Conditions: Opioid Toxicity Pupillary Miosis Respiratory Depression
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: yes

Brief summary:
This study will establish the relationship between magnitude of opioid exposure and a pupillary measure referred to as PUAL (pupillary unrest in ambient light), in subjects aged 40-60. Previous investigation demonstrated that loss of PUAL was a sensitive, discriminative indicator of opioid toxicity and respiratory depression among subjects aged 20-40 years old. Population data indicate that pupil size and PUAL decline slightly with age. The investigators will explore whether PUAL proves to be a sensitive indicator of opioid exposure and respiratory depression in this older group.

Detailed description:
Healthy volunteer subjects aged 40-60 will receive a standardized weight-based 10-minute remifentanil infusion protocol to achieve a peak estimated remifentanil effect site concentration of approximately 6 ng/mL. Pupillary measures will be taken at baseline and regular time intervals during and after the infusion, over a period of 35 minutes.

Arms:
arm 1: Participants underwent a 10-minute remifentanil infusion. Pupillary measures were taken a baseline and every 2.5 minutes during the 10-minute infusion and 25-minute recovery period.

Interventions: intervention 1: Remifentanil Hydrochloride intervention 2: Pupillometry measurement
Intervention descriptions: intervention 1: Infusion of 0.2 µg/k/m for 5 minutes, the 0.3 µg/k/m for 5 minutes. intervention 2: Pupillary measurements were taken at baseline and every 2.5 minutes during the 10-minute infusion and 25-minute recovery period.

Protocol document:
Prot_SAP_000.pdf: 
Title: 
 
Pupillary Unrest as an Indicator of Central Opioid Effect in Subjects 40-60 Years of Age   
 
Investigators: 
 
Rachel Eshima McKay 
Department of Anesthesia and Perioperative Care 
University of California San Francisco 
 
Merlin D. Larson 
Department of Anesthesia and Perioperative Care 
University of California San Francisco 
 
 
 
NCT05391555 
 
Document Date: September 6, 2024 
 
 


 
 
ABSTRACT 
 
Opioid-induced respiratory depression (OIRD) confers significant safety risk, but its onset 
can be challenging to recognize.  Hypoxia and related sequelae from OIRD may present 
abruptly, giving the clinician insufficient time to intervene and rescue before harm reaches 
the patient. Previous data showed that among healthy 20-39-year-old volunteers, 
incremental decline and eventual obliteration of pupillary unrest in ambient light (PUAL) 
occurred in a consistent manner during escalating opioid concentration from remifentanil 
infusion. Low and often obliterated PUAL were consistent markers of high-risk remifentanil 
exposure and coincident episodes of hypoxic respiratory depression, even while subjects 
remained alert. In this young adult age group, specific PUAL values discriminated between 
zero or low versus high-risk intensive opioid exposure with outstanding discrimination 
(AUROC = 0.9671 [0.9384 – 0.9958]).1 We anticipate PUAL will develop into a useful tool in 
the future to guide clinical decision-making in patients receiving opioids on matters including 
choice of appropriate level of monitoring, consideration of supplemental oxygen, possible 
opioid de-escalation, and timely pursuit of non-opioid analgesic alternatives and support 
when necessary. To explore the generalizability of these findings, we plan to perform a 
similar study among subjects in an older age range (40-60 years). Although we anticipate 
that the PUAL decline and opioid intensity relationship will probably be similar across age 
ranges, the predictive value of specific PUAL thresholds may differ in older individuals due to 
age-related changes in normal pupil measurements and characteristics. Recent unpublished 
data from ambulatory subjects showed a modest decline in resting PUAL in subjects aged 50 
and older compared to younger adult subjects. The physiologic vulnerability of older patients 
elevates the importance of early, reliable OIRD detection. Aging is accompanied by 
alteration of a variety of vital protective mechanisms, including blunting of chemoreceptor-
mediated ventilatory responses to hypoxia and hypercapnia.2,3 Among subjects with sleep 
disordered breathing, older age is associated with more severe, prolonged desaturation 
episodes during upper airway obstruction.3   
 
