730

REVIEW/UPDATE

Persistent opioid use in cataract surgery

pain management and the role of
nonopioid alternatives
Richard S. Davidson, MD, Kendall Donaldson, MD, MS, Maggie Jeffries, MD, Sumitra Khandelwal, MD,
Michael Raizman, MD, Yasaira Rodriguez Torres, MD, Terry Kim, MD

Cataracts are a leading cause of preventable blindness globally. this, pain and discomfort persist in some patients and are under-
Although care varies between developing and industrialized coun- appreciated in modern cataract surgery. Although pain management
tries, surgery is the single effective approach to treating cataracts. has progressed, opioids remain a mainstay intraoperatively and, to a
From the earliest documented primitive cataract removals to to- lesser extent, postoperatively. This article discusses the evolution of
day’s advanced techniques, cataract surgery has evolved dramat- pain management in cataract surgery, particularly the use of opioids
ically. As surgical techniques have developed, so have approaches and the associated risks as well as how ophthalmology can have a
to surgical pain management. With current cataract surgical pro- positive impact on the opioid crisis.
cedures and advanced technology, anesthesia and intraoperative
pain management have shifted to topical/intracameral anesthetics, J Cataract Refract Surg 2022; 48:730–740 Copyright © 2021 The Author(s).
with or without low-dose systemic analgesia and anxiolysis. Despite Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS

become the most common surgery worldwide.4–9 Phacoe-

T
he United States is in the midst of an opioid epidemic.
The use of opioids is increasing, and those most at risk mulsification is now performed in 96% to 97% of all cataract
are individuals over age 50 years.1–3 This is also the surgeries in the United States.8,10,11 Further advances such as
population in which cataract surgery, the most common out- femtosecond lasers, premium intraocular lens, pupil ex-
patient surgical procedure worldwide, is most frequently pansion devices, intraoperative dyes, and options for topical
performed.4–9 Opioids, which carry a high risk for addiction and anesthesia have made today’s cataract surgery elegant and
overdose, are used perioperatively in cataract surgery anesthesia safe with a very high success rate (Figure 1).4–9,11–21
protocols and postoperatively for pain management in some
cases. When considered collectively, the use of opioids in this EVOLUTION OF PAIN MANAGEMENT/ANESTHESIA
cataract surgery population creates a perfect storm for potential Cataract surgery pain management has also advanced. Since the
opioid use disorder (OUD). The literature lacks a comprehensive ancient Egyptians and Assyrians used carotid compression to
review of opioids and their relationship to cataract surgery. This render patients unconscious for cataract surgery, anesthesia and
article discusses the evolution of cataract surgery and associated pain management have included a range of general, regional,
pain management, particularly the role and use of opioids in and topical approaches.12,22–25 With newer surgical techniques,
cataract surgery, the associated risks of opioid use in this vul- instrumentation, and technology, most cataract surgery is
nerable population, and how ophthalmologists and optometrists performed using a combination of local and topical anesthetics
can help combat the opioid crisis by using nonopioid alternatives along with monitored anesthesia care (MAC) (Figure 2).12,22–28
to manage pain in their cataract surgery patients.
MAC
EVOLUTION OF CATARACT SURGERY TECHNIQUES Many cataract surgeries are performed under MAC, de-
From couching in the fifth century BCE, a procedure in fined by The American Society of Anesthesiologists as “a
which the lens is dislocated into the vitreous via a needle, to specific anesthesia service performed by a qualified anes-
today’s phacoemulsification procedures, cataract surgery has thesia provider for a diagnostic or therapeutic procedure.

Submitted: March 24, 2021 | Final revision submitted: October 26, 2021 | Accepted: October 31, 2021
From the University of Colorado Eye Center, Denver, Colorado (Davidson); the Bascom Palmer Eye Institute, Plantation, Florida (Donaldson); the Houston Eye Associates,
Houston, Texas (Jeffries); the Eye Center of Texas, Houston, Texas (Jeffries); the Baylor College of Medicine, Cullen Eye Institute, Houston, Texas (Khandelwal); the Tufts
University School of Medicine, New England Eye Center, Boston, Massachusetts (Raizman); the Kresge Eye Institute, Detroit, Michigan (Rodriguez Torres); the Elmquist
Eye Group, Fort Myers, Florida (Rodriguez Torres); the Duke Eye Center, Duke University, Durham, North Carolina (Kim).
Writing support was funded by Omeros Corporation.
Corresponding author: Terry Kim, MD, Duke Eye Center, 2351 Erwin Rd, Box 3802 Durham, NC 27705. Email: [email protected].

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS 0886-3350/$ - see frontmatter
Published by Wolters Kluwer Health, Inc. https://doi.org/10.1097/j.jcrs.0000000000000860
 NONOPIOID ALTERNATIVES IN CATARACT SURGERY 731

Figure 1. Evolution of cataract surgery techniques. References: a4–9; b5,6; c5,6,8,11,12; d5,6,11–13; e5,6,8,9,11,14; f6,11,15,16; g6,11,14;
h
11,17; i18; j5; k19; l6; m11; n8; o11; p5,6,14; q5,6; r20; s21. ECCE = extracapsular cataract extraction; ICCE = intracapsular cataract
extraction; OR = operating room; PC = posterior chamber

