Application of Economics & Social Psychology to Improve Opioid Prescribing Safety Trial 2 (AESOPS-2): Availability of Opioid Harm
Phase: NA
Conditions: Opioid Abuse
Sponsor: University of Southern California

1 
STUDY PROTOCOL 
The Protocol of the Application of Economics & Social Psychology to Improve Opioid Prescribing Safety Trial 2 
(AESOPS-2): Availability of Opioid Harm 
Principal Investigator:  
Jason N. Doctor, Ph.D., Associate Professor, University of Southern California 
Mark Sullivan, Professor, University of Washington 
Supported by: 
The National Institute on Aging 
R33AG057395 
Version date: September 18, 2025 

2 
 
 
 
 
A. Background and Status of the Problem 
 
The objective of this study is to evaluate an extension to an existing quality improvement 
program in Los Angeles County addressing opioid stewardship. Much of the increase in 
opioid prescribing rates from 1999 until the past decade was driven by the liberal attitudes 
toward prescribing opioids for non-cancer pain [1, 2]. Opioids carry significant risks of 
overdose and addiction, and there is evidence that non-opioid alternatives are safer and 
as effective [3]. The greater availability of prescription opioids has been accompanied by 
an alarming rise in the negative consequences related to opioid use. In 2017, there were 
17,029 prescription opioid overdose deaths in the US [4]. The costs of prescription opioid 
adverse outcomes are staggering. Aggregate costs for prescription opioid harms are 
estimated at over $78.5 billion (in 2013 USD), and almost 25% of the aggregate economic 
burden is publicly funded (for instance, through Medicaid, Medicare, and veterans' 
programs) [5]. 
 
In 2016, the United States Centers for Disease Control and Prevention (CDC) issued the 
“CDC Guideline for Prescribing Opioids for Chronic Pain” which encourages the use of 
alternatives to opioids and other practices that minimize harm to patients [6]. Despite the 
introduction of this guideline, primary care clinicians, who prescribe 45% of all opioid 
prescriptions in the US, report practical challenges in implementing these 
recommendations [7]. The dynamics of opioid use make following guidelines difficult. 
Since opioid analgesia from a given dose declines with chronic use due to tolerance, 
doses end up increasing the chance of harm. Over time, the primary benefit of opioids for 
many patients is the avoidance of withdrawal. As patients become dependent on opioids, 
they may misconstrue the easing of withdrawal hyperalgesia that occurs with the 
consumption of opioids as ongoing effectiveness, and they may become reluctant to stop 
opioids [8]. More cautious opioid prescribing (including fewer new starts, avoidance of 
high doses, and slow, collaborative tapers for those already on high dose long-term 
therapy) may improve the balance of benefits and harms for patients with chronic pain. 
To become a more cautious prescriber, a clinician may need to be informed that opioid 
risks are present and relevant to his or her own patients. 
 
A prior quality assurance study found that clinicians judge risk to patients as greater after 
information about a patient's fatal overdose is available to them [9]. Of course, not all 
clinicians prescribe to patients who suffer a fatal overdose, so the question remains 
whether providing feedback concerning non-fatal overdoses will have a similar impact on 
prescribing clinicians. Thus, the Application of Economics & Social psychology to improve 
Opioid Prescribing Safety (AESOPS) Availability of Harm trial will test whether or not 
providing feedback to clinicians on both fatal and non-fatal overdoses results in more 
judicious prescribing of opioids. The objective of the AESOPS Availability of Harm trial is 
to dampen the intensity and frequency of opioid prescribing in accordance with the 
Centers for Disease Control and Prevention recommendation to “go low and slow”. We 

3 
 
aim to accomplish this by increasing the mental availability of risks associated with opioid 
use by notifying clinicians of harmful patient outcomes. 
 
 
B. Method of Study in Detail 
 
a)  Purpose and hypotheses to be tested: 
 
Study Synopsis 
Application of Economics & Social psychology to improve Opioid Prescribing Safety 
(AESOPS) Trial 2 is a multi-site randomized trial that takes place among a clinic 
organization in Los Angeles, California (AltaMed Health Services) and one in Chicago, 
Illinois (Northwestern University). Participants in the trial are clinicians. Observations are 
visits where opioids are prescribed. Clinicians are randomized to receive either: 1) 
guidelines on opioid prescribing, or 2) information on an opioid harm experienced by one 
of their patients (non-fatal or fatal overdose). In Los Angeles, fatal overdose letters are 
already required by the County, therefore, only non-fatal overdose letters will be sent to 
clinicians in Los Angeles. These will be signed by the County Public Health Officer. In 
Chicago, Illinois, both types of letters will be sent. Outcomes are milligram morphine 
equivalents ordered by each participating clinician per week. A secondary outcome is 
referrals to medication assisted treatment. These data are collected from the electronic 
health record systems at AltaMed and Northwestern Medical Center. Determining 
overdoses involves connecting data on overdoses between hospital systems, or in the 
case of Illinois, state vital records. More specifically, non-fatal overdoses in Los Angeles 
connect opioid prescribing at AltaMed with Los Angeles County emergency department 
data (See Appendix 1, Figure 1a), non-fatal overdoses at Chicago's Northwestern 
University involve a search of the internal database that connects that University's 
outpatient clinic data with emergency department data (See Appendix 1, Figure 1b), and 
fatal overdoses among patients at Northwestern connect data from that institution with 
Illinois State Vital records (Illinois Department of Public Health (IDPH); See Appendix 1, 
Figure 1c). A pilot study was originally approved for the data exchange in Figure 1c and 
the secure data sharing exercise was successful. 
 
