory processing, autonomic nervous system function, genetic and plasma biomarkers associated with neurodegenerative disease risk, and patient-reported experiences across multiple domains of recovery.

A central feature of the study is the evaluation of pain modulatory function using quantitative sensory testing methodologies. Quantitative sensory testing provides a standardized approach for examining responses to experimentally applied stimuli and allows investigation of mechanisms that cannot be fully evaluated through self-report measures alone. Repeated assessments over time will permit examination of how surgery may influence pain processing and whether trajectories differ according to preoperative cognitive status.

The study also evaluates autonomic nervous system activity through measurements of heart rate variability. Reduced parasympathetic regulation has been associated with impaired inhibitory control of pain and may represent an important physiological mechanism linking cognitive impairment and altered pain regulation. Characterizing autonomic function before and after surgery may provide insight into pathways through which neurocognitive changes influence postoperative recovery.

Another objective is to explore the contribution of biomarkers associated with Alzheimer's disease risk and neurodegeneration. Genetic susceptibility and circulating biomarkers may provide information regarding underlying neuropathological processes that are not fully captured through cognitive testing alone. By integrating biomarker data with physiological and clinical assessments, the study seeks to identify factors that may explain heterogeneity in postoperative recovery among older adults.

The study further aims to examine relationships among cognitive function, sensory processing, autonomic regulation, and healthcare outcomes. Recovery after surgery is multifaceted and extends beyond resolution of acute postoperative symptoms. A comprehensive understanding of recovery requires evaluation of functional status, healthcare utilization, medication exposure patterns, and changes in cognitive performance. Longitudinal follow-up will allow assessment of these interrelated domains and facilitate identification of factors associated with favorable and unfavorable recovery trajectories.

Because cognitive impairment often remains unrecognized in routine clinical practice, findings from this study may also inform future strategies for perioperative risk stratification. Identification of measurable physiological or biomarker signatures associated with altered recovery could support development of screening approaches that help clinicians recognize patients who may benefit from tailored perioperative management. Such approaches could include modifications to pain management strategies, enhanced postoperative monitoring, or targeted interventions designed to promote recovery and minimize treatment-related complications.

Data generated through this investigation will contribute to understanding of interactions among cognitive aging, neurodegenerative risk, pain regulation, and postoperative recovery. By integrating cognitive, physiological, sensory, biomarker, and clinical data collected over a six-month postoperative period, the study aims to advance knowledge regarding mechanisms that influence recovery in older surgical patients. The resulting information may provide a foundation for future mechanistic studies and intervention trials designed to improve outcomes for older adults with cognitive impairment undergoing major surgery.

Primary outcomes

• Past 24-Hour Average Pain Intensity [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Average postoperative pain intensity will be measured using an 11-point Numeric Rating Scale (NRS) ranging from 0 (No Pain) to 10 (Worst Possible Pain). Participants will rate their average pain during the previous 24 hours at each assessment. Results will be reported as the mean NRS score and standard deviation for each study group at each time point, as well as the mean change from baseline. Between-group differences in pain trajectories across the postoperative period will be assessed.
• Cumulative Postoperative Opioid Use [Postoperative Discharge through 6 months after surgery.]: Postoperative opioid use will be quantified through pill counts and electronic health record review. All opioid medications consumed will be converted to morphine milligram equivalents (MME). Results will be reported as the cumulative MME consumed during each follow-up interval and cumulatively through 6 months after surgery. Mean MME, standard deviation, median, and range will be reported for each study group.
• Heat Pain Threshold Temperature [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Heat pain threshold will be assessed using the Medoc TSA2 Air quantitative sensory testing system. The outcome measure is the average temperature in degrees Celsius at which thermal stimulation is first perceived as painful across four testing trials. Results will be reported as mean threshold temperature (°C), standard deviation, and mean change from baseline. Lower temperatures indicate increased pain sensitivity.
• High-Frequency Heart Rate Variability (HF-HRV) [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Cardiac vagal regulation will be assessed from a 5-minute resting electrocardiographic recording. The primary outcome will be high-frequency heart rate variability derived using Kubios HRV software according to established HRV analysis methods. Results will be reported as mean HF-HRV values and mean change from baseline for each study group. Higher values indicate greater vagal inhibitory control.

