Chronic Use of Tramadol after an Acute Pain Episode ... · Study Journal: BMJ Manuscript ID...

Confidential: For Review OnlyChronic Use of Tramadol after an Acute Pain Episode: Cohort

Study

Journal: BMJ

Manuscript ID BMJ-2018-048304.R1

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 15-Feb-2019

Complete List of Authors: Thiels, Cornelius; Mayo Clinic, SurgeryHabermann, Elizabeth; Mayo Clinic, Health Services ResearchHooten, W. Michael; Mayo Clinic, Anesthesiology; Mayo Clinic Minnesota, Jeffery, Molly; Mayo Clinic, Health Care Policy Research

Keywords: opioid, narcotic, tramadol, ultram, chronic opioid use, surgery, dependence

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review Only

1

[Journal: BMJ; Category: Original Investigation]

Chronic Use of Tramadol after an Acute Pain Episode: Cohort Study

Cornelius A. Thiels, DO, MBA1,2

Elizabeth B. Habermann, MPH, PhD2

W. Michael Hooten, MD3

Molly M. Jeffery, PhD 2

Author Affiliations:

1Department of Surgery, Mayo Clinic, Rochester, MN.

2Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery and

Department of Health Services Research, Mayo Clinic, Rochester, MN.

3Department of Anesthesiology, Mayo Clinic, Rochester, MN

Corresponding Author and Reprints: Molly M. Jeffery, Mayo Clinic, 200 First St SW, Rochester,

MN 55905 ([email protected], Phone: 507-293-2508).

Keywords: opioid; dependence; surgery; tramadol, ultram; chronic opioid use.

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Author Statements

Contributors: CAT, EBH, WMH, and MMJ conceived and designed this work. MMJ and CAT

cleaned and analyzed the data. CAT, EBH, and MMJ interpreted the data and all authors were

responsible for drafting the work and revising it critically for important intellectual content. All

authors gave final approval of the version to be published and agree to be accountable for all

aspects of the work in ensuring that questions related to the accuracy or integrity of any part of

the work are appropriately investigated and resolved. MMJ acts as guarantor, accepting full

responsibility for the work; she had access to the data and controlled the decision to publish. The

corresponding author attests that all listed authors meet authorship criteria and that no others

meeting the criteria have been omitted.

Funding: This study had no external funding

Competing interests: All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the

submitted work; no financial relationships with any organisations that might have an interest in

the submitted work in the previous three years; no other relationships or activities that could

appear to have influenced the submitted work.

Patient Consent: Not applicable.

Ethical Approval: This study was determined to be exempt from review by the Mayo Clinic

Institutional Review Board.

Data Sharing: OptumLabs data are available for research through a virtual data warehouse. The

authors are not able to distribute the data.

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Summary Box

WHAT IS ALREADY KNOWN ON THIS TOPIC: Tramadol is a unique short-acting opioid

that is considered by many physicians to be safer than short-acting opioids. However, data to

support the safety and lower risk of prolonged use of tramadol is lacking.

WHAT THIS STUDY ADDS: Tramadol use was associated with a higher rate of prolonged

opioid use in patients with an acute episode of pain compared to other short-acting opioids.

Providers should use caution when prescribing tramadol in the setting of acute pain.

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ABSTRACT

Objective: Due to theorized lower abuse potential and less risk of dependence, tramadol is

considered by the Federal Drug Enforcement Agency and many providers to be safer than other

short-acting opioids. We aimed to determine the risk of prolonged opioid use in patients

receiving tramadol compared to other short-acting opioids.

Design: Observational study of administrative claims data

Setting: United States commercial and Medicare Advantage insurance claims (OptumLabs Data

Warehouse) January 1, 2009 through June 30, 2018.

Participants: Opioid-naive patients undergoing elective surgery

Main Outcome Measure: Risk of persistent opioid use after discharge for patients prescribed

tramadol alone versus other short-acting opioids, using three commonly used definitions of

prolonged opioid use from the literature: (1) additional opioid use (defined as at least one opioid

fill 90 to 180 days after surgery), (2) persistent opioid use (any span of opioid use starting in the

180 days after surgery and lasting at least 90 days), and (3) CONSORT definition (an opioid use

episode starting in the 180 days after surgery that spans at least 90 days and including either 10

or more opioid fills or 120 or more days’ supply of opioids).

Results: Of 444,764 patients meeting our inclusion criteria, 357,884 filled a discharge

prescription for one or more opioids associated with one of twenty included operations. The most

commonly prescribed post-surgery opioids were hydrocodone (51.4% of those filling any

opioid), followed by short-acting oxycodone (37.7%), and tramadol (4.1%). The unadjusted rates

of prolonged opioid use after surgery were 7.1% (N=31,431) with additional opioid use, 1.0%

(N=4,457) with persistent opioid use, and 0.5% (N=2,027) meeting the CONSORT definition.

Receipt of tramadol alone was associated with a 6% increase in the risk of additional opioid use

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relative to people receiving other short-acting opioids (IRR 95% CI: 1.00 to 1.13; risk difference

0.5 percentage points; P=0.049), 47% increase in the adjusted risk of persistent opioid use (IRR

95% CI: 1.25 to 1.69; risk difference 0.5 percentage points; P<0.001), and 41% increase in the

adjusted risk of a CONSORT chronic opioid use episode (95% CI [1.08 to 1.75]; risk difference

0.2 percentage points; P=0.013).

Conclusions: People receiving tramadol alone after surgery had similar to somewhat higher risks

of prolonged opioid use compared to those receiving other short-acting opioids. Federal

governing bodies should consider reclassifying tramadol and providers should use equal caution

when prescribing tramadol in the setting of acute pain as compared to other short-acting opioids.

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PRINT ABSTRACT

Study Question: What is the risk of prolonged opioid use in patients receiving tramadol

compared to other short-acting opioids.

Methods: Observational study of opioid-naive patients undergoing elective surgery utilizing the

United States commercial and Medicare Advantage insurance administrative claims data

(OptumLabs Data Warehouse) from January 1, 2009 through June 30, 2018. Primary outcomes

was the risk of persistent opioid use after discharge for patients prescribed tramadol alone versus

other short-acting opioids, using three commonly used definitions of prolonged opioid use from

the literature: (1) additional opioid use, (2) persistent opioid use, and (3) CONSORT definition.

Study answer and limitations: Receipt of tramadol alone was associated with a 6% increase in

the risk of additional opioid use relative to people receiving other short-acting opioids (IRR 95%

CI: 1.00 to 1.13; risk difference 0.5 percentage points), 47% increase in the adjusted risk of

persistent opioid use (IRR 95% CI: 1.25 to 1.69; risk difference 0.5 percentage points), and 41%

increase in the adjusted risk of a CONSORT chronic opioid use episode (95% CI [1.08 to 1.75];

risk difference 0.2 percentage points). The findings of this study are limited to commercially

insured and Medicare Advantage patients in the United States and other aspects of the safety

profile of tramadol were not studied.

What this study adds: People receiving tramadol alone after surgery had similar to somewhat

higher risks of prolonged opioid use compared to those receiving other short-acting opioids.

Providers should use caution when prescribing tramadol in the setting of acute pain.

Funding, competing interests, data sharing: This study had no external funding, no competing

interest to disclose and while OptumLabs data are available for research through a virtual data

warehouse the authors are not able to distribute the data.

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INTRODUCTION

Despite increased public and medical community awareness[1,2] the United States opioid

epidemic continues to result in an economic cost of over 500 billion dollars[3], while the

proportion of people using prescribed opioids has not substantially decreased in recent years[4].

In the setting of acute pain, some prescribers have focused on limiting the number of pills

prescribed[5,6] or maximizing the use of multi-modal and non-opioid based pain control[7]. In

addition to these strategies, tramadol has seen a surge in use in the last few years[8], likely due to

its perceived benefits, including what physicians may consider a favorable side-effects profile

and the wide-spread assumption that is safer and less addictive than other short-acting opioids.

As a result, tramadol is now among the most commonly prescribed opioids in the United

States[4] and is frequently used by surgeons for the treatment of post-operative acute pain.

Tramadol is a centrally acting synthetic weak μ-opioid receptor agonist and is

phenotypically distinct from conventional short-acting opioids[9]. While tramadol was first

developed in Germany in the late 1970s, it did not receive US Food and Drug Administration

(FDA) approval until 1995, first becoming a controlled substance in the United States (Schedule

IV drug) in 2014[10,11]. Similarly, in the United Kingdom, Tramadol was not classified as a

controlled substance until 2014[12]. It remained unscheduled until 2018 in Canada[13].

Tramadol’s lower affinity for the μ-opioid receptor has given it a reputation for having a more

favorable side effect profile, including lower rates of constipation, respiratory depression,

overdose, and addiction[14–17]. For these reasons, the US FDA continues to classify tramadol at

a lower level than other opioids like morphine and oxycodone, both Schedule II[11]. As a result,

many studies investigating the risks of opioid use have gone as far as to exclude tramadol,[18–

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20] and a recent randomized clinical trial included tramadol in the non-opioid prescribing

arm[20]. Box 1 summarizes basic information about tramadol[11,12,21–24].

Box 1: Tramadol Fast Facts

Brand Names

United Kingdom: Invodol, Larapam, Mabron, Maneo, Marol, Maxitram, Oldaram, Tilodol, Tradorec, Tramquel, Tramulief, Zamadol, Zeridame and Zydol.

United States: Ultram, Ultram ER [discontinued], and ConZip.Canada: Durela, Ralivia, Tridural, Ultram, and Zytram XL.

Primary Mechanism of Action

1. Tramadol undergoes demethylation in the liver predominately by CYP2D6 enzymes to the active metabolite O-desmethyltramadol, which is a mu-opioid receptor agonist that results in inhibition of ascending pain pathways

2. Tramadol also directly inhibits norepinephrine and serotonin reuptake inhibitor, which are neurotransmitters involved in the inhibitory pain pathway

Use/off-label useUnited States: labelled for pain management in people for whom non-opioid medications are contraindicated or ineffective; off-label use for premature ejaculation and refractory restless legs syndrome

United Stated Boxed Warnings

1. Addiction, abuse, and misuse2. Opioid analgesic Risk Evaluation and Mitigation Strategy

(REMS)3. Life-threatening respiratory depression4. Accidental ingestion5. Ultra-rapid metabolism of tramadol and other risk factors

for life-threatening respiratory depression in children6. Neonatal opioid withdrawal syndrome7. Interactions with drugs affecting cytochrome P450

isoenzymes8. Risks from concomitant use with benzodiazepines or other

CNS depressants

Schedule/Control

United States: Schedule IV since 2014, previously unscheduledUnited Kingdom: Class C, Schedule 3 since 2014, previously unscheduledCanada: Schedule 1 since 2018, previously unscheduled

Common Adverse Effects (>10%)

Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth

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Data to support the reputed safety and lower dependence risk of tramadol are lacking.

Recently, a study from the Centers for Disease Control (CDC) unexpectedly found that for

Medicare patients, tramadol was associated with a higher rate of transition from acute to

prolonged use at one and three years than other short-acting opioids[25]. Our aim was to

determine the risk of transitioning from acute to prolonged use in opioid naïve patients treated

with tramadol for post-operative pain.

METHODS

Data Source and Study Population

The study involves a retrospective analysis of claims data from the OptumLabs® Data

Warehouse (OptumLabs), which includes de-identified claims data for commercial and Medicare

Advantage enrollees in a large, private, U.S. health plan. The commercial population includes

people who receive healthcare coverage through their or a family member’s employer or who

purchase coverage on the individual market. The Medicare Advantage group includes people

who qualify for public insurance due to age (65+) or long-term disability; Medicare-eligible

people have the choice of enrolling in coverage directly from the government (known as fee-for-

service Medicare) or from private companies in a program called Medicare Advantage. As of

2017, 33% of Medicare beneficiaries opted for Medicare Advantage coverage[26]. Because it

uses pre-existing, de-identified data, this study was determined to be exempt from review by the

Mayo Clinic Institutional Review Board.

OptumLabs contains longitudinal health information on enrollees, representing a diverse

mixture of ages, ethnicities and geographical regions across the United States; see Supplemental

Materials for a comparison of the OptumLabs population to the broader insured US population.

The health plan provides comprehensive insurance coverage for physician, hospital, and

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prescription drug services. We used data from January 1, 2009 through June 30, 2018, with a last

day of surgery being December 31, 2017 to account for required follow-up.

We identified 20 commonly performed surgical procedures including 7 common general

surgery procedures (laparoscopic cholecystectomy with or without intraoperative cholangiogram,

minimal-invasive inguinal hernia repair, open inguinal hernia repair, simple mastectomy without

reconstruction, breast lumpectomy with or without axillary node biopsy,

pancreaticoduodenectomy [Whipple] and parathyroidectomy), 6 orthopedic operations (carpal

tunnel release, knee arthroscopic minesectomy, rotator cuff surgery, total knee replacement, total

hip replacement, and lumbar laminotomy or laminectomy via posterior approach), 2 colorectal

procedures (minimal-invasive low anterior resection with or without ostomy and partial

colectomy with or without ostomy), 2 urology procedures (minimal-invasive partial or total

nephrectomy and minimal-invasive prostatectomy), 2 thoracic procedures (open lung lobectomy

and Video-Assisted Thoracoscopic Surgery [VATS] Lung Wedge) as well as minimal-invasive

hysterectomy. The procedures were chosen with the aim of including common inpatient and

outpatient procedures across multiple specialties and spanning varying degrees of expected post-

operative pain. The array of surgeries allows us to assess the extent to which discharge

prescription characteristics are related to expected pain after surgery.