The goal of the project is to dampen the intensity and frequency of opioid prescribing and 
to increase awareness and use of medication assisted therapy for persons with opioid 
use disorder through a cluster randomized trial. Overdose notification letters (See 
Appendix 2 and 3) will be sent to primary care clinicians randomized to the experimental 
study arm and meeting inclusion criteria at AltaMed Health Services or Northwestern 
Medicine. Both letters will include "if/when/then" language which advises the clinician 
to keep the letter’s recommendations close when their next patient presents with pain. 
Clinicians notified of their patient’s overdose will be compared to a control group 
receiving guideline education and no notification of their patient’s overdose (Appendix 
6). To quantify the effect of the notification letter, we will measure the change in clinician 
weekly milligram morphine equivalent (MME) prescribed to all of their patients in 6-month 
periods before and after receiving overdose feedback letters. The secondary outcomes 
include the change in proportion of patients prescribed at least 50 daily MME, 
buprenorphine referrals for medication assisted therapy, and access rates for referral 
links included in the letter. 

4 
 
 
Because the letters include patient identifying information linked to outpatient prescribing 
records, we requested a HIPAA waiver of authorization to match outpatient records to 
mortality and non-fatal overdose records. The research could not feasibly be conducted 
if research participants’ authorization were required. AltaMed will release information 
under the auspices of a waiver of HIPAA authorization. USC and AltaMed have a 
fully executed Business Associates Agreement,  Memorandum of Understanding and 
Data Use Agreement; Northwestern and IDPH and USC and Northwestern have a fully 
executed Data Use Agreement. AltaMed and Northwestern will cede to the County IRB 
as the IRB of record for this study. 
 
To create the list of overdose patients for whom opioids were prescribed, outpatient 
records will be linked to the emergency department and, in the case of Northwestern 
patients, IDPH death records. Overdose data will be linked with outpatient records using 
matching software that complies with institutional security and privacy standards at IDPH 
and Los Angeles County. Where an existing direct link code is available (e.g. MRN), we 
will use the code. 
 
Primary hypotheses: 
1. Clinicians randomized to the overdose notification group will exhibit a 
greater reduction in weekly MME from the pre- to post-period compared 
to clinicians randomized to the control group for fatal and non-fatal 
overdoses. 
2. Among the clinicians who prescribed at least one opioid in the study 
period, those randomized to the overdose notification group will exhibit 
a greater reduction in the proportion of a clinician’s patients prescribed 
at least 50 daily MME from the pre- to post-period compared to clinicians 
randomized to the control group for fatal and non-fatal overdoses. 
 
b)  Number of subjects: 
AltaMed Health Services is a private health system in Los Angeles, California. AltaMed 
has 35 clinics with 134 clinicians with 17,674 such patients. Clinicians meeting inclusion 
criteria will be enrolled in the study. Northwestern Medicine is a regional health system 
affiliated with an academic medical center located in the Chicago region of Illinois and 
includes 60 primary care clinics that contain 387 clinicians with 12,552 patients using 
chronic opioid therapy for noncancer pain—on opioids for greater than three months. 
 
c)  Mechanism for subject selection or exclusion: 
Eligible physicians and patients will be identified using outpatient opioid prescribing data 

5 
 
from electronic medical records. A clinician is eligible for inclusion if: 1) s/he prescribed a 
qualifying scheduled drug to a patient in the 12 months prior to their fatal or non-fatal overdose 2) 
the patient is 18 years old or older at the time of the overdose, 3) s/he practices within a health 
system enrolled in the study, and 4) the overdose occurs during the 12-month observation period. 
 
A patient is eligible for identification in a physician notification if s/he (a) has been 
prescribed an opioid by an eligible clinician (b) has a documented overdose event in EHR 
or mortality data. Patients without overdose events will be excluded. Patients with fatal 
overdoses in Los Angeles County will be excluded to avoid redundancy with existing 
notification practices. 
 
d)  Duration of intervention: 
The duration of the overdose notification intervention is one day. 
 
e)  Total duration which study will be performed (data collection, intervention, and analysis period): 
The total duration of the study is 37 months, with 3 months devoted to data analysis, 
including a total of 40 months. We will look back 24 months for qualifying prescriptions. 
The pre-intervention period begins after the 12-month observation period and consists 
of the 6 months before the date on which the letter is sent. The post-intervention period 
consists of the 6 months following the 30-day washout period after the date on which 
the letter is sent. The 30-day washout period is used to account for differential time until 
receipt and opening of the notification envelope. See timeline below. 
 
Figure 2. Study Timeline 
 
 
f)  Frequency, character, amount and types of collections: 
This study will also collect primary data from the medical examiner’s office, state vital 
records, emergency departments, and insurance claims. 

8 
 
List of Patients and Providers with Outpatient Opioid Prescriptions. We will use 
outpatient EHR data from Northwestern and Altamed to identify patients with opioid 
prescriptions and prescribing clinicians. 
 
