Clinical trial NCT06161805: Esketamine as Treatment for Chronic Pain Due to Endometriosis: a RCT Study
Official title: Esketamine as Treatment for Chronic Pain Due to Endometriosis: a RCT Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Endometriosis
Chronic Pelvic Pain Syndrome
Lead sponsor: Reinier de Graaf Groep
Sponsor class: OTHER
First posted: 2023-12-08
Enrollment: 56
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 randomization
Primary purpose: TREATMENT

Brief summary: The goal of this randomized controlled trial is to investigate the effect of esketamine versus placebo on the NRS score for chronic pelvic pain. Secondary endpoints are to assess pain scores, side-effects, quality of life, depressive symptoms and pain coping.

Detailed description: Endometriosis is a chronic inflammatory disease affecting approximately 10% of reproductive-aged women. Severe pain symptoms and subfertility result in a lower quality of life, higher prevalence of depression and loss of productivity. Consequently, the economic impact of endometriosis is high. Treatment options to suppress chronic pain symptoms in patients with (deep) endometriosis are inadequate, resulting in increased opioid consumption. Ketamine (in our study we will use the S-enantiomer, esketamine), is a versatile drug with analgesic, anti-inflammatory and antidepressant effects and is commonly used in the treatment of chronic pain patients and has shown promising outcomes. However, whilst esketamine targets multiple aspects of endometriosis simultaneously (pain, inflammation, depression), studies on esketamine as treatment for chronic pain due to endometriosis have never been reported. Therefore we aim to conduct a randomized controlled trial to assess the efficacy of esketamine infusion versus placebo in the treatment of chronic endometriosis-induced pain.

Eligibility criteria: Inclusion Criteria:

* Women
* All pre-menopausal women aged above 18 years
* Diagnosed with endometriosis (ultrasound, MRI or previous laparoscopic and/or diagnostic surgery) according to the #Enzian classification \[52\]. This means that endometriosis is present in the following compartments:

  * Rectovaginal space (minimal A1) and/or
  * Sacrouterine ligaments, cardinal ligaments, pelvic sidewall (minimal B1) and/or
  * Rectum (minimal C1) and/or
  * Endometriosis of the intestines, diaphragm and/or
  * Adenomyosis (according to the morphological uterus sonographic assessment (MUSA) or evident adenomyosis on the MRI) \[53, 54\] and/or
  * Peritoneal / superficial endometriosis (diagnosed laparoscopically and not treated during surgery).
* Mild to severe chronic pelvic pain (NRS scale \>= 6). The 11-point NRS scale ranges from '0' representing no pain to '10' representing the worst pain imaginable.
* Resistant to current recommended lines of analgesics (paracetamol, NSAIDs)
* Usage of strong opioids must not have been prescribed or otherwise have been discontinued for more than 1 week.
* An indication for endometriosis resection surgery or on the waiting list for surgical treatment
* Ability to understand the patient information letter and to give oral and written informed consent
* No alteration in the utilization of hormonal therapy ≤1 months prior to inclusion.

Exclusion Criteria:

* Pain score \<6 out of 10 (NRS) for chronic pelvic pain
* Endometriosis affecting the bladder and ureter
* Increased intracranial pressure
* Poorly regulated hypertension, \>180/100mmHg at rest
* Patients with thyroid disease
* Patients with cancer
* History of psychiatric illness (schizophrenia, psychosis, delirium, manic depression)
* Serious medical disease (e.g., cardiovascular, renal , pulmonary or liver disease)
* Severe liver disease
* Patients with glaucoma
* Usage of strong opioid medication
* Usage of xanthine derivatives or ergometrine
* Unstable angina, heart failure, history of cerebral vascular accident (CVA)
* Patients suffering from an active infection
* Patients with epilepsy
* Patients trying to achieve pregnancy and or patients who are breastfeeding
* Not being able to answer questionnaires (in Dutch)
* Mentally incompetent (patients not able to make decisions that are in their best interests, this will be evaluated by their treating physician (e.g. patients with an intellectual disability or mental retardation))
* Alcohol or drug abuse
* Patient with a known (es)ketamine allergy
* Abnormal liver enzyme levels at baseline (ASAT, ALAT, GGT, AF, Bilirubin total)

Patients are allowed to continue the following pain medications: paracetamol, non-steroidal anti-inflammatory drugs as described previously by Sigtermans et al. (Trial NL466 (NTR507))\* according to their stable use in dose and frequency.

\*in case of tramadol, amitriptylin, selective serotonin reuptake-inhibitors, gabapentin and pregabalin, the usage may also be continued during this study.

Primary outcomes:
measure: Chronic pelvic pain
timeFrame: 4 weeks after the 8 hour infusion treatment.
Secondary outcomes:
measure: Dysmenorrhea
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Dyschezia
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Dysuria
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Dyspareunia
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Chronic pelvic pain
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Depressive symptoms
timeFrame: Baseline, 4 weeks after infusion treatment
measure: Endometriosis associated Quality of Life
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Quality of life in general
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Quality of life in general
timeFrame: Baseline and week 4, 8, 12 after the 8 hour infusion treatment
measure: Productivity costs
timeFrame: 12 weeks post-infusion treatment
measure: Medical costs
timeFrame: Baseline, 12 weeks post-infusion treatment
measure: Pain coping and cognition
timeFrame: Baseline, 12 weeks post-infusion treatment
measure: The effect infusion treatment psychedelic effects
timeFrame: On the day of infusion (prior to infusion and during infusion)
measure: Treatment experience
timeFrame: Directly after infusion
Other outcomes:
Locations:
city: Delft
country: Netherlands
facility: Nederlandse Endometriose Kliniek, Reinier de Graaf Gasthuis
Study officials:
References:
citation: Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14.