Clinical trial NCT03249558
Conditions: Chronic Low Back Pain Chronic Neck Pain
Keywords: Pain Pain Management
Sponsor: Massachusetts General Hospital
Start date: 2018-03-12; Completion date: 2022-04-05
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A double-blind, randomized, and placebo-controlled clinical study examining whether duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), could enhance opioid analgesia and reduce overall opioid use. Positive outcomes will help improve the overall effectiveness of clinical opioid therapy and reduce unnecessary opioid dose escalation.

Detailed description:
Subjects will participate in a 10-week study consisting of three phases: Phase I is the dose titration period of 4 weeks, Phase II is the dose maintenance period of 4 weeks, and Phase III is the dose taper period of 2 weeks. Seven office visits (Initial visit/baseline, weeks 1, 3, 5, 7, 9, and end of week 10) and four follow up phone calls (weeks 2, 4, 6, and 10) will be used to collect data. Since this is a prospective study, we will be able to first determine baseline QST and VAS pain score, followed by assessing their longitudinal changes at each office visit. To assess OIH, QST will be performed at each office visit before subject takes the next dose of the study drugs. We will also measure plasma morphine concentration during the titration and maintenance phase to help validate morphine intake.

Arms: arm 1: Subjects will take a maximum dose of 60 mg/day of extended release morphine capsules and 60 mg of duloxetine capsules. arm 2: Subjects will take a maximum dose of 60 mg/day of extended release morphine capsules and placebo duloxetine capsules. arm 3: Subjects will take placebo morphine capsules and 60 mg of duloxetine capsules.
Interventions: intervention 1: Morphine intervention 2: Duloxetine intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects will be randomized into one of the treatment groups and will follow the assigned medication schedule for 10 weeks. Quantitative Sensory Testing (QST) will be performed on the subjects to compare pain threshold, pain tolerance, and wind up. intervention 2: Subjects will be randomized into one of the treatment groups and will follow the assigned medication schedule for 10 weeks. Quantitative Sensory Testing (QST) will be performed on the subjects to compare pain threshold, pain tolerance, and wind up. intervention 3: Subjects will be randomized into one of the treatment groups and will follow the assigned medication schedule for 10 weeks. Quantitative Sensory Testing (QST) will be performed on the subjects to compare pain threshold, pain tolerance, and wind up.

Protocol documents:
Prot_SAP_000.pdf: 
P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effect of Combined Morphine and Duloxetine on Chronic Pain  
 
NCT03249558 
 
02/18/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
2 
 
Effect of Combined Morphine and Duloxetine on Chronic Pain  
Principal Investigator: Jianren Mao, M.D., Ph.D. 
Detailed Protocol 
 
 
I. BACKGROUND AND SIGNIFICANCE 
a. Historical Background 
Patients suffering from chronic pain often present with comorbidities such as depression and 
require multi-modality treatment including medications.  Preclinical studies on the 
pathophysiology of pain suggests that pain symptoms may be treated by targeting distinctive 
underlying mechanisms, but a number of obstacles have so far made it difficult to translate 
preclinical findings to clinical applications (Mao, 2013).  To date, several categories of 
medications are commonly used in chronic pain management including non-steroidal anti-
inflammatory drugs, acetaminophen, opioids, antidepressants, antiepileptic drugs including 
gabapentinoids, and topical agents (Mao et al. 2011; Cohen, Mao, 2014).  Moreover, the concept 
of combination drug therapy for pain management has been known for several decades, which 
refers to the combined use of different categories of pain medications in order to achieve improved 
pain relief as a primary goal (Vorobeychik et al., 2011).  While opioids are strong analgesics for 
the treatment of moderate to severe pain, their use is often complicated by side effects and 
sometimes adverse outcomes such as addiction, abuse, and paradoxical opioid-induced 
hyperalgesia (OIH) (e.g., Mao, 2002; 2010; Chu et al., 2006, 2011; Ram et al., 2008; Chen et al., 
2009).  Although it is uncommon for clinicians to use opioids as a single drug treatment for chronic 
pain, few clinical trials have adequately assessed opioid therapies in combination with a non-
opioid adjunct such as an antidepressant with regard to 1) analgesic effect, 2) side effect profile, 
and 3) adverse outcomes including opioid dependence and OIH.  Accordingly, we propose to 
conduct a double-blind, randomized, and placebo-controlled clinical study in order to examine 
whether duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), could enhance 
opioid analgesia and decrease overall opioid use.  We expect that this prospective human study 
will yield timely and much-needed clinical data on the effectiveness, or lack thereof, of adding an 
adjunct to opioid therapy in chronic pain management.  Positive outcomes of this study will help 
improve opioid analgesia and reduce unnecessary opioid dose escalation. 
 
b. Previous studies 
Combination drug therapy with opioid and antidepressant – preclinical studies 
A number of preclinical studies have demonstrated the efficacy of various drug combinations in 
rodent or primate models of tissue injury (Banks et al., 2010; Sikka et al., 2011; Li et al., 2011).  
In addition, combining monoamine reuptake inhibitors with morphine enhanced the morphine anti-
nociceptive effect in rats (Taiwo et al., 1985; Shen et al., 2013).  Fluoxetine, a selective serotonin 
reuptake inhibitor (SSRI), influenced isolation-induced morphine self-administration in rodents by 
restoring the central serotonin function (Raz, Berger, 2010), prevented morphine tolerance in mice 
(Nayebi et al., 2009), and attenuated morphine withdrawal signs in neonatal rats (Sills, Fletcher, 
1997; Wu et al., 2005).  Moreover, maprotiline, a non-selective antidepressant, enhanced morphine 
antinociception when both drugs were injected intrathecally in rats (Pettersen et al., 2009).  Of 
note, most preclinical studies on the interaction between opioid and SSRI were conducted in 
healthy rodents and their clinical relevance remains to be determined.   
 