Secondary outcomes

• Temporal Summation of Pain [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Temporal summation will be assessed using repeated standardized pinprick stimulation. The outcome measure will be calculated as the difference between the pain intensity rating following a single stimulus and the maximum pain intensity rating reported during a train of ten repeated stimuli. Results will be reported as mean temporal summation scores and changes from baseline. Higher positive values indicate greater central sensitization.
• Suprathreshold Heat Pain Intensity Rating [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participants will rate the intensity of four suprathreshold heat stimuli using an 11-point Numeric Rating Scale ranging from 0 (No Pain) to 10 (Worst Possible Pain). The outcome measure will be the mean pain intensity rating across all suprathreshold stimuli. Results will be reported as mean ratings, standard deviations, and mean change from baseline.
• Suprathreshold Heat Pain Unpleasantness Rating [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participants will rate the unpleasantness associated with suprathreshold thermal stimuli using an 11-point Numeric Rating Scale ranging from 0 (Not Unpleasant at All) to 10 (Most Unpleasant Possible). The outcome measure will be the average unpleasantness score across all test stimuli. Results will be reported as mean scores and mean changes from baseline. Higher scores indicate greater affective pain response.
• Past 24-Hour Pain Unpleasantness [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participants will rate the overall unpleasantness of pain experienced during the previous 24 hours using an 11-point Numeric Rating Scale ranging from 0 (Not Unpleasant at All) to 10 (Most Unpleasant Possible). Results will be reported as mean unpleasantness scores and change from baseline values for each study group.
• Past 24-Hour Worst Pain Intensity [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participants will rate the worst pain intensity experienced during the previous 24 hours using an 11-point Numeric Rating Scale ranging from 0 (No pain at All) to 10 (Most Intense Pain Possible). Results will be reported as mean worst pain scores and change from baseline values for each study group.
• Past 24-Hour Least Pain Intensity [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participants will rate the least pain intensity experienced during the previous 24 hours using an 11-point Numeric Rating Scale ranging from 0 (No pain at All) to 10 (Most Intense Pain Possible). Results will be reported as mean worst pain scores and change from baseline values for each study group.
• Past 24-Hour Average Pain Intensity [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participants will rate the average pain intensity experienced during the previous 24 hours using an 11-point Numeric Rating Scale ranging from 0 (No pain at All) to 10 (Most Intense Pain Possible). Results will be reported as mean worst pain scores and change from baseline values for each study group.
• PROMIS Pain Interference T-Score [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: The effect of pain on daily activities, social participation, emotional functioning, and physical functioning will be assessed using the PROMIS Pain Interference Short Form 8a. Raw scores will be converted to standardized PROMIS T-scores. Results will be reported as mean T-scores, standard deviations, and mean changes from baseline. Higher T-scores indicate greater pain-related interference.
• Short-Form McGill Pain Questionnaire-2 Total Score [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Pain quality will be measured using the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2). The outcome measure will be the total questionnaire score derived according to instrument scoring procedures. Results will be reported as mean total scores, standard deviations, and mean changes from baseline. Higher scores indicate greater pain symptom burden.
• Pain Assessment in Impaired Cognition (PAIC) Total Score [Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.]: Pain-related behaviors will be assessed using the Pain Assessment in Impaired Cognition (PAIC) instrument. Total scores will be calculated according to published scoring procedures. Results will be reported as mean PAIC scores and mean changes from baseline. Higher scores indicate greater observed pain-related behaviors.
• Michigan Body Map Pain Site Count [Baseline and 6 months after surgery.]: The number of body regions affected by persistent or recurrent pain will be identified using the Michigan Body Map. The outcome measure will be the total count of painful body sites. Results will be reported as mean number of painful body regions and mean changes from baseline. Higher values indicate more widespread pain.
• Opioid Side Effect Severity Score [2 weeks, 1 month, 3 months, and 6 months after surgery.]: Participant-reported opioid-related adverse effects will be assessed using visual analog scales measuring symptom severity. The outcome measure will be the severity score for each side effect and a composite side-effect burden score derived from all reported symptoms. Results will be reported as mean scores and changes over time. Higher scores indicate greater side-effect burden.
• Participants Experiencing Unplanned Healthcare Utilization [From surgery through 6 months postoperatively.]: Healthcare utilization will be assessed through medical record review. The outcome measure will be the number and percentage of participants experiencing at least one postoperative emergency department visit, hospital readmission, urgent care visit, or unplanned provider visit related to surgical recovery. Results will be reported as participant counts and percentages for each study group.
• Caregiver-Reported Opioid Management Difficulties [2 weeks, 1 month, 3 months, and 6 months after surgery.]: Number and percentage of caregivers reporting missed doses, extra doses, medication administration concerns, or medication management difficulties during postoperative follow-up.

