Dronabinol As an Adjunct for Reducing Pain (DARP)-Texas Children's Hospital

This exploratory, proof-of-concept study is a double-blind (participants and investigators will be blinded), placebo-controlled, randomized, two-arm clinical trial of Marinol \[dronabinol, synthetic Δ9-tetrahydrocannabinol (THC)\] for e endometriosis-associated chronic pelvic pain (endo-CPP) with a 2:1 allocation ratio. Up to 75 subjects will be enrolled in this pilot study and randomized to receive doses of THC (up to 30 mg/day), orally, over 8 weeks. This study will be conducted at a single site; it does not include any stratifications, and there is no interim analysis planned. Notably, the goal is to determine whether there is enough evidence of the safety of THC to support the development of later-phase clinical trials. Thus, detailed developmental plans are contingent on the outcomes of this study.

Endometriosis is a progressive, chronic inflammatory disorder that affects approximately 10% of women of reproductive age, with up to 70% to 90% of patients experiencing pelvic pain symptoms, thereby reducing their quality of life, and decreasing labor productivity. Current standard treatments for endometriosis-associated chronic pelvic pain (endo-CPP) include progestin-based hormonal treatments, such as combined oral contraceptive (OC) pills, gonadotropin-releasing hormone (GnRH) analogs, and laparoscopic surgeries. However, endo-CPP often persists even after laparoscopic excision of endometriosis lesions, indicating that controlling disease progression does not necessarily lead to pain relief. As pain is an important factor in endometriosis, optimal analgesia should be sought, which, to date, has primarily been treated with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole, or, in extreme cases, opioids. However, the response to NSAIDs is often ineffective. Additionally, NSAIDs are associated with a higher risk of gastrointestinal bleeding. As for metamizole, agranulocytosis is the most notorious adverse event, along with metamizole-associated hepatotoxicity. Although opioids are generally not recommended for pain relief in women with endometriosis, opioid prescriptions have been identified for women diagnosed with endometriosis within the past year in the United States (As-Sanie S, 2021). Patients undergoing robotic surgery for endometriosis use over two times as many opioids postoperatively as patients without endometriosis and experience higher perceived postoperative pain. Women with endometriosis have a four-fold greater risk of chronic opioid use compared to those without endometriosis. Opioids are highly addictive, and the use of both synthetic and natural opioids can quickly result in dependence, which includes physical and/or psychological dependence, as well as opioid use disorder. Side effects of opioid medications are generally dose-dependent and include constipation, miosis, sedation, and respiratory depression. However, the efficacy of THC in endo-CPP remains uncertain.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Ability to take oral medication per protocol.
4. Female, aged 18-64 years.
5. Females aged ≥ 18 years clinically diagnosed with endometriosis meeting one of the following criteria: a. Patients with previous surgical confirmation of endometriosis and a high suspicion of recurrence b. Patients with imaging (MRI or ultrasonography) findings highly suggestive of endometriosis and confirmed after surgery.
6. Has chronic endometriosis pain that has persisted at least 3 months and has resulted in pain as determined by the Endometriosis Health Profile Questionnaire (EHP-30).
7. For females of reproductive potential: currently practicing an effective form of two types of birth control, which are defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, for at least 1 month prior to screening and agrees to use such a method during study participation and for an additional 4 weeks after the end of study medication administration unless she is surgically sterile, partner is surgically sterile, or she is postmenopausal (one year): a. contraceptive sponge, b. patch, c. double barrier (diaphragm/spermicidal or condom/spermicidal), d. intrauterine contraceptive system, e etonogestrel implant, f. medroxyprogesterone acetate contraceptive injection, g. complete abstinence from sexual intercourse, and/or hormonal vaginal contraceptive ring.
8. Patients using oral contraceptives, vaginal ring for contraception and/or management of endometriosis, can be included if both they and their primary provider agree to stopping their medication and transitioning to dronabinol (THC) as the primary treatment of endometriosis throughout the study period
9. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration.
10. On a stable pain treatment (pharmacological or otherwise) for ≥3 months at the time of the screening and agree to refrain from adding new analgesic medications or increasing their current dose of analgesic medications for the duration of the study.
11. Due to the inability to translate patient facing documents into various languages the investigators will only recruit English speaking participants

Exclusion Criteria:

1. Current and unwilling to stop use of cannabis/marijuana and any other cannabinoids (CBD), including over the counter CBD products.
2. Known allergic reactions to cannabis, CBD, THC, or components of the study interventions.
3. Have Blood Urea Nitrogen or Creatinine levels outside the normal range, or other clinically significant laboratory abnormalities
4. Current use of automated external defibrillator (AED)
5. Chronic daily opioid use and any chronic pain or frequently reoccurring pain condition, other than endometriosis, that is treated with opioids for \> 14 days per month
6. Women with a BMI \> 35 kg/m2
7. Current use of barbiturates, benzodiazepines, ethanol, lithium, buspirone, muscle relaxants which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
8. Current use of amphetamines, other sympathomimetic agents, atropine, amoxapine, scopolamine, antihistamines, other anticholinergic agents, amitriptyline, or desipramine, within 3 months of randomization
9. Treatment with another investigational drug or other intervention within 3 months of the screening visit.
10. Pregnancy, plans to become pregnant, or lactation.
11. Any interventional pain procedures within 6 weeks prior to screening or at any point during study enrollment.
12. Surgical intervention or introduction/increased dose of an opioid or analgesic regimen at any point during study enrollment
13. Implanted spinal cord or dorsal root ganglion stimulator for pain treatment.
14. Meets DSM-V criteria for a current major psychiatric illness, such as bipolar disorder, or psychosis which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
15. Have a history of substance abuse or dependence which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
16. Have an increased risk of suicide that necessitates inpatient treatment or warrants therapy excluded by the protocol, and/or current suicidal plan, per investigator clinical judgement, based on interview and defined on the Columbia Suicidality Severity Rating Scale (C-SSRS).
17. Have a history of seizures which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
18. Have uncontrolled renal, hepatic, or other systemic disorders that in the opinion of the clinician may jeopardize the patient's safe participation in this study.
19. Have a history of cardiac disorders which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
20. Myocardial infarction or stroke in the previous 6 months.
21. Resting heart rate of \> 120 or Systolic blood pressure \> 140 mm Hg, or diastolic blood pressure \> 90 mm Hg.
22. Any uncontrolled communicable disease (e.g., HIV/AIDS, tuberculosis, COVID, etc.) which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
23. Have any other illness, condition, or use of medications, which in the opinion of the P.I. and/or the admitting clinician would preclude the safe and/or successful completion of the study.
24. Have ECG abnormalities at screening including but not limited to bradycardia (less than 55 beats per minute); prolonged QTc interval (greater than 450 msec); Wolff-Parkinson White syndrome; wide complex tachycardia; 2nd degree, Mobitz type II heart block; 3rd degree heart block; left or right bundle branch block.
25. Have chronic alcohol use (defined as greater then 3 drinks per day, averaged over one week)
26. Known history of or suspected breast cancer on screening physical exam
27. Current use of a progestin-containing contraceptive implant