Combination drug therapy for chronic pain management – clinical studies 
 
 
 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
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Although effective in some cases, using single drug therapy often fails to provide adequate 
analgesia for many chronic pain conditions.  Indeed, clinicians regularly use more than one 
medication in pain treatment regimens in order to improve analgesia and/or reduce side effects.  
Some of the commonly used combinations of pain medications include gabapentin or pregabalin 
with a tricyclic antidepressant, opioid with gabapentin or a tricyclic antidepressant, and an oral 
medication (e.g., gabapentin) with a topical agent such as lidocaine patch or cream (Bril et al., 
2011; Vorobeychik et al., 2011; McCormick et al., 2014).  For example, a previous study has 
shown that combining gabapentin with an opioid analgesic is effective to reduce pain and produces 
fewer side effects (Gilron et al., 2005).  Fluoxetine has also been shown to improve drug-related 
side effects such as morphine-induced pruritus and sedation (Erjavec et al., 2000).  However, 
several studies using combination drug therapy have yielded either negative or equivocal results.  
In a study of 28 completed subjects, morphine (15-90 mg), either alone or in combination with 
nortriptyline (25-100 mg), produced no significant analgesic effect on sciatic pain (Khoromi et al., 
2007).  In another study of 16 subjects with neuropathic pain due to advanced cancer, adding 
amitriptyline (up to 50 mg) to opioid therapy also produced no significant pain improvement 
(Mercadante et al., 2002).  While the number of clinical studies on combination drug therapies is 
still limited, several preliminary indications have emerged from these studies (Mao et al., 2011; 
Vorobeychik et al., 2011).  (1) Most studies demonstrate some benefits by including 
gabapentinoids in combination drug therapy for pain related to diabetic neuropathy and post-
herpetic neuropathy.  (2) High concentration topical capsaicin or 5% lidocaine patch seems to be 
effective as add-on therapies to oral pain medications.  (3) Most clinical studies suggest that the 
effectiveness of combination drug therapy is dependent on the type of pain conditions and dose 
regimens.  Therefore, we feel that several key issues must be addressed in a combination drug 
therapy in order to evaluate its clinical effectiveness, including patient population, choice of 
medications, treatment regimen, and appropriate outcome assessment. 
 
c. Rationale for using duloxetine as an adjunct to opioid therapy 
Duloxetine is an SNRI and approved by the FDA to treat diabetic neuropathic pain, fibromyalgia, 
and musculoskeletal pain (www.FDA.gov).  In this project, we choose to study the effectiveness 
of duloxetine as an adjunct to opioid therapy for several reasons.  First, SNRI such as venlafaxine 
has been shown to modulate morphine analgesia in a rodent neuropathy model. Its acute effect 
improved and chronic effect reduced morphine antinociception, respectively (Cegielska-Perun et 
al., 2012, 2014, 2015). Venlafaxine also attenuated morphine dependence and withdrawal in naive 
rats (Lu et al., 2001).  Preclinical studies have shown that duloxetine also attenuated morphine 
tolerance and morphine withdrawal signs in rodents without persistent nociception (Ozdemir et 
al., 2012; Charkhpour et al, 2014).  Duloxetine itself has been shown to reduce nociceptive 
behavior in both inflammation (Jones et al., 2005) and post-operative pain (Obata et al., 2010) 
models in rats. The effect of duloxetine on pain modulation may be due to its ability to increase 
the spinal norepinephrine level (Meske et al., 2014).  Of interest to note is that, in a rat nerve injury 
model, morphine appears to be more effective to reduce mechanical allodynia whereas duloxetine 
is more effective to diminish neuroma-induced nociception (Miyazaki, Yamamoto, 2012).  
Second, duloxetine has been shown to reduce morphine requirement in patients with knee 
replacement surgery in a small (50 subjects) clinical study (Ho et al., 2010).  An earlier human 
study also suggests that increasing the central serotonin level may enhance morphine analgesia 
(Coda et al., 1993).  To our knowledge, no randomized, placebo-controlled clinical studies have 
been carried out to examine the effect of duloxetine on opioid analgesia in patients with chronic 
neck and back radicular pain symptoms.  Third, duloxetine is an FDA-approved drug for 
depression and pain treatment with a relatively good safety profile (but with a warning for suicidal 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
4 
 
risk in young subjects; www.FDA.gov).  Since its approval by FDA for chronic pain treatment, 
duloxetine has been increasingly used in clinical settings.  Fourth, among SNRIs including 
milnacipran and venlafaxine, duloxetine (60 mg, oral) has a pharmacokinetic profile that favors a 
chronic course of treatment with minimal day-to-day dose adjustment, including about 6 hours to 
reach the peak plasma level, an elimination half-life of 8-17 hours (average 12 hours), and a 50% 
oral bioavailability (www.FDA.gov).  In comparison, milnacipran involves a more complicated 
titration schedule and is approved for fibromyalgia treatment whereas venlafaxine is used off-lable 
for pain treatment and has a rather short half-life requirig 2-3 daily doses (www.FDA.gov).  
Therefore, we choose to add duloxetine (generic formula; daily doing) to an opioid therapy in this 
clinical study.  We expect that this combination therapy will enhance opioid analgesia and reduce 
overall opioid use, thereby diminishing opioid dependence/withdrawal and OIH. 
 
II. SPECIFIC AIMS 
This study has two specific aims: 
1. To examine changes in VAS scores and to determine total versus rescue opioid use 
(primary outcomes) after each treatment 
2. To compare secondary outcomes including a) side effect profile, b) dropout rate, c) 
functional status, d) physiologic opioid dependence, e) OIH, and f) urine drug screening 
 
 
III. SUBJECT SELECTION 
a. Inclusion/Exclusion Criteria 
Inclusion Criteria: 
1. Subject is 18-70 years old. 
2. Subject has chronic neck or back pain for at least 3 months. 
3. Subject has a VAS ≥ 6. 
4. Has not taken duloxetine in the last 3 months. 
5. Has not taken an opioid in the last 3 months, but has taken one in the past without 
sufficient pain control OR has never taken opioids but has failed at 3 (or more) non-opioid 
treatments. 
 