Indications include, but are not limited to, the nature of the Further evidence of the common use of fentanyl during
procedure, the patient’s clinical condition, or the need for cataract surgery can be seen by reviewing the clinical re-
deeper levels of analgesia and sedation than can be provided search literature, looking specifically at studies in which all
by moderate sedation (including potential conversion to a cataract surgery patients receive fentanyl and those that use
general or regional anesthetic).”29 fentanyl as a comparator. The widespread use of both of
Unlike general anesthesia, MAC does not require in- these approaches in clinical trials speaks indirectly to the
tubation or ventilation and can be titrated according to pervasive use of fentanyl in cataract surgery overall. A
patient and surgeon needs.30 Approximately one-third of cursory search of PubMed for “cataract surgery” AND
outpatient procedures in the United States, whether di- “fentanyl” yields results from both the ophthalmology and
agnostic or therapeutic, use MAC.31,32 The most common the anesthesiology literature. A representation of the
medications that comprise MAC in the United States are publications of the last 20 years is summarized in Table 2.
shown in Table 1. To assess whether opioids are used as part of routine
institutional practice or MAC protocols in cataract surgery,
OPIOIDS IN MAC a group from Duke University performed a single-center
In the United States, approximately 99% of patients who retrospective study of 2659 patients (3764 cases) un-
undergo any surgery receive opioid analgesics at some point dergoing routine cataract surgery over a 2-year period.
perioperatively.38 Fentanyl and remifentanil are the most Patients were excluded if they required combined surgery
commonly used opioids in MAC, and this decision is with a glaucoma, corneal, or retina procedure. The anes-
typically based on the clinicians’ preference, duration of the thesia for each case was reviewed, and it was found that
procedure, cost, and convenience. 3649 cases (96.9%) received at least 1 dose of fentanyl.51
Opioids such as fentanyl remain a cornerstone of MAC Although cataract surgery is often considered a minor,
during cataract surgery. A Mayo Clinic (Rochester, Minne- relatively low pain procedure, opioids are widely admin-
sota) study analyzed sedation and recovery in 20 116 oph- istered to patients undergoing cataract surgery.
thalmologic procedures. Of these, 76.1% were cataract
surgeries, with MAC being the most common (84.8%) an- OPIOID CRISIS
esthesia technique. Overall, 79.5% of ophthalmic surgery Opioid pain medications were used for pain management
patients received fentanyl as part of their anesthesia protocol. in patients with cancer starting in the 1980s, when it was
Prolonged anesthesia recovery was linked to intraoperative believed that the risk for addiction was rare.52 In the 1990s,
fentanyl use, postoperative pain, and postoperative require- pain experts pushed for pain to be considered the fifth vital
ments for opioids. Of those patients with prolonged recovery, sign.53 Between then and 2010, there was a 4 fold increase in
97.2% had received fentanyl compared with 77.5% of patients opioid pain medication use and corresponding increases in
who had an expected course of recovery. This study also found overdose death rates and hospital admissions.54 From 1999
that perioperative opioids resulted in a prolonged duration of to 2016, over 200 000 deaths in the United States were
anesthesia.39 Part of the reason for this prolonged recovery attributed to overdoses involving prescription opioids.55
with fentanyl is the increased incidence of postoperative Most people addicted to opioids are first exposed through
nausea and vomiting associated with the use of opioids.40 prescription medications.56 Both longer duration of

Figure 2. Advances in cataract surgery pain management. References: a22; b12,22,23; c12; d12; e12,23,27; f12,23,24,28; g12,25; h12,23;
i
12,23,24; j12,26. MAC = monitored anesthesia care

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732 NONOPIOID ALTERNATIVES IN CATARACT SURGERY

Table 1. Medications That May Comprise MAC in the United States.

Drug class Medication Properties of note
Benzodiazepines Midazolam Short-acting; anxiolytic, amnesic, and sedative effects; no
analgesic effects22,33
Remimazolam FDA approved in 2020; slow IV bolus33
Diazepam Potentially used for its anxiolytic and hypnotic effects; rapid
onset of action (up to 30 min), but long half-life (20 to 80 h)22
IV anesthetic induction agents (nonbarbiturate Propofol Rapid onset, short-acting sedative/hypnotic; modest amnestic
sedative/hypnotics) and antiemetic properties at subhypnotic doses; no analgesic
effects22,23,33,34; associated with faster emergence from
anesthesia22
Etomidate Rapid onset of action and short duration of sedation; fewer
hemodynamic and respiratory effects; no analgesic effects34
Ketamine (NMDA antagonist) Produces a dissociative state with amnesia and intense
analgesia; minimal respiratory depression at sedative doses
(ketamine 0.25 to 0.5 mg/kg IV); often administered in small
doses during MAC to enhance analgesia and decrease the
need for opioids; rapid onset of action (∼1 min) and relatively
short duration of action (10 to 20 min, with an elimination half-
life of 2 to 3 h)33; downsides include cardiovascular
stimulation, increased intraocular pressure, muscle
hyperactivity, and emergence phenomenon22
Barbiturate Methohexital Rapid onset, ultrashort-acting barbiturate derivative used in IV
doses for sedation26,35
Narcotic analgesics Fentanyl (synthetic opioid) Highly lipid-soluble opioid commonly used for sedation/
analgesia34; small, intermittent IV boluses of 25 to 50 mg IV
(reduced doses in older adults or when administered in
combination with other sedatives/hypnotics); rapid onset of
action (∼1-3 min) with a peak effect in approximately 6
min33,34,36; duration of action ∼30 to 60 min33,36 and half-life
of 2-7 h22; no antianxiety and antiamnesia effects; quick
passage across the blood–brain barrier34; emetic and
depressive effects may be present postoperatively37
Remifentanil Only available as a powder that must be diluted for use;
ultrashort acting with a very rapid onset of effect (60 to 90 s)
due to the ability to cross the blood–brain barrier22,33; can be
used to provide intense, titratable analgesia during stimulating
portions of a procedure of any duration, without residual
respiratory depression when stimulation is over33
Alpha-2-adrenergic agonist Dexmedetomidine Selective alpha-2-adrenergic agonist with sedative, anxiolytic,
and modest analgesic effects22,26,33,36; for sedation,
dexmedetomidine thought to have less respiratory depression
than other sedatives33; administered intramuscularly or
IV22,26; may decrease the need for propofol and/or opioids36
FDA = U.S. Food and Drug Administration; MAC = monitored anesthesia care

