Comparing Effectiveness of Duloxetine and Desipramine in Patients With Chronic Pain: A Pragmatic Trial Using Point of Care Randomization
Phase: PHASE4
Conditions: Chronic Pain
Sponsor: Stanford University

Comparing Effectiveness of Duloxetine and Desipramine 
in Patients with Chronic Pain: A Pragmatic Trial Using 
Point of Care Randomization   
 
NCT03548454 
May 17, 2022 
 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
The purpose of this study is to compare effectiveness of duloxetine and desipramine in 
(1) decreasing pain, (2) improving function, (3) improving depression and (4) decreasing 
pain interference in patients with chronic pain. We will also compare compliance of 
patients with these two medications. We will apply a novel point of care randomization 
method which allows integration of randomized comparative effectiveness research with 
patient care. 
b. 
Objectives 
The importance of the proposed research has two aspects: 1) it establishes how pragmatic 
clinical trials can be integrated with patient care. This will lead to numerous more trials in 
future that can generate more evidence and direction for medical practice in perioperative 
and pain medicine; 2) it will determine if either a tricyclic antidepressant or a serotonin 
norepinephrine reuptake inhibitor is superior in treating patients with chronic pain. The 
subgroup analysis proposed will provide information about characteristics of patients 
who respond to these medications differently. 
c. 
Rationale for Research in Humans 
The study is comparing effectiveness of duloxetine and desipramine in patients with 
chronic pain. Administration of these medications to human subjects is necessary for the 
purpose of the study. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
Study Design: We will conduct a prospective open label randomized trial comparing 
effectiveness of duloxetine and desipramine. 
 
Randomization (research): After obtaining research informed consent, the participants are 
going to be randomized by the treating pain provider using point of care randomization 
during the clinic visit. Point of care randomization will be done through Collaborative 

May 17, 2022 
 
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Health Outcomes Information Registry (CHOIR) using computer generated random 
numbers. 
 
Intervention: (standard of care) The participants are going to receive either duloxetine or 
desipramine. Duloxetine will be started at 20 mg per day. It will be increased to 40 mg 
per day at the beginning of week two, and then to 60 mg per day at the beginning of week 
three. Desipramine will be started at 25 mg per day. It will be increased to 50 mg per day 
at the beginning of week two, and then to 75 mg per day at the beginning of week three. 
These treatments will be continued for at least 6 months provided that the patients can 
tolerate the side effects and are willing to continue the treatment. Further titration of 
doses based on participants’ tolerance and response is allowed based on clinical decision 
of the treating pain provider. Concomitant use of other analgesics or pain medications as 
well as pain interventions are also allowed. 
 
Data collection: (standard of care and research) The participants are going to receive 
monthly electronic surveys which are already part of their routine clinical care. These 
surveys are going to be abbreviated to include average and worst Numerical Rating Scale 
(NRS) of pain; National Institute of Health (NIH) Patient Reported Outcomes 
Measurement Information System (PROMIS) measures for function, depression and pain 
interference; and questions about medication compliance, dose and adverse events. Data 
about use of other analgesics and medications, and pain interventions will also be 
recorded at these intervals from participants’ electronic health records. If the participants 
do not complete the surveys within five days of receipt of the survey link, they will be 
contacted to be reminded of the survey. We will also record participants’ baseline 
characteristics including age, sex, main pain diagnosis, other pain diagnoses, 
psychological comorbidities, medical comorbidities, medication use, and education. 
b. 
Procedure Risks 
The medications studied are both commonly used medications for patients with chronic 
pain. There is no additional risk with participation in the study. 
c. 
Use of Deception in the Study 
Deception will not be used. 
d. 
Use of Audio and Video Recordings 
Audio or video recording will not occur. 
e. 
Alternative Procedures or Courses of Treatment 
No alternative treatment is withheld from the patients. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Participant will continue to receive their usual care from Stanford Pain Management 
Center after completion of the study. If one medication is proven to be superior, then the 
participants' physicians will be notified. 