Non-Fatal Overdose Records: Los Angeles. AltaMed will securely transfer a list of 
providers and patients with opioid prescriptions and unique study identifiers to the Los 
Angeles County Department of Health Services. This list will be compared to Los Angeles 
County emergency department records for non-fatal overdose. Identifying non- fatal 
overdose events will involve non-fatal overdose diagnoses (ICD-10 codes; See Appendix 
4), diagnosis codes for falls, and evidence of naloxone administration. Patient identifiers 
will be matched using LACDHS identity management software based on name, birthdate, 
and address information. Data from patients without overdose events will be destroyed. To 
avoid redundant messaging with existing LAC notifications of fatal overdoses, fatal 
overdoses will not be included. The list of AltaMed prescribers and patients with overdose 
events will be delivered to the Los Angeles County Department of Public Health to prepare 
notification letters. 
 
Non-Fatal Overdose Records: Northwestern University. A one time data extract 
will be generated at the beginning of the study, looking back 24 months to identify 
clinicians who prescribed a qualifying scheduled drug to a patient in the 12 months prior 
to their non-fatal overdose. The list of patients with outpatient opioid prescriptions will  
be  used  to  retrieve  overdose  records that occur within the 12 month 
observation period. Emergency  department  and  outpatient records at Northwestern 
are secured in the same EHR. The list will be delivered to Northwestern study 
staff to prepare notification letters. 
 
Quarterly Fatal Overdose Records. Opioid-related death data will be gathered from the 
Illinois Department of Public Health (IDPH). Each quarter, Northwestern study personnel 
will securely transfer IDPH a list of identifiers for patients who received an opioid 
prescription at a participating clinic. IDPH will use this information to identify if the patient 
is deceased. If so, IDPH will send back the date of death, cause of death, and whether 
the death was opioid-related via a secure file transfer process to Northwestern Medicine. 
IDPH will not send back information if a patient is not deceased. Analysts at Northwestern 
Medicine will link opioid-related decedents to identify opioid prescriptions and prescribers. 
The list of patients with fatal overdose will be returned to Northwestern Medicine for 
preparation of notification letters. 
 
As described above, each system’s enterprise software and identifiers will be 
employed to match patients and their providers across settings. 
 
Allocation Data Set and Study Identifiers. Each patient and prescriber will be assigned 
a unique study identifier based on outpatient data before overdose data is added. The 

9 
 
randomization and allocation procedure described in Experimental Procedures (below) 
will be applied by the Los Angeles Department of Health Services and Northwestern 
Study Staff to create the final list of notifications. 
 
HIPAA Limited Data Set. At the conclusion of the study period, each health system will 
prepare a HIPAA limited data set for analysis. The data set will include dates of overdose 
events, post-intervention opioid prescribing, and unique study identifiers. Study 
assignment, physician notification information, and overdose data from Los Angeles 
County Department of Public Health will be de-identified retaining unique study identifiers. 
Data will be transferred to USC Schaeffer Center HIPAA data enclave for analysis. No 
USC study personnel will have access to any patient identifying information. Links 
between identified data and study identifiers will be destroyed at the conclusion of the 
analysis. 
 
C. List of Experimental Procedures to be Employed 
 
a) List and detail risks: 
 
● Mitigation of risk to participating physicians 
○ Letters are a normal aspect of quality review. Letters notifying clinicians of 
a fatal overdose are mandated in Los Angeles County. [see LA County 
Board of Supervisors Meeting https://youtu.be/hBefHyAL5I8 ]. Therefore, 
risks faced by participants do not exceed that of normal clinical practice. 
We will take every precaution to mitigate risk to participating clinicians by 
keeping this disclosure private. All correspondence will be private and 
conducted through delivery using one of the following approaches: 1) US 
Postal Service, 2) institutional email, or 3) Epic inbox message, and will 
not be shared outside of the study. 
● Mitigation of risk to patients 
○ Risk of correspondence adds no additional risk compared to what is 
already being sent in the mail or by email (such as prior authorization 
letters by insurers or billing). Further, the HIPAA conduit exception allows 
HIPAA-covered entities to use the US Postal Service, institutional email, 
and Epic inbox messaging for the transmission of personal health 
information. US Letters and email are private and tampering with private 
mail is a federal offense. 
○ The NIH has established a Data and Safety Monitoring Board for this 
study. The board consists of individuals with expertise in opioids, 
overprescribing, biostatistics or research methods. When notified of an 
unanticipated event following the intervention, the board will convene and 
make a decision as to whether the study should continue. 
○ A potential risk is an adverse event, defined by the CDC as an abrupt 

10 
 
discontinuation of opioids for persons whose most recent prescription 
exceeds 49 MME daily dose; or as reported to study staff (10). 
If there is a significant difference in the prevalence of these adverse events 
or overdoses between the treatment and control groups, the differences will 
be reported to the Data and Safety Monitoring Board and in the publication 
of the study results. It is important to note that prior quality evaluations of 
these letters observed no additional risk of abrupt changes to opioid 
prescribing 
upon 
receipt 
of 
a 
letter 
(https://pubmed.ncbi.nlm.nih.gov/30093595/ ). 
 