treatment and higher dosages of opioids can increase the outside the context of surgery.58 In general, patients un-
risk for OUD, overdose, and death. Although the annual dergoing abdominal/pelvic and orthopedic procedures
prescribing rate decreased by 19% from 2006 to 2017, the have fewer opioids left over than patients having non-
amount of opioid in morphine milligram equivalents—a abdominal soft tissue surgeries. In addition, open surgical
calculation of the total amount of opioids allowing for procedures resulted in fewer leftover opioids than lapa-
differences in drug type and strength—prescribed per roscopic surgeries. The study concluded that postsurgical
person is about 3 times higher than in 1999. Looking at it a prescribing regulations for opioids should not be un-
different way, approximately 58 opioid prescriptions were dertaken without considering the type and nature of the
written for every 100 Americans in 2017, with an average of surgery.58 Although cataract surgery was not explicitly
18 days per prescription.57 included in this analysis, one could surmise that phacoe-
A meta-analysis of 44 studies found that 61% of opioids mulsification is a relatively low pain procedure, and opi-
prescribed after surgery are not used, resulting in large oids, if prescribed postsurgically, may go unused, thereby
quantities of opioids potentially available in the community increasing the risk for diversion into the community.

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 NONOPIOID ALTERNATIVES IN CATARACT SURGERY 733

Table 2. Sample of Clinical Trials From a PubMed Search Using “Cataract Surgery” and “Fentanyl”.
Year Brief study description Journal Lead author
2003 Patients received retrobulbar anesthesia either with or without fentanyl. Journal of Cataract and Refractive Surgery Inan41
2004 Comparison between fentanyl in balanced salt solution and balanced salt Journal of Clinical Anesthesia Aydin42
solution with no analgesic.
2008 Patients received midazolam with or without fentanyl. Acta Anesthesiologica Belgica Cok43
2008 All patients received midazolam and were randomized to receive either Saudi Medical Journal Cok44
fentanyl or remifentanil.
2009 Comparison in pediatric patients of sub-Tenon block vs fentanyl. Anesthesia and Analgesia Ghai45
2012 All patients received fentanyl in combination with intraocular irrigation with Nepal Journal of Ophthalmology Miratashi46
balanced salt solution + epinephrine or balanced salt solution alone.
2012 Comparison between fentanyl (control) and buprenorphine Saudi Journal of Anesthesiology Anaraki47
2015 All patients received midazolam and were randomized to receive fentanyl or Archives of Anesthesiology and Critical Care Alipour48
acetaminophen.
2015 Comparison between propranolol and fentanyl + ketamine. Global Journal of Health Sciences Fazel49
2018 All patients received fentanyl and were randomized to also receive Anesthesia and Pain Medicine Haddadi50
melatonin, acetaminophen, or placebo.
2019 All patients received fentanyl in combination with 1 of the following: Anesthesiology and Pain Medicine Adinehmehr34
etomidate, propofol, or midazolam.
2020 Comparison between pethidine (meperidine) and fentanyl. All patients Journal of Research in Medical Sciences Shetabi51
received propofol.

RISK FACTORS FOR OPIOID USE IN THE ELDERLY 0.136%. The procedures with the lowest rate of chronic
The elderly cataract surgery patient population is not opioid use after surgery were cesarean delivery (∼0.12%),
immune to this national crisis. Not only does opioid use cataract extraction (∼0.14%), and laparoscopic cholecys-
pose a public health burden, but these elderly patients are tectomy (∼0.18%).60 Although the rate of chronic opioid
also at an increased risk for OUD and for intraoperative use after cataract surgery was low, because this is the most
and postoperative cataract surgery complications.59 common surgery worldwide, even a small percentage of
There are several intertwining risk factors for opioid potential patients with chronic opioid use result in a large
abuse. Age is a factor, with studies citing patients from age number of patients at risk for OUD.65–67
50 to 80 years as being at risk for excessive opioid Specific comorbidities may also increase the risk for OUD
use.1,3,60,61 The mean age for cataract extraction in the after surgery.1 A study analyzed 39 140 opioid-naive patients
United States is about 68 years.62 It has been shown that aged 66 years or older who underwent major elective surgery.
opioid misuse/abuse is growing fastest in the 50–64 year age It found that patients with diabetes, heart failure, and pul-
group.2,3 For chronic pain or medical/surgical procedures, monary disease had greater risk for prolonged opioid use.64
older adults are often prescribed opioids, which can lead to Because the cataract surgery population is older, they are
OUD. In addition, the elderly may experience anxiety, a more likely to have 1 or more of these comorbidities.
decrease in independence, or the loss of a partner, any of Another risk factor for OUD is simply age-related
which could potentially lead to a dependence on these physiologic changes. The pharmacokinetics and pharma-
medications.3 Older age may also result in accidental codynamics of drugs can be vastly different in the elderly
misuse due to forgetfulness, confusion, or impaired judg- compared with younger patients.2,40,66 Geriatric patients
ment due to polypharmacy.2 tend to require smaller doses, have delayed onset of action,
With over 300 million surgeries globally occurring each and experience prolonged effects of a drug. In addition,
year, surgery is a risk factor for OUD, with postoperative both cardiac and respiratory depression are more signifi-
pain a leading cause.1,60,63,64 Sun et al. analyzed inpatient cant in this patient population.40 Overall, elderly patients
and outpatient data from a large administrative health are more sensitive to the adverse effects of opioids.68 It has
claims database. They assessed 11 surgical procedures also been found that the required dose of fentanyl decreased
between January 2001 and December 2013, identifying significantly with age, with 1 study noting a 50% decrease
specific diagnosis and procedure codes as well as pharmacy from age 20 to age 89 years and another estimating that
claims. They included 641 941 opioid-naive surgical pa- opioid dosing should decrease by 25% to 50% in elderly
tients and compared them with 18 011 137 opioid-naive patients.42,68 Paradoxically, elderly patients are often
nonsurgical patients, looking at the incidence of chronic preferentially given fentanyl because of the risks from
opioid use, defined as having filled ≥10 prescriptions or benzodiazepines such as respiratory depression, deeper
more than 120 days’ supply of an opioid in the first year sedation, delirium, and exacerbated dementia.69
after surgery.60 Patients undergoing open cholecystectomy
or total knee arthroplasty had the highest rates of chronic INCREASED RISK WITH INCREASED EXPOSURE
opioid use, with 1.2% and 1.4% incidence, respectively. Several studies have shown that there is increased risk for
Nonsurgical patients had a chronic opioid use rate of addiction and overdose with each episode of opioid use.70,71