 
Exclusion Criteria: 
1. Subject has major psychiatric disorders requiring recent hospitalization (within 3 months) 
such as major depression, bipolar disorder, schizophrenia, anxiety disorder, or psychotic 
disorder. 
2. Subject is using illicit drugs or alcohol detected by urine toxicology/drug screen. 
3. Subject has a history of alcohol use disorder within 6 months. 
4. Subject is pregnant or lactating/breast feeding. 
5. Subject is allergic to morphine or duloxetine. 
6. Subject is on an antidepressant including SNRI, SSRI, tricyclic antidepressant. 
7. Subject has a history of suicidal attempts or current suicidal ideation. 
8. Subject takes monoamine oxidase inhibitors, antipsychotics, triptan drugs such as 
sumatriptan, lithium, linezolid, tramadol (Ultram), St. John’s Wort, Kratom, CNS 
stimulants such as amphetamine, methylphenidate, methamphetamine, phentermine, 
diethylpropion, sibutramine, cocaine, or thiordazine. 
9. Subject takes drugs that cause loss of potassium such as diuretics and corticosteroids. 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
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10. Subject takes digoxin, cyclosporine, methenamine, or high doses of salicylates (i.e. 
aspirin). 
11. Subject takes anticonvulsants such as topiramate, phenytoin and zonisamide. 
12. Subject has uncontrolled narrow-angle glaucoma. 
13. Subject has sensory deficits on arms or Raynaud’s Syndrome. 
14. Subject has a pending litigation related to chronic pain condition. 
15. Subject is on methadone or suboxone treatment for addiction. 
16. Subject has a lifetime history of opioid addiction. 
17. Subject has an allergy to morphine, duloxetine, acetazolamide, or other sulfa drugs. 
18. Subject scores 18 or higher on the Screener and Opioid Assessment for Patients with 
Pain-Reversed (SOAPP-R) questionnaire. 
 
All potential subjects will be reviewed by a study physician to determine inclusion.  The study 
physician will review: 1) information obtained during the IRB approved phone screen, 2) Partners 
LMR and 3) medical records received from the PCP or prescribing physician.  Subjects will be 
informed that the information obtained is solely for the purpose of making sure it is safe for them 
to participate in the study. 
 
b. Source of subjects and recruitment methods 
Study subjects will be recruited from: 1) pools of patients under treatment at the MGH Center for 
Pain Medicine, 2) MGH internal medicine department and orthopedic spine center, and 3) the local 
community through advertisements and physician referrals from our counterparts in the Harvard 
medical system including Brigham & Women’s Hospital, Beth Israel and Deaconess Medical 
Center, Spaulding Rehabilitation Hospital, Newton-Wellesley Hospital, etc.  Our established 
referral network and advertisement venues (e.g., RSVP: a Healthcare Database from the Partners’ 
system including MGH and Brigham & Women's Hospital) will be used to facilitate subject 
recruitment.  
 
IV.  SUBJECT ENROLLMENT 
a. Methods of enrollment 
1. Study subjects will be recruited through advertisements, U.S. post, or in person by a study 
staff member at the MGH Center for Pain Medicine.  Study subjects can contact the MGH 
Center for Translational Pain Research for information about the study.   
2. The principal investigator will ask his physician colleagues working at Partners facilities 
to help identify their patients who may be eligible for this study. The primary healthcare 
provider will first explain the research study to the identified patient or give him/her a 
Research Invitation.  If the patient is interested, the primary healthcare provider will 
provide the study staff’s contact information or will obtain the patient’s permission 
(verbally or by use of Research Invitation) to be contacted by study staff. If the patient’s 
primary healthcare provider is one of the study investigators, the patient will be recruited 
using one of the following methods: 
i. 
A Research Invitation will be sent to the patient.  If interested, the patient 
can contact the study investigator or study staff. 
ii. 
The study investigator can ask a physician colleague to initially explain the 
study to the potential subject. 
iii. 
The study investigator can present the study to the patient and then ask a 
physician colleague to re-contact the patient. 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
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iv. 
The study investigator can present the study to the patient and provide the 
patient with the Consent Form to take home.  If interested, the patient can 
contact the study investigator or study staff. 
 
b. Procedures for obtaining informed consent 
The potential subject will be provided with information about the research through 
advertisements, Research Invitations, or reading a copy of the Consent Form.  The potential 
subject can learn more about the study including potential benefits, risks, and discomforts by 
speaking with the study staff.  The subject will be given as much time as needed to consider 
participating in the study.  If the subject is eligible and decides to participate, he/she will be 
scheduled for a visit at the MGH Center for Translational Pain Research.  At the first visit, the 
subject will read the Consent Form and then meet with a study physician via phone call to review 
and discuss the details of the study that are outlined in it. Any questions pertaining to the study 
will be answered at that time.  If the subject agrees to participate, he/she will sign the Consent 
Form through a survey on REDCap with Adobe sign feature using a laptop provided or personal 
electronic device. The study physician will then log into REDCap right after and sign their 
signature. Two copies of the Consent Form will be printed with signatures from the REDCap 
website. The subject will take one copy and the other copy will be kept in his/her study folder.  
Subjects will have the option to meet with a study physician who is not their pain physician. 
 
c. Treatment Assignment and Randomization 
A total of 135 subjects will be enrolled for this double-blind, randomized study.  Subjects will be 
randomized into three groups (n=45 subjects/group) using a computer-generated randomization 
protocol (Randomization.com). 
Group 1: morphine + placebo with acetazolamide 
Group 2: morphine + duloxetine with acetazolamide  
Group 3: placebo + duloxetine with acetazolamide 
 
The duloxetine and placebo for duloxetine are specifically compounded with acetazolamide (15 
mg), which will be used as a tracer to determine a subject’s compliance with the study medication. 
 