○ Management of overdose and prescribing data poses no more than minimal 
privacy risks. USC, health systems and IDPH comply with all local and 
federal security regulations protecting privacy. Identified patient data will be 
destroyed after the notifications have been prepared. A HIPAA Limited Data 
Set that includes outpatient prescribing records, overdose events, and 
notification status will be transferred to USC for data analysis in USC’s 
HIPAA compliant enclave. 
 
b) Experimental Procedures: 
 
Randomization and Allocation. Overdose clusters are the units of randomization in this 
study. A cluster consists of all clinicians who prescribed one or more of the included 
scheduled drugs to the patient in the year prior to the overdose. Overdose clusters will 
be randomized to the overdose notification group or the control group, stratified by the 
health system which defines the cluster in the year prior to the overdose event. 
Allocation will be concealed until after the study groups are assigned. Clinicians who 
practice at multiple clinics will be assigned to the clinic at which the majority of their 
visits occurred in the year prior to the overdose event. If clinicians belong to more than 
one cluster (have multiple patients with opioid-related overdoses), they will be randomly 
assigned to one of those patients and placed in the corresponding study group. If 
clinicians belonging to more than one cluster are randomized to the intervention group, 
they will only receive an overdose notification regarding the one patient to whom they 
were randomly assigned. 
 
Intervention. Clinicians in the intervention group receive a letter notifying them of their 
patient's fatal or non-fatal overdose. As described above, we will identify overdoses 
from electronic health record data from emergency departments and state vital records. 

11
If randomized to the overdose notification group, physicians who prescribed a qualifying 
prescription to the deceased or surviving patient in the year prior to their overdose will 
be informed of the overdose via letter. The letters will alert prescribers to the patient’s 
opioid-related overdose, recommend the use of their state’s PDMP, and list evidence- 
based interventions to lower opioid-related overdoses (Appendix 2 and 3). 
Controls. Clinicians in the control group will receive guideline education in the form of 
the CDC pocket guide and no notification of a patient overdose event (See Appendix 
5). https://www.cdc.gov/drugoverdose/pdf/TurnTheTide_PocketGuide-a.pdf 
D. Statistical Analysis Plan
Patients who experienced an opioid overdose will be randomized to either the letter intervention or control. 
We will analyze how the prescribing behavior of those patients’ clinicians changed pre-to-post intervention. 
We will use means and medians for continuous measures for sample descriptive statistics, frequencies for 
count data and standard deviations, and interquartile ranges for variance. We will evaluate changes in 
opioid prescribing rates by group using an intent-to-treat difference-in-differences regression model on 
clinician hydrocodone morphine equivalent weekly dose. The coefficient for the group assignment, 
overdose type, and time interaction, also known as the difference-in-differences estimator, denotes the 
change over time in 5 MME hydrocodone pills for prescribers in the intervention group compared to 
prescribers in the control group for both fatal and nonfatal overdose victims. The use of a mixed-effects 
hierarchical knotted spline Poisson regression model offers a flexible way to accommodate non-linear 
trends in prescribing by group before and after introducing the intervention. This model places a knot at the 
intervention start date allowing slopes before and after the introduction of the intervention to vary for each 
group. Our primary outcome is the daily average number of 5 MME hydrocodone pills. If we have an excess 
of data clustering at zero, indicating weeks during which a physician wrote no opioid prescriptions, we will 
use a zero-inflated or left-censored regression. The regression model estimating the association between 
letter assignment and weekly 5 MME hydrocodone pills prescribed is shown in Eq. 1:
where (pills)ijk* denotes the dependent variable for clinician i in week j, Timeij is the study week indexed by j, 
t* is the spline knot for the start of the intervention, (Timeij - t*) is a truncated line function that is equal to 
(Timeij - t*) when Timeij > t* and 0 otherwise to allow for nonlinear trends in prescribing following the 
intervention, Groupi is dichotomous for the overdose notification intervention group, Overdose Typek is 
dichotomous for a fatal overdose, η is the clinic random effect, and δi(k) is the random effect for each 
clinician i who prescribed to patient k who suffered an overdose.
The mixed logistic regression model for our secondary outcomes is shown in Eq. 2:
s 

12
where (high dose Rx)ijk is whether the visit had a high dose prescription of 50 MME or greater (yes vs. no) 
for clinician i, Timeij is the study period (pre- vs. post-intervention) indexed by j, Groupi is dichotomous for 
the overdose notification intervention group, Overdose Typek is dichotomous for a fatal overdose, η is the 
clinic random effect, and δi(k) is the random effect for each clinician i who prescribed to patient k who 
suffered an overdose. We will compute the estimated pre- to post-intervention change in the mean 
proportion of high dose patient visits for each of the four intervention groups: nonfatal control, nonfatal 
letter, fatal control, fatal letter. The proportion will be calculated by dividing the total number of patient 
visits where an opioid of at least 50 MME was prescribed by the total number of opioid prescriptions.
E. Privacy of Individuals and Confidentiality of Data
We will utilize two types of data for this study: 
Quality assurance program data: Data will include patient and physician identifiers. USC, health 
systems and IDPH comply with all local and federal security regulations protecting privacy. Identified 
patient data will be destroyed after the notifications have been prepared. 
Program evaluation data. A HIPAA Limited Data Set that includes outpatient prescribing records, 
overdose, and notification status will be transferred to USC for data analysis in USC’s HIPAA 
compliant enclave. Management of overdose and prescribing data poses no more than minimal 
privacy risks. 
Waiver of Informed Consent. As our study design necessitates that physicians not be made aware 
they are participants in a research study, we are requesting a waiver of consent. We provide the 
following justification for this clinician waiver of consent: The Common Rule” (§46.116) specifies that 
informed consent can be waived when: “(1) The research involves no more than minimal risk to the 
subjects; (2) The research could not practicably be carried out without the requested waiver or 
alteration; (3) If the research involves using identifiable private information, the research could not be 
practicably carried out without the identifiable information; (4) The waiver or alteration will not 
adversely affect the rights and welfare of the subjects; [and] (5) Whenever appropriate, the subjects 
will be provided with additional pertinent information after participation.” 
Debrief. We will have a participant debrief following completion of the study. Clinicians will be sent a 
debriefing statement (see Appendix 6) which contains the following information: a description of the 
nature and purpose of the study, specification of what data were collected about participants, and that 
the data will be aggregate and not linked back to individual providers or patients. 
References: 
1. G. P. Guy Jr et al., “Vital Signs: Changes in Opioid Prescribing in the United States, 2006-
2015,” MMWR Morb. Mortal. Wkly. Rep., vol. 66, no. 26, pp. 697–704, Jul. 2017.
2. D. Boudreau et al., “Trends in long-term opioid therapy for chronic non- cancer pain,”
Pharmacoepidemiol. Drug Saf., vol. 18, no. 12, pp. 1166–1175, 2009.
3. E. E. Krebs et al., “Effect of Opioid vs Nonopioid Medications on Pain- Related