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734 NONOPIOID ALTERNATIVES IN CATARACT SURGERY

Elderly patients are more likely to have chronic conditions or severe pain to be as high as 35%.73 This analysis con-
and temporally adjacent procedures, resulting in greater cludes that although most recovery from cataract surgery is
cumulative opioid exposure potential.71,72 With the cata- largely uneventful, a meaningful percentage of patients do
ract surgery patient population generally being over age 65 experience significant postoperative pain that should be
years, long-term opioid use and OUD are risks. Given that followed and managed.
OUD risk increases with repeated exposures or cumulative With the widespread adoption of small incision pha-
doses, preventing any individual point of opioid exposure coemulsification, the pain associated with cataract surgery
may reduce the overall medical risk. has been minimized but not eliminated. Nonopioid pain
relievers, such as nonsteroidal anti-inflammatory drugs
PAIN IN CATARACT SURGERY (NSAIDs) and acetaminophen, can often control post-
It is argued that cataract surgery pain is present but poorly operative pain and discomfort in place of an opioid.70
understood and potentially underestimated.65,73–75 Pain
during cataract surgery is managed with MAC and other INTRAOPERATIVE OPIOIDS INFLUENCE POSTOP-
intraoperative pain management strategies; however, some ERATIVE OPIOID REQUIREMENTS
patients still report moderate to severe discomfort. A 2015 Opioids prescribed perioperatively may lead to long-term
study found that 35% of 106 patients undergoing first-eye use, regardless of prior patient exposure to opioids.79 In
cataract surgery reported intraoperative pain. This number some patients, more opioids used intraoperatively lead to a
was even higher in patients’ second eyes, with 87% re- greater requirement for opioids postoperatively; this has
porting pain during surgery.76 This may be due to increased been referred to as the opioid paradox.38 One may think
awareness of the procedure leading to greater anxiety; thus, that opioids intraoperatively would decrease the post-
patients report greater pain.77 operative need for opioids, but this is not always the case.
Another study assessed 63 patients undergoing pha- Although postoperative pain control is important, there is a
coemulsification with just topical anesthesia and had pa- known link between surgery and chronic opioid use;
tients grade their pain at different stages during surgery.75 therefore, perioperative pain management decisions should
Patients used the Keele verbal pain chart, grading their pain be carefully considered.64
from 0 to 4 (none, mild, moderate, severe, and unbearable), A study of U.S. adults of ages 18 to 64 years from a
toward the beginning, middle, and end of their cataract nationwide 2013 to 2014 insurance claims database as-
extraction. Analyzing scores from all surgical stages, 10.5% sessed the incidence of new persistent opioid use after
of patients experienced no pain throughout the procedure. major or minor surgery.80 These patients were considered
Of those experiencing pain, the mean total pain score from opioid naive, having filled no opioid prescriptions in the
all 3 stages combined was 3.05 (SD = 1.242) of 12. There year before their respective procedures. For patients filling a
were no statistically significant differences based on age, perioperative opioid prescription, the incidence of persis-
sex, or laterality. Reports of pain varied based on the tent opioid use for >90 days was calculated, and the pre-
cataract type, with patients having either corticonuclear + dictors of persistent opioid use after both major and minor
posterior subcapsular cataracts or white mature cataracts surgical procedures were assessed. This study defined new
experiencing greater pain levels than those having posterior persistent opioid use as an opioid prescription filled be-
subcapsular cataracts alone.75 tween 90 and 180 days after surgery. The 7109 patients
Postoperative pain has been assessed as well. Although undergoing major and 29 068 patients undergoing minor
most patients report no, slight, or mild discomfort after surgical procedures had a rate of new persistent opioid use
cataract extraction, there may be approximately 5% of from 5.9% to 6.5% compared with the nonsurgery control
patients who experience moderate to severe pain.65,78 A group, which had a rate of 0.4%.80 Although this study did
study in Finland analyzed 201 cataract surgeries in which not include cataract surgery, and the maximum patient age
only topical anesthesia was used. Postoperative pain was was 64 years, there could be some translation of these data
assessed, and 10% of patients reported ocular pain with a to cataract surgery as a minor procedure.
median pain score of 4 to 5/10 at 24 hours after surgery. By Another study found that approximately 5% of patients
6 weeks after surgery, 7% of patients reported ocular pain were prescribed an opioid after cataract surgery.63 This study
with a median pain score of 3 to 4/10.78 also assessed long-term risk for patients’ dependence on
In another study, Porela-Tiihonen et al. systematically opioids after low-risk surgical procedures. Patients un-
reviewed the incidence, prevalence, and management of dergoing cataract surgery who received a postoperative
pain after cataract surgery. Twenty-one studies were ulti- opioid prescription were approximately 60% more likely to
mately assessed, and some trends emerged. Whether as- be using opioids long term than those not receiving an opioid
sessed immediately postoperatively, within the first 72 prescription. Of the low-risk surgeries assessed (cataract
hours, or weeks after surgery, pain was lower across the surgery, laparoscopy cholecystectomy, transurethral prostate
board in the groups receiving interventions to reduce in- resection, and varicose vein stripping), cataract surgery
flammation and pain compared with the control groups. actually had the largest odds ratio for risk for long-term
Having said that, the authors found that cataract surgery is opioid use. Cataract surgery patients were 1.62 times more
associated with significant postoperative pain in some likely to use opioids long term compared with the other
patients, with 1 study reporting the incidence of moderate procedures, which ranged from 1.33 to 1.41 times.63