AIMS 
 
We will establish the relationship between PUAL, estimated remifentanil concentration, and 
incidence and onset of OIRD indicated by decline in SpO2 < 90% in an extended age range 
(40-60 years). In this older age group, we will examine the magnitude and consistency of the 
opioid-PUAL relationship and compare risk of OIRD at various ranges of PUAL and estimated 
opioid effect site concentration. The purpose of doing so is to establish PUAL’s validity in 
discriminating risk of OIRD across a broader population, and to determine whether the PUAL 
OIRD prediction scale requires modification or is invalid in older subjects. The overall goal is 
to extend the benefit of sensitive opioid monitoring across a broader patient population. 


BACKGROUND AND RATIONALE 
 
Within the past decade, opioid-related adverse events have grown at unprecedented rates. 
Age-adjusted opioid overdoses have risen from 3.0 to 14.9 events per 100,000 people 
between 2000 -2017, surpassing motor vehicles accidents and firearms as causes of 
accidental death in the United States.6 In 2020, 621 citizens suffered opioid-related deaths in 
the city of San Francisco by December, compared 173 deaths attributed to COVID-19 at that 
same time-point; compared to the eight month period prior to March 2020, weekly opioid-
attributed deaths increased 50% during the subsequent 8 month period.6-9 Although the 
majority of opioid overdoses occur in the community, cases among hospitalized patients 
continue to be reported, with iatrogenic respiratory arrest from opioid mismanagement 
cited as a significant source of preventable harm.10  A recent administrative database 
reviewing hospital-related opioid-related cardiopulmonary arrest cases showed that 
approximately half of such incidents occurred in the intensive care unit, despite continuous 
assessment and monitoring.11  Iatrogenic opioid-related respiratory depression (OIRD) 
carries severe liability; a closed claim analysis showed that among reported OIRD cases, > 
75% produced death or serious brain injury, 1/3 occurred during continuous pulse oximetry 
monitoring, and 16% occurred within 15 minutes of an uneventful nursing check.12 These 
reports confirm that OIRD is difficult to recognize and predict.  One favored approach 
currently under investigation involves remote monitoring systems to acquire and integrate 
vast quantities of patient data.13 However, we ask whether nociceptive or conversational 
stimulation might obscure recognizable indicators of opioid toxicity, rendering common 
clinical parameters inadequately sensitive.  We propose that an approach involving pupillary 
testing may be more reliable than conventional measures in assessing opioid effect. 1,14-17  
 
Under static levels of ambient light, the normal human eye exhibits continuous, bilaterally 
synchronous pupil size fluctuation.18,19 Within specific frequency bands, Fourier waveform 
analysis converts these oscillations to a measure known as pupillary unrest in ambient light 
(PUAL).20 By convention, PUAL is expressed in arbitrary units (AU); additional details on the 
measurement appear in previous publications.17,21-22 When an alert subject is in a dark 
environment,23 or undergoes general anesthesia,24 these oscillatory movements are 
abolished. Although its origins are unproven, PUAL appears to be mediated by fluctuating 
inhibitory activity within the parasympathetic Edinger Westphal nucleus, possibly driven 
indirectly by the locus coeruleus. 25,26 
 
Previous authors have cited variable decline in PUAL among surgical patients after a single 1 
mcg/kg dose of fentanyl before surgery.20 Others have noted correlation between decline in 
numeric pain scale and higher PUAL values after a single dose of opioid, suggesting that 
once the PUAL declines to low values, further analgesic benefit from opioid may be limited.21 
However, these studies only involved a single dose of opioid, and did not systematically 
increase opioid exposure to the point at which respiratory depression was likely to be 
reached. 
 