13
 
Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: 
The SPACE Randomized Clinical Trial,” JAMA, vol. 319, no. 9, pp. 872–882, Mar. 
2018. 
4. L. Scholl, “Drug and Opioid-Involved Overdose Deaths — United States, 2013–
2017,” MMWR Morb. Mortal. Wkly. Rep., vol. 67, 2019, doi: 
10.15585/mmwr.mm6751521e1. 
5. C. S. Florence, C. Zhou, F. Luo, and L. Xu, “The Economic Burden of 
Prescription Opioid Overdose, Abuse, and Dependence in the United States, 
2013,” Med. Care, vol. 54, no. 10, pp. 901–906, Oct. 2016. 
6. D. Dowell, T. M. Haegerich, and R. Chou, “CDC Guideline for Prescribing Opioids 
for Chronic Pain - United States, 2016,” MMWR Recomm. Rep., vol. 65, no. 1, pp. 
1–49, Mar. 2016. 
7. K. Kroenke et al., “Challenges with Implementing the Centers for Disease Control 
and Prevention Opioid Guideline: A Consensus Panel Report,” Pain Med., vol. 20, 
no. 4, pp. 724–735, Apr. 2019. 
8. D. N. Juurlink, “Rethinking ‘doing well’ on chronic opioid therapy,” CMAJ, vol. 189, 
no. 39, pp. E1222–E1223, Oct. 2017. 
9. J. N. Doctor et al., “Opioid prescribing decreases after learning of a patient’s fatal 
overdose,” Science, vol. 361, no. 6402, pp. 588–590, Aug. 2018. 
10. D. Dowell, T. Haegerich, and R. Chou, “No Shortcuts to Safer Opioid Prescribing,” 
      N. Engl. J. Med., vol. 380, no. 24, pp. 2285–2287, Jun. 2019. 

14
 
F. 
Appendix 
 
1. Figures 1a-1c 
2. Fatal overdose notification letter 
3. Nonfatal overdose notification letter 
4. Nonfatal opioid overdose diagnosis codes 
5. Guideline Education (Control) – CDC pocket card 
6. Clinician Debrief letter 
 
 
 

15
 
Appendix 1. Figures 1a-1c 
 
Figure 1a. Schematic view of study procedures for communicating non-fatal overdose in Los Angeles. (Fatal 
overdose letters are mandated by Los Angeles County and are not part of the study). 
 
 
 
 
 

16
 
Figure 1b. Schematic view of study procedures for communicating non-fatal overdose in Chicago, 
Illinois.  
 
 
 
 

17
 
Figure 1c. Schematic view of study procedures for communicating fatal overdose in Chicago, 
Illinois. A pilot project has already been completed. 
 
 
 
 
 
 

18
 
Appendix 2. Fatal Overdose Notification Letter to Clinician 
Dear (Name of Prescriber), 
This letter is to inform you that your patient, {Name, Date of Birth}, died on {Date}. Prescription 
opioid overdose was either the primary cause of death or contributed to the death. 
Northwestern Medicine is tracking outcomes for patients on opioids and other scheduled drugs. 
A significant proportion of overdoses are due to the combination of opioids with a sedative medication. Patients may 
obtain legitimate prescriptions for opioids, benzodiazepines, muscle relaxants, and sleep aids from more than one 
prescriber. When taken in any combination, these medications put patients at greater risk of overdose and death. 
Many fatal and non-fatal overdoses are a result of long-term therapeutic prescribing or of combined prescription 
medications with drugs obtained from other sources. 
Our aim is to alert clinicians to the potential dangers of opioid medications and how common 
death from misuse of these medications is in Chicago and throughout Illinois. 
Northwestern Medical Group would like to remind you that Illinois has a prescription drug 
monitoring program called the Illinois Prescription Monitoring Program (ILPMP) which helps prescribers avoid 
prescribing controlled substances when they are likely to do more harm than good. 
ILPMP contains information about whether and when other clinicians have prescribed controlled 
substances to your patient within the last 12 months. With few exceptions, prescribers are 
required by state law to check the ILPMP when prescribing opioids. Review of the ILPMP 
could alert you to problematic medication usage, potential addiction or diversion, and help inform safe 
medication prescribing and monitoring. 
This information is available through Epic and at https://www.ilpmp.org/CDC/login.php. 
You may show your commitment to being a safe prescriber by using the following evidence-based interventions to 
lower overdose rates: 
1.  Avoid co-prescribing an opioid and a benzodiazepine. Opioids and benzodiazepines can have additive 
central nervous system depressant effects.  
2.  Avoid opioid prescribing for chronic pain and avoid/minimize opioid prescribing for acute pain. 
According to the Centers for Disease Control and Prevention (CDC), clinicians should avoid opioids for 
chronic pain, and when necessary for acute pain, start with the lowest effective dose of immediate-release 
opioids. Three days or less is often sufficient to address acute pain. Opioids should not be considered first-line 