To reduce confounding as much as possible, we constructed a cohort with minimal

clinical complexity. We excluded patients who were taking opioids prior to surgery--defined as

patients who had no opioid fills in the prior six months—as well as those who may be in

treatment for opioid use disorder by requiring no buprenorphine or methadone in the 90 days

after surgery. In addition, we included only patients with at least 6 months of continuous

enrollment in both medical and prescription coverage before surgery. To limit the clinical

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complexity of the cohort, we excluded patients having multiple unrelated procedures on the same

day (see Supplemental Materials), those with an inpatient stay greater than 7 days, and those

admitted as an inpatient more than 1 day before surgery was performed. Patients receiving non-

cancer surgeries were excluded if they had cancer, as were any patients receiving hospice

services. To ensure we were capturing post-surgery opioid fills, we limited the sample to those

who were discharged home and did not have a skilled nursing facility stay within a day of

discharge (surgery date for those who were not admitted as inpatients). Finally, we required 90

days of insurance enrollment after surgery to ensure that patients survived surgery when

evaluating continued opioid use. See Supplement Figure 1 for cohort flow chart.

Discharge prescriptions were summarized into one of five mutually exclusive and

collectively exhaustive categories: no opioid fill, any long-acting opioid (with or without any

short-acting opioid, including tramadol), tramadol only, a short-acting opioid other than tramadol

alone, or tramadol plus another short-acting opioid. Throughout, we use the “tramadol only”

category as the tramadol comparison category, as people who receive multiple opioids at

discharge may be different in important, unobserved ways.

Patients were followed until they were censored by one of the following events:

1. The end of the study period (6-30-2018)

2. Disenrollment from insurance

3. Another surgery, as defined by a claim for an anesthesia service (See

Supplemental Materials for a list of CPT codes used).

The analysis of discharge prescriptions included patients with at least 30 days of

uncensored follow-up who had an opioid fill of less than 1400 MME (excludes top 0.5% of

discharge fills). The analyses of chronic opioid use included patients with any post-surgery

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opioid fill and at least 180 days of uncensored follow-up. Note that all patients in all analyses

had at least 90 days of post-surgery insurance coverage, which was used to ensure patients had

survived surgery. Patients included in the main outcome analyses had 180 days with no further

surgeries, in addition to having insurance coverage during that time.

Outcomes

We identified all opioid fills for the cohort. See Supplemental Materials for the drugs

included. Discharge opioid prescriptions for each patient were grouped into five mutually

exclusive and collectively exhaustive categories: (1) short acting opioids only, excluding

tramadol (reference), (2) tramadol only, (3) tramadol and any other short-acting opioids (no

long-acting), (4) any long-acting opioids, and (5) no opioids. Using conversion factors from the

CDC, we converted active ingredient doses to mg of morphine equivalents (MME)[27]. We used

a different conversion factor for propoxyphene than is given in the CDC table, where we used

conversion factor 0.23 for propoxyphene HCl and 0.15 for propoxyphene napsylate (corrected

conversion factor for the napsylate salt based on information in the monograph)[28]. A single fill

was defined as the total amount of a single drug filled on a single day. For example, if a patient

filled prescriptions for 5 mg and 10 mg tabs of oxycodone, we summed the total MME for both

formulations and counted it as a single oxycodone fill.

To identify the discharge prescription, we looked for opioid fills between 7 days before

surgery and 7 days after surgery (7 days after discharge for those who were admitted as

inpatients). We selected the earliest fill within that time span as the date of the discharge fill and

summed the total MME of all opioids filled on that date.

Definitions of Prolonged Opioid Use

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To assess the risk of prolonged opioid use after surgery, we performed logistic regression

at the individual level on the cohort with at least 180 days of uncensored follow-up time. Given

the varying definitions used in the literature, three definitions of prolonged opioid use were

selected a priori. See Box 2.

A single episode of opioid use was defined as a period of time during which the

individual goes no more than 30 days without opioids available. Opioids were considered

available from the date of fill until the number of days supplied elapsed.

Box 2: Prolonged opioid use definitions

Additional Opioid Use

after Surgery

This definition used in the surgical literature

defines chronic opioid use as at least one opioid

fill 90 to 180 days after surgery[29–32].

Persistent Opioid Use

after Surgery

This definition identifies any span of opioid use

starting in the 180 days after surgery and lasting

at least 90 days[33,34].

CONSORT Definition

of Long-term Opioid

Therapy.

This definition was developed by the

CONsortium to Study Opioid Risks and Trends

for studying de facto long-term opioid therapy in

patients being treated for chronic non-cancer

pain[35,36]. It has been operationalized here as an

opioid use episode starting in the 180 days after

surgery that spans at least 90 days and including

either 10 or more opioid fills or 120 or more days’

supply of opioids.

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Patient Involvement

No patients were involved in setting the research question or the outcome measures, nor

were they involved in developing plans for design or implementation of the study. No patients

were asked to advise on interpretation or writing up of results. There are no plans to disseminate

the results of the research to study participants or the relevant patient community.

Statistical Analysis

We summarized the total MME dispensed in post-surgery discharge fills using a box plot

to display median, 25th and 75th percentiles, and Tukey lower and upper adjacent values. This

analysis included patients with at least 30 uncensored days of follow-up (i.e., no other surgeries

in those 30 days) who filled 1 to 1399 MME of opioids at discharge.

Regression models were adjusted for gender, race/ethnicity, type of surgery, beneficiary

type (commercially insured, Medicare Advantage aged 65+, Medicare Advantage disabled),

census region, age, and whether the person received any long-acting opioids at discharge; Huber-

White robust standard errors were specified. After regression, we calculated the adjusted

proportion with the outcome among those who received tramadol at discharge and those who

didn’t. We present the estimated rate ratio with 95% confidence intervals and the rate difference.

RESULTS

We identified 524,318 patients meeting our inclusion criteria, of whom 444,764 had at

least 180 uncensored days of follow-up; 357,884 of those had a discharge prescription for one or

more opioids. The most common discharge prescription type over the entire study period was

one or more short-acting opioids other than tramadol (Figure 1; 74.9%, N=333,289); 3.0%

(N=13,519) received tramadol alone, and 1.2% received tramadol with another short-acting

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opioid (N=5,457) (Table 1). Women were more likely to receive tramadol alone (women

represented 62.1% of tramadol alone vs. 49.0% of total cohort).

Discharge prescription characteristics (cohort with 30+ days follow-up and any opioid fill)

Among those with any post-surgery opioid prescription fill and at least 30 days of

uncensored follow-up, the median amount of opioids dispensed was 225 MME, the equivalent of

45 5-mg tablets of hydrocodone (30 5-mg tablets of oxycodone). The surgeries with the lowest

median discharge fill were carpal tunnel, lumpectomy, and parathyroidectomy, each with 150

MME filled. The surgeries with the highest median discharge fill were THA and TKA, each with

450 MME. (Figure 2).

Among those who received a single commonly prescribed opioid (at least 1% of sample

received the drug) at discharge (N=401,864; 95.4% of people with 30 days uncensored follow-up

and any opioids at discharge), the largest prescriptions were written for propoxyphene (median

discharge fill 450 MME). The most commonly prescribed opioid after surgery was hydrocodone

(N=212,987; 53.0% of those filling a single common opioid; median fill 200 MME), followed by

short-acting oxycodone (N=150,785; 37.5%; median fill 300 MME), tramadol (N=16,059; 4.0%;

median fill 150 MME), codeine (N=12,377; 3.1%; median fill 135 MME), hydromorphone

(N=4,831; 1.2%; median fill 400 MME), and propoxyphene (N=4,825; 1.2%). Propoxyphene

was only available in the first part of the study period, through November 2010. During the

period it was available, propoxyphene was the third most commonly prescribed drug, with 5.8%

of single-drug discharge prescriptions.

Prolonged opioid use

We analyzed three separate measures of prolonged opioid use and calculated adjusted

proportions of the sample meeting each measure. Additional use of opioids (defined as one or

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more opioid fills 90 to 180 days after surgery) was seen in 7.1% (N=31,431) of the sample with

at least 180 days of uncensored follow-up. One percent of the sample met criteria for persistent

opioid use after surgery, which was defined as opioid use episodes lasting 90 or more days that

started in the 180 days after surgery (N=4,457; 1.00%). The most stringent—the CONSORT

definition requiring an opioid use episode lasting at least 90 calendar days and including either

10 or more opioid fills or 120 or more days’ supply—was present in 0.46 percent (N=2,027) of

the sample with at least 180 days of uncensored follow up time (Table 2).

Among those meeting this definition of additional opioid use, 72% (N=22,779) had no

opioids 31 to 60 days after surgery, 75% (N=23,630) had no opioids 61 to 90 days after surgery,

and 64% (N=20,258) had no opioids 31 to 90 days after surgery. For comparison, 11% (N=488)

of those meeting the persistent opioid use definition (an episode lasting at least 90 days) and 14%

(N=281) of those meeting the CONSORT definition had no opioids 31 to 90 days after surgery.

Association of discharge prescription volume with prolonged use of opioids

Larger discharge prescriptions were associated with a higher risk of prolonged opioid use

across all three definitions of prolonged use (Table 3). Receipt of 500 or more MME of opioids

was associated with a nearly 5 times the risk of prolonged opioid use compared to those

receiving 1 to 199 MME using the CONSORT definition of prolonged use, more than 6 times the

risk of persistent use, and 1.5 times the risk of additional use.

Association of tramadol at discharge with prolonged use of opioids

Receiving tramadol at discharge was associated with increased adjusted risk of all three

definitions of prolonged opioid use (Table 4). Receipt of tramadol alone was associated with a

6% increase in the risk of additional opioid use relative to people receiving other short-acting

opioids (IRR 95% CI: 1.00 to 1.13; risk difference 0.5 percentage points; P=0.049), a 47%

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increase in the adjusted risk of persistent opioid use (IRR 95% CI: 1.25 to 1.69; risk difference

0.5 percentage points; P<0.001), and a 41% increase in the adjusted risk of a CONSORT chronic

opioid use episode (95% CI [1.08 to 1.75]; risk difference 0.2 percentage points; P=0.013).

DISCUSSION

Statement of principal findings

Our study suggests that tramadol carries a similar or somewhat greater risk of

transitioning from acute to prolonged use compared to other short-acting opioids. Although

prescribing was relatively infrequent (4% of patients with opioid fills, including those who

received tramadol with other short-acting opioids), tramadol was the third most frequently

prescribed opioid in this study (after hydrocodone and short-acting oxycodone), and its use

appears to be increasing (Figure 1). The low overall prescription rate likely masks variation in

tramadol use across health systems; other studies have found anywhere from 3 to 25% of patients

receive tramadol prescriptions after surgery[37,38]. Our findings suggest that from the

standpoint of dependency risk, clinicians prescribing tramadol for acute pain should exercise a

level of caution similar to that surrounding the prescribing of other short-acting opioids,

including those on higher DEA schedules.

Larger discharge prescriptions were associated with a higher unadjusted risk of prolonged

opioid use across all three definitions of prolonged use (Table 3). In the adjusted analyses, doses

of 300 MME and larger were associated with higher risk of prolonged use, though with smaller

effect sizes than the unadjusted analysis (odds ratios 1.1 to 1.6, see details in Supplementary

Materials). This aligns with CDC data suggesting that the rate of prolonged use increases

significantly when patients are prescribed more opioids[25].

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Although tramadol remains largely unregulated in developing world, the rates of abuse,

and awareness of the risks, have been increasing outside the U.S[39–42]. While data to support

the avoidance of long-acting opioids in the acute setting remains strong,[43–45] there remain no

clear data on the risks versus benefits of other short-acting opioids compared to tramadol.

Therefore, the choice to prescribe tramadol rather than another short-acting opioid remains

largely dependent on the provider and scenario.

Comparison to past studies

Prior to our work, the strongest study investigating the risk of long-term tramadol use

was the finding noted in the 2017 Centers for Disease Control (CDC) report on opioid

prescribing. That study found that tramadol was associated with a 13.7% rate of continued use at

one-year compared to 4.7 to 8.9% for other short-acting opioids[25]. Notably the CDC study

defined discontinuation of opioids as ≥180 days without opioid use and included commercially

insured people in managed care plans but did not limit the sample to people receiving surgery.

Other than the CDC publication, most other studies assessing the risk of long-term use for an

acute episode of pain either do not include tramadol or do not provide rates of prolonged use by

opioid type.

Pharmacological and neurological mechanisms for abuse potential

Recent publications have shown an increased rate of complications, emergency

department visits, and misuse in patients using tramadol[46,47]. Consequently, the

pharmacological and neural mechanisms responsible for the abuse potential of tramadol warrant

further consideration. The analgesic effects of tramadol are attributed to two mechanism of

action; (1) mu-opioid receptor agonist; and (2) norepinephrine reuptake inhibitor. Tramadol

undergoes demethylation in the liver to the active metabolite desmetramadol. However,

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individual phenotypic variation in the quantity and efficiency of the CYP2D6 enzyme influences

the bioavailability of that active metabolite which can range from 3% among individuals who are

poor metabolizers to 86% among individuals who are extensive metabolizers[48]. This is

clinically significant because O-desmethyltramadol has a 700-times greater affinity for the mu-

opioid receptor than the parent compound[49]. In functional activity assays, O-

desmethyltramadol, but not the parent compound, demonstrates high intrinsic activity at the mu-

opioid receptor comparable to morphine[50]. Thus, the desmetramadol metabolite is responsible

for the opioid effects of tramadol. In experimental human studies, the reinforcing effects of

supratherapeutic doses of tramadol (400 mg administered as a single oral dose) were comparable

to oxycodone[16]. These observations are supported by the findings of a functional magnetic

resonance imaging study where reward anticipation was associated with increased neural activity

in the nucleus accumbens following tramadol administration[51].