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 NONOPIOID ALTERNATIVES IN CATARACT SURGERY 735

annually. About 1% of ophthalmologists wrote 100+ opioid

prescriptions per year. The average ophthalmologist wrote
7 opioid prescriptions per year with a 5-day mean supply.70
This study concluded that ophthalmologists are generally
judicious in their prescribing patterns for opioids, but,
given the opioid crisis, prescribing protocols should be
reviewed as, even with a limited 5-day supply, up to 10% of
patients can become chronic opioid users at 1 year.70,82
In another study, Kolomeyer et al. analyzed a large
administrative medical claims database, identifying
2 407 962 incisional ocular surgeries from 2000 to 2016,
which met strict enrollment criteria surrounding length
of data available and timing of any opioid prescriptions.
Of these patients, 45 776 were prescribed a postopera-
tive opioid. The study assessed the rates of filled opioid
prescriptions and found that the rate increased for all
types of incisional ocular surgery over time.71 With the
ongoing national opioid crisis, understanding these pat-
Figure 3. Pyramid of cataract surgery pain management. NSAID = terns may help ophthalmologists participate in addressing
nonsteroidal anti-inflammatory drug the epidemic.
Among ophthalmology subspecialties, cataract surgery
had the highest number of filled opioid prescriptions in this
In a memorandum included in public comments to the limited database, with approximately 20 000 written during
Centers for Medicare and Medicaid Services’ Calendar Year this 17-year period.71 Of these patients, 77% also received
2020 proposed rule for the hospital outpatient prospective topical NSAIDs and/or steroids preoperatively, post-
payment system and the Medicare ambulatory surgical operative, or both. This suggests that topical treatments
center payment system, David J. Clark, MD, PhD, Veterans may not adequately address postoperative pain and high-
Affairs Palo Alto and Stanford University Department of lights the need for alignment and coordination of cataract
Anesthesiology, Perioperative Medicine, and Pain, stated, surgery pain management between ophthalmologists and
“Reducing exposure to opioids even after small surgeries anesthesiologists or other MAC providers.72
may have even greater benefits in that it could reduce the
cumulative risk resulting from multiple opioid exposures. DIVERSION OF OPIOIDS IN THE COMMUNITY
Those in the elderly patient population may undergo According to the Center for Behavioral Health Statistics
multiple temporally related procedures (eg, cardiovascular and Quality, 50.5% of the estimated 4.3 million nonmedical
procedures, total joint replacements, etc.), almost all of users of prescription opioid drugs in 2014 obtained them
which entail opioid administration both during surgery and for free from a prescription intended for a friend or relative,
postoperatively.”81 whereas 22.1% obtained them from a physician.2,67,83 This
Whether patients are taking opioids prior to surgery, widespread community availability of opioids ultimately
simply undergoing surgery is a risk factor for chronic stems from the large supply of opioid prescriptions, thus
opioid use postoperatively. Assessing the surgical pop- contributing to the public health crisis. The quantity of
ulation as a whole, including patients taking opioids prior opioids sold to hospitals, doctors’ offices, and pharmacies
to surgery, postoperative chronic opioid use ranges from increased by a factor of 4 from 1999 to 2010.2 In 2012, U.S.
9.2% to 13%.76,79 By decreasing the overall prevalence of physicians wrote nearly 260 million opioid prescriptions, a
chronic opioid use postoperatively, the goal is also to de- staggering 70% of the global supply of opioids.2,84 There-
crease opioid-related adverse events, which are the hall- fore, it is reasonable to expect that opioids given to patients
mark of the current opioid crisis.79 may be opioids given to the entire community.

OUTPATIENT OPIOID PRESCRIBING PATTERNS NONOPIOID PAIN MANAGEMENT STRATEGIES IN

AMONG OPHTHALMOLOGISTS CATARACT SURGERY
Ophthalmology as a whole prescribes opioids at a lower rate Pain management during cataract surgery may be ap-
(4%) compared with the national average across all pre- proached in a stepwise fashion. Figure 3 shows an algo-
scribers (6.8%). Contrast these values to the median rates rithm in which opioids and opiates, although potentially
for surgeons as a whole (36.5%), pain medicine (48.6%), necessary in some cases, can be used more sparingly as a
and physical medicine and rehabilitation (35.5%).67 later intervention. At the other end of the spectrum, cat-
A study analyzing the Medicare Part D Prescriber Data aract surgery may actually be performed without IV an-
from 2013 to 2015 looked at opioid prescribing patterns esthesia. A study assessed 100 randomly selected patients
among ophthalmologists. The study revealed that 88% to from a 2-year period who received only topical anesthesia
89% of ophthalmologists wrote <10 opioid prescriptions during cataract surgery.15 Patients received 1 drop of