Other outcomes

• Difference in Pain Outcomes by APOE4 Carrier Status [Baseline through 6 months after surgery.]: Participants will be categorized as APOE4 carriers or non-carriers. Outcomes including pain intensity, opioid utilization, heat pain threshold, temporal summation, and vagal inhibitory function will be compared between groups. Results will be reported as mean values, mean differences, and estimated effect sizes.
• Difference in Pain Outcomes by Plasma Amyloid Beta 42/40 Ratio [Baseline through 6 months after surgery.]: Participants will be categorized according to plasma amyloid beta 42/40 ratio status. Postoperative pain, opioid use, quantitative sensory testing measures, and heart rate variability outcomes will be compared between biomarker-defined groups. Results will be reported as mean outcome values, group differences, and estimated effect sizes.
• Change in Hopkins Verbal Learning Test-Revised Total Recall Score [Baseline and 6 months after surgery]: Memory performance will be assessed using the Hopkins Verbal Learning Test-Revised (HVLT-R). The outcome measure will be the change in total recall score from baseline to 6 months following surgery. Results will be reported as mean scores at each assessment, mean change from baseline, and between-group differences. Higher scores indicate better memory performance.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

PATIENT PARTICIPANTS:

* Aged 65 years or older
* Ability to provide informed consent
* English literacy sufficient to complete study measures
* No daily opioid use in the prior 3 months
* Residence within a 1-hour drive of Nashville
* Deemed healthy enough for quantitative sensory testing (QST) procedures by surgical Co-Investigators
* Undergoing elective surgical procedures including tier 2 or 3 procedures (e.g., posterior cervical fusion, thoracic/lumbar fusion >= 3 levels)

CAREGIVER PARTICIPANTS:

* Age >= 18 years at the time of consent
* Identified as the patient's spouse/partner, adult family member, or other unpaid informal caregiver-and, for a patient scoring <= 14.5 on the University of California San Diego Brief Assessment of Capacity to Consent (UBACC), the designated surrogate/legally authorized representative (LAR) under the applicable institutional and state hierarchy
* In regular contact with the patient (in person, by phone, or by video) across the 6-month follow-up period, sufficient to observe the patient's home opioid use
* Able to read and respond to study materials in English
* Able and willing to provide written consent-for their own participation and/or on the patient's behalf as surrogate/LAR
* Passes the pre-consent caregiver cognitive/capacity screen

Exclusion Criteria:

PATIENT PARTICIPANTS:

* Emergency or urgent surgeries
* Reoperation after prior total hip, knee, or complex spine surgery
* Current or past dementia diagnosis
* History of cerebrovascular disease or stroke
* Diagnosis of postoperative or post-intensive care neurocognitive disorder within the 12 months

CAREGIVER PARTICIPANTS:

* Unable or unwilling to provide written consent
* Evidence of impaired decisional capacity (e.g., known dementia, acute intoxication, or acute medical or psychiatric condition)-disqualifying particularly for a caregiver serving as surrogate/LAR
* Sensory, motor, cognitive, or language limitation precluding reliable self-completion of questionnaires
* Paid/professional caregiver serving in a formal capacity (e.g., hired aide or private-duty nurse), as the study targets informal caregiving
* Declines participation

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• Cowan RL, Beach PA, Atalla SW, Dietrich MS, Bruehl SP, Deng J, Wang J, Newhouse PA, Gore JC, Monroe TB. Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer's Disease: A Cross-Sectional Brief Report. J Alzheimers Dis. 2017;60(4):1633-1640. doi: 10.3233/JAD-170532. PMID 28968238
• Kertai MD, Monroe TB, Cowan RL, Bruehl S. Mild cognitive impairment and postsurgical pain in older adults: A call for research. J Clin Anesth. 2025 Jan;100:111669. doi: 10.1016/j.jclinane.2024.111669. Epub 2024 Nov 1. No abstract available. PMID 39488443

NIH grants: R01AG098934