Endometriosis and Pain Treatment by Intraoperative Administration of Low-dose Ketamine

RCT comparing intraoperative administration of low-dose ketamine during laparoscopic endometriosis operation and the postoperative pain outcome

Endometriosis affects 10% of women of childbearing age and 25% - 50% of infertile women worldwide. Although most patients with endometriosis are completely asymptomatic, there are still a significant proportion of patients whose quality of life is impaired by the disease, resulting in chronic pelvic pain.

Hysterectomy is the most common surgical procedure performed in nonpregnant women when conservative strategies are ineffective. However, there is a poor correlation between objective findings of significant endometriosis and pain severity. Women with endometriosis are at a four-fold greater risk of long-term opioid use than those without endometriosis. Approximately 30% of women who undergo surgery for endometriosis report persistent pain after the surgical removal of the lesion(s). In addition to surgical trauma, other predisposing factors can influence the recovery or progression of chronic diseases, which should be considered when selecting perioperative treatment. Furthermore, studies have shown that in many surgical procedures, incision size and degree of tissue trauma are poorly related to postoperative pain intensity, depending on the pain treatment. After surgery, postoperative pain may be severe overall but usually resolves within the first day of surgery with a Numeric Rating Scale (NRS) pain score ≤ 4. Pain from laparoscopic endometriosis operation includes incisional pain, which may also be severe initially but subsides within the first half of the day; visceral pain that takes longer to resolve (up to a day); and shoulder pain (e.g., shoulder tip pain) that is milder. However, approximately 80% of women develop this condition after gynecologic laparoscopy procedures, which usually disappears within 24 hours and may last for several days. The typical duration of opioid rescue medication use is approximately four days. They should not cause discomfort or limit postoperative recovery.

Although the cause of endometriosis is not yet fully understood, chronic inflammation(s) and increased menstrual bleeding often leads to iron deficiency and even anemia. Iron deficiency anemia is the most common form of anemia, accounting for 50%. In 2019, the prevalence of girls and women of childbearing age (15 - 49 years) with anemia worldwide averaged 30%. For Switzerland, iron deficiency anemia is reported at 11.2 % and is well below the global average. Since iron and its deficiency play an important role in the pathogenesis of endometriosis and possibly also maintain it, it does not surprise that endometriosis patients have an increased risk of iron deficiency or anemia.These patients with a latent or manifest iron deficiency also complain of pain. Up to now, there are only indications that iron could play a role in the proinflammatory pain transmission pathways in endometriosis and could probably maintain and trigger chronic pain. As with nonsurgical chronic pain, psychological and social factors have an important impact that may persist for months or years after surgery. Suboptimal treatment of acute pain has many negative consequences including increased morbidity, impaired physical function and quality of life, slower recovery, prolonged opioid use during and after hospitalization, and increased care costs. Furthermore, in a significant proportion of patients, early postoperative pain appears to trigger pain that may persist for several months. Specifically, younger age, non-white race, lower education, history of sleep disorders, current smoking and alcohol use, high preoperative fibromyalgia screening scores, and high anxiety levels were associated with higher pain severity and excessive pain and may be underlying determinants. Also previous opioid consumption contributes to persistent postoperative pain. As pain is both a sensory and an emotional experience, psychological factors such as mood, disability, and pain coping (e.g., pain self-efficacy and pain catastrophizing) play an important role in this setting. Therefore, patients, particularly those with a predisposition or known tendency for depression, anxiety, or catastrophic symptoms, are at a high risk of developing chronic postsurgical pain. However, in some patients, acute postoperative pain persists beyond the tissue-healing period and develops into a chronic pain state. Approximately 10% of the patients undergoing surgery and 30% of those with endometriosis experience chronic pain. Patients, who have already taken preoperative painkillers or have significantly excessive postoperative analgesic consumption are at a risk of developing chronic pain. Nevertheless, opioids are often overused, particularly during the post discharge period. Even today, acute pain management in the setting of trauma, exacerbation of chronic painful conditions, and postsurgical pain, particularly in patients who are opioid-tolerant remains a challenge in the perioperative setting. In this context, ketamine can be used, generally at subanesthetic doses. However, some patients reported severe debilitating side effects of ketamine administration that did not tolerate higher ketamine doses, an adequate balance of analgesia, and adverse effects in continuous low-dose ketamine in the range of 0.1 - 0.5 mg·kg-1·h-1 was described as sufficient.

Eligibility Criteria:
Inclusion Criteria:

* Patients undergoing surgery for endometriosis operation requiring general anaesthesia at the Inselspital, Bern University Hospital, University of Bern, Department of gynaecology and obstetrics.
* Age ≥ 18 years
* American Society of Anesthesiologist (ASA) physical status 1-3
* Patients with known or suspected endometriosis
* Written informed consent.

Exclusion Criteria:

* Age \< 18 years
* ASA physical status ≥4
* Higher-grade atrioventricular block without pacemaker
* Severe hypovolemia or bradycardia
* Uncontrolled hyper- or hypotension
* Liver disease
* Known malignant hyperthermia
* Cardiovascular instability or severe heart failure (New York Heart Association classification (NYHA) \> III)
* Myocardial infarction during the last 30 days prior to surgery
* Increased intracranial or increased intraocular pressure
* Limited peripheral autonomic activity, hypersensitivity to ketamine or propofol or its components
* Pregnancy
* Rejection or lack of consent of the patient or relatives