In a study of 150 unmedicated ambulatory participants recruited from the waiting area of the 
UCSF preoperative clinic, average PUAL was modestly but significantly lower in subjects in 
older age categories. We present below the results of the previously mentioned study 
showing a significant relationship between PUAL decline in conjunction with opioid increase 
and incremental risk of respiratory depression in 20-39-year-old subjects. We therefore 
intend to verify the relationship between PUAL, opioid exposure and ventilatory depression 
in subjects in aged 40-60 years. To ensure realistic demographic representation of San 
Francisco at large, we will strive to enroll at least 40-60% female, 25% black or Latinx, and 35-
40% Asian/Pacific Islander subjects. 
 
PRELIMINARY DATA 
 
We cite a case report in which low or absent PUAL was observed in a patient with OIRD and 
very high PUAL was observed in a patient undergoing opioid withdrawal.17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subsequently we studied 20 healthy volunteers aged 20-39 years, to determine whether 
progressive decline of PUAL to zero or a lower limiting value would occur consistently as 
opioid exposure increased to the point of respiratory depression.1 Participants received an 
intravenous infusion of remifentanil, an ultra-short acting opioid medication. As the dose 
and effect site concentrations incrementally rose, serial pupillary measures were taken every 
2.5 minutes, including at times coinciding which clinically significant respiratory depression. 
We sought to determine whether PUAL declines consistently to zero or near zero in all 
subjects as opioid concentration builds to the point of respiratory depression. We found that 
in this group of participants aged 20-39, PUAL declined significantly over the course of the 
remifentanil infusion and rose significantly during recovery (p < 0.0001). Nearly all subjects 
reached 90% or greater PUAL suppression. PUAL showed outstanding discrimination in 


distinguishing higher versus absent-moderate opioid exposure (AUROC = 0.957 [0.929 to 
0.985] in all runs). For exploratory purposes this study had two infusion sequences, one 
conducted under normal “quiet” conditions, and the other during stimulating “interactive” 
conditions to estimate what if any role environmental stimulation may play in delaying or 
mitigating OIRD. Findings in younger subjects used for subsequent comparison to the older 
group will use the data from the control (“quiet”) arm, or from both infusion sequences as 
appropriate.  
 
In a separate study, to estimate normative ranges of PUAL in the general population across 
age groups, we evaluated 150 de-identified ambulatory subjects, collecting information only 
on age-range, (18-29, 30-49, 50-69, and ≥70 years), diabetes, and use of opioid or beta-
blocker medication in the previous 24-hour period. In that cohort we found a modest but 
statistically significant impact of age on PUAL, where subjects ≥ 50 years of age had lower 
median PUAL values versus subjects under 50 years of age. 
 
 
EXPERIMENTAL DESIGN AND METHODOLOGY OF PROPOSED STUDY 
 
Design: 
Volunteers aged 40-60 years will be recruited to participate. All will undergo a 35-minute 
remifentanil infusion regimen. After an 8-hour fasting period, subjects will arrive at the UCSF 
Department of Anesthesia Hypoxia Lab, which will be equipped with standard resuscitative 
equipment and medications (including naloxone, atropine, and epinephrine). Lighting 
conditions (200 lux) will be strictly controlled, and the room will remain free of distracting 
noise. After providing written informed consent, subjects will undergo peripheral IV 
placement, baseline pupillary and vital-sign measurements, and will receive prophylactic 
antiemetic medications (aprepitant 40 mg + ondansetron 4 mg).  
 
Measurements: 
Pupillary measurements will be obtained with a hand-held infrared pupillometer (Neuroptics 
PLR-3000, Laguna Hills, California), with each subject looking into a dark grey single-use 
rubber cone-shaped eye piece with the left eye. This eye piece will be situated to exclude 
ambient light, while the operator’s left hand will cover the contralateral eye. Since the pupil 
diameter does not fluctuate in darkness, a soft blurred disk of white light from a 50 µ-watt 
source, at approximately 350 lux illumination, will be directed at the measured eye to initiate 
the oscillation in pupil size, and a 10-second infrared video of the pupil will be taken. The 
videos will be processed post hoc to fast Fourier transformation to quantitate the PUAL 
measurement. Previous calibration of the PUAL, obtained by measuring metal holes of 
known diameter (2.6 – 4.8 mm), allowed subtraction of inherent noise and establishment of 
zero at the lower scale boundary.17 Participants will undergo an infusion and recovery 
sequence with an intravenous infusion of remifentanil, in a manner similar to that used in the 
previous study of 20-39-year-olds (0.2 µg/k/minute x 5 minutes, then 0.3 µg/kg/minutes x 5 
minutes, then off), with pupillary measures taken every 2.5 minutes, for the 10-minute 


