Effect of Combined Morphine and Duloxetine on Chronic Pain

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.

• Morphine (Drug), also known as Morphine Sulfate Contin, Morphine Sulfate Instant Release: 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.
• Duloxetine (Drug), also known as Cymbalta: 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.
• Placebo (Drug), also known as Sugar pill: 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.

Primary outcomes

• Overall Opioid Dose (Morphine-equivalent Dose in mg) [10 weeks]: The investigators will compare overall opioid dose (in morphine-equivalent dose in mg) between the morphine/duloxetine group and the morphine/placebo group and compare rescue dose among all three groups. The higher overall opioid dose, the more consumption of opioid.
• Visual Analog Scale (VAS) [10 weeks]: To examine changes in pain intensity measured on a Visual Analog Scale with units on a scale ranging from 0 cm-10 cm (0 cm being lowest and 10 cm being the higher the score, where values closer to 10 cm reflect more pain) and to determine total versus rescue opioid use after each treatment.

Sex: All, ages: 18 Years to 70 Years

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 ≥ 5.
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 detected by urine toxicology/drug screen.
3. Subject is pregnant or lactating/breast feeding.
4. Subject is allergic to morphine or duloxetine.
5. Subject is on an antidepressant including serotonin-norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitor (SSRI), tricyclic antidepressant.
6. Subject has a history of suicidal attempts or current suicidal ideation.
7. Subject takes monoamine oxidase inhibitors, antipsychotics, triptan drugs such as sumatriptan, lithium, linezolid, tramadol (Ultram), St. John's Wort, central nervous system (CNS) stimulants such as amphetamine, methylphenidate, methamphetamine, phentermine, diethylpropion, sibutramine, cocaine, or thioridazine.
8. Subject has uncontrolled narrow-angle glaucoma.
9. Subject has sensory deficits on arms or Raynaud's Syndrome.
10. Subject has a pending litigation related to chronic pain condition.
11. Subject is on methadone or suboxone treatment for addiction.

Participant flow

Outcome results

• Overall Opioid Dose (Morphine-equivalent Dose in mg) (Primary), Mean, mg: Morphine, Duloxetine 19.6 +/- 2.05; Morphine, Placebo Duloxetine 19.6 +/- 2.16; Placebo Morphine, Duloxetine 19.6 +/- 2.16
• Visual Analog Scale (VAS) (Primary), Mean, cm: Morphine, Duloxetine 2.8 +/- 3.05; Morphine, Placebo Duloxetine 2.33 +/- 3.05; Placebo Morphine, Duloxetine 4.66 +/- 3.05

Adverse events

Time frame: The adverse events were monitored and assessed through study completion, an average of 6 months.

Limitations and caveats: In this study we did not enroll enough participants to reach the number needed for our analysis to have power which is a limitation.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-02-18)

• Jianren Mao, MD, PhD, Principal investigator, Massachusetts General Hospital