V. STUDY PROCEDURES 
a. Study visits and parameters to be measured 
Subjects will participate in a 10 week study consisting of three phases: Phase I is the dose 
titration period of 4 weeks, Phase II is the dose maintenance period of 4 weeks, and Phase III is 
the dose taper period of 2 weeks. 
 
Seven office visits (screening visit, weeks 1, 3, 5, 7, 9, and end of week 10)and four follow up 
phone calls ( weeks 2, 4, 6, and 10) will be used to collect data.  Since this is a prospective study, 
we will be able to first determine baseline quantitative sensory testing (QST) and VAS pain score, 
followed by assessing their longitudinal changes at each office visit.  To assess OIH, QST will be 
performed at each office visit before subject takes the next dose of the study drugs.  We will also 
measure plasma morphine concentration during the titration and maintenance phase to help 
validate morphine intake. 
 
Urine Screening 
Subjects who are using illicit drugs detected by urine toxicology/drug screen including stimulants, 
benzos, alcohol, opioid (other than the study opioid), cocaine will be withdrawn from the study. 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
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Given the increasing use of marijuana in general population and the knowledge of a minimal 
impact of occasional marijuana use on opioid effects, we will use the following plan to monitor 
marijuana use. 
a. If subjects test positive for marijuana use at the initial screening, the subjects will be given the 
chance to have a second urine test in one week.  If the second test is negative, subjects will be 
allowed to participate in the study. If the urine test is positive, subjects will be withdrawn. 
b. During the study, subjects take a urine drug test at each office visit.  Similarly, if the subject 
tests positive for marijuana use at one of these office visits, the subject will be given the chance 
to have a second test in one week while continuing the study.  If the second test is also positive, 
the subject will be dismissed from the study with a proper monitoring and management of 
withdrawal symptoms. 
 
Screening Visit 
1. Subject will meet with a study physician to review pain and medical history to confirm 
inclusion/exclusion criteria 
2. Informed consent will be obtained by a study physician 
3. Vital signs (blood pressure, oxygen saturation, and pulse) will be taken 
4. Urine sample will be collected for drugs of abuse (DOA) and pregnancy test 
5. The following questionnaires will be completed: Pain Questionnaire, Short-form McGill 
Pain Questionnaire (SF-MPQ2), Short-form 36 (SF-36), Beck Depression Inventory 
(BDI-II), Prescription Drug Use Questionnaire (PDUQ), Screener and Opioid 
Assessment for Patients with Pain- Reversed (SOAPP-R) and Anxiety Sensitivity Index 
(ASI) 
6. Sensory test at QST site 
7. QST testing 
 
Visit 1 
1. Vital signs will be taken 
2. Urine sample will be collected for DOA and acetazolamide/creatinine measurement 
3. Provide study medication and review medication instructions, daily pain log, and daily 
medication log 
4. The following questionnaires will be completed: Pain Questionnaire, Short-form McGill 
Pain Questionnaire (SF-MPQ2), Short-form 36 (SF-36), Anxiety Sensitivity Index (ASI), 
Beck Depression Inventory (BDI-II), and Prescription Drug Use Questionnaire (PDUQ) 
5. Schedule future study visits 
6. Blood draw (10 cc) to measure plasma morphine concentration to confirm subject is not 
taking morphine  
 
Visits 2, 3 and 5 
1. Vital signs will be taken 
2. Urine sample will be collected for DOA and acetazolamide/creatinine measurement 
3. Collect and count unused study medication and provide study medication for the next 
phase 
4. Review daily pain and medication logs and provide subject with new logs 
5. The following questionnaires will be completed: Pain Questionnaire, Short-form McGill 
Pain Questionnaire (SF-MPQ2), Short-form 36 (SF-36), Anxiety Sensitivity Index (ASI), 
Beck Depression Inventory (BDI-II), and Prescription Drug Use Questionnaire (PDUQ) 
6. QST testing 


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
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Visits 4 
1. Vital signs will be taken 
2. Urine sample will be collected for DOA and acetazolamide/creatinine measurement 
3. Collect and count unused study medication and provide study medication for the next 
phase 
4. Review daily pain and medication logs and provide subject with new logs 
5. The following questionnaires will be completed: Pain Questionnaire, Short-form McGill 
Pain Questionnaire (SF-MPQ2), Short-form 36 (SF-36), Anxiety Sensitivity Index (ASI), 
Beck Depression Inventory (BDI-II), and Prescription Drug Use Questionnaire (PDUQ) 
6. Perform QST 
7. Blood draw (10 cc) to measure plasma morphine concentration and biomarkers 
 
Visit 6 
1. Vital signs will be taken 
2. Urine sample will be collected for DOA and acetazolamide/creatinine measurement 
3. Collect and count unused study medication 
4. Review daily pain and medication logs 
5. The following questionnaires will be completed: Pain Questionnaire, Short-form McGill 
Pain Questionnaire (SF-MPQ2), Short-form 36 (SF-36), Anxiety Sensitivity Index (ASI), 
Beck Depression Inventory (BDI-II), Clinical Opioid Withdrawal Scale (COWS), and 
Prescription Drug Use Questionnaire (PDUQ) 
6. Perform QST 
7. Remuneration form completed 
 
Phone Calls 
Trained study staff will call subjects at weeks 2, 4, 6 and 10 to monitor subject safety and 
compliance.  Subjects will be asked about their pain, medication schedule, medication side effects, 
and overall health.  Subjects will have an opportunity to ask questions and speak to a study 
physician.  
 