infusion and 25-minute recovery period. In addition to PUAL, the average pupil diameter 
(millimeters) will be recorded, and for exploratory purposes, other measurements will be 
taken at regular intervals (constriction velocity, light reflex, and light off response), for some 
measurements using a second instrument (Neuroptics NPi - 200).  
 
Study Protocol: 
In each 35-minute test sequence, vital signs will be continuously monitored with pupillary 
measurements taken every 2.5 minutes. During the first 10 minutes of the 35-minute 
sequence, remifentanil will be infused at a predetermined rate described below. Sedation 
assessment will be made using the Pasero Opioid-Induced Sedation (POSS) Scale.29  
 
Opioid Infusion: 
The remifentanil will be infused for 10 minutes- at a rate of 0.2µg/kg/minute for the first 5 
minutes, followed by 0.3µg/kg/minute for the next 5 minutes. After remifentanil 
discontinuation, pupillary measurements will continue every 2.5 minutes for the remaining 
25-minute recovery phase. To avoid the costs and stimulating effect of sequential blood 
drawing, or the added discomfort of arterial line placement to facilitate repeated blood 
sampling, we do not plan to measure remifentanil blood concentration, choosing instead to 
use an infusion protocol based on the Minto model that, when given to eligible subjects, 
should achieve an estimated maximum effect site concentration of 4-6 ng/mL, a level known 
to produce near-maximum isoflurane MAC reduction and high probability of apnea. 29-31  
 
Outcomes: 
Primary outcome is the correlation between PUAL and intensity of opioid exposure 
(represented by time-points corresponding to progressively increasing and declining 
estimated opioid concentrations) and the ability to discriminate zero-moderate versus high-
toxic opioid effect. The discrimination of PUAL to identify high-risk opioid exposure will be 
determined by construction of receiver operator characteristic (ROC) curves.  
 
Subjects: 
Eligible subjects will be 40-60 years of age, recruited from flyers posted around the UCSF 
campus, and from an advertisement placed on Craigslist. Exclusion criteria will include use of 
opioid agonist or antagonist within the prior thirty days, any cardiopulmonary or neurologic 
condition, baseline SpO2 < 95%, diabetes, obstructive sleep apnea (OSA), BMI > 35 kg/m2, 
current or previous substance use disorder, ocular disease (including glaucoma), prior ocular 
surgery, use of any prescription ocular medication, use of medications known to affect 
pupillary characteristics (see below), blindness, previous episodes of serotonin syndrome, or 
inability to provide written informed consent.  
 
Subjects will be instructed to fast for at least 8 hours prior to arrival for the study. The study 
team will instruct the subjects on which if any prescription medications should be taken on 
the day of the study prior to arrival. Failure to adhere to fasting instructions will disqualify 
the subject from participation. 


 
 