Similar to the analgesic effects of tramadol, these studies suggest that the abuse potential

of tramadol is due to the effects of O-desmethyltramadol on the mu-opioid receptor, which could

be influenced by individualized variations in CYP2D6 expression[14,48]. Contrary to the

primary effects of O-desmethyltramadol on opioid receptor mediated analgesia, the parent

compound, tramadol, is directly responsible for analgesia related to the inhibition of

norepinephrine and serotonin. This important mechanism of action is also responsible for the

increased risk of serotonin syndrome, which typically occurs with the use of other

proserotonergic drugs. Clinically important drug-drug interactions can occur with concomitant

use of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors,

tricyclic antidepressants, monoamine oxidase inhibitors, antipsychotics, triptans,

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antiparkinsonian medications, and over the counter drug combinations containing

dextromethorphan[52].

Prolonged opioid use definitions

There remains a paucity of data to support or refute the risk of tramadol use due, in part,

to the absence of structured approaches for investigating the transition from acute to prolonged.

In previous work, we developed a conceptual model to better understand the mediators and

moderators of unintended prolonged opioid use[53]. The proposed conceptual framework was

composed of three domains including patient characteristics, practice environment

characteristics, and opioid prescriber characteristics that interact to either facilitate or impede

unintended prolonged opioid use.

Our study found that prolonged opioid use as defined by either persistent opioid use (at

least 90 days of continuous opioid use in the 180 days after surgery) or the CONSORT definition

was relatively rare (<=1%, Table 2). However when we used the less stringent definition found

in many studies which defined prolonged use as at least one opioid fill in the 90 to 180 days after

surgery, this rate of additional use was much higher (7%). This more closely aligns with

published rates in the setting of acute pain that vary from 6% in all individuals with acute

pain[54], 6% after general surgery[29], 10% after curative intent surgery for cancer[30], 15%

after lung resection[31], to as high as 24% after orthopedic surgery[55]. However, these studies

all used less stringent definitions of prolonged opioid use. Studies using claims data and more

stringent definitions suggest significantly lower rates of prolonged use in the setting of acute pain

(0.1%)[56]. We observed that nearly two-thirds of those meeting the additional use definition

(one or more opioid fill in 90 to 180 days after surgery) had no opioids in the 30 to 90 days after

surgery. This pattern suggests that rather than prolonged use of opioids, these patients may be

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experiencing separate episodes of opioid use separated by one or more months. The additional

opioid use definition may therefore measure a separate problem whereby patients who are once

exposed to opioids are more likely to receive them for other pain-related problems. We did not

test this hypothesis, but the fact that 4.4% of the patients who received no opioids at discharge

met the prolonged use definition (Table 4), while 7.7% who did have a fill met this definition,

may suggest an avenue for further research.

Limitations of study

The findings of this study are most directly applicable to commercially insured and

Medicare Advantage patients in the United States undergoing elective surgery of the types we

included. Given that our study used claims data, we were also unable to determine actual opioid

consumption or capture prescriptions that were not submitted to insurance; however, prior

studies suggest this rate to be low[57]. Although we excluded patients taking opioids prior to

surgery and those with additional operations after the index operation, we were unable to

ascertain the reason patients received additional opioid prescriptions. Lastly, given the available

data and scope of the study we were unable to address other aspects of the safety profile of

tramadol compared to other opioids, including notable benefits like a potentially lower risk of

respiratory depression[58]. Further research in this area prior to implementing policy changes is

warranted.

Conclusions

We found that tramadol, a drug that is currently scheduled at a lower risk level than other

common short-acting opioids (schedule IV vs. schedule II for hydrocodone and oxycodone), has

a similar or somewhat greater risk of prolonged opioid use after surgery. Although all factors

related to the safety of a medication must be considered, from the standpoint of opioid

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dependence, the Drug Enforcement Administration (DEA) and FDA should consider

rescheduling tramadol to a level that better reflects its risks of prolonged use.

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ACKNOWLEDGEMENTS

Support provided by the Mayo Clinic Robert D. and Patricia E. Kern Center for the

Science of Health Care Delivery.

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REFERENCES

1 Thiels CA, Hanson KT, Cima RR, Habermann EB. From Data to Practice: Increasing Awareness of Opioid Prescribing Data Changes Practice. Ann Surg 2018;267:e46–7.

2 Blendon RJ, Benson JM. The Public and the Opioid-Abuse Epidemic. N Engl J Med 2018;378:407–11.

3 The Underestimated Cost of the Opioid Crisis (Council of Economic Advisers). November 2017. Available at: https://www.whitehouse.gov/sites/whitehouse.gov/files/images/The Underestimated Cost of the Opioid Crisis.pdf. Accessed November 20, 2018.

4 Jeffery MM, Hooten WM, Henk HJ, et al. Trends in opioid use in commercially insured and Medicare Advantage populations in 2007-16: retrospective cohort study. BMJ 2018;:k2833.

5 Howard R, Waljee J, Brummett C, Englesbe M, Lee J. Reduction in Opioid Prescribing Through Evidence-Based Prescribing Guidelines. JAMA Surg 2018 Mar 1;153(3):285-287.

6 Thiels CA, Ubl DS, Yost KJ, et al. Results of a Prospective, Multicenter Initiative Aimed at Developing Opioid-prescribing Guidelines After Surgery. Ann Surg 2018;268:457–68.

7 Siddiqui NT, Fischer H, Guerina L, Friedman Z. Effect of a preoperative gabapentin on postoperative analgesia in patients with inflammatory bowel disease following major bowel surgery: a randomized, placebo-controlled trial. Pain Pract 2014;14:132–9.

8 Manchikanti L, Helm S, Fellows B, et al. Opioid epidemic in the United States. Pain Physician 2012;15:ES9-38.

9 Power I. An update on analgesics. Br J Anaesth 2011;107:19–24.

10 Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R. Trends in Tramadol. Anesth Analg 2017;124:44–51.

11 Harrigan TM. Schedules of Controlled Substances: Placement of Tramadol Into Schedule IV. Drug Enforc. Adm. Dep. Justice. 2013. Available at https://www.deadiversion.usdoj.gov/fed_regs/rules/2013/fr1104.htm

12 Tramadol reclassified as a controlled drug (Monthly Index of Medical Specialities). Published June 9, 2019. Available at https://www.mims.co.uk/tramadol-reclassified-controlled-drug/surgery/article/1297952. Accessed February 14, 2019.

13 Regulations amending Schedule I to the Controlled Drugs and Substances Act and the Schedule to the Narcotic Control Regulations to add tramadol and related substances (Health Canada). Published October 12, 2018. Available at https://www.canada.ca/en/health-

Page 24 of 59


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


25

canada/corporate/about-health-canada/legislation-guidelines/acts-regulations/forward-regulatory-plan/2018-2020/tramadol.html. Accessed February 14, 2019.

14 Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43:879–923.

15 Radbruch L, Grond S, Lehmann KA. A risk-benefit assessment of tramadol in the management of pain. Drug Saf 1996;15:8–29.

16 Babalonis S, Lofwall MR, Nuzzo PA, et al. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend 2013;129:116–24.

17 Benzon, H. (2014). Practical management of pain. Philadelphia, Pa.: Elsevier/Saunders.

18 Dobscha SK, Morasco BJ, Duckart JP, Macey T, Deyo RA. Correlates of Prescription Opioid Initiation and Long-term Opioid Use in Veterans With Persistent Pain. Clin J Pain 2013;29:102–8.

19 Lev R, Lee O, Petro S, et al. Who is prescribing controlled medications to patients who die of prescription drug abuse? Am J Emerg Med 2016;34:30–5.

20 Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA 2018 Mar 6;319(9):872-882.

21 Tramadol (Micromedex Solutions). Truven Health Analytics, Inc. Ann Arbor, MI. Available at: http://www.micromedexsolutions.com. Accessed February 14, 2019.

22 UK Government. List of most commonly encountered drugs currently controlled under the misuse of drugs legislation. Published June 1, 2017. Available at https://www.gov.uk/government/publications/controlled-drugs-list--2/list-of-most-commonly-encountered-drugs-currently-controlled-under-the-misuse-of-drugs-legislation. Accessed February 14, 2019.

23 National Association of Pharmacy Regulatory Authorities (NAPRA) Drug Schedule. Available at: https://napra.ca/nds/tramadol-or-its-salts. Accessed February 14, 2019.

24 U.S. Food and Drug Administration Medication Guide. Published August 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf. Accessed February 14, 2019.

Page 25 of 59


BMJ

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26

25 Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use — United States, 2006–2015. MMWR Morb Mortal Wkly Rep 2017;66:265–9.

26 Jocobson G, Damico A, Neuman T. Medicare Advantage 2017 Spotlight: Enrollment Market Update. 2017. https://www.kff.org/medicare/issue-brief/medicare-advantage-2017-spotlight-enrollment-market-update/

27 Agency Medical Directors’ Group Opioid Dose Calculator v2.01. Available at: http://www.agencymeddirectors.wa.gov/Calculator/DoseCalculator.htm Accessed November 20, 2018.

28 Propoxyphene. Micromedex Solutions. Truven Health Analytics, Inc. Ann Arbor, MI. Available at: http://www.micromedexsolutions.com. Accessed February 14, 2019.

29 Brummett CM, Waljee JF, Goesling J, et al. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg 2017;152:e170504.

30 Lee JS-J, Hu HM, Edelman AL, et al. New Persistent Opioid Use Among Patients With Cancer After Curative-Intent Surgery. J Clin Oncol 2017;35:4042–9.

31 Brescia AA, Harrington CA, Mazurek A, et al. Factors Associated with New Persistent Opioid Usage After Lung Resection. Ann Thorac Surg 2018. Published Online First: 11 October 2018.

32 Harbaugh CM, Nalliah RP, Hu HM, Englesbe MJ, Waljee JF, Brummett CM. Persistent Opioid Use After Wisdom Tooth Extraction. JAMA 2018;320:504.

33 Delgado MK, Huang Y, Meisel Z, et al. National Variation in Opioid Prescribing and Risk of Prolonged Use for Opioid-Naive Patients Treated in the Emergency Department for Ankle Sprains. Ann Emerg Med 2018;:1–12.

34 Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ 2014;348:g1251–g1251.

35 Jeffery MM, Hooten WM, Hess EP, et al. Opioid Prescribing for Opioid-Naive Patients in Emergency Departments and Other Settings: Characteristics of Prescriptions and Association With Long-Term Use. Ann Emerg Med 2018;71:326–336.e19.

36 Von Korff M, Korff M Von, Saunders K, et al. De facto long-term opioid therapy for noncancer pain. Clin J Pain 2008;24:521–7.

37 Thiels CA, Anderson DS, Ubl DS, et al. Wide Variation and Overprescription of Opioids After Elective Surgery. Ann Surg 2017;266(4):564-573.

Page 26 of 59


BMJ

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38 Larach DB, Waljee JF, Hu H-M, et al. Patterns of Initial Opioid Prescribing to Opioid-Naive Patients. Ann Surg 2018. Published Online First: Jul 24 2018.

39 Salm-Reifferscheidt L. Tramadol: Africa’s opioid crisis. Lancet 2018 May 19;391(10134):1982-1983.

40 Bassiony MM, Abdelghani M, Salah El-Deen GM, Hassan MS, El-Gohari H, Youssef UM. Opioid Use Disorders Attributed to Tramadol Among Egyptian University Students. J Addict Med 2018;12:150–5.

41 Moulis F, Rousseau V, Abadie D, et al. Serious adverse drug reactions with tramadol reported to the French pharmacovigilance database between 2011 and 2015. Therapie 2017;72:615–24.

42 Zhang H, Liu Z. The investigation of tramadol dependence with no history of substance abuse: a cross-sectional survey of spontaneously reported cases in Guangzhou City, China. Biomed Res Int 2013;2013:283425.

43 Gold LS, Strassels SA, Hansen RN. Health Care Costs and Utilization in Patients Receiving Prescriptions for Long-acting Opioids for Acute Postsurgical Pain. Clin J Pain 2016;32:747–54.

44 Thorson D, Biewen P, Bonte B, et al. Acute Pain Assessment and Opioid Prescribing Protocol. Institute for Clinical Systems Improvement (ICSI). Published January 2014. Available at https://crh.arizona.edu/sites/default/files/u35/Opioids.pdf

45 Musclow SL, Bowers T, Vo H, Glube M, Nguyen T. Long-acting morphine following hip or knee replacement: a randomized, double-blind, placebo-controlled trial. Pain Res Manag;17:83–8.

46 Bus DM. The CBHSQ Report: Emergency Department Visits for Adverse Reactions Involving the Pain Medication Tramadol. Subst. Abus. Ment. Heal. Serv. Adm. Cent. Behav. Heal. Stat. Qual. 2015;:Rockville, MD.https://www.samhsa.gov/data/sites/default/files/report_1965/ShortReport-1965.html

47 Fournier J-P, Azoulay L, Yin H, Montastruc JL, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med 2015;175:186–93.