Remuneration 
Subjects will receive $300 for completing the study, plus $10 as a travel stipend for each office 
visit (up to $370). Payment will be in the form of one check which will be mailed to the subject 
about 4-6 weeks after their last visit.   
 
The following guidelines have been created for cases concerning pro-rated remuneration: 
1. Subjects testing positive for illicit drugs or undisclosed prescriptions or subjects who are 
non-compliant with the study medication schedule will receive zero payment. Non-
compliance will be determined by the study physicians on a case by case basis. We cannot 
define an objective set of criteria for non-compliance since every scenario will differ based 
on study phase, potential side effects, and subject reported information (such as incomplete 
logs or missed phone calls, and CleverCap discrepancy). 
2. Subjects who do not complete the study through their own decision will receive full 
payment and the travel stipend for the visits attended. 
3. Subjects who are withdrawn by an investigator by no fault of their own will receive full 
payment for the visits attended.  


P.I. Jianren Mao, M.D., Ph.D. 
 
Version Date: 2/18/2022 
 
 
 
 
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4. Subjects who fail to return the loaned CleverCaps will not receive payment to allow for 
the purchase of replacements. 
5.  Subjects who test positive for marijuana will be allowed to re-take the urine test in one 
week or at the next scheduled visit. If the second test is negative they will be allowed to 
continue in the study. If the second test is positive they will be withdrawn from the study 
and will not receive payment. 
 
All prorated remuneration will be documented via progress notes and kept with the subject’s 
research folder. 
 
The pro-rated remuneration for visits attended is as follows: 
1.  
Screening Visit:  
$40 + $10 travel stipend or parking pass 
Visit 1:  
 
$50 + $10 travel stipend or parking pass 
Visit 2:  
 
$40 + $10 travel stipend or parking pass 
Visit 3:  
 
$40 + $10 travel stipend or parking pass 
Visit 4:  
 
$50 + $10 travel stipend or parking pass 
Visit 5:  
 
$40 + $10 travel stipend or parking pass 
Visit 6  
 
$40 + $10 travel stipend or parking pass 
 
b. Drugs to be used: 
 
Dose of study medications 
Group 1: Extended release morphine (15 mg) + placebo with acetazolamide (15 mg): Subjects will 
be titrated onto extended release morphine until their pain level is reduced to a VAS ≤ 3 or until 
the maximal tolerable dose (up to 60 mg/day) is reached.  The placebo will be a sugar pill and will 
be compounded with acetazolamide (15 mg).   
Group 2: Extended release morphine (15 mg) + duloxetine (30 mg) with acetazolamide (15 mg):  
Subjects will be titrated onto extended release morphine until pain level is reduced to a VAS ≤ 3 
or until the maximal tolerable dose (up to 60 mg/day) is reached.  Subjects will be titrated onto 
duloxetine until they have reached 60 mg/day.  The duloxetine will be compounded with 
acetazolamide (15 mg). 
Group 3: Placebo + duloxetine (30 mg) with acetazolamide (15 mg)The placebo will be a sugar 
pill.  Subjects will be titrated onto duloxetine until they have reached 60 mg/day.  The duloxetine 
will be compounded with acetazolamide (15 mg). 
 
Morphine placebo and duloxetine placebo will have similar weight and packaging to the true 
morphine and true duloxetine in order to maintain blinding for subjects and study staff.  The 
morphine/morphine placebo pills will be packaged in a different colored capsule than the 
duloxetine/duloxetine placebo so subjects can differentiate between the two pills.  All medications 
will be taken orally, and will be prepared, dispensed, and coded by the MGH Research Pharmacy.  
The assignment will not be disclosed to the study subject or study staff. 
 
Rescue medication: 
Subjects in all three groups will be asked to stay on the same non-opioid pain medications, if any, 
without change once the study starts. Although no progression of overall pain condition is expected 
for study subjects, there may be sporadic breakthrough pain on top of an otherwise stable pain 
condition (i.e., no worsening of underlying pathology).  This would be more likely to occur in the 


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10 
 
doluxetine and placebo group. Subjects will be titrated onto the rescue medication and will be 
allowed to take up to two 15 mg instant release morphine pills/day, so that the total maximum dose 
of morphine (extended release + instant release) is 90 mg/day. Subjects will be tapered off the 
rescue morphine before they finish the study. To avoid overdosing, subjects will be instructed to 
wait at least 2 hours after taking their other study medication (extended release morphine or 
placebo) before taking the rescue dose.  They will also be asked to wait at least 2 hours before 
taking the next dose of the study medication.    
 
Medication schedule: 
Subjects will participate in this 10 week study that consists of three phases: Phase I is the dose 
titration period of 4 weeks, Phase II is the dose maintenance period of 4 weeks, and Phase III is 
the dose taper period of 2 weeks.  Study medications will be dispensed at weeks 1, 3, 5, 7, and 9.  
For the subject’s safety, study medication for the titration and maintenance periods will be 
dispensed with up to an additional three days of medication; this will prevent medication 
withdrawal if the subject has to reschedule a visit.  Subjects will take the medication according to 
the table below: 
   
TITRATION PERIOD 
Week 
Extended Release Morphine 
(15mg) or Placebo 
Rescue medication: Instant Release 
Morphine (15 mg) 
Week 
Duloxetine or 
Placebo (30mg) 
Morning 
Evening 
As needed 
Evening 
1 
0 
1 
≤1 
1 
1 
2 
1 
1 
≤2 
2 
2 
3 
1 
2 
≤2 
3 
2 
4 
2 
2 
≤2 
4 
2 
 
 
 
 
 
 
 
MAINTENANCE PERIOD 
Week 
Extended Release Morphine 
(15mg) or Placebo 
Rescue medication: Instant Release 
Morphine (15 mg) 
Week 
Duloxetine or 
Placebo (30mg) 
Morning 
Evening 
As needed, no more than 2 pills/day 
Evening 
5-8 
2 
2 
≤2 
5-8 
2 
 