The following classes of medication exert known impact on resting pupil size and use of any 
of the following will preclude participation:32  
1/ Alpha blockers, primarily used for their ability to relax the bladder and prostate smooth 
muscle to address lower urinary tract symptoms (tamsulosin, alfuzosin, terazosin, 
doxazosin), although may also be used to treat hypertension or hair loss (labetalol, saw 
palmetto); 
2/ Anticholinergic medications, including medication used for chronic obstructive pulmonary 
disease (ipratropium) and overactive bladder (including oxybutynin, tolterodine, solitenacin, 
darifenacin, fesoterodine, and mirabegron); 
3/ Antidepressant medications, including tricyclic antidepressants, selective serotonin 
reuptake inhibitors, selective-norepinephrine reuptake inhibitors, MAO-I, and mianserin.  
4/ Antipsychotic or mood stabilizing medications, which mostly act by postsynaptic blockade 
of D2 receptors. Examples include first generation (haloperidol, thioridazine, thiothixene) 
and second generation (olanzapine, quetiapine, risperidone) drugs; 
5/ Phosphodiesterase inhibitors, including tadalafil, sildenafil, and tadalafil; 
6/ Stimulant or appetite-suppressant medications, including dextroamphetamine, 
phentermine, or methylphenidate; 
7/ Antihypertensive or antiarrhythmic medications, including clonidine, beta blockers, alpha 
blockers, and calcium channel blockers. 
8/ Topical eye medications used for glaucoma, including dorzolamide, latanoprost, and 
timolol. 
 
One important element of the evaluation is to identify conditions that may predispose the 
subject to adverse cardiovascular outcome. The current consensus guidelines from the 
American Heart Association and American College of Cardiology on preoperative evaluation 
of the patient prior to noncardiac surgery state that even for patients with one or multiple 
procedural or medical risk factors for adverse postoperative cardiovascular outcome, those 
able to perform > 4 METS of work may reasonably proceed to surgery without additional 
cardiovascular testing.33 To determine functional capacity, we will ask potential subjects to 
undergo a modified 4-item Duke Activity Scale Index questionnaire to indicate the likelihood 
of VO2max > 16 mL/kg/minute, which translates to the ability to perform ≥ 4.6 METS of 
work.34,35 To determine risk of obstructive sleep apnea (OSA), an 8-item STOP-BANG score 
(validated screening tool for presence and severity of OSA) will be administered.36 A 
Subjects must have a modified DASI score of 4 and STOP-BANG score of < 3 to qualify for 
participation.  
 
Inclusion criteria are as follows: 
 
Age 40-60 years of age 
Able to read and understand the informed consent 
Able to follow NPO instructions 
Must have a responsible adult to escort subject home from UCSF after the study 


Must show proof of COVID vaccination and negative COVID PCR test obtained ≤ 72 hours 
prior to the study 
 
 
Exclusion criteria are as follows: 
 
BMI > 35 kg/m2 
Current or previous opioid or other substance use disorder 
Current or recent (within prior 30 days) use of any µu- opioid agonist, partial agonist, or 
antagonist 
Significant or uncontrolled gastroesophageal reflux disease (GERD) 
History or symptoms of ischemic heart disease (pain or pressure in the chest/arm/jaw, 
shortness of breath or light-headedness with moderate exertion; previous myocardial 
infarction; any coronary intervention or revascularization) 
Known or suspected arrhythmias (atrial fibrillation, atrial flutter, palpitations associated with 
light-headedness, syncope or light-headedness with exercise) 
History of heart failure, pulmonary hypertension, or congenital heart disease 
Known or suspected obstructive sleep apnea (confirmed diagnosis on sleep study, or STOP-
BANG score ≥ 5 if untested) 
Current or recent use (within 7 days) of antihypertensive medication (beta blocker, calcium 
channel blocker, clonidine, ACE inhibitor, angiotensin-receptor blocker) 
Use of any alpha-adrenergic blocking medication for urinary symptoms or anticholinergic 
medications 
History or ocular surgery (ie, cataract surgery, vitrectomy), ocular disease (ie, glaucoma), or 
use of topical eye medications 
Use of mood stabilizers or antidepressant medications (including serotonin-reuptake 
inhibitors or MAO-inhibitors) within past 30 days 
Use of stimulant medications (amphetamines, including medications used for appetite 
suppression or attention deficit disorder) 
Use of phosphodiesterase inhibitor medications (usually given for erectile dysfunction) 
within the past 7 days 
Inability to read or understand English 
Any condition prohibiting delivery of oxygen by nasal cannula 
Anxiety or panic disorders 
Severe motion sickness or intractable vomiting after prior anesthesia 
Fever, upper respiratory infection, or illness of any variety within 8 weeks of participation 
 
Exclusion criteria involving opioid use or substance use disorder will be determined by self-
report from the potential subject.  
 