48 Kirchheiner J, Keulen J-THA, Bauer S, et al. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol 2008;28:78–83.

49 Raffa RB, Buschmann H, Christoph T, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother 2012;13:1437–49.

Page 27 of 59


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50 Minami K, Sudo Y, Miyano K, Murphy RS, Uezono Y. µ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1). J Anesth 2015;29:475–9.

51 Asari Y, Ikeda Y, Tateno A, Okubo Y, Iijima T, Suzuki H. Acute tramadol enhances brain activity associated with reward anticipation in the nucleus accumbens. Psychopharmacology (Berl) 2018;235:2631–42.

52 Park SH, Wackernah RC, Stimmel GL. Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants? J Pharm Pract 2014;27:71–8.

53 Hooten WM, Brummett CM, Sullivan MD, et al. A Conceptual Framework for Understanding Unintended Prolonged Opioid Use. Mayo Clin Proc 2017;92:1822–30.

54 Hooten WM, St Sauver JL, McGree ME, Jacobson DJ3, Warner DO. Incidence and Risk Factors for Progression From Short-term to Episodic or Long-term Opioid Prescribing: A Population-Based Study. Mayo Clin Proc 2015;90:850–6.

55 Jiang X, Orton M, Feng R, et al. Chronic Opioid Usage in Surgical Patients in a Large Academic Center. Ann Surg 2017;265(4):722-27.

56 Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and Risk Factors for Chronic Opioid Use Among Opioid-Naive Patients in the Postoperative Period. JAMA Intern Med 2016;176(9):1286-93.

57 Cepeda MS, Fife D, Denarié M, Bradford D, Roy S, Yuan Y. Quantification of missing prescriptions in commercial claims databases: results of a cohort study. Pharmacoepidemiol Drug Saf 2017;26:386–92.

58 Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth 1997;9:582–5

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TABLES

Table 1. Cohort characteristics of all patients with at least 180 days of follow-up; cohort characteristics for all patients with at least 30

days of uncensored follow-up provided in Supplemental Materials.

All patients No opioid fill Tramadol onlyOther short-

acting

Tramadol + other short-

actingAny long-

acting

Percent N Percent N Percent N Percent N Percent N Percent N

Category Total 100.0 444,764 19.5 86,880 3.0 13,519 74.9 333,289 1.2 5,457 1.3 5,619

Sex

Female 49.0 217,855 52.1 45,256 62.1 8,389 47.7 158,921 53.4 2,914 42.3 2,375

Age

18-24 3.7 16,282 3.1 2,695 2.1 281 3.9 13,007 1.9 105 3.5 194

25-34 7.0 30,914 4.9 4,237 5.5 741 7.7 25,553 3.4 184 3.5 199

35-44 13.0 57,936 9.7 8,437 9.8 1,329 14.2 47,371 6.8 369 7.7 430

45-54 21.5 95,802 18.6 16,180 17.5 2,366 22.6 75,207 15.4 839 21.5 1,210

55-64 25.4 112,956 23.8 20,690 24.8 3,349 25.6 85,400 28.1 1,532 35.3 1,985

65-74 19.4 86,476 23.6 20,479 24.7 3,340 17.9 59,696 30.5 1,666 23.1 1,295

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acting


actingAny long-

acting


75+ 10.0 44,398 16.3 14,162 15.6 2,113 8.1 27,055 14.0 762 5.5 306

Race/ethnicity

White 78.3 348,275 77.5 67,365 76.4 10,325 78.4 261,329 83.1 4,533 84.1 4,723

Black 7.8 34,758 7.9 6,873 6.9 931 7.9 26,270 6.1 334 6.2 350

Hispanic 8.4 37,474 8.7 7,535 11.7 1,577 8.3 27,801 5.8 316 4.4 245

Asian 2.3 10,043 2.3 2,030 1.8 245 2.3 7,589 1.4 74 1.9 105

Unknown/Other 3.2 14,214 3.5 3,077 3.3 441 3.1 10,300 3.7 200 3.5 196

Region

New England 4.0 17,696 4.8 4,139 2.5 343 3.9 12,929 1.7 92 3.4 193

Mid Atlantic 6.6 29,330 7.3 6,378 5.5 737 6.5 21,798 4.3 235 3.2 182

East North Central 18.7 83,253 18.0 15,657 19.0 2,562 18.7 62,201 25.0 1,364 26.1 1,469

West North Central 14.7 65,309 18.3 15,921 12.6 1,706 13.7 45,658 17.4 948 19.2 1,076

South Atlantic 25.4 112,763 23.9 20,769 23.5 3,172 26.1 86,811 19.2 1,047 17.2 964

East South Central 3.9 17,369 3.7 3,193 1.9 256 4.1 13,664 2.3 127 2.3 129

West South Central 11.8 52,518 10.0 8,642 23.3 3,153 11.9 39,682 14.3 781 4.6 260

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acting


actingAny long-

acting


Mountain 9.3 41,421 8.5 7,344 8.2 1,103 9.4 31,397 11.8 642 16.6 935

Pacific/Unk/Other 5.6 25,105 5.6 4,837 3.6 487 5.8 19,149 4.1 221 7.3 411

Coverage type

Commercial 72.3 321,365 61.6 53,479 61.8 8,348 75.7 252,186 58.5 3,194 74.0 4,158

Medicare—aged 25.9 115,000 36.2 31,441 36.4 4,915 22.5 75,138 39.8 2,172 23.7 1,334

Medicare—disabled 1.9 8,399 2.3 1,960 1.9 256 1.8 5,965 1.7 91 2.3 127

Surgery

Carpal tunnel release 7.6 33,730 10.9 9,475 8.6 1,167 6.9 22,984 1.5 84 0.4 20

Knee arthroscopic minesectomy (scope)

20.3 90,064 17.5 15,229 13.8 1,869 21.5 71,764 9.5 516 12.2 686

Lap chole w/ and w/out IOC

23.7 105,346 24.5 21,264 22.7 3,068 24.2 80,598 7.0 380 0.6 36

Lap inguinal hernia repair

5.6 24,806 5.1 4,463 3.4 453 5.9 19,800 1.4 75 0.3 15

Lap low anterior resection w/o or w/out stoma

0.3 1,132 0.4 368 0.4 48 0.2 710 – – – –

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acting


actingAny long-

acting


Lap nephrectomy partial or total

0.4 1,733 0.5 429 0.5 68 0.4 1,217 – – – –

Lap prostate w/ or w/out robot

2.0 8,804 1.8 1,561 4.5 608 2.0 6,601 – – – –

Lap/Robotic hysterectomy

0.7 3,042 1.0 845 0.8 103 0.6 2,069 – – – –

Lumbar laminotomy/ laminectomy (posterior)

3.8 16,695 4.2 3,653 4.7 635 3.7 12,159 2.3 126 2.2 122

Lumpectomy w/ and w/out SLNB

3.9 17,181 5.4 4,673 6.3 846 3.5 11,593 1.0 57 0.2 12

Open Lung Lobectomy

0.2 767 0.2 153 0.2 31 0.2 553 0.2 13 0.3 17

Open inguinal hernia repair

9.7 43,052 8.5 7,345 5.4 734 10.4 34,779 3.1 171 0.4 23

Parathyroidectomy 1.3 5,872 2.9 2,532 1.2 156 1.0 3,176 – – – –

Partial colectomy w/ or w/out stoma

0.4 1,694 0.7 636 0.4 53 0.3 1,000 – – – –

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acting


actingAny long-

acting


Rotator Cuff Surgery 5.1 22,587 3.4 2,920 2.0 274 5.3 17,811 5.3 291 23.0 1,291

Simple Mastectomy w/out reconstruction

1.0 4,317 1.5 1,336 1.1 145 0.8 2,807 – – – –

TKA 9.1 40,250 6.5 5,621 13.2 1,786 8.4 28,061 43.6 2,379 42.8 2,403

Total hip 5.2 23,068 4.8 4,190 10.7 1,441 4.6 15,213 23.0 1,255 17.3 969

Other 0.1 624 0.2 187 0.3 34 0.1 394 – – – –

Depression comorbidity 2.8 12,349 2.7 2,331 3.4 460 2.7 9,074 4.7 255 4.1 229

Obesity 4.3 18,897 4.0 3,438 5.4 725 4.1 13,571 11.7 637 9.4 526

Diagnosis of Rheumatoid Arthritis or other collagen disorder

1.3 5,607 1.5 1,298 2.0 272 1.1 3,804 2.2 121 2.0 112

– Cell value suppressed to preserve patient deidentification; IOC: intraoperative cholangiogram; chole: cholecystectomy TKA: Total Knee Arthroplasty; w/: with; SNLB: sentinel lymph node biopsy; Lap: laparoscopic

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Table 2: Rates of unadjusted persistent opioid use (3 definitions) for patients who received short acting opioids excluding tramadol,

tramadol only, tramadol and another short acting opioids, any long-acting opioids, or no opioids at discharge. (cohort with 180 days

follow-up)

All Patients No opioid fill Tramadol onlyOther Short

Acting


actingAny long-

acting% N % N % N % N % N % N

Additional opioid use after surgery*

7.07% 31,431 4.43% 3,849 7.89% 1,066 7.62% 25,388 9.95% 543 10.41% 585

Persistent Opioid use after surgery**

1.00% 4,457 0.36% 314 1.44% 194 1.07% 3,559 2.73% 149 4.29% 241

CONSORT definition of chronic opioid use***

0.46% 2,027 0.20% 175 0.58% 78 0.47% 1,573 1.30% 71 2.31% 130

*Additional Opioid Use is defined as at least one opioid fill 90 to 180 days after surgery. **Persistent Opioid Use is defined as any span of opioid use starting in the 180 days after surgery and lasting at least 90 days. ***CONSORT Definition is defined as an opioid use episode starting in the 180 days after surgery that spans at least 90 days and including either 10 or more opioid fills or 120 or more days’ supply of opioids.

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35

Table 3: Rates of unadjusted persistent opioid use (3 definitions) by amount of opioids prescribed at discharge.

No opioid fillN=86,880

1 to 199 MME

N=116,813

200 to 299 MME

N=90,393

300 to 399 MME

N=69,301

400 to 499 MME

N=36,156500+ MMEN=45,221

% N % N % N % N % N % NAdditional opioid use after surgery

4.43 3,849 6.79† 7,930 7.00 6,326 7.79† 5,397 8.89† 3,216 10.42† 4,713

Persistent Opioid use after surgery

0.36 314 0.49† 570 0.68† 618 1.21† 837 1.90† 688 3.16† 1,430

CONSORT definition of chronic opioid use

0.20 175 0.27† 317 0.34† 303 0.55† 379 0.74† 266 1.30† 587

*Additional Opioid Use is defined as at least one opioid fill 90 to 180 days after surgery. **Persistent Opioid Use is defined as any span of opioid use starting in the 180 days after surgery and lasting at least 90 days. ***CONSORT Definition is defined as an opioid use episode starting in the 180 days after surgery that spans at least 90 days and including either 10 or more opioid fills or 120 or more days’ supply of opioids.†Statistically significantly different risk than previous dose group (p<0.05; Bonferroni corrected)

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36

Table 4: Adjusted† rate ratios of persistent opioid use (3 definitions) in patients who received tramadol only, tramadol and another

short acting opioid, or any long-acting opioids (reference group: short acting opioids excluding tramadol).

Additional Opioid Use after Surgery*

Persistent Opioid Use After Surgery**

CONSORT Definition of

Opioid Dependence***

Opioid TypeOther Short-Acting ref ref ref

Tramadol Only 1.06 (1.00 to 1.13)P=0.049

1.47 (1.25 to 1.69) P<0.001

1.41 (1.08 to 1.75) P=0.013

Tramadol + Short Acting 1.05 (0.96 to 1.14) P=0.261

1.04 (0.86 to 1.21) P=0.685

1.40 (1.05 to 1.74) P=0.022

Any Long-Acting 0.95 (0.87 to 1.03) P=0.218

1.18 (1.02 to 1.35) P=0.029

1.69 (1.36 to 2.02) P<0.001

† Rate ratios calculated as ratio of predictive margins after logistic regression including the following covariates: year, surgery, female, beneficiary type, race/ethnicity, Census division, age category, categorical measurement of MME at discharge, and flags for each of the Elixhauser comorbidities; see Supplemental Materials for full regression outputP-values from hypothesis test that rate ratio does not equal 1

*Additional Opioid Use is defined as at least one opioid fill 90 to 180 days after surgery. **Persistent Opioid Use is defined as any span of opioid use starting in the 180 days after surgery and lasting at least 90 days. ***CONSORT Definition is defined as an opioid use episode starting in the 180 days after surgery that spans at least 90 days and including either 10 or more opioid fills or 120 or more days’ supply of opioids.

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37

FIGURE LEGENDS

Figure 1.Discharge opioid prescriptions after surgery by type of opioid.

Figure 2. Total amount of opioids prescribed at discharge after surgery in oral Morphine

Milligram Equivalents (MME) for each procedure.

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Confidential: For Review Only0

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Confidential: For Review OnlySupplemental Materials

Supplemental Figure 1: Cohort flow chart.