May 17, 2022 
 
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g. 
Study Endpoint(s) 
We will not have any interim analysis; thus, we will be able to assess the superiority of 
one treatment at conclusion of the study. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Chronic pain is a major healthcare problem affecting more than 100 million Americans. 
Chronic pain is a disease that can significantly compromise patients’ quality of life and 
cause disability. It bears annual cost of around 635 billion Dollars on United States 
Healthcare System. The number of treatment modalities available for this condition is 
disproportionately low; moreover, the quality of data available for these modalities is not 
optimal either.(1) Pain medicine literature like other specialties faces problems with 
reproducibility and generalizability. In an attempt to test reproducibility of present 
literature, investigators could reproduce the results of only six (11%) out of 53 
hematology-oncology trials. Interestingly, all these manuscripts had been published in 
reputable peer-reviewed journals with impact factors of above five.(2) We do not expect 
perioperative and pain medicine literature to be remarkably different. 
 
The other problem with current literature is generalizability of the data. Large clinical 
trials usually have stringent inclusion and exclusion criteria. By restricting enrollment of 
patients with more serious comorbidities and psychological conditions, the observed 
differences can be attributed to interventions studied. By decreasing variability, statistical 
power to detect a treatment effect can be increased with the same number of patients. The 
disadvantage of this approach is that the results cannot easily be generalized to a large 
population of patients with more serious comorbidities and psychological conditions. 
This cohort of the patient is usually more difficult to treat.(3,4) Our current literature 
lacks high quality data to guide clinicians providing care to these patients. A simple 
example is implant to trial ration in patients undergoing trial of spinal cord stimulation. 
Most large clinical trials show that around 90% of patients have a successful trial of 
spinal cord stimulation and proceed with implantation.(5) However, case series published 
by large academic centers report that around 70% of the patients undergoing trial of 
spinal cord stimulation proceed to receiving an implanted device. (6,7) Comparative 
effectiveness research integrated with patient care can be one of the solutions to the 
current problem. These trials have a less stringent inclusion and exclusion criteria 
targeting patients who routinely receive clinical care. Therefore, the patients enrolled in 
these studies will better represent patients with chronic pain. Integration of research into 
patient care will allow enrollment of larger number of patients. This will enable the 
researchers to analyze known and unknown effects of treatments in the whole sample as 
well as in specific subgroups.3,4 Outcomes Research Consortium has already shown the 
benefits of this approach in perioperative medicine.(8) Comparative effectiveness trials 
focus more on effectiveness rather than efficacy. A specific treatment might be 
efficacious but not effective, especially in long term administration. In addition to 
efficacy, there are other factors than can affect effectiveness of a treatment including 
compliance, accessibility, ease of administration, etc. In chronic conditions, it is essential 

May 17, 2022 
 
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to study long term effectiveness of a treatment modality in order to achieve meaningful 
sustainable improvement for patients. 
 
We will leverage the advantages of a comparative effectiveness trial to answer an 
important question in pain medicine. Antidepressants are widely used to treat patients 
with chronic pain. Initial choice of antidepressant is usually based on clinical judgement 
of the clinician considering potential benefits versus risks of individual medications. Two 
most important classes of antidepressants used in patients with chronic pain are tricyclic 
antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs). 
Duloxetine is an SNRI that is approved by United States Food and Drug Administration 
for treatment of fibromyalgia, painful diabetic neuropathy and chronic musculoskeletal 
pain. Two previous small size trials compared the efficacy of duloxetine with TCAs after 
a short course of treatment (4-6 weeks). The investigators could not find a difference 
between duloxetine and amitriptyline.(9,10) Moreover, meta-analysis of studies that 
compared these two groups of medications with placebo could not find any difference 
between these medications. However, none of the initial trials included in the meta-
analysis compared these TCAs and SNRIs directly.(11) One retrospective study showed 
decreased healthcare utilization in patients prescribed duloxetine compared to patients 
taking amitriptyline, pregabalin or gabapentin.(12,13) 
 
While most TCAs share the side effect of drowsiness, desipramine can be a better 
comparison for duloxetine. Like duloxetine, desipramine does usually not cause 
sleepiness or drowsiness. To the best of our knowledge, there has not been any clinical 
trials comparing long-term efficacy or effectiveness of duloxetine and desipramine. 
b. 
Findings from Past Animal Experiments 
Not applicable 
4. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Investigational Drugs, Biologics, Reagents, or Chemicals 
N/A 
b. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
Duloxetine 
Dosage: 
20-120 mg per day 
Administration Route 
Oral, Capsule 
New and different use? (Y/N) 
No 
Commercial Product 2 
Name: 
Desipramine 
Dosage: 
25-150 mg per day 
Administration Route 
Oral, Tablet 
New and different use? (Y/N) 
Yes 
5. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
N/A 