 
 
 
 
 
 
TAPER PERIOD 
Day 
Extended Release Morphine 
(15mg) or Placebo 
Day 
Rescue medication: 
Instant Release 
Morphine (15 mg) 
Day 
Duloxetine or 
Placebo (30mg) 
Morning 
Evening 
As needed, no more than 1 pill/day 
Evening 
56-60 
1 
2 
56-62 
≤1 
56-62 
1 
61-65 
1 
1 
63, 65, 67, 69 
0 
63, 65, 67, 69 
0 
66-69 
0 
1 
64, 66, 68 
≤1 
64, 66, 68 
1 
 
Study drug compliance 
We will use the following methods to monitor subjects’ compliance with the study medication: 
1. We will provide study subjects with a log sheet to record their daily medication intake 
(date and time).  Study subjects will be asked to bring the medication and log to each 
scheduled study visit.  The medication will be counted to make sure the returned quantity 
matches the balance between total given and taken based on the log sheet.  
2. Study medication vials will be secured with a CleverCap Pro which is a tamper resistant 
electronic cap that dispenses medication at a pre-set interval and a pre-set amount. 


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CleverCaps also record when the dose is dispensed so study staff will review these times 
and compare them to the subject’s daily medication log.      
3. The duloxetine and placebo for duloxetine are specifically compounded with 
acetazolamide (15 mg), which will be used as a tracer to determine a subject’s 
compliance with the study medication. We will collect a urine sample at each visit and 
test for levels of acetazolamide and creatinine. An acetazolamide/creatinine ratio will be 
used to determine if the subject has been taking the study medication containing 
acetazolamide if the cut-off ratio is set at 1. The urine samples will be sent to WuXi 
AppTec for the acetazolamide analysis. Blood will also be drawn at two visits to monitor 
the morphine plasma level. 
 
Noncompliance with medication and study visits, which affects the subject’s health or data 
integrity, may require withdrawal from the study.   
 
c. Electronic medical record 
When subjects enroll in this study, a notation will be made in their electronic medical record, which 
associates the subject with the study. We will also upload a copy of their signed Consent Form. 
Once subjects are associated with the study, anytime they are admitted to a Partners Hospital or 
visit a Partners Hospital Emergency Department, the study doctors will be alerted electronically. 
 
d. Hospital Admissions Alert System 
MGH uses an electronic system that automatically alerts your study doctors if you are admitted to 
a Partners Hospital or if you visit a Partners Hospital Emergency Department. The study doctors 
can know if you experience any side effects or other problems while partaking in the study. 
 
e. Devices to be used 
Medoc Thermal Sensory Analyzer (TSA), a thermal quantitative sensory testing device. This 
device is FDA approved in diagnosing neuropathic pain syndromes. The MGH Bioengineering 
Department inspects this device annually. 
 
f. Procedures/surgical interventions 
QST is a commonly used pain assessment tool both for human pain studies and clinical diagnosis. 
The thermode-skin interface will change temperature at 1 ºC/second from a baseline of 32 ºC to a 
maximum of 53 ºC. The subject can withdraw from the stimulation at any time. The following are 
examples of QST using heat stimulation. 
To detect heat pain threshold, a contact thermode will be placed to a designated body part (e.g., 
forearm).  Subjects will stop the stimulation by pressing a button when pain is first felt.  This same 
test will be repeated three times with a 20 second interval and the average of three threshold 
temperatures from these tests will be used as the pain threshold temperature (in degrees Celsius). 
To detect heat pain tolerance, a contact thermode will be placed to a designated body site (e.g., 
forearm). Subjects will stop the stimulation by pressing a button when the pain is no longer 
tolerable.  This same test will be repeated three times with a 1 minute interval and the average of 
three threshold temperatures from these tests will be used as the pain tolerance temperature (in 
degrees Celsius). 
To examine windup (temporal summation of second pain), a train of four identical stimuli at 47 
ºC (supra-threshold heat stimulation), separated by a 2.2 second interval between each stimulus, 
will be applied. Subjects will be asked to rate pain intensity by VAS following each of the four 
stimuli. The test will also be repeated three times.  


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To detect diffuse noxious inhibitory control (DNIC), we will use a protocol described in a recent 
study (Ram et al, 2009) and that has been employed in our research center.  Four heat stimuli (HS) 
of 47 ºC, each lasting 4 seconds, will be delivered according to pre-set intervals.  Subjects will be 
asked to rate the pain (VAS) after each heat stimuli.  Pain score in response to the first heat stimulus 
will serve as baseline (Trial 1).  The second heat stimulus (Trial 2) will be delivered during the 
final 4 seconds of a 30 second period when the subject’s hand (opposite to the side of QST) is 
immersed in a cold water (12 ºC) bucket.  Two additional heat stimuli will be delivered at 15 and 
30 seconds after removal of the hand from cold water (Trial 3 and Trial 4, respectively).  Pain 
scores from Trials 2-4 will be compared with the baseline (Trial 1) to determine the degree of 
DNIC (Ram et al, 2008).  This same test will be repeated three times and the average of these tests 
will be used. 
 
g. Data to be collected 
Seven office visits (screening visit, weeks 1, 3, 5, 7, 9, and end of week 10) and four follow up 
phone calls (at weeks 2, 4, 6, and 10) will be used to collect data. 
 