Person-surgery days January 1,2009 to June 30, 2018:

3,856,110

• Did not have both medical and pharmacycoverage 6 months before and 3 monthsafter surgery: 2,155,939

• Filled prescription for buprenorphine,methadone, or naloxone in the 90 daysafter surgery: 635

• Had prescription opioids available in the 6months prior to surgery: 754,920

• Admitted as an inpatient more than 1 dayprior to surgery: 38,590

• Total LOS exceeded 7 days: 11,386• Not discharged home: 38,976• Under age 18: 84,849• Multiple included procedures on the

same day: 5,339• Other unrelated procedures on the same

day: 51,708• Hospice: 582• Received a non-cancer surgery, but had

cancer in the prior 6 months: 76,539• Admitted to a skilled nursing facility

within 1 day of discharge: 12,008• More than one eligible surgery (dropped

all after the first observed): 36,585• Less than 30 days of uncensored follow-

up time (e.g., had another surgicalprocedure): 63,736

Eligible for analysis of dischargeprescription size:

524,318

Eligible for persistent opioid useanalysis:444,764

Less than 180 days of uncensored follow-uptime (e.g., had another surgical procedure,

discontinued insurance coverage):79,554

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Confidential: For Review OnlySupplemental Table 2: Comparison of OLDW and US under 65 privately insured population, 2015

US privately insuredOLDW

commercial Race/ethnicity

White 66% 70%Asian 7% 6%Hispanic 15% 14%Black 11% 11%American Indian 1% N/A

Female 50% 49%Age

0 to 17 24% 22%18 to 24 11% 11%25 to 34 16% 18%35 to 44 15% 17%45 to 54 17% 18%55 to 59 9% 8%60 to 64 7% 6%

Census DivisionNew England 5% 3%Mid Atlantic 13% 7%East North Central 15% 16%West North Central 6% 11%South Atlantic 20% 22%East South Central 6% 4%West South Central 12% 18%Mountain 7% 10%Pacific 16% 9%

OLDW commercial includes people with both medical and prescription coverage; excludes people with unknown race/ethnicity, year of birth, or sex

Source: CPS ASEC (Current Population Survey—Annual Social and Economic Supplement), data for 2015, using https://www.census.gov/cps/data/cpstablecreator.html; Includes only people listed with a single race. Hispanic includes people of any single race who indicated they were of Hispanic origin

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https://www.census.gov/cps/data/cpstablecreator.html

Confidential: For Review OnlySupplemental Table 3: Comparison of OLDW and US Medicare Advantage population, 2015

US Medicare Advantage

OLDW Medicare Advantage

Race/ethnicityWhite 76% 76%Black 11% 12%Hispanic 8% 9%Other 6% 3%

Female 55% 57%Census Division

New England 3% 6%Mid Atlantic 15% 15%East North Central 15% 18%West North Central 6% 12%South Atlantic 20% 31%East South Central 6% 5%West South Central 10% 4%Mountain 7% 5%Pacific 18% 3%

OLDW Medicare Advantage includes people with both medical and prescription coverage; excludes people with unknown race/ethnicity or sexUS Medicare Advantage source: Kaiser Family Foundation, 2015 data https://www.kff.org/state-category/medicare/medicare-advantage/

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Supplemental Table 4: Cohort characteristics for all patients with at least 30 days of uncensored follow-up

All patients No opioid fill Tramadol only Other short-acting


acting Any long-acting

col% N col% N col% N col% Ncol% N

col% N

Total (Row% / N) 100 524,318 19.7 103,117 3.1 16,059 74.7 391,922 1.2 6,483 1.3 6,737

SexFemale 49.4 258,956 52.4 54,017 62.4 10,014 48.1 188,585 53.4 3,459 42.8 2,881

Age18-24 3.5 18,582 3.0 3,121 2.0 323 3.8 14,800 1.9 121 3.2 21725-34 7.0 36,426 4.9 5,055 5.6 893 7.7 30,028 3.3 213 3.5 23735-44 12.8 67,230 9.6 9,919 9.7 1,549 14.0 54,807 6.7 434 7.7 52145-54 21.4 112,326 18.5 19,039 17.6 2,829 22.5 88,025 15.5 1,006 21.2 1,42755-64 25.7 134,826 24.0 24,718 25.3 4,063 26.0 101,756 28.9 1,873 35.9 2,41665-74 19.7 103,177 23.9 24,602 24.6 3,943 18.1 71,101 30.5 1,975 23.1 1,55675+ 9.9 51,751 16.2 16,663 15.3 2,459 8.0 31,405 13.3 861 5.4 363

Race/ethnicityWhite 78.3 410,567 77.6 79,975 76.7 12,315 78.4 307,267 82.7 5,359 83.9 5,651Black 7.9 41,344 7.9 8,185 6.9 1,103 8.0 31,222 6.3 406 6.4 428Hispanic 8.4 43,983 8.6 8,893 11.4 1,836 8.3 32,558 6.2 400 4.4 296Asian 2.3 11,799 2.4 2,426 1.8 287 2.3 8,875 1.3 85 1.9 126Unknown/Other 3.2 16,625 3.5 3,638 3.2 518 3.1 12,000 3.6 233 3.5 236

RegionNew England 3.9 20,638 4.7 4,843 2.5 402 3.8 15,047 1.6 105 3.6 241Mid Atlantic 6.5 34,304 7.4 7,586 5.3 853 6.5 25,360 4.4 285 3.3 220

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col% N

East North Central 18.5 97,078 17.7 18,206 18.7 3,006 18.5 72,542 24.8 1,606 25.5 1,718West North Central 14.8 77,441 18.8 19,384 12.7 2,039 13.7 53,619 17.5 1,136 18.8 1,263South Atlantic 25.4 133,346 23.9 24,637 23.4 3,761 26.2 102,570 18.8 1,219 17.2 1,159East South Central 4.0 20,864 3.7 3,816 2.0 327 4.2 16,413 2.4 153 2.3 155West South Central 12.0 62,728 10.1 10,384 23.6 3,797 12.1 47,272 14.9 968 4.6 307Mountain 9.3 48,676 8.4 8,648 8.0 1,291 9.4 36,807 11.6 751 17.5 1,179Pacific/Unk/Other 5.6 29,243 5.4 5,613 3.6 583 5.7 22,292 4.0 260 7.4 495

Coverage typeCommercial 72.5 380,125 61.8 63,735 62.6 10,047 75.9 297,419 59.9 3,886 74.8 5,038Medicare—aged 25.6 134,194 35.9 37,048 35.5 5,705 22.3 87,411 38.3 2,484 23.0 1,546Medicare—disabled 1.9 9,999 2.3 2,334 1.9 307 1.8 7,092 1.7 113 2.3 153

SurgeryCarpal tunnel release

8.1 42,264 11.3 11,631 9.2 1,480 7.4 29,023 1.7 108 0.3 22

Knee arthroscopic minesectomy (scope)

19.9 104,125 17.1 17,661 13.7 2,194 21.2 82,879 9.2 595 11.8 796

Lap chole w/ and w/out IOC

23.5 123,262 24.4 25,182 22.7 3,650 24.0 93,928 7.1 458 0.7 44

Lap inguinal hernia repair

5.4 28,401 4.9 5,075 3.3 528 5.8 22,701 1.3 81 0.2 16

Lap low anterior resection w/o or w/out stoma

0.3 1,525 0.5 476 0.4 70 0.3 972

Lap nephrectomy partial or total

0.4 2,166 0.5 530 0.5 84 0.4 1,532

Lap prostate w/ or w/out robot

1.9 10,042 1.7 1,798 4.3 696 1.9 7,509

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col% N

Lap/Robotic hysterectomy

0.7 3,642 1.0 1,010 0.7 115 0.6 2,489

Lumbar laminotomy/ laminectomy (posterior)

3.8 19,916 4.3 4,452 4.6 742 3.7 14,425 2.3 150 2.2 147

Lumpectomy w/ and w/out SLNB

4.0 20,958 5.5 5,680 6.3 1,003 3.6 14,191 1.1 71 0.2 13

Open Lung Lobectomy

0.2 983 0.2 198 0.2 38 0.2 707 0.3 17 0.3 23

Open inguinal hernia repair

9.4 49,209 8.3 8,511 5.3 851 10.1 39,626 3.0 192 0.4 29

Parathyroidectomy 1.3 6,817 2.8 2,929 1.1 177 0.9 3,702Partial colectomy w/ or w/out stoma

0.4 2,250 0.8 835 0.4 62 0.3 1,344

Rotator Cuff Surgery 5.0 26,185 3.3 3,407 2.0 323 5.3 20,634 5.2 336 22.0 1,485Simple Mastectomy w/out reconstruction

1.1 5,595 1.6 1,658 1.2 197 0.9 3,699 0.4 28 0.2 13

TKA 9.4 49,064 6.7 6,894 13.3 2,130 8.7 34,176 44.4 2,876 44.4 2,988Total hip 5.2 27,104 4.8 4,949 10.4 1,673 4.6 17,873 22.6 1,466 17.0 1,143Other 0.2 810 0.2 241 0.3 46 0.1 512

Depression comorbidity 2.9 15,106 2.8 2,836 3.6 576 2.8 11,099 4.7 305 4.3 290Obesity 4.4 22,918 4.1 4,203 5.4 867 4.2 16,423 11.9 773 9.7 652Diagnosis of Rheumatoid Arthritis or other collagen disorder

1.3 6,844 1.5 1,591 2.0 322 1.2 4,641 2.3 148 2.1 142

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Confidential: For Review OnlySupplemental Table 5: Complete regression results

CONSORT chronic opioid

dependencePersistent opioid use after surgery

Additional opioid use after surgery

Post-surgery opioid categoryAny long-acting opioid 1.709 1.191 0.945

[1.397,2.090] [1.029,1.377] [0.861,1.036]

Tramadol only 1.424 1.499 1.071[1.120,1.811] [1.283,1.751] [1.002,1.144]

Tramadol plus another short-acting opioid 1.408 1.038 1.057

[1.094,1.813] [0.870,1.238] [0.962,1.162]

Non-tramadol short-acting opioid only Ref Ref Ref

YearYR=2009 Ref Ref Ref

YR=2010 0.985 0.952 0.934[0.843,1.152] [0.850,1.067] [0.893,0.977]

YR=2011 0.615 0.738 0.626[0.512,0.739] [0.651,0.837] [0.595,0.658]

YR=2012 0.605 0.665 0.621[0.504,0.726] [0.585,0.755] [0.590,0.653]

YR=2013 0.604 0.634 0.586[0.503,0.725] [0.557,0.721] [0.557,0.617]

YR=2014 0.509 0.638 0.532[0.418,0.620] [0.560,0.728] [0.504,0.562]

YR=2015 0.415 0.496 0.493[0.338,0.509] [0.433,0.568] [0.467,0.520]

YR=2016 0.365 0.43 0.466[0.299,0.446] [0.376,0.492] [0.442,0.491]

YR=2017 0.273 0.357 0.524[0.224,0.332] [0.314,0.406] [0.500,0.550]

SurgeryCarpal tunnel release Ref Ref Ref

Knee arthroscopic 0.489 0.602 0.689

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Confidential: For Review OnlyCONSORT

chronic opioid dependence

Persistent opioid use after surgery


minesectomy (scope)[0.382,0.626] [0.504,0.718] [0.653,0.727]

Lap chole w/ and w/out IOC 0.504 0.456 0.639

[0.399,0.637] [0.382,0.545] [0.607,0.674]Lap inguinal hernia repair 0.444 0.347 0.535

[0.301,0.653] [0.251,0.480] [0.494,0.581]Lap low anterior resection w/o or w/out stoma 1.953 2.493 1.028

[0.950,4.014] [1.521,4.085] [0.810,1.305]Lap nephrectomy partial or total 1.56 1.423 0.723

[0.829,2.938] [0.868,2.332] [0.586,0.890]Lap prostate w/ or w/out robot 0.338 0.413 0.476

[0.189,0.605] [0.275,0.620] [0.423,0.536]Lap/Robotic hysterectomy 0.895 1.026 0.813

[0.451,1.778] [0.644,1.634] [0.694,0.954]Lumbar laminotomy/laminectomy (posterior) 2.143 2.398 1.032

[1.644,2.793] [1.980,2.904] [0.957,1.112]Lumpectomy w/ and w/out SLNB 0.75 0.802 0.887

[0.523,1.074] [0.619,1.038] [0.822,0.956]Open Lung Lobectomy 3.348 3.7 1.109

[1.979,5.665] [2.506,5.462] [0.878,1.401]Open inguinal hernia repair 0.535 0.522 0.557

[0.399,0.718] [0.417,0.653] [0.521,0.595]Parathyroidectomy 0.649 0.629 0.649

[0.340,1.241] [0.388,1.019] [0.563,0.748]Partial colectomy w/ or w/out stoma 2.199 2.701 1.094

[1.267,3.819] [1.843,3.958] [0.905,1.324]Rotator Cuff Surgery 1.084 1.992 0.926

[0.821,1.431] [1.656,2.395] [0.864,0.993]Simple Mastectomy w/out reconstruction 1.448 1.759 1.21

[0.913,2.296] [1.285,2.408] [1.076,1.360]TKA 1.448 1.759 1.21

[0.913,2.296] [1.285,2.408] [1.076,1.360]

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Total hip 0.819 1.129 0.663[0.607,1.104] [0.922,1.382] [0.615,0.715]

VATS Wedge 0.819 1.129 0.663[0.607,1.104] [0.922,1.382] [0.615,0.715]

Whipple, open 0.886 0.888[0.126,6.226] [0.446,1.766]

Female 1.067 1.186 1.22[0.960,1.186] [1.106,1.272] [1.185,1.255]

Insurance groupCommercial Ref Ref Ref

Aged Medicare 1.092 1.132 0.96[0.845,1.413] [0.957,1.339] [0.895,1.030]

Disabled Medicare 3.426 2.733 1.879[2.799,4.194] [2.357,3.170] [1.743,2.025]