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736 NONOPIOID ALTERNATIVES IN CATARACT SURGERY

preservative-free 0.5% tetracaine, with additional drops or a An FDA-approved local nonopioid option specific to
tetracaine-soaked pledget if discomfort escalated. A change cataract surgery is Omidria [(phenylephrine and ketorolac
in patients’ vital signs was used as a surrogate for pain. injection) 1%/0.3% (Omeros Corporation)], a combination
Patients’ blood pressure increased by 1%, whereas the drug containing 1% phenylephrine, a mydriatic agent, and
heart rate and respiratory rate decreased by 2% and 1%, 0.3% ketorolac, an NSAID.86 Added to the irrigating so-
respectively.15 Fichman concluded that overall, patients lution for continuous intracameral administration during
were very comfortable during cataract surgery despite re- cataract surgery, phenylephrine/ketorolac 1.0%/0.3% mini-
ceiving no IV sedation. mizes intraoperative and postoperative (ie, total perioper-
With the refinement of cataract surgery, some surgeons ative) opioid exposure while, at the same time, decreasing
use this local/regional approach to pain without sedation.36 postoperative pain.
Providing patient education about the procedure and In 2 phase 3 prospective, randomized, double-blind clinical
perioperative experience and setting realistic expectations trials, 808 patients were randomized to receive treatment (n =
may be adequate in addressing patient anxiety, which can 403) or placebo (n = 405) administered intracamerally with
decrease pain during surgery and lead to a decreased need irrigation solution during cataract surgery. Mydriasis was
for opioid pain management.1,36 maintained better in patients receiving phenylephrine/ketorolac
Although eliminating sedation during cataract surgery 1.0%/0.3%, with the treatment group having a mean change in
may not work for all patients, there are other approaches that area under the curve of 0.08 mm compared with the placebo
do not include opioids. Multimodal analgesia can be an group, which had a change of 0.50 mm (95% CI, 0.51-0.65;
effective pain management technique for cataract extraction P < .0001).87 There was also a significant reduction in early
in which 2 or more medications or nonpharmacologic in- postoperative ocular pain measured via visual analog scale
terventions (eg, transcutaneous electrical nerve stimulation) (VAS) scores. Within the first 12 hours, the VAS scores in the
having different mechanisms of action are used to address phenylephrine/ketorolac 1.0%/0.3% group were >50% lower
postoperative pain.79,84 Drugs or classes of drugs such as than in the placebo group. In addition, the use of oral analgesics
acetaminophen, NSAIDs (especially cyclooxygenase [COX]- on the day of surgery was significantly lower in the treatment
2 inhibitors), gabapentinoids, corticosteroids, ketamine, and group compared with the placebo group (P = .001). The
local or regional anesthetics can be used perioperatively proportion of patients who were pain free at all measured time
and/or postoperatively to avoid some of the side effects of points was significantly higher, and concurrently, the pro-
opioids, especially in the elderly cataract surgery pop- portion of patients experiencing moderate to severe pain at any
ulation.66,79 The combination of treatments likely has an time was significantly lower in the phenylephrine/ketorolac
additive effect on opioid-sparing.79,84 Care should be taken, 1.0%/0.3% group.87
however, to consider the potential side effects of these al- The ketorolac component of phenylephrine/ketorolac
ternative medications. 1.0%/0.3% is an NSAID that inhibits both COX-1 and
One option found to be an effective nonopioid sedative COX-2, which in turn inhibits surgical trauma-induced
for cataract surgery is the sublingual MKO Melt (com- prostaglandin production downstream, thereby reducing
pounded by ImprimisRx), which contains midazolam, postoperative inflammation and pain.88 Ketorolac has been
ketamine, and ondansetron. Jeffries et al. prospectively demonstrated in therapeutic concentrations in the aqueous
studied 611 patients undergoing cataract surgery by 2 and vitreous up to 10 hours postdose in canines receiving
surgeons. Patients were randomized to receive diazepam intracameral phenylephrine/ketorolac 1.0%/0.3% compared
alone, diazepam/tramadol/ondansetron, or compounded with topical dosing.89 Consistent findings were noted after
midazolam/ketamine/ondansetron.85 All patients received topical dosing in humans. Ketorolac is nearly undetectable in
topical anesthetic with additional anesthetic administered the aqueous immediately after cataract surgery and in the
intracamerally (surgeon 1) or topically (surgeon 2). Although vitreous immediately after vitrectomy when preoperative
the midazolam/ketamine/ondansetron group showed a ketorolac is administered topically.90,91 In contrast, intra-
statistically significant reduced need for IV medications cameral phenylephrine/ketorolac 1.0%/0.3%, by remaining in
(P = .013) compared with the other groups, patients across the aqueous and vitreous well after the procedure is com-
all 3 groups required additional IV medications 32.1% of pleted, contributes to the management of postoperative pain.
the time. No significant differences were found between Similar pain management benefits of phenylephrine/
surgical or discharge times across patient groups, surgeon ketorolac 1.0%/0.3% have been demonstrated in children.
or patient satisfaction, or side-effect profile between In a randomized, double-masked, active-control phase 3
groups.85 The authors concluded that, “when used for pediatric study, mean pain scores, as measured by the Alder
cataract surgery, midazolam/ketamine/ondansetron offers Hey Triage Pain Scale, were significantly lower in the
an opioid-sparing alternative to conscious sedation that is phenylephrine/ketorolac 1.0%/0.3% group compared with
safe, effective, and superior to diazepam in reduction of the phenylephrine 1.0% group. Although this study was not
anxiety and need for IV medications.” It is important to powered to detect a difference in pain scores, significantly
note that compounded midazolam/ketamine/ondansetron lower mean scores were seen at both 6 hours and 24 hours
has not been assessed for safety or efficacy by the U.S. Food postoperatively (P = .029 and .021, respectively).92
and Drug Administration (FDA) and carries the patient Knowing that phenylephrine/ketorolac 1.0%/0.3% lessens
risks inherent in compounded products. patient pain, of interest is the impact it may have on decreasing