19
 
or routine therapy for chronic pain.  
3.  Taper opioids to safer doses. The CDC recommends that for patients already on long-term high-dose opioid 
therapy, taper to a dose that is lower than 50 morphine milligram equivalents (MME) and consider slow opioid 
tapers as well as pauses in the taper if needed for long-term users.  
4.  Avoid “the 90-day cliff.” One California study found that nearly 70% of patients who died of prescription-
related overdoses were prescribed scheduled drugs for 3 consecutive months. i The CDC recommends 
opioids should be discontinued if benefits do not outweigh risks (if realistic goals for pain and function have not 
been met).  
5.  The CDC recommends prescribing naloxone to patients on higher than 50 MME of opioids per day.  
6.  Prescribed medications for opioid use disorder. Clinicians should offer medications for opioid use 
disorder, such as buprenorphine/naloxone, to their patients with opioid use disorder. Physicians, physician 
assistants, and advanced practice nurses can file a waiver to prescribe buprenorphine for the indication of 
opioid use disorder by visiting the SAMHSA website (http://www.samhsa.gov/medication-assisted-
treatment/become-buprenorphine-waivered-practitioner) or by calling SAMHSA at 866-287-2728. On April 28, 
2021, SAMHSA announced that it will waive the training requirement for physicians, physician assistants, and 
advanced practice nurses to become waivered to prescribe buprenorphine for the indication of opioid use 
disorder. Further, you can use the Epic Social Determinants of Health (at the bottom left of your Storyboard), 
click on “Select Community Resources”, and find “Substance Use” resources.  
 
When your next patient presents with pain, keep the above 6 recommendations close at hand to assist with their safe 
care. Also, be comfortable voicing your concern about prescribing safety with them so that they are also aware of the 
dangers associated with scheduled drugs. We also encourage you to routinely log into ILPMP and learn more about 
the prescriptions your patient received leading up to the death. 
 
Again, this letter is meant to be informative only, is not affiliated with other initiatives, and there is no expectation of 
reply. We understand that learning of your patient’s death can be difficult. We hope that you will take this as an 
opportunity to join us in preventing future deaths from drug overdose. 
Sincerely, 
[Medical Director or other similar role] 
 
1 Lev, R., Petro, S., Lee, O., Lucas, J., Stuck, A., Vilke, G. M., & Castillo, E. M. (2016). A description of Medical Examiner prescription-related 
deaths and prescription drug monitoring program data. The American journal of emergency medicine, 34(3), 510–514. 
https://doi.org/10.1016/j.ajem.2015.12.023 
 

20
 
Appendix 3. Nonfatal Overdose Notification Letter to Clinician 
Dear (Name of Prescriber), 
This is a courtesy notification to inform you that your patient, {Name, Date of Birth}, visited the Emergency department 
on {Date} with a nonfatal opioid overdose. 
Northwestern Medicine is tracking outcomes for patients on opioids and other scheduled drugs. 
A significant proportion of overdoses are due to the combination of opioids with a sedative medication. Patients may 
obtain legitimate prescriptions for opioids, benzodiazepines, muscle relaxants, and sleep aids from more than one 
prescriber. When taken in any combination, these medications put patients at greater risk of overdose and death. 
Many fatal and non-fatal overdoses are a result of long-term therapeutic prescribing or of combined prescription 
medications with drugs obtained from other sources. 
Our aim is to alert clinicians to the potential dangers of opioid medications and how common death from misuse of 
these medications is in Chicago and throughout Illinois. 
Northwestern Medical Group would like to remind you that Illinois has a prescription drug monitoring program called 
the Illinois Prescription Monitoring Program (ILPMP) which helps prescribers avoid prescribing controlled substances 
when they are likely to do more harm than good. 
ILPMP contains information about whether and when other clinicians have prescribed controlled substances to your 
patient within the last 12 months. With few exceptions, prescribers are required by state law to check the ILPMP when 
prescribing opioids. Review of the ILPMP could alert you to problematic medication usage, potential addiction 
or diversion, and help inform safe medication prescribing and monitoring. This information is available through 
Epic and at https://www.ilpmp.org/CDC/login.php. 
Emergency department visits for an overdose strongly suggest a diagnosis of opioid use disorder. The one-year 
mortality following an opioid overdose is high at 10%. If your patient’s overdose was due to opioid use disorder, 
medications for opioid use disorder, such as buprenorphine/naloxone, can be safely prescribed in any setting of care 
and greatly reduce mortality risks through prevention of future overdose. Medications for opioid use disorder improve 
your patients’ chances of recovery.  
You may show your commitment to being a safe prescriber by using the following evidence-based interventions to 
lower overdose rates: 
1.  Avoid co-prescribing an opioid and a benzodiazepine. Opioids and benzodiazepines can have additive 
central nervous system depressant effects.  