Race/EthnicityWhite Ref Ref Ref

Black 1.155 1.456 1.247[0.986,1.353] [1.316,1.611] [1.195,1.302]

Hispanic 0.77 1.072 0.982[0.623,0.951] [0.943,1.218] [0.936,1.030]

Asian 0.873 0.946 0.797[0.605,1.259] [0.738,1.212] [0.723,0.880]

Unk/other 0.873 0.946 0.797[0.605,1.259] [0.738,1.212] [0.723,0.880]

Census DivisionNew England Ref Ref Ref

Mid Atlantic 1.116 1.03 0.943[0.752,1.657] [0.797,1.332] [0.859,1.035]

East North Central 1.566 1.495 1.292[1.125,2.180] [1.208,1.849] [1.196,1.397]

West North Central 1.538 1.279 1.239[1.100,2.150] [1.028,1.591] [1.144,1.342]

South Atlantic 1.828 1.576 1.376[1.320,2.530] [1.278,1.943] [1.275,1.485]

East South Central 1.909 1.829 1.619[1.307,2.787] [1.429,2.342] [1.476,1.776]

West South Central 1.869 1.873 1.672

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[1.325,2.637] [1.503,2.335] [1.544,1.812]Mountain 1.576 1.399 1.352

[1.113,2.230] [1.117,1.752] [1.244,1.469]Pacific 1.765 1.381 1.195

[1.214,2.566] [1.076,1.771] [1.089,1.310]Unk/Other 5.109 2.955 1.685

[2.184,11.95] [1.484,5.886] [1.233,2.303]Age group

18-24 Ref Ref Ref

25-34 5.684 5.982 1.101[2.285,14.14] [3.033,11.80] [1.005,1.206]

35-44 6.648 6.987 1.155[2.727,16.21] [3.598,13.57] [1.062,1.256]

45-54 9.187 9.458 1.277[3.798,22.23] [4.897,18.27] [1.178,1.384]

55-64 7.425 8.468 1.271[3.065,17.99] [4.382,16.37] [1.172,1.378]

65-74 5.976 6.707 1.292[2.399,14.88] [3.414,13.17] [1.168,1.430]

75-84 4.416 5.26 1.169[1.733,11.25] [2.647,10.45] [1.043,1.310]

85+ 5.242 5.584 1.024[1.535,17.90] [2.376,13.12] [0.820,1.280]

Discharge opioid prescription volume

1-199 MME 1 1 1[1,1] [1,1] [1,1]

200-299 MME 1.064 1.147 1.027[0.903,1.255] [1.018,1.292] [0.991,1.064]

300-399 MME 1.304 1.386 1.056[1.101,1.544] [1.229,1.562] [1.016,1.099]

400-499 MME 1.32 1.562 1.099[1.088,1.603] [1.369,1.783] [1.047,1.153]

500+ MME 1.588 1.876 1.196[1.309,1.926] [1.648,2.136] [1.138,1.257]

Elixhauser comorbiditiesCHF 0.731 0.912 1.214

[0.477,1.122] [0.698,1.191] [1.087,1.355]ARRHYTHMIA 1.005 0.987 1.07

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[0.810,1.248] [0.855,1.140] [1.003,1.141]VALVULAR 0.969 0.96 0.948

[0.662,1.420] [0.744,1.239] [0.845,1.065]PULM_CIRC 1.596 1.277 1.236

[0.959,2.653] [0.876,1.861] [1.025,1.489]PERIPH_VASC 1.645 1.333 1.266

[1.151,2.349] [1.029,1.726] [1.124,1.426]HTN_UNCOMP 1.132 1.181 1.135

[1.008,1.270] [1.093,1.275] [1.098,1.172]HTN_COMP 1.305 1.103 1.004

[0.917,1.857] [0.868,1.402] [0.894,1.127]OTH_NEURO 1.45 1.302 1.093

[0.999,2.106] [0.991,1.711] [0.960,1.244]CHRON_PULM 1.527 1.534 1.308

[1.297,1.799] [1.372,1.714] [1.238,1.382]PEP_ULCER 2.741 2.573 1.292

[1.313,5.719] [1.502,4.408] [0.965,1.728]DM_WO_CC 1.237 1.283 1.229

[1.070,1.430] [1.166,1.412] [1.176,1.285]DM_W_CC 1.152 1.05 1.156

[0.854,1.552] [0.862,1.279] [1.058,1.262]PARALYSIS 0.963 1.13 1.05

[0.316,2.933] [0.528,2.418] [0.733,1.504]RENAL 0.816 1.008 1.077

[0.550,1.213] [0.786,1.292] [0.963,1.205]LIVER 1.525 1.606 1.118

[1.084,2.144] [1.258,2.050] [1.010,1.239]RHEUM_ARTH_COLL 1.168 1.228 1.368

[0.858,1.589] [1.003,1.503] [1.246,1.503]HYPOTHYROID 1.004 1.01 1.028

[0.838,1.203] [0.897,1.137] [0.972,1.087]COAGULOPATHY 1.648 1.245 1.2

[1.133,2.399] [0.935,1.657] [1.037,1.388]OBESITY 1.047 1.076 1.116

[0.881,1.244] [0.961,1.205] [1.056,1.181]FLUID_ELECTROLYTE 1.326 1.301 1.077

[1.055,1.667] [1.114,1.520] [0.995,1.166]BLOOD_LOSS_ANEMIA 1.255 1.111 1.207

[0.703,2.240] [0.738,1.672] [0.972,1.498]DEFICIENCY_ANEMIA 1.43 1.459 1.156

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[0.957,2.135] [1.110,1.917] [1.007,1.327]ALCOHOL 1.705 1.831 1.477

[1.034,2.814] [1.275,2.631] [1.227,1.779]DRUG_ABUSE 3.442 2.118 1.47

[1.918,6.178] [1.264,3.550] [1.110,1.947]PSYCHOSIS 0.792 0.67 0.848

[0.316,1.985] [0.321,1.400] [0.626,1.149]DEPRESSION 1.868 1.526 1.41

[1.560,2.236] [1.337,1.742] [1.322,1.503]N 357,794 357,884 357,884

Exponentiated coefficients; 95% confidence intervals in brackets

Anesthesia procedures: All anesthesia CPT codes except codes between 99141 and 99157

(procedural sedation codes)

Included opioids: buprenorphine, butorphanol, codeine, dihydrocodeine, fentanyl, hydrocodone,

hydromorphone, levomethadyl, levorphanol, meperidine, methadone, morphine, opium,

oxycodone, oxymorphone, pentazocine, tapentadol, tramadol.

Excluded procedures: Includes procedure codes observed on the same date as one of our

surgeries and determined to be a separate unrelated procedure beyond the scope of the primary

operation. Excluded CPT codes include:

1. Carpal tunnel release: 10060, 11010, 11011, 11012, 11043, 11044, 11308, 11311, 11312, 11313, 11400, 11403, 11421, 11422, 11423, 11600, 11602, 11621, 11622, 11624, 11626, 11719, 11740, 11755, 11760, 11762, 11765, 11900, 11960, 12001, 12004, 12005, 12006, 12011, 12013, 12014, 12020, 12032, 12044, 12046, 12052, 13121, 13122, 13131, 14020, 14060, 14350, 15002, 15003, 15004, 15100, 15120, 15130, 15170, 15220, 15221, 15240, 15274, 15430, 15574, 15650, 15736, 15750, 15756, 15821, 15847, 15851, 17000, 17004, 17110, 17272, 17311, 17312, 17999, 19316, 19350, 19357, 19370, 20103, 20527, 20604, 20606, 20650, 20680, 20692, 20693, 20694, 20696, 20805, 20824, 20827, 20900, 20930, 20931, 20936, 20937, 20999, 21011, 21337, 21390, 22220, 22522, 22551, 22552, 22558, 22585, 22610, 22830, 22845, 22846, 22849, 22850, 22851, 22855, 22856, 22858, 23000, 23020, 23076, 23120, 23184, 23190, 23412, 23415, 23430, 23440, 23466, 23472,

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Confidential: For Review Only23515, 23615, 23630, 23700, 23935, 24000, 24006, 24065, 24066, 24073, 24076, 24079, 24100, 24101, 24102, 24110, 24140, 24147, 24149, 24155, 24201, 24300, 24305, 24310, 24330, 24340, 24342, 24343, 24344, 24345, 24346, 24357, 24360, 24363, 24366, 24400, 24420, 24435, 24495, 24505, 24515, 24535, 24538, 24545, 24546, 24579, 24586, 24600, 24605, 24615, 24620, 24650, 24655, 24665, 24666, 24670, 24999, 25001, 25020, 25023, 25024, 25025, 25028, 25031, 25040, 25065, 25066, 25073, 25075, 25077, 25078, 25085, 25100, 25101, 25105, 25107, 25109, 25110, 25111, 25112, 25116, 25118, 25119, 25120, 25126, 25135, 25136, 25145, 25150, 25151, 25170, 25215, 25240, 25250, 25259, 25260, 25263, 25265, 25270, 25272, 25274, 25275, 25280, 25290, 25295, 25300, 25301, 25310, 25312, 25315, 25332, 25337, 25350, 25355, 25360, 25390, 25391, 25394, 25400, 25405, 25420, 25425, 25430, 25431, 25440, 25441, 25442, 25445, 25446, 25447, 25449, 25490, 25515, 25525, 25526, 25535, 25545, 25565, 25574, 25600, 25606, 25607, 25609, 25622, 25624, 25628, 25630, 25635, 25645, 25650, 25651, 25652, 25660, 25670, 25671, 25675, 25676, 25680, 25685, 25690, 25695, 25805, 25810, 25820, 25825, 25830, 25999, 26010, 26011, 26020, 26025, 26030, 26035, 26037, 26040, 26045, 26070, 26075, 26080, 26100, 26110, 26111, 26113, 26117, 26118, 26123, 26125, 26130, 26135, 26140, 26145, 26170, 26180, 26185, 26230, 26236, 26260, 26320, 26340, 26341, 26350, 26352, 26356, 26357, 26358, 26370, 26372, 26373, 26390, 26412, 26415, 26418, 26420, 26428, 26433, 26440, 26442, 26445, 26449, 26450, 26455, 26460, 26471, 26474, 26476, 26477, 26478, 26479, 26483, 26485, 26489, 26490, 26492, 26494, 26496, 26497, 26498, 26499, 26500, 26502, 26508, 26510, 26516, 26518, 26520, 26525, 26530, 26531, 26535, 26536, 26540, 26541, 26542, 26546, 26548, 26550, 26565, 26567, 26591, 26593, 26600, 26605, 26608, 26615, 26645, 26650, 26665, 26670, 26675, 26676, 26685, 26686, 26706, 26715, 26727, 26735, 26746, 26750, 26756, 26770, 26775, 26776, 26785, 26820, 26841, 26844, 26850, 26852, 26860, 26861, 26910, 26952, 27193, 27228, 27245, 27250, 27266, 27360, 27427, 27506, 27524, 27535, 27600, 27601, 27602, 27632, 27680, 27691, 27696, 27769, 27780, 27786, 27814, 27842, 27880, 28008, 28035, 28041, 28045, 28055, 28060, 28080, 28086, 28120, 28200, 28234, 28270, 28272, 28289, 28299, 28313, 28470, 28475, 28496, 28510, 28525, 28605, 28725, 28750, 28825, 29806, 29828, 29873, 29900, 29901, 29999, 30130, 30901, 34111, 34471, 35045, 35207, 35261, 35458, 35523, 37618, 37765, 38500, 42415, 43999, 44721, 49572, 49587, 50020, 54450, 56740, 57240, 58563, 58670, 61000, 61548, 62368, 62370, 63001, 63015, 63020, 63045, 63046, 63048, 63057, 63075, 63081, 63082, 63685, 64510, 64605, 64704, 64712, 64716, 64719, 64722, 64726, 64782, 64783, 64787, 64790, 64792, 64818, 64820, 64821, 64822, 64823, 64831, 64832, 64834, 64835, 64836, 64837, 64856, 64859, 64874, 64890, 64891, 64893, 64895, 64896, 64897, 64905, 66982, 66984, 67875, 67900, 67950, 69631, 97597, 97810, 99490, G0127,

2. Knee arthroscopic minesectomy (scope): 0263T, 10160, 10180, 11401, 11422, 11750, 13120, 14020, 14060, 15040, 15300, 15823, 15833, 15850, 15852, 17004, 19101, 19380,