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 NONOPIOID ALTERNATIVES IN CATARACT SURGERY 737

perioperative opioid administration, particularly fentanyl, P < .001), as were the mean VAS pain scores at 10 minutes
which is often used as part of MAC. Donnenfeld et al. (0.9 vs 2.1; P < .001) and 1 day (0.2 vs 0.6; P < .001)
compared intracameral phenylephrine/ketorolac 1.0%/0.3% to postoperatively, representing pain score reductions of 57.1%
epinephrine (1 mg/mL) on pain reduction and opioid usage and 66.7%, respectively.93
during cataract surgery. Sixty patients were prospectively
enrolled, 41 in the phenylephrine/ketorolac 1.0%/0.3% group MINIMIZING PRESURGICAL AND
and 19 in the epinephrine group, all of whom received topical POSTSURGICAL OPIOIDS
lidocaine gel, intracameral preservative-free lidocaine 1%, and In addition to perioperative opioid considerations, prescribing
a standardized regimen of preoperative and postoperative patterns for postsurgical opioids is important, too. Jackson et al.
topical medications.72 If patients complained of pain intra- looked at real-world opioid prescribing after cataract surgery in
operatively, IV fentanyl was administered. Endpoints included patients who received phenylephrine/ketorolac 1.0%/0.3%. This
pain as measured by the mean VAS score from 0 to 10, as- retrospective study assessed data from the MarketScan databases
sessed 10 minutes postoperatively; administration of fentanyl of patients undergoing cataract surgery with or without
intraoperatively; and a composite endpoint of patients con- phenylephrine/ketorolac 1.0%/0.3%. A group of 218 672 pa-
sidered responders who did not require fentanyl and had no to tients was identified from the data between January 1, 2015, and
minimal pain (defined as ≤3 on VAS). July 15, 2019. Of these, 5145 received phenylephrine/ketorolac
The mean VAS pain scores were 48.9% lower in the 1.0%/0.3% during surgery. In the 2-day postoperative period,
phenylephrine/ketorolac 1.0%/0.3% study group com- 0.50% of the phenylephrine/ketorolac 1.0%/0.3% group and
pared with the control epinephrine group (2.3 vs 4.5; P < 0.68% of the 213 527 control group patients (P = .135) filled at
.001). The proportion of patients with a VAS score ≤3 least 1 opioid prescription. The opioid pill count for the
was greater in the phenylephrine/ketorolac 1.0%/0.3% first prescription for patients receiving phenylephrine/ketorolac
group (85.0%) than that of the control group (31.6%; P < 1.0%/0.3% was significantly lower than for patients in
.001). Also, a significantly smaller proportion of patients the control group, with 20 pills and 45 pills prescribed, re-
in the study group (9.8% vs 42.1%; P = .006) required spectively (P = .015). The findings were similar when assessing a
intraoperative fentanyl. With respect to the composite 7-day postoperative window. Despite demonstrating a statisti-
endpoint, the patients receiving phenylephrine/ketorolac cally significant lower number of opioids prescribed, the
1.0%/0.3% were 94% less likely to require fentanyl or to phenylephrine/ketorolac 1.0%/0.3% patients, as a whole, were
have moderate to severe pain than those in the epi- also significantly more likely to have 1 or more presurgical
nephrine group.72 comorbidity or risk factors for complex surgery than the control
Overall, intracameral phenylephrine/ketorolac 1.0%/0.3% group (46.6% vs 31.3%; P < .001), which would be expected to
led to an almost 80% decrease in the need for opioids in- have resulted in increased postoperative pain.94
traoperatively and, concurrently, an approximate 50% de- Overall, this study demonstrated a reduction in the quantity
crease in mean VAS pain scores. The authors of this study of opioids prescribed for patients receiving intracameral
postulated that the patients in the study group experienced phenylephrine/ketorolac 1.0%/0.3% during cataract surgery
less pain as a result of the ketorolac but may have also despite these patients having greater burden of both co-
experienced less pain because of the phenylephrine pro- morbidities and surgical risk factors. The investigators hy-
viding dilation sufficient to decrease the need for iris ma- pothesize that the use of phenylephrine/ketorolac 1.0%/0.3%
nipulation, thereby additionally decreasing the resultant intraoperatively may decrease patient exposure to opioids
pain. Phenylephrine/ketorolac 1.0%/0.3% also allowed for a after cataract surgery and the volume of pills that may be
13% reduction in surgical time, further decreasing the po- diverted into the community.94
tential for tissue manipulation, prostaglandin release, and Although perioperative opioid use can lead to intra-
patient pain.72 operative and postoperative issues, preoperative opioid use
In a subsequent prospective, single-center, randomized, can cause problems during cataract surgery as well. A study
double-masked, self-controlled clinical trial, Donnenfeld from Kresge Eye Institute assessed consecutive cataract
again compared pain control and the need for fentanyl surgery patients from January 1, 2017, to April 30, 2018,
during cataract surgery with intracameral use of either noting patient self-reports about whether they were using a
phenylephrine/ketorolac 1.0%/0.3% or epinephrine during prescription opioid at the time of surgery. Rodriguez Torres
cataract surgery. In this study, a total of 112 eyes of 56 analyzed intraoperative complications, both minor and
patients undergoing bilateral cataract surgery were en- severe, as well as visually significant or vision-threatening
rolled, with 1 eye randomized to treatment and the other to complications within a 90-day period postoperatively. A
epinephrine as the control.93 total of 169 patients were assessed, 26 of which were using
Overall, the number of patients requiring intra- an opioid at the time of surgery; the opioid user and
operative fentanyl analgesia was significantly lower in the nonuser groups were similar demographically.59
phenylephrine/ketorolac 1.0%/0.3% group compared The overall rates of intraoperative complications (odds
with the epinephrine group (12.5% vs 33.9%; P = .013). ratio 5.018, 95% CI, 1.250-20.140, P = .013) and post-
Mean VAS pain scores intraoperatively were also sig- operative complications (odds ratio 3.068, 95% CI, 0.851-
nificantly (56.7%) lower in the phenylephrine/ketorolac 11.058, P = .074) were higher in the opioid users than the
1.0%/0.3% group than in the epinephrine group (1.3 vs 3; nonusers. Both visually significant and vision-threatening