21
 
2.  Avoid opioid prescribing for chronic pain and avoid/minimize opioid prescribing for acute pain. 
According to the Centers for Disease Control and Prevention (CDC), clinicians should avoid opioids for 
chronic pain, and when necessary for acute pain, start with the lowest effective dose of immediate-release 
opioids. Three days or less is often sufficient to address acute pain. Opioids should not be considered first-line 
or routine therapy for chronic pain.  
3.  Taper opioids to safer doses. The CDC recommends that for patients already on long-term high-dose opioid 
therapy, taper to a dose that is lower than 50 morphine milligram equivalents (MME) and consider slow opioid 
tapers as well as pauses in the taper if needed for long-term users.  
4.  Avoid “the 90-day cliff.” One California study found that nearly 70% of patients who died of prescription-
related overdoses were prescribed scheduled drugs for 3 consecutive months.ii  The CDC recommends 
opioids should be discontinued if benefits do not outweigh risks (if realistic goals for pain and function have not 
been met).  
5.  The CDC recommends prescribing naloxone to patients on higher than 50 MME of opioids per day.  
6.  Prescribed medications for opioid use disorder. Clinicians should offer medications for opioid use 
disorder, such as buprenorphine/naloxone, to their patients with opioid use disorder. Physicians, physician 
assistants, and advanced practice nurses can file a waiver to prescribe buprenorphine for the indication of 
opioid use disorder by visiting the SAMHSA website (http://www.samhsa.gov/medication-assisted-
treatment/become-buprenorphine-waivered-practitioner) or by calling SAMHSA at 866-287-2728. On April 28, 
2021, SAMHSA announced that it will waive the training requirement for physicians, physician assistants, and 
advanced practice nurses to become waivered to prescribe buprenorphine for the indication of opioid use 
disorder. Further, you can use the Epic Social Determinants of Health (at the bottom left of the Storyboard), 
click on “Select Community Resources,” and find “Substance Use” resources.  
 
When your next patient presents with pain, keep the above 6 recommendations close at hand to assist with their safe 
care.  Also, be comfortable voicing your concern about prescribing safety with them so that they are also aware of the 
dangers associated with scheduled drugs.  We also encourage you to routinely log into ILPMP and learn more about 
the prescriptions your patient received leading up to the overdose. 
 
This letter is meant to be informative only and there is no expectation of reply. We understand that learning of your 
patient’s overdose can be difficult. We hope that you will join us in our effort to prevent future drug overdoses. Please 
take this as an opportunity to talk with your patient and perhaps other patients in your practice who may be at-risk. 
 
Sincerely, 

22
 
[Medical Director or similar role] 
 
 
i Lev, R., Petro, S., Lee, O., Lucas, J., Stuck, A., Vilke, G. M., & Castillo, E. M. (2016). A description of Medical Examiner prescription-related 
deaths and prescription drug monitoring program data. The American journal of emergency medicine, 34(3), 510–514. 
https://doi.org/10.1016/j.ajem.2015.12.023 
 
 
 
 

PRESCRIBING OPIOIDS 
FOR CHRONIC PAIN
ADAPTED FROM CDC GUIDELINE
Opioids can provide short-term benefits for moderate to severe pain. Scientific 
evidence is lacking for the benefits to treat chronic pain. 
IN GENERAL, DO NOT PRESCRIBE OPIOIDS AS THE FIRST-LINE TREATMENT FOR 
CHRONIC PAIN (for adults 18+ with chronic pain > 3 months excluding active cancer, 
palliative, or end-of-life care).
BEFORE  PRESCRIBING
1 
ASSESS PAIN & FUNCTION
Use a validated pain scale. Example: PEG scale where the score = average 3 individual 
question scores (30% improvement from baseline is clinically meaningful). 
Q1: What number from 0 – 10 best describes your PAIN in the past week?              
(0 = “no pain”, 10 = “worst you can imagine”)
Q2: What number from 0 – 10 describes how, during the past week, pain has interfered 
with your ENJOYMENT OF LIFE? (0 = “not at all”, 10 = “complete interference”)
Q3: What number from 0 – 10 describes how, during the past week, pain has interfered 
with your GENERAL ACTIVITY? (0 = “not at all”, 10 = “complete interference”)
2 
CONSIDER IF NON-OPIOID THERAPIES ARE APPROPRIATE
Such as: NSAIDs, TCAs, SNRIs, anti-convulsants, exercise or physical therapy, 
cognitive behavioral therapy.  
TALK TO PATIENTS ABOUT TREATMENT PLAN
3 
• Set realistic goals for pain and function 
• Set criteria for stopping or continuing 
based on diagnosis.
opioid. Set criteria for regular progress 
• Discuss benefits, side effects, and risks 
assessment. 
(e.g., addiction, overdose).
• Check patient understanding about 
treatment plan.
4 
EVALUATE RISK OF HARM OR MISUSE. CHECK:
• Known risk factors: illegal drug use; 
• Urine drug screen to confirm presence 
prescription drug use for nonmedical 
of prescribed substances and for 
reasons; history of substance use 
undisclosed prescription drug or illicit 
disorder or overdose; mental health 
substance use. 
conditions; sleep-disordered breathing.
• Medication interactions. AVOID 
• Prescription drug monitoring program 
CONCURRENT OPIOID AND 
data (if available) for opioids or 
BENZODIAZEPINE USE WHENEVER 
benzodiazepines from other sources. 
POSSIBLE.
WHEN YOU PRESCRIBE
START LOW AND GO SLOW. IN GENERAL:
• Start with immediate-release (IR) 
• If prescribing ≥ 50 MME/day, increase 
opioids at the lowest dose for the 
follow-up frequency; consider offering 
shortest therapeutic duration. IR 
naloxone for overdose risk. 
opioids are recommended over ER/LA 
• For acute pain: prescribe < 3 day 
products when starting opioids.
supply; more than 7 days will rarely   
• Avoid ≥ 90 MME/day; consider 
be required.
specialist to support management of 
• Counsel patients about safe storage 
higher doses.
and disposal of unused opioids.