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Confidential: For Review Only20225, 20526, 20606, 20611, 20694, 20920, 20922, 21030, 21340, 21899, 22524, 23076, 23105, 23120, 23130, 23420, 23470, 23472, 23515, 23700, 23931, 24075, 24105, 24341, 24342, 24350, 24358, 24359, 24635, 25000, 25076, 25118, 25130, 25210, 25230, 25310, 25320, 25447, 25608, 25628, 25825, 26010, 26116, 26121, 26145, 26160, 26200, 26340, 26341, 26445, 26525, 26540, 26608, 26727, 26755, 26862, 26863, 26951, 27065, 27097, 27137, 27165, 27170, 27244, 27275, 27299, 27303, 27306, 27323, 27326, 27327, 27329, 27331, 27332, 27333, 27334, 27335, 27347, 27350, 27356, 27364, 27372, 27381, 27386, 27390, 27396, 27400, 27403, 27405, 27407, 27409, 27412, 27415, 27416, 27420, 27422, 27424, 27429, 27430, 27435, 27438, 27440, 27441, 27442, 27445, 27446, 27448, 27495, 27497, 27498, 27503, 27509, 27510, 27511, 27513, 27514, 27520, 27530, 27532, 27535, 27540, 27557, 27558, 27566, 27600, 27603, 27605, 27606, 27613, 27614, 27620, 27632, 27634, 27635, 27638, 27647, 27650, 27652, 27658, 27659, 27664, 27675, 27676, 27685, 27695, 27696, 27700, 27704, 27707, 27720, 27724, 27734, 27745, 27756, 27766, 27792, 27832, 27870, 27881, 27882, 27893, 27894, 27899, 28002, 28022, 28024, 28039, 28043, 28045, 28046, 28050, 28060, 28072, 28092, 28100, 28104, 28107, 28112, 28113, 28118, 28119, 28120, 28160, 28190, 28192, 28250, 28285, 28288, 28289, 28290, 28292, 28296, 28297, 28298, 28300, 28304, 28306, 28490, 28740, 28810, 28899, 29805, 29807, 29824, 29828, 29866, 29868, 29905, 30520, 30802, 30930, 36460, 37722, 37765, 38206, 38220, 38232, 38240, 40800, 42821, 49560, 49570, 53447, 56605, 57282, 57285, 58545, 58558, 62362, 64455, 64892, 64910, 66984, 95920, C5272, C5273, G0472,

3. Lap chole w/ and w/out IOC: 22902, 38570, 43280, 43644, 43752, 43775, 44204, 44205, 44238, 44979, 47001, 47379, 47490, 47564, 47579, 47605, 47999, 49020, 49080, 49329, 49565, 49572, 49585, 58660,

4. Lap inguinal hernia repair: 0249T, 0336T, 10021, 10022, 10160, 11005, 11201, 11302, 11402, 11404, 11406, 11424, 11441, 11442, 11443, 11444, 11446, 11606, 11622, 11643, 11644, 11770, 11771, 12034, 12052, 13101, 14001, 14021, 14301, 15240, 15241, 15360, 15361, 15734, 15830, 15847, 15877, 17003, 17110, 19260, 19300, 19325, 19371, 20680, 21012, 21552, 21554, 21556, 21935, 22905, 24071, 24076, 24201, 25248, 27001, 27006, 27045, 27047, 27048, 27327, 27345, 27347, 27364, 27618, 27632, 27680, 27698, 28110, 28238, 28240, 28308, 30140, 33517, 35206, 35665, 35840, 36478, 37202, 37722, 37765, 38589, 39502, 41112, 41120, 42140, 43246, 43282, 43332, 43450, 43499, 43644, 43651, 43659, 43752, 43770, 43774, 44110, 44180, 44213, 44227, 44320, 44604, 44615, 44799, 44970, 45171, 45905, 45990, 46220, 46221, 46230, 46320, 46505, 46924, 46930, 46945, 46946, 49002, 49204, 49322, 49324, 49326, 49400, 49402, 49435, 49495, 49500, 49507, 49525, 49540, 49550, 49553, 49557, 49580, 49582, 49590, 49600, 50590, 51999, 52630, 52640, 52648, 53500, 53600, 53605, 54055, 54056, 54150, 54162, 54512, 54522, 54530, 54650, 54692, 54699, 54860, 55000, 55040, 55041, 55060, 55110, 55120, 55200, 55450, 55535, 55540, 55550, 55899, 56800, 57210, 57240, 57250, 57260, 57265, 57268, 57280,

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Confidential: For Review Only57283, 57287, 57295, 57423, 57426, 58260, 58262, 58270, 58410, 58541, 58545, 58546, 58550, 58552, 58555, 58565, 58578, 58600, 58661, 58662, 58671, 58673, 58700, 58825, 58999, 62361, 64761, 64763, 64776, 65222, 69110, 92950, 97813, 97814,

5. Lap low anterior resection w/o or w/out stoma: 11008, 12013, 14302, 20926, 21011, 22902, 27339, 32505, 32506, 32556, 32900, 33967, 37617, 38129, 39560, 39599, 43775, 44005, 44110, 44120, 44145, 44146, 44188, 44202, 44203, 44212, 44345, 44602, 44620, 44650, 44660, 44661, 44701, 44799, 44950, 44955, 45111, 45114, 45136, 45171, 45172, 45395, 45397, 45399, 45400, 45800, 45805, 45910, 45915, 45990, 46220, 46710, 46744, 47000, 47122, 47371, 47399, 48000, 49010, 49021, 49203, 49204, 49321, 49322, 49323, 49327, 49557, 49999, 50220, 50230, 50541, 50785, 51500, 53660, 54060, 54700, 55875, 55899, 57106, 57107, 57260, 57305, 57426, 58350, 58353, 58541, 58542, 58544, 58548, 58554, 58611, 58720, 58953, 93460,

6. Lap nephrectomy partial or total: 15830, 23078, 32320, 32608, 34151, 34802, 34812, 34825, 34826, 35122, 35471, 35761, 36248, 37242, 38101, 38115, 38120, 39501, 43282, 43611, 43775, 44020, 44205, 44213, 44899, 47100, 47120, 47370, 47785, 47900, 49205, 49320, 49321, 49402, 50010, 50060, 50080, 50130, 50135, 50200, 50205, 50225, 50234, 50236, 50240, 50250, 50280, 50325, 50328, 50360, 50380, 50389, 50400, 50435, 50540, 50547, 50590, 50650, 50706, 50780, 50830, 51040, 51555, 51570, 52356, 52400, 52601, 53500, 53899, 54161, 55550, 57107, 57283, 58661, 58740, 58940, 58957, 60540, 62223, 88037, 93455, G0269,

7. Lap prostate w/ or w/out robot: 11626, 12045, 15115, 15275, 27045, 27049, 35840, 36246, 37211, 38542, 38700, 38765, 44137, 44150, 44238, 44310, 44603, 44800, 44955, 45562, 48999, 49000, 49323, 49325, 49326, 49400, 49402, 49585, 49606, 49651, 49659, 50393, 50432, 50525, 50544, 50605, 50800, 50815, 50820, 50860, 50940, 50947, 50948, 51050, 51101, 51520, 51530, 51555, 51575, 51590, 51595, 51596, 51597, 51800, 51820, 51980, 51992, 51999, 52649, 53020, 53215, 53400, 53410, 53431, 53440, 53449, 53899, 54057, 54405, 55600, 55650, 55810, 55812, 55815, 55840, 55842, 55845, 55865, 55876, 64581, 64590, 64910, 92950, 93454,

8. Lap/Robotic hysterectomy: 0171T, 0249T, 11042, 11056, 111, 11100, 112, 11200, 11301, 11302, 11307, 11400, 11402, 11403, 11404, 11406, 11420, 11423, 11470, 11623, 11624, 11721, 11730, 11954, 11976, 11980, 12015, 12041, 121, 13101, 14001, 14041, 14302, 15101, 15274, 15430, 15757, 15777, 15879, 17000, 17003, 19000, 19285, 19286, 19290, 19302, 19307, 19318, 19328, 19330, 19340, 19342, 19370, 20206, 20696, 20920, 22900, 22901, 23410, 24200, 27045, 27301, 28055, 28293, 28485, 28715, 33320, 35571, 35870, 36260, 36830, 37242, 37660, 38900, 38999, 43659, 43772, 43840, 44025, 44111, 44130, 44187, 44202, 44206, 44210, 44212, 44602, 44605, 44615, 44680, 44700, 44979, 45130, 45395, 45397, 45400, 45402, 45499, 45505, 45540, 45541, 45560, 45562, 45999, 46220, 46230, 46250, 46260, 46750, 46761, 46946, 46999, 47001, 47579, 49215, 49322,

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Confidential: For Review Only49323, 49324, 49329, 49402, 49406, 49418, 49421, 49425, 49560, 49566, 49570, 49587, 49610, 49651, 49905, 50020, 50386, 50390, 50392, 50405, 50549, 50600, 50660, 50700, 50722, 50900, 50945, 50948, 51010, 51020, 51040, 51525, 51535, 51565, 51585, 51725, 51840, 51841, 51845, 51865, 51900, 51990, 52500, 52700, 53200, 53210, 53230, 53265, 53275, 53430, 53460, 53500, 53502, 53661, 53665, 55980, 56420, 56440, 56442, 56501, 56515, 56625, 56630, 56631, 56700, 56740, 56820, 56821, 57000, 57010, 57023, 57061, 57065, 57130, 57230, 57250, 57265, 57267, 57270, 57284, 57287, 57288, 57289, 57296, 57308, 57320, 57335, 57420, 57421, 57423, 57455, 57461, 57520, 57522, 57530, 57558, 57720, 58120, 58145, 58146, 58263, 58270, 58275, 58280, 58285, 58290, 58291, 58345, 58353, 58356, 58400, 58520, 58559, 58560, 58561, 58562, 58565, 58578, 58579, 58671, 58673, 58679, 58750, 58770, 58800, 58805, 58825, 58920, 58943, 58951, 58952, 58954, 58956, 58957, 58958, 58960, 58970, 59300, 59812, 59871, 60260, 60650, 62365, 64581, 64590, 64630, 64858, 64862, 64874, 97810, G0269, G0339, G0436,

9. Lumbar laminotomy/laminectomy (posterior): 0171T, 0172T, 0195T, 0274T, 0275T, 0334T, 10022, 10121, 10140, 111, 11200, 11400, 12021, 13102, 13133, 13152, 13160, 14301, 15271, 15731, 15770, 15933, 17003, 20220, 20251, 20661, 20665, 20900, 20957, 20975, 20985, 21210, 21600, 22015, 22100, 22101, 22103, 22110, 22112, 22116, 22206, 22207, 22208, 22212, 22214, 22216, 22224, 22226, 22305, 22315, 22325, 22326, 22327, 22328, 22505, 22510, 22511, 22512, 22513, 22514, 22515, 22521, 22522, 22524, 22525, 22526, 22532, 22533, 22534, 22551, 22554, 22556, 22586, 22600, 22612, 22614, 22630, 22632, 22633, 22634, 22800, 22802, 22804, 22808, 22810, 22812, 22818, 22840, 22841, 22842, 22843, 22844, 22846, 22848, 22852, 22855, 22856, 22857, 22861, 22862, 22899, 23930, 24120, 24358, 27279, 27280, 27830, 27840, 28220, 28496, 29999, 30903, 31500, 31603, 33405, 33533, 35184, 35221, 38206, 38220, 38221, 38230, 38241, 39220, 40831, 45520, 51102, 51710, 53601, 57461, 61510, 61795, 62230, 62272, 62280, 62282, 62287, 62305, 62351, 62360, 62362, 63001, 63003, 63012, 63015, 63016, 63017, 63035, 63040, 63043, 63044, 63050, 63051, 63055, 63056, 63057, 63064, 63076, 63077, 63078, 63081, 63082, 63087, 63088, 63090, 63091, 63101, 63102, 63103, 63173, 63185, 63190, 63200, 63250, 63252, 63265, 63266, 63267, 63268, 63270, 63271, 63272, 63273, 63276, 63277, 63278, 63281, 63282, 63287, 63650, 63655, 63661, 63662, 63685, 63688, 63702, 63707, 63709, 63710, 64595, 64622, 64623, 64626, 64627, 64635, 64636, 64714, 64718, 64719, 64911, 69930, 90870, 92973, 92982, 93567, 95961, 95962, G0283, G0436,

10. Lumpectomy w/ and w/out SLNB: 0239T, 10120, 10140, 11000, 11300, 11301, 11306, 11403, 11404, 11406, 11421, 11426, 11450, 11622, 11642, 11900, 11952, 11954, 11970, 11971, 11976, 12031, 12037, 13102, 13151, 14020, 14021, 14041, 14060, 14301, 15003, 15130, 15170, 15200, 15260, 15272, 15273, 15330, 15570, 15650, 15734, 15740, 15777, 15879, 19000, 19081, 19082, 19083, 19084, 19085, 19086, 19100, 19126, 19271, 19282, 19284, 19296, 19297, 19298, 19305, 19306, 19324, 19325, 19328, 19330, 19340, 19355,

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Confidential: For Review Only19361, 19366, 19371, 19499, 20660, 20926, 21012, 21014, 21501, 21550, 21552, 21554, 21557, 21558, 21630, 21930, 21931, 22900, 22901, 22903, 23071, 23076, 25075, 26990, 27337, 27610, 28515, 28525, 30465, 30930, 31720, 33284, 35216, 35246, 35800, 35820, 37182, 37766, 38300, 38305, 38308, 38700, 38724, 38746, 39220, 42410, 44005, 46270, 46288, 46922, 49320, 49555, 50389, 55876, 56405, 58120, 58262, 58561, 58562, 58563, 58660, 59820, 60220, 60240, 60252, 60512, 61108, 61592, 62350, 64492, 64633, 67028, 67210, 67840, 68525, 77785, 77786, 79005, 92920, 92950, 97811, 97813, 97814, 99183, C9728, G0300,