VI. BIOSTATISTICAL ANALYSIS  
a. Specific data variables being collected 
• Pain Questionnaire and Follow-up Pain Questionnaire 
• Beck Depression Inventory (BDI-II) 
• Short-form 36 (SF-36) 
• Anxiety and Sensitivity Index (ASI) 
• Short-form McGill Pain Questionnaire (SF-MPQ2) 
• Prescription Drug Use Questionnaire (PDUQ) 
• Clinical Opiate Withdrawal Scale (COWS) 
• Screener and Opioid Assessment for Patients with Pain- Revised (SOAPP-R) 
• Neurological examination including a detailed sensory examination (e.g., von Frey, cotton 
swab, pinprick, tuning fork, alcohol wipe) 
• A check on routine vital signs (blood pressure, pulse, blood oxygen level) 
• Urine drug and pregnancy tests 
• Acetazolamide/creatinine ratio 
•  CleverCap 
• Blood plasma drug concentration 
• Pain and medication log 
 
QST will include the following: 
• Heat pain threshold, heat pain tolerance, windup, and DNIC.  A cut-off of 53 0C will be 
preset to avoid tissue damage. 
 
b. Study endpoints 
Aim 1 (primary outcomes)  
1. Changes in VAS pain score after each treatment- we will make both within group and 
between group comparisons of VAS changes.  VAS scores from a given study group will 
be compared across various time points (e.g., weeks 0, 4, 8, and 10).  VAS scores will 
also be compared among the three groups at the same time points (weeks 0, 4, 8, and 10). 
2. Overall opioid dose (extended release morphine + rescue immediate release morphine) 
and rescue opioid dose (immediate release morphine)- we will compare overall opioid 


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dose between the morphine/duloxetine group and the morphine/placebo group and 
compare rescue dose among all three groups. 
Aim 2 (secondary outcomes)-We will compare secondary outcomes among three groups 
including:  
1. Side effect profile 
2. Dropout rate using Kaplan Myer survive curve 
3. Functional status and co-morbidities (scores on questionnaires)  
4. Opioid dependence 
5. OIH- we will compare QST responses along with VAS changes across three groups 
including changes in: 
a. Heat pain threshold 
b. Temporal summation and DNIC 
c. Mechanical pain threshold (von Frey filament) 
d. Pain location and quality as compared to pre-existing pain (e.g., aching vs. burning 
pain, localized vs. diffuse pain based on questionnaires 
6. Urine drug screening 
 
c. Statistical methods 
Our research center has used Redcap as the database for several previous and ongoing clinical 
studies.  For this study, we will also use Redcap to setup and maintain a designated research 
database.  The statistical packages will include both descriptive and quantitative data analyses 
using Sigma Stat (version 11) with the significance level at P< 0.05.  Ms. Trudy Poon (20% effort), 
a statistician in our department, will be available for consultation.  Descriptive analysis will be 
used to analyze the data obtained from various questionnaires (e.g., SF-MPQ-2; SF-36).  Percent 
(%) changes in each category will be analyzed using the Chi-square test.  Quantitative analysis 
will be used to analyze the data obtained from QST and VAS.  (A) The Mann Whitney U test will 
be used to analyze the non-parametric data (e.g., results from the von Frey filament test).  (B) For 
the parametric data, two-way repeated measure analysis of variance (ANOVA) will be used to 
examine differences across multiple groups at a given time point (between-group comparison) or 
across different test points for a given group (within-group comparison).  The post hoc Waller-
Duncan k-ratio t-test will be used to determine the source(s) of differences.  Since ANOVA 
analyses do not take into consideration the fixed (e.g., drug dose) versus random (pain duration, 
age, etc.) effects on study outcomes, we will also use a simple mixed effects modeling (SPSS 
program) to analyze the interception among these factors.  (C) Spearman Correlation Coefficient 
test will be used to examine correlations between clinical data (e.g., VAS change) and QST data.  
We will recruit equal numbers of male and female subjects so if there is sufficient statistical power 
for subgroup analysis, we will also analyze the sex/gender and ethnicity differences in our research 
data. 
 
d. Power analysis 
Estimation of group size (power analysis): Since VAS score change is a primary study outcome 
and previous studies have suggested that a VAS change of 2 points (or 30% from baseline) could 
be considered as clinically meaningful (Farrar et al., 2001; Cepeda et al., 2003; Grilo et al., 2007; 
Turk et al., 2008; Dworkin et al., 2009; Chen et al., 2009), we will use this parameter as the basis 
of power analysis.  Thus, a group size of 37 subjects will have 80% power assuming that the 
standard deviation is less than 2 points (VAS).  We anticipate a dropout rate of around 20%.  
Accordingly, we will recruit up to 45 subjects for each study group.  If the dropout rate increases 
above 20%, we will add more subjects in each group to replace the dropouts beyond the estimated 


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20% rate.  Since a) the MGH pain clinic alone receives over 15,000 visits per year, b) other pain 
clinics in the Boston area have a similar number of chronic pain patient visits (e.g., Brigham & 
Women’s Hospital and Beth Israel Deaconess Medical Center), and c) we have established a 
referral network and have recruited about 500 subjects in our OIH studies, we are confident that 
we will be able to recruit the proposed number of subjects for this project. 
 
VII. RISKS AND DISCOMFORTS 
a. Complications of surgical and non-surgical procedures 
1. Risks of QST 
Common: Heat stimulation for pain threshold and tolerance tests, although transient may 
elicit pain.  Heat stimulation may cause temporary skin sensitivity similar to mild sunburns.  
Immersion of a hand into a cool water (12 0C) bucket can be uncomfortable for subjects, 
particularly for those with pain in their upper extremities.  
Uncommon: If a skin change persists, the subject will be withdrawn from the study and 
proper treatment will be given or the subject will be referred to a dermatologist. 
 
2. Risks of blood drawing 
Subjects may experience slight pain, discomfort, bleeding, bruising or, rarely, an infection 
from the blood draws. A total of 20 cc of blood will be drawn over the course of the study.  
 
b. Drug side effects and toxicities 
1. Morphine  
Common side effects: decreased blood pressure, sleepiness, dizziness, drowsiness, dry 
mouth, upset stomach or throwing up, hard stools (constipation), headache, feeling tired 
or weak, abdominal pain, sweating, and pruritis. 
Uncommon side effects: bronchospasm, change in pulse, hives, trouble breathing, loss of 
appetite, blurred or double vision, nervousness, sweating, and chills. 
 
