Mild Cognitive Impairment (MCI)NCT07885085
Postsurgical Pain and Opioid Use in Older Adults: Effects of Mild Cognitive Impairment
An observational study of Mild Cognitive Impairment (MCI) and Opioid Use, run by Miklos Kertai at 1 site in United States.
Trial summary
Mild cognitive impairment (MCI) affects a substantial proportion of older adults undergoing major surgery and may alter pain processing, pain experience, and opioid use after surgery. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mild Cognitive Impairment (MCI), Opioid Use, Cognitive Dysfunction
- How many people
- 552 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2027to Jan 2032
- Phase
- Observational
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: The study population includes two cohorts of surgical patients aged 65 years and older undergoing elective orthopedic or complex spine surgery and one cohort of adult informal caregivers aged 18 years and older associated with enrolled patients.
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Vanderbilt Health
Nashville, Tennessee, 37212
Miklos Kertai, MD
About this study
Mild cognitive impairment (MCI) affects a substantial proportion of older adults undergoing major surgery and may alter pain processing, pain experience, and opioid use after surgery. This prospective observational cohort study will compare older adults with MCI and cognitively intact older adults undergoing major orthopedic and complex spine procedures. Participants will undergo preoperative assessment of cognitive function, quantitative sensory testing, heart rate variability, clinical pain, and biomarkers associated with Alzheimer's disease risk. Postoperative pain trajectories, opioid use, pain responsiveness, and cognitive outcomes will be evaluated for six months following surgery. The study aims to determine whether MCI is associated with differences in postoperative pain and opioid use outcomes and whether APOE4 status and plasma amyloid beta 42/40 ratio contribute to observed differences.
Read the detailed description
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.
- Keywords
- Mild Cognitive Impairment, MCI, Postoperative pain, Opioid Analgesics, Quantitative Sensory testing, Heart Rate Variability, APOE4, Amyloid Beta, Older Adults, Total Knee Arthroplasty, Total Hip Arthoplasty, Spine Fusion
- Medical subject headings
- Cognitive Dysfunction, Pain, Postoperative, Plaque, Amyloid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Older Adults with Mild Cognitive Impairment | Older adults aged 65 years or older undergoing elective major orthopedic or complex spine surgery who meet protocol-defined psychometric criteria for mild cognitive impairment. Follow-up includes cognitive, pain, quantitative sensory testing, heart rate variability, biomarker, and opioid use assessments. | |
| Cognitively Intact Older Adults | Older adults aged 65 years or older undergoing elective major orthopedic or complex spine surgery who do not meet criteria for mild cognitive impairment. Participants undergo the same longitudinal assessments as the MCI cohort. | |
| Caregiver Participants | Adult informal caregivers of enrolled patient participants. Caregivers may serve as spouses/partners, adult family members, or other unpaid caregivers. Caregiver participants complete questionnaires regarding observations of patient pain, recovery, medication management, and home opioid use during postoperative follow-up. Caregiver enrollment is voluntary and independent of patient enrollment except when a caregiver serves as a surrogate/LAR for consent purposes. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Past 24-Hour Average Pain Intensity
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Cumulative Postoperative Opioid Use
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.
Measured: Postoperative Discharge through 6 months after surgery.
Heat Pain Threshold Temperature
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
High-Frequency Heart Rate Variability (HF-HRV)
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Secondary outcomes (14)
Temporal Summation of Pain
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Suprathreshold Heat Pain Intensity Rating
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Suprathreshold Heat Pain Unpleasantness Rating
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Past 24-Hour Pain Unpleasantness
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Past 24-Hour Worst Pain Intensity
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Past 24-Hour Least Pain Intensity
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Past 24-Hour Average Pain Intensity
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
PROMIS Pain Interference T-Score
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Short-Form McGill Pain Questionnaire-2 Total Score
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Pain Assessment in Impaired Cognition (PAIC) Total Score
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.
Measured: Baseline, 2 weeks, 1 month, 3 months, and 6 months after surgery.
Michigan Body Map Pain Site Count
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.
Measured: Baseline and 6 months after surgery.
Opioid Side Effect Severity Score
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.
Measured: 2 weeks, 1 month, 3 months, and 6 months after surgery.
Participants Experiencing Unplanned Healthcare Utilization
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.
Measured: From surgery through 6 months postoperatively.
Caregiver-Reported Opioid Management Difficulties
Number and percentage of caregivers reporting missed doses, extra doses, medication administration concerns, or medication management difficulties during postoperative follow-up.
Measured: 2 weeks, 1 month, 3 months, and 6 months after surgery.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2026
- Study startJan 2027 (estimated)
- Primary completionJan 2031 (estimated)
- Study completionJan 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Mild Cognitive Impairment (MCI)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 552 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Miklos Kertai
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Sponsor-investigator, Miklos Kertai, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07885085
- Sponsor's protocol ID
- 261018
- Other IDs
- R01AG098934
- Status last verified
- Oct 2026
- First submitted
- 13 Oct 2026
- Last updated
- 21 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Monroe TB, Gibson SJ, Bruehl SP, Gore JC, Dietrich MS, Newhouse P, Atalla S, Cowan RL. Contact heat sensitivity and reports of unpleasantness in communicative people with mild to moderate cognitive impairment in Alzheimer's disease: a cross-sectional study. BMC Med. 2016 May 10;14:74. doi: 10.1186/s12916-016-0619-1.
PubMed 27164846Cowan 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.
PubMed 28968238Kertai 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.
PubMed 39488443