11. Open inguinal hernia repair: 0078T, 0079T, 0080T, 0081T, 11005, 11008, 11042, 11046, 11055, 11201, 11300, 11306, 11307, 11310, 11421, 11422, 11424, 11426, 11443, 11444, 11446, 11463, 11471, 11601, 11604, 11606, 11640, 11641, 11642, 11643, 11771, 12001, 12002, 12013, 12031, 12044, 13121, 14301, 15220, 15221, 15271, 15400, 15431, 15736, 15738, 15877, 17262, 19101, 19300, 19307, 19342, 19364, 19371, 19380, 20000, 20005, 20102, 20922, 21012, 21615, 21920, 21931, 21932, 21933, 22900, 22905, 23071, 23397, 23412, 24071, 24075, 24200, 25065, 25071, 25111, 25115, 26055, 26105, 26160, 26235, 26426, 26990, 27035, 27041, 27043, 27059, 27065, 27087, 27098, 27245, 27324, 27326, 27328, 27337, 27339, 27599, 27614, 27618, 27899, 28001, 28039, 28047, 30140, 32555, 33210, 33234, 33249, 33967, 34803, 34812, 35226, 35286, 35301, 35302, 35371, 35565, 35583, 35585, 35646, 35656, 35665, 35860, 35883, 36005, 36247, 36475, 36821, 36832, 37202, 37204, 37212, 37236, 37766, 37785, 38221, 38505, 38510, 38564, 38571, 38745, 38760, 39540, 42804, 43107, 43335, 43458, 43610, 43659, 43752, 43773, 44010, 44050, 44121, 44155, 44180, 44340, 44626, 44820, 44850, 45395, 45505, 45905, 46030, 46040, 46080, 46200, 46221, 46255, 46505, 46700, 46754, 46917, 46922, 46947, 47379, 47380, 47505, 47560, 47780, 48120, 49010, 49082, 49083, 49204, 49205, 49255, 49325, 49400, 49421, 49422, 49435, 49491, 49492, 49495, 49500, 49501, 49507, 49520, 49521, 49525, 49550, 49555, 49582, 49590, 49659, 49900, 49905, 50040, 50220, 50325, 50360, 50385, 50393, 50395, 50398, 50728, 51045, 51597, 51999, 52647, 52648, 52649, 53410, 53440, 53445, 53447, 53449, 53450, 53500, 53852, 54055, 54057, 54060, 54100, 54150, 54161, 54162, 54163, 54235, 54300, 54360, 54401, 54406, 54408, 54410, 54415, 54416, 54500, 54505, 54512, 54520, 54535, 54550, 54620, 54640, 54660, 54690, 54800, 54830, 54840, 54861, 55100, 55150, 55175, 55180, 55400, 55500, 55530, 55540, 55559, 55810, 55815, 55821, 55831, 55845, 55875, 56810, 57065, 57120, 57135, 57200, 57220, 57267, 57282, 57284, 57296, 57540, 57550, 58140, 58152, 58540, 58559, 58565, 58578, 58600, 58662, 58954, 59514, 59515, 62270, 62361, 64520, 64702, 64708, 64740, 64752, 64755, 64766, 64771, 64772, 64786, 64795, 64999, 68815, 69100, 69110, 92928, 92973, 92980, 96567, C1300, G0283,

12. Open Lung Lobectomy: 11721, 19260, 19272, 20101, 21556, 21632, 21811, 31600, 31805, 31899, 32095, 32096, 32098, 32100, 32120, 32124, 32141, 32220, 32225, 32310,

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Confidential: For Review Only32405, 32421, 32440, 32488, 32500, 32501, 32503, 32504, 32505, 32506, 32507, 32555, 32608, 32609, 32667, 32668, 32669, 32670, 32674, 32900, 32940, 32997, 32998, 32999, 33020, 33025, 33030, 33050, 33335, 33518, 33530, 33572, 33724, 33917, 33925, 33999, 34201, 35201, 35211, 35271, 37620, 38381, 38542, 42826, 43101, 43335, 43640, 49203, 49568, 53620, 58150, 60521, 60522, 62281, 63085, 64492, 93503,

13. Parathyroidectomy: 11101, 11305, 11403, 11420, 11440, 11643, 11644, 11720, 12051, 13132, 13133, 15175, 15576, 15740, 20100, 20926, 21016, 21453, 21501, 30117, 31365, 31367, 31750, 31780, 31786, 31800, 32673, 35201, 35701, 36011, 36522, 36625, 37700, 37761, 37785, 38500, 38525, 38720, 38724, 39000, 39010, 41100, 42104, 42106, 42182, 42420, 42500, 42505, 42699, 43450, 46261, 46922, 49561, 57283, 58552, 60100, 60200, 60210, 60212, 60225, 60254, 60270, 60271, 60280, 60281, 60300, 60502, 60520, 60600, 60659, 60699, 64553, 64555, 64716, 64788, 69205, 69505, 69540, 99490,

14. Partial colectomy w/ or w/out stoma: 11006, 11043, 11401, 11404, 11601, 12006, 12014, 12051, 12054, 14302, 15170, 15171, 15274, 15830, 15920, 19020, 19307, 20102, 20525, 20690, 21620, 22904, 22905, 22999, 23500, 25020, 25575, 25605, 25609, 25670, 25676, 26765, 26990, 27086, 27220, 27766, 27810, 32110, 33213, 33315, 33910, 34401, 34502, 35226, 35236, 35572, 35654, 35661, 36148, 36248, 36251, 36253, 36260, 36299, 36800, 37191, 37236, 37243, 37244, 37617, 37799, 38101, 38102, 38115, 38120, 38999, 39541, 39545, 43122, 43282, 43327, 43332, 43415, 43500, 43605, 43610, 43611, 43620, 43621, 43631, 43632, 43633, 43634, 43635, 43653, 43760, 43774, 43800, 43830, 43848, 43860, 43880, 44010, 44020, 44021, 44025, 44055, 44125, 44126, 44135, 44137, 44147, 44151, 44155, 44204, 44227, 44300, 44314, 44340, 44345, 44346, 44603, 44604, 44625, 44626, 44640, 44661, 44680, 44700, 44701, 44799, 44820, 44850, 44900, 44960, 45020, 45100, 45110, 45111, 45112, 45113, 45123, 45126, 45171, 45172, 45399, 45402, 45550, 45800, 45915, 46050, 46060, 46320, 46740, 47010, 47122, 47125, 47300, 47350, 47360, 47361, 47370, 47380, 47382, 47399, 47480, 47490, 47510, 47610, 47630, 47760, 48120, 48140, 48145, 48155, 48500, 48545, 49002, 49021, 49040, 49060, 49061, 49080, 49083, 49084, 49203, 49250, 49321, 49405, 49419, 49420, 49421, 49440, 49521, 49566, 49585, 49606, 49659, 49904, 49999, 50075, 50500, 50605, 50715, 50727, 50760, 50825, 50840, 50947, 51040, 51550, 51565, 51590, 51800, 51900, 51960, 53502, 53899, 55250, 56606, 56620, 57105, 57110, 57267, 57282, 57283, 57295, 57300, 57305, 57307, 58140, 58180, 58200, 58210, 58240, 58542, 58558, 58611, 58672, 58700, 58760, 58805, 58823, 58900, 58925, 58950, 58951, 58952, 58953, 58954, 58956, 58958, 58960, 58999, 59510, 60545, 840, 96910, 99183,

15. Rotator Cuff Surgery: 0263T, 10040, 11047, 11055, 11403, 11623, 12002, 12011, 15330, 15777, 15879, 19125, 19290, 19291, 20103, 20205, 20206, 20245, 20526, 20611, 20827, 20902, 20924, 20975, 21320, 21330, 21555, 21899, 21931, 22903, 23000, 23020, 23030, 23031, 23040, 23044, 23065, 23066, 23073, 23075, 23077, 23078, 23101, 23105, 23106,

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Confidential: For Review Only23107, 23125, 23130, 23140, 23150, 23156, 23170, 23180, 23182, 23200, 23210, 23330, 23331, 23333, 23334, 23395, 23405, 23406, 23415, 23450, 23455, 23460, 23462, 23465, 23466, 23470, 23480, 23485, 23491, 23530, 23550, 23552, 23585, 23600, 23615, 23616, 23625, 23655, 23660, 23665, 23670, 23800, 24065, 24066, 24116, 24301, 24340, 24341, 24343, 24357, 24359, 24430, 24515, 24999, 25071, 25116, 25215, 25295, 25320, 25420, 25530, 26055, 26060, 26080, 26115, 26145, 26210, 26410, 26432, 26480, 26842, 27236, 27337, 27380, 27418, 27570, 27630, 27698, 27781, 27823, 27824, 27826, 27827, 27828, 27829, 27899, 28086, 28090, 28108, 28297, 28298, 28299, 28310, 28600, 28730, 29824, 29828, 29866, 29873, 29999, 32405, 33967, 35302, 35372, 36475, 38220, 38232, 38243, 42900, 47362, 49587, 57106, 62350, 62360, 64510, 66821, 69436, 93458, 95920, 96910, G0460,

16. Simple Mastectomy w/out reconstruction: 0239T, 0245T, 10160, 10180, 11045, 11046, 11100, 11101, 11303, 11311, 11402, 11420, 11440, 11450, 11601, 11603, 11640, 11900, 11901, 11921, 11971, 12007, 12011, 12031, 12036, 12037, 12042, 12047, 12057, 13100, 13102, 13133, 14001, 14021, 15003, 15004, 15005, 15100, 15110, 15111, 15130, 15131, 15150, 15151, 15170, 15171, 15175, 15200, 15201, 15272, 15277, 15278, 15300, 15301, 15330, 15331, 15335, 15340, 15341, 15361, 15400, 15401, 15570, 15600, 15732, 15757, 15758, 15839, 15850, 15877, 17111, 19020, 19100, 19102, 19103, 19120, 19125, 19126, 19281, 19283, 19285, 19286, 19287, 19288, 19295, 19297, 19298, 19305, 19306, 19318, 19324, 19361, 19367, 19368, 19369, 19370, 20102, 20200, 20240, 20910, 21026, 21557, 21700, 21899, 21932, 22899, 22902, 22903, 23395, 27645, 27759, 31599, 32422, 32550, 32820, 33284, 34051, 34520, 34530, 35236, 35246, 35251, 35875, 35876, 36262, 37202, 37616, 38308, 3852, 38520, 38530, 38550, 38555, 38720, 38745, 42962, 44139, 49010, 49561, 49904, 58291, 58925, 62230, 64633, 64713, 64722, 64727, 64784, 64857, 64893, 64898, 64911, 67314, 67917, 69145, 75756, 88037, 92240, 97597, 97598, 97811, C5271, C5274, C9728,

17. TKA: 0054T, 11056, 11300, 11406, 11719, 11720, 11721, 11952, 120, 12032, 12034, 12035, 12037, 13120, 13152, 15331, 15738, 20240, 20245, 20520, 20690, 20902, 20930, 20938, 20983, 21930, 22840, 22851, 24101, 25000, 25607, 25800, 26116, 26437, 26517, 26548, 27090, 27100, 27137, 27147, 27170, 27200, 27240, 27266, 27305, 27310, 27324, 27329, 27330, 27331, 27332, 27333, 27339, 27350, 27355, 27356, 27358, 27364, 27385, 27386, 27391, 27392, 27393, 27394, 27409, 27412, 27418, 27422, 27425, 27428, 27429, 27430, 27438, 27440, 27442, 27443, 27445, 27454, 27455, 27457, 27465, 27470, 27472, 27477, 27486, 27487, 27488, 27497, 27511, 27514, 27524, 27536, 27556, 27558, 27599, 27605, 27619, 27632, 27637, 27640, 27645, 27687, 27709, 27720, 27740, 27745, 27810, 28010, 28041, 28122, 28232, 28270, 28307, 28755, 30560, 33210, 34203, 35151, 35256, 35303, 35305, 35556, 35741, 36012, 37191, 37226, 38240, 42410, 51102, 54001, 60000, 62273, 63700, 64455, 64774, 67500, 68761, 92980, 93454, G0299,

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Confidential: For Review Only18. Total hip: 0055T, 0263T, 10061, 11401, 12001, 12004, 12034, 12035, 12052, 121, 15852,

20900, 20936, 24130, 24332, 24545, 24685, 25545, 25600, 25905, 26992, 27000, 27005, 27025, 27027, 27033, 27036, 27048, 27054, 27060, 27062, 27066, 27070, 27071, 27076, 27090, 27100, 27110, 27120, 27125, 27132, 27134, 27138, 27140, 27146, 27147, 27151, 27156, 27161, 27165, 27187, 27216, 27217, 27220, 27226, 27227, 27230, 27235, 27238, 27244, 27248, 27252, 27254, 27259, 27265, 27269, 27275, 27305, 27357, 27360, 27365, 27397, 27437, 27450, 27466, 27487, 27495, 27506, 27507, 27570, 27619, 27705, 27786, 28116, 28400, 31720, 35721, 36246, 37618, 46210, 5371, 58615, 62282, 64415, 64520, 64712, 64718, 66761, 68750, 8028, 92941, 92973, 93455, 97810, 97811, G0299, G0415,

19. VATS Wedge: 15732, 21558, 21810, 21811, 30100, 31899, 32096, 32097, 32100, 32124, 32141, 32215, 32405, 32482, 32484, 32507, 32550, 32555, 32607, 32609, 32669, 32670, 32672, 32673, 32815, 33030, 33322, 33533, 35022, 35276, 39200, 39501, 39540, 39545, 39560, 39561, 39599, 42415, 43101, 47130, 49406, 49422, 58662, 60659, 62355, 64746, 79005,

20. Whipple, open: 17999, 35221, 35231, 35251, 35281, 35341, 35521, 35572, 37565, 38100, 38102, 42000, 43246, 43332, 43520, 43820, 43832, 43860, 43870, 44120, 44130, 4465, 44970, 45800, 47420, 47460, 47700, 47711, 47715, 47741, 47760, 47765, 47785, 47801, 47999, 48100, 48140, 48152, 48400, 48510, 48999, 49020, 49327, 49440, 50230, 50240, 77786,

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