The Office of the 
Surgeon General    
See below for MME comparisons. For MME conversion factors and calulator,
go to TurnTheTideRx.org/treatment. 
50 MORPHINE MILLLIGRAM 
EQUIVALENTS (MME)/DAY:
90 MORPHINE MILLLIGRAM 
EQUIVALENTS (MME)/DAY:
• 50 mg of hydrocodone (10 tablets of 
• 90 mg of hydrocodone (18 tablets of 
hydrocodone/acetaminophen 5/300)
hydrocodone/acetaminophen 5/300)
• 33 mg of oxycodone (~2 tablets of 
• 60 mg of oxycodone (4 tablets of 
oxycodone sustained-release 15mg)
oxycodone sustained-release 15mg)
 
AFTER INITIATION OF OPIOID THERAPY 
ASSESS, TAILOR & TAPER
• Reassess benefits/risks within 1-4 
• If over-sedation or overdose risk, 
weeks after initial assessment.
then taper. Example taper plan: 10% 
• Assess pain and function and 
decrease in original dose per week or 
compare results to baseline. Schedule 
month. Consider psychosocial support.
reassessment at regular intervals (≤ 3 
• Tailor taper rates individually to 
months).
patients and monitor for withdrawal 
• Continue opioids only after confirming 
symptoms.
clinically meaningful improvements in 
pain and function without significant 
risks or harm.
TREATING OVERDOSE & ADDICTION
• Screen for opioid use disorder 
• Learn about medication-assisted 
(e.g., difficulty controlling use; see 
treatment (MAT) and apply to be a 
DSM-5 criteria). If yes, treat with 
MAT provider at www.samhsa.gov/
medication-assisted treatment (MAT).
medication-assisted-treatment. 
MAT combines behavioral therapy 
• Consider offering naloxone if high risk 
with medications like methadone, 
for overdose: history of overdose or 
buprenorphine, and naltrexone. Refer to 
substance use disorder, higher opioid 
findtreatment.samhsa.gov. Additional 
dosage (≥ 50 MME/day), concurrent 
resources at  TurnTheTideRx.org/
benzodiazepine use.
treatment and www.hhs.gov/opioids.
ADDITIONAL RESOURCES
CDC GUIDELINE FOR PRESCRIBING OPIOIDS FOR CHRONIC PAIN:
www.cdc.gov/drugoverdose/prescribing/guideline.html
SAMHSA POCKET GUIDE FOR MEDICATION-ASSISTED TREATMENT (MAT):  
store.samhsa.gov/MATguide
NIDAMED: www.drugabuse.gov/nidamed-medical-health-professionals
ENROLL IN MEDICARE: go.cms.gov/pecos
Most prescribers will be required to enroll or validly opt out of Medicare for their 
prescriptions for Medicare patients to be covered. Delay may prevent patient access 
to medications.
JOIN THE MOVEMENT 
of health care practitioners committed to ending the opioid crisis at TurnTheTideRx.org. 

Appendix 6. Clinician debrief letter 
 
Dear <name>: 
 
Physicians in [institution name] are always looking for ways to prescribe more safely.  We 
are interested in reducing unnecessary scheduled drug prescribing. This past [season], we 
evaluated whether providing clinical information to physicians led to more judicious 
scheduled drug prescribing. For some physicians, we connected different data sources to 
identify harmful events (fatal and nonfatal overdoses) among patients they treated with 
scheduled drugs. Those physicians for whom there were harmful events received a letter 
notifying them of their patient’s clinical outcome. We did not identify harmful events for 
patients of other physicians and those physicians did not receive a letter. If you did not 
receive a letter, you were either in the control group or did not have any patients with 
harmful events that were identified. We want to know whether these letters had an impact 
on prescribing behavior compared to usual clinic operations that do not involve such 
notifications.  
 
I am writing to let you know that data from visits at which you treated patients with 
scheduled drugs will be among the millions of records that will be combined to make this 
comparison. The comparison will be made without using your name or patient names or any 
identifying information other than date of service. This research study has been approved 
by the Los Angeles County Department of Public Health Institutional Review Board (IRB), 
University of Southern California IRB and Northwestern University IRB, which is the body 
that oversees human subjects research. 
 
I hope you are as pleased as I am that you can play a role in helping us find better ways to 
encourage safe prescribing. I would be happy to answer any questions that you have. 
 
Sincerely, 
 
[Medical Director or similar role]