2. Duloxetine 
Common side effects: drowsiness, dry mouth, nausea, constipation, loss of appetite, 
tiredness, sweating, and lightheadedness. 
Uncommon side effects: headache, muscle ache, diarrhea, vomiting, heartburn, stomach 
ache, decreased interest in sex, dizziness, weakness, trouble breathing, dark-colored 
urine, and tremor.   
 
3. Acetazolamide- It is important to note that associated side effects are on-target, dose-
related effects so using ultra low, sub-therapeutic doses will reduce the risk of 
experiencing side effects. Clinical doses range from 250-1000 mg/dose and subjects will 
only be taking a maximum dose of 30 mg/day. 
Common side effects: tingling, nausea, fatigue, weight loss, dizziness, lightheadedness, or 
increased urination. 
Uncommon side effects: transient myopia, sensitivity to light, hives, headache, and 
glucose or blood in urine. 
 
 
c. Device complications/malfunctions 


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The QST device (Medoc) is FDA-approved and is inspected on a routine schedule established by 
the MGH Bioengineering Department. 
 
d. Psychosocial (non-medical) risks 
1. Morphine- feelings of euphoria or dysphoria, dependence, and addiction. 
2. Duloxetine- worsening depression and emergence of suicidality. 
  
e. Radiation risks 
Not applicable.  
 
VIII. Potential Benefits 
a. Potential benefits to participating individuals 
Study subjects randomized into the medication groups taking morphine + placebo, morphine + 
duloxetine or placebo + duloxetine may have pain relief from the study medication. 
 
b. Potential benefits to society 
We expect for this study to yield important data regarding the effectiveness, or lack thereof, of 
adding an adjunct to opioid therapy in chronic pain management.  Positive outcomes will help 
improve the overall effectiveness of clinical opioid therapy and reduce unnecessary opioid dose 
escalation.   
 
IX. MONITORING AND QUALITY ASSURANCE 
a. Independent monitoring of source data 
The PI, study staff and an independent Data and Safety Monitoring Board (DSMB) will monitor 
the validity and integrity of the data and adherence to the IRB-approved protocol. The department 
statistician will also monitor the source data and help with the data analysis upon request. The 
study staff will review the accuracy and completeness of study documents, source documents and 
informed consent on a weekly basis after data is collected. Any issues are immediately reported to 
the PI, as the PI is ultimately responsible for monitoring the quality of the data and study outcomes 
throughout the study. The PI, co-investigators and study staff also meet on a monthly basis to 
review adherence to the protocol and any other matters regarding the study. The DSMB meetings 
will take place annually or more often as needed.  DSMB meeting minutes will be provided upon 
request. 
 
b. Safety monitoring 
A Data and Safety Monitoring Board will be formed to monitor the study progress.  The Board 
will consist of (3-5) members with experiences in opioid therapy, pain management, regulatory 
oversight, and patient safety.  These members are not associated with this research project and thus 
will work independently of the PI.  They are qualified to review the patient safety data generated 
by this study because of their unique expertise in the area of pain management and clinical studies. 
 
The PI will monitor this study for safety. Subjects will be discontinued from the study if, during 
the study, they develop profound sedation, dizziness, constipation, dry mouth, or symptoms of 
serotonin syndrome. Cumulative Minor Deviation and Adverse Event logs will be submitted at 
continuing review if there are events to report. A VAS pain score greater than 6 would also trigger 
withdrawal from the study. 
The Beck Depression Inventory (BDI) will be scored based on the user manual to monitor reports 
of mood changes, depression, and suicidal ideation.  If a subject scores within the moderate 


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depression category or indicates suicidal ideation, a study staff member will recommend that he 
or she talk to a professional caregiver about depression.  Study physicians will be paged 
immediately if a subject scores within the severe depression category, answers 2 or 3 on Question 
9 or reports any signs of spontaneous suicidality. Steps such as referring the subject to the ED, 
Urgent Care Clinic, or PCP will be taken following this evaluation.  MGH Acute Psychiatric 
Services (APS) will be informed about this study and the possibility that such subjects may be 
presented to the APS. 
Subjects who cannot tolerate the study drugs or are noncompliant will be safely withdrawn from 
the study.  Up to three visits will be scheduled to provide the subject with a medication taper 
schedule and to collect any unused study medication.  A study physician will be present, and visits 
may include additional study procedures (i.e. QST) at the discretion of the PI. 
Subjects will fill out questionnaires regarding opioid dependence/withdrawal.  Study physicians 
will be paged immediately if a subject scores within the moderate to severe 
dependence/withdrawal categories or if a subject has symptoms of opioid withdrawal (e.g., 
yawning, tearing, agitation, diarrhea, abdominal cramping).   The study physician will contact the 
subject’s treating physician to manage the withdrawal such as using clonidine.  If the withdrawal 
symptoms are severe and urgent, the subject will be directed to the local emergency department. 
The study physician will contact the ED team to report the subject’s condition including the history 
of participating in this study to facilitate the management. Additional information, advice or 
guidance can be provided by a study physician at the subject’s request. 
A study physician will be available 24/7 by page to address any concerns or issues with subjects 
(e.g. side effects, adverse events, study medication instructions, etc.).  If necessary, the subject will 
be referred for further evaluation and treatment including referral to emergency room visits. 
 
Unanticipated problems involving risks to subjects or others including adverse events will be 
reported to the PHRC in accordance with PHRC unanticipated problems including adverse events 
reporting guidelines.Any mild or moderate events will be reported to the PHRC and NIH in a 
progress report at the annual continuing review. 
 
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