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6. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
Accepting type I error of 0.05 with 90% power, we will require 107 participants per 
group to detect one unit between-group difference in NRS pain scale. We are proposing a 
more conservative (larger) sample size to: (1) preserve power if the effect size is 
underestimated secondary to low medication adherence; and (2) preserve power for our 
subgroup analyses. We will therefore add 50% to our sample size to a total of 160 
patients in each arm. Correlation between repeated measure will decrease variance and 
increase the power of the proposed study. 
b. 
Age, Gender, and Ethnic Background 
Men and women of any ethnic background who are 18 years old or above will be 
enrolled. 
c. 
Vulnerable Populations 
We will not enroll potentially vulnerable subjects. 
d. 
Rationale for Exclusion of Certain Populations 
We are studying the comparative effectiveness of these two medications in adults. Study 
of chronic pain in children is beyond the scope of our study. 
e. 
Stanford Populations 
Not applicable 
f. 
Healthy Volunteers 
Not applicable 
g. 
Recruitment Details 
All adult patients with chronic pain receiving care from Stanford Pain Management 
Center will be assessed for eligibility by their treating pain physician during each clinical 
visit. If eligible, the treating pain physician will go through the oral consent script. If the 
patient consents to participate, he/she will be randomized to receiving either duloxetine 
or desipramine. Open label prescription will be then sent to participants' pharmacy. 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
1. Age of 18 years old or above 
2. Persistent pain for more than 3 months 
3. Candidate for treatment by anti-depressant based on treating pain provider 

May 17, 2022 
 
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ii. 
Exclusion Criteria 
1. Prior failure of duloxetine and/or desipramine (patients who have failed other 
TCAs or SNRIs can be considered for the trial based on the reason for previous 
medication failure) 
2. Contraindication to taking duloxetine or desipramine 
3. Patient refusal 
i. 
Screening Procedures 
We do not collect any PHI prior to enrollment. 
j. 
Participation in Multiple Protocols 
Participants will be asked if they are enrolled in any other research study. 
k. 
Payments to Participants 
Participants will not receive any payment for taking part in this study. 
l. 
Costs to Participants 
Cost of the study medication will be borne by the participants and/or insurance company 
as part of standard of care. The study itself does not incur any cost in addition to standard 
of care. 
m. 
Planned Duration of the Study 
We estimate the study to be completed in 5 years as below: 
1. Enrollment: 48 months 
2. Follow up for last enrolled patient: 6 months 
3. Data analysis and reporting the results: 6 months 
7. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
None 
ii. 
Investigational drugs 
None 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Potential adverse events are based on package insert approved by United States Food and 
Drug Administration: 
 
Duloxetine 
Reactions are categorized by body system according to the following definitions: 
frequent adverse reactions are those occurring in at least 1/100 patients; infrequent 

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adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those 
occurring in fewer than 1/1000 patients. 
Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and 
tachycardia. 
Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus. 
Endocrine Disorders — Infrequent: hypothyroidism. 
Eye Disorders — Frequent: vision blurred; Infrequent: diplopia and visual disturbance. 
Gastrointestinal Disorders — Frequent: flatulence; Infrequent: eructation, gastritis, 
halitosis, and stomatitis; Rare: gastric ulcer, hematochezia, and melena. 
General Disorders and Administration Site Conditions — Frequent: chills/rigors; 
Infrequent: feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait 
disturbance. 
Infections and Infestations — Infrequent: gastroenteritis and laryngitis. 
Investigations — Frequent: weight increased; Infrequent: blood cholesterol increased. 
Metabolism and Nutrition Disorders — Infrequent: dehydration and hyperlipidemia; 
Rare: dyslipidemia. 
Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; 
Infrequent: muscle tightness and muscle twitching. 
Nervous System Disorders — Frequent: dysgeusia, lethargy, and parasthesia/ 
hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor 
quality sleep; Rare: dysarthria. 
Psychiatric Disorders — Frequent: abnormal dreams and sleep disorder; Infrequent: 
apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide 
attempt; Rare: completed suicide. 
Renal and Urinary Disorders — Infrequent: dysuria, micturition urgency, nocturia, 
polyuria, and urine odor abnormal. 
Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; 
Infrequent: menopausal symptoms, and sexual dysfunction. 
Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: 
throat tightness. 
Skin and Subcutaneous Tissue Disorders — Infrequent: cold sweat, dermatitis contact, 
erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: 
ecchymosis. 
Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, 
and peripheral coldness." 
 