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738 NONOPIOID ALTERNATIVES IN CATARACT SURGERY

complications were higher in the prescription opioid user There have been several legislative approaches as well,
group as well. Overall, prescription opioid users were 5 such as the 2018 Substance Use-Disorder Prevention that
times more likely to experience intraoperative complica- Promotes Opioid Recovery and Treatment for Patients and
tions during cataract surgery and 3 times more likely to Communities Act which, among other provisions, directed
have postoperative complications.59 the Center for Medicare and Medicaid Services to review
As the opioid crisis continues, a number of surgical spe- payment structures to remove financial incentives for
cialties have looked at their opioid prescribing patterns. As practitioners to use and prescribe opioids instead of
discussed, there have been just a few studies looking at nonopioid alternatives.95 Another bill that generated strong
prescribing trends within ophthalmology, focusing primarily bipartisan support in the 116th Congress in both the Senate
on prescriptions written without looking at how many are and the House of Representatives and has been re-
actually filled.67,70 The Kolomeyer study found that the introduced in both chambers of the 117th Congress is the
overall rate of opioid prescriptions filled after cataract surgery Non-Opioids Prevent Addiction In the Nation Act.96,97 If
was increasing from 2000 to 2016. During that period, opioid passed, the Non-Opioids Prevent Addiction In the Nation
prescriptions were filled following 0.95% per cataract surgery Act would amend the Social Security Act to combat the
procedure.71 Ocular incisional surgeries as a group were opioid crisis by promoting access to nonopioid treatments
associated with a 1.9% rate of filled opioid prescriptions; in the hospital outpatient setting. Each of these public
however, the greatest number of surgeries performed in this health measures appropriately seeks to address an im-
group were cataract extractions, which, when excluded, re- portant aspect of the opioid epidemic.
sulted in a 7.57% rate of filled opioid prescriptions across the
remaining ocular incisional procedures, collectively.71 LIMITATIONS TO CURRENT KNOWLEDGE
Of interest, although cataract surgery techniques, equip- Although much has been learned about the opioid crisis and
ment, and technology have advanced, resulting in less invasive how cataract surgeons can respond, there are some limitations
procedures, both patient-perceived pain and opioid pre- and gaps in the current data. There have been no compre-
scriptions are increasing. Kolomeyer et al. postulated several hensive studies assessing pain management and analgesia at all
potential reasons for this paradox, including deficient phy- points in the cataract surgery process, nor have there been
sician education about opioid prescribing or pain assessment, studies assessing the prescribing patterns by provider type and
greater focus on pain as the fifth vital sign, lack of state and/or the ways in which ophthalmologists and anesthesiologists could
national standardization of opioid prescribing regulations, more effectively collaborate, providing patients the best possible
increased awareness by physicians about patient pain/pain surgical experience and outcome without exposing them, or
perception and the correlation with physician and hospital their communities, to the risks of opioid medications.
satisfaction scores, and drug company marketing strategies.71
The authors of the Kolomeyer study encouraged ophthal- THE ROLE OF CATARACT SURGEONS IN THE
mologists to evaluate their opioid prescribing habits. Particularly BATTLE AGAINST THE OPIOID CRISIS
in light of the national opioid crisis, it is time for ophthal- Although cataract surgeons do not prescribe opioids for
mologists as a whole, including cataract surgeons, to assess the postoperative pain at a high rate, the sheer volume of cataract
role of opioids in pain management for cataract surgery. With surgeries performed both in the United States and worldwide
nonopioid pain management strategies such as multimodal means that there are a large number of patients who receive
anesthesia, phenylephrine/ketorolac 1.0%/0.3%, postoperative and fill opioid prescriptions, with which comes the risk for
topical pain medications, and even patient education, cataract potential opioid misuse, abuse, and diversion. There are
surgeons can positively influence patients away from opioids. several ways that cataract surgeons can actively combat the
opioid crisis. First, understand that there is a persistent dis-
PUBLIC HEALTH AND SYSTEMIC STRATEGIES connection between pain management and patient pain ex-
The U.S. government’s public health response to the opioid perience in cataract surgery despite increasingly refined
crisis has focused on stopping abuse, decreasing the opioids surgical techniques and take the opportunity to assess, change,
diverted into the community, and minimizing demand.67 and improve standard care practices. Second, take a holistic
One example of a systemic strategy is the Veterans Ad- approach when caring for these elderly cataract surgery pa-
ministration’s approach to addressing OUD, developed in tients. By doing so, cataract surgeons can not only mitigate the
2017, called S.T.O.P. P.A.I.N., a comprehensive, multi- risk for OUD but also help prevent polypharmacy issues in
pronged approach to prevent opioid abuse and treat those this population. Third, be particularly mindful of cataract
who become addicted.3 surgery patients already on an opioid regimen for another
S–Stepped Care Model condition and take mitigating steps to decrease the potential
T–Treatment alternatives/complementary care for complications. Finally, reevaluate your standard protocols
O–Ongoing monitoring of usage for pain management and analgesia surrounding cataract
P–Practice Guidelines surgery and consider using FDA-approved nonopioid alter-
P–Prescription monitoring natives such as phenylephrine/ketorolac 1.0%/0.3% and, if and
A–Academic Detailing when approved, midazolam/ketamine/ondansetron; non-
I–Informed consent for patients pharmacologic support; or some combination of these non-
N–Naloxone distribution opioid strategies. The goal of ophthalmologists should be to

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 NONOPIOID ALTERNATIVES IN CATARACT SURGERY 739

balance patients’ pain control needs with judicious use of Available at: https://www.aao.org/exhibition-detail/cataract-surgery-
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Volume 48 Issue 6 June 2022