 
 


 
DATA COLLECTION 
 
Subject data including subject number, initials, age, sex, race, height and weight, along with 
time-stamped drug administration and vital signs, will be collected on a source document 
anesthetic record, which will be scanned and stored on a HIPAA-compliant secure location. 
Pupillary measures will be collected on a Neuroptics PLR-3000 device, and the date and 
times of the scans will be correlated to the times of each subject’s data. The pupillary scans 
will be downloaded by Bluetooth to a csv file that will be stored on an encrypted laptop 
computer.  
 
 
DATA ANALYSIS 
 
We plan to test 20 subjects aged 40-60 under paired conditions- absent versus uninterrupted 
conversational interaction- over a 35-minute period. Interim analysis is planned after 10 
subjects are studied. 
 
Correlation between PUAL and opioid concentration: 
We will examine PUAL and estimated opioid effect site concentration during both drug 
infusion (0-10 minutes, where opioid concentrations progressively increased) and recovery 
(10-35 minutes, where opioid concentrations progressively decline). Each 2.5-minute point 
will be treated as an ordinal variable “time”, and opioid effect-site concentrations will be 
calculated at each time point according to the Minto pharmacokinetic model estimates.29 
The effect of time (as surrogate for opioid concentration) on PUAL will be assessed using a 
linear mixed effects model.  
 
Distinguishing between zero-low risk versus high-risk, toxic opioid conditions by PUAL: 
We will collect PUAL data at times when estimated opioid effect site concentrations in all 
subjects are consistently low (< 2.0 ng/mL) versus high (>2.4 ng/mL). A receiver operating 
characteristic analysis using dichotomized PUAL values will be constructed to determine 
PUAL’s ability to distinguish between low-risk versus high-risk opioid exposure in the 40-60-
year-old subjects. This ROC curve will be compared to that of subjects in the 20-39 year-old 
range, and interval likelihood ratios that identify high, indeterminant and low risk will be 
reported. 
 
SAMPLE SIZE CALCULATION 
 
The primary objective of this study is to assess PUAL’s ability to identify high-risk opioid 
effect in older adults.  In the previous study in younger adults, we used a remifentanil 
infusion that consistently produced zero to moderate opioid effect at 2 time points (baseline 
and 2.5 minutes) and high opioid effect at 4 time points (5.0, 7.5, 10.0, and 12.5 minutes).  We 
assessed the ability of PUAL to discriminate using the area under the ROC curve (AUROC).  


In that study the AUROC was slightly lower under quiet vs. interactive conditions (0.95 vs 
0.97), and the standard error of the summary AUROC was 0.01.   If the discrimination is 
substantially lower in older adults, we would expect an AUROC of 0.875.  A sample size of 20 
participants would produce a 95% confidence interval of width 0.12 (0.81 to 0.93) and a 
standard error of 0.0275.37 The standard error of the difference in AUROCs would be 0.03 
and would provide 80% power to detect a difference in AUROCs of 7.5% at the 0.05 
significance level.38  
 
In addition, we intend to evaluate the same PUAL intervals as found in our previous analysis 
of 20-39-year-old subjects:  
• PUAL 0.00 to <0.04 = high-risk opioid effect, interval likelihood ratio = 14.59;  
• PUAL ≥ 0.04 to 0.13 = indeterminate effect, interval likelihood ratio = 1.12;  
• PUAL ≥ 0.14 = zero or low risk opioid effect, interval likelihood ratio = 0.02.  
We will calculate interval likelihood ratios in the 40-60-year-olds.39 For high opioid effect, we 
expect an interval likelihood ratio of approximately 10.  Our sample size of 20 should allow 
estimation with a 95% confidence interval 3.3 to 30.   
 
 
 
 
 
 
 
 
 
 
 
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