Desipramine 
"ADVERSE REACTIONS 
Included in the following listing are a few adverse reactions that have not been reported 
with this specific drug. However, the pharmacologic similarities among the tricyclic 
antidepressant drugs require that each of the reactions be considered when NORPRAMIN 
is given. 

May 17, 2022 
 
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Cardiovascular: Hypotension, hypertension, palpitations, heart block, myocardial 
infarction, stroke, arrhythmias, premature ventricular contractions, tachycardia, 
ventricular tachycardia, ventricular fibrillation, sudden death 
There has been a report of an "acute collapse" and "sudden death" in an 8-year-old (18 
kg) male, treated for 2 years for hyperactivity. 
There have been additional reports of sudden death in children. (See PRECAUTIONS-
Pediatric Use) 
Psychiatric: Confusional states (especially in the elderly) with hallucinations, 
disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; 
hypomania; exacerbation of psychosis 
Neurologic: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, 
tremors; peripheral neuropathy; extrapyramidal symptoms; seizures; alterations in EEG 
patterns; tinnitus 
Symptoms attributed to Neuroleptic Malignant Syndrome have been reported during 
desipramine use with and without concomitant neuroleptic therapy. 
Anticholinergic: Dry mouth, and rarely associated sublingual adenitis; blurred vision, 
disturbance of accommodation, mydriasis, increased intraocular pressure; constipation, 
paralytic ileus; urinary retention, delayed micturition, dilation of urinary tract 
Allergic: Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive 
exposure to sunlight), edema (of face and tongue or general), drug fever, cross-sensitivity 
with other tricyclic drugs Hematologic: Bone marrow depressions including 
agranulocytosis, eosinophilia, purpura, thrombocytopenia 
Gastrointestinal: Anorexia, nausea and vomiting, epigastric distress, peculiar taste, 
abdominal cramps, diarrhea, stomatitis, black tongue, hepatitis, jaundice (simulating 
obstructive), altered liver function, elevated liver function tests, increased pancreatic 
enzymes 
Endocrine: Gynecomastia in the male, breast enlargement and galactorrhea in the female; 
increased or decreased libido, impotence, painful ejaculation, testicular swelling; 
elevation or depression of blood sugar levels; syndrome of inappropriate antidiuretic 
hormone secretion (SIADH) 
Other: Weight gain or loss; perspiration, flushing; urinary frequency, nocturia; parotid 
swelling; drowsiness, dizziness, proneness to falling, weakness and fatigue, headache; 
fever; alopecia; elevated alkaline phosphatase" 
iv. 
Procedures 
None 
v. 
Radioisotopes/radiation-producing machines 
None 
vi. 
Physical well-being 
Not applicable 

May 17, 2022 
 
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vii. 
Psychological well-being 
Not applicable 
viii. 
Economic well-being 
Not applicable 
ix. 
Social well-being 
Not applicable 
x. 
Overall evaluation of risk 
Low 
b. 
International Research Risk Procedures 
Not applicable 
c. 
Procedures to Minimize Risk 
Study medications will be administered as open label prescription. Both duloxetine and 
desipramine are commercially used medications at Stanford Pain Management Center; 
hence, all our clinicians have extensive experience in prescribing these medications and 
monitoring participants afterwards. We will continue safety monitoring procedure of 
Stanford Pain Management Center for these medications which includes regular follow-
up visits as well as an open line of communication with nurses and physicians of our 
clinic. Moreover, the participants will have the contact information of the protocol 
directors and can consult them with any further questions or concerns. 
d. 
Study Conclusion 
The study will terminate at the completion of follow-up for last patient enrolled. Study 
medication will be stopped if the participant decides to discontinue the medication. Since 
the medications used are part of standard clinical care that the patients receive in our 
clinic, the participants can continue the medication after the completion of the study if 
they would like to. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
The treatments in the study are not different from routine clinical practice; therefore, 
adverse events will be monitored as a part of participants' clinical care by their clinic 
providers. Protocol Director (PD) will monitor for protocol deviations. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
Data and safety will be monitored by investigators and PD. 
iii. 
Frequency of DSMB meetings 
N/A 

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iv. 
Specific triggers or stopping rules 
N/A 
v. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Yes 
f. 
Risks to Special Populations 
N/A 
8. 
BENEFITS 
There is no potential benefit related to participation in the study. 
Any benefit can be attributed to clinical administration of these two 
medications that are commonly used in adult patients with chronic 
pain. 
9. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health.