Effects of Intraoperative Low-Dose Ketamine on Persistent Postsurgical Pain after Breast Cancer Surgery: A Prospective, Randomized, Controlled, Double-Blind Study

Abstract

Background: Compared to acute postsurgical pain, studies regarding the role of ketamine in persistent postsurgical pain (PPSP) are limited. Objectives: The aim of this clinical trial was to test if intraoperative low-dose ketamine without postoperative infusion would reduce PPSP development after breast cancer surgery. Study design: We used a randomized, double-blinded, placebo study design. Setting: This study was conducted at Pusan National University Hospital, Republic of Korea, between December 2013 and August 2016. Methods: A total of 184 patients scheduled for breast cancer surgery were randomly assigned to either the control or ketamine group. Before skin incision, a bolus (0.5 mg/kg of ketamine or placebo), followed by a continuous infusion (0.12 mg/kg/h of ketamine or placebo), was administered until the end of the surgery. The patients were interviewed via telephone 1, 3, and 6 months after surgery. The first question was whether the patient had surgery-related pain. If answered affirmatively, questions from the Numeric Rating Scale for pain at rest (NRSr) and for coughing (NRSd) were also asked. Our primary outcome was the incidence of PPSP at 3 months after surgery. Results: For PPSP analysis, 168 patients were included. The number of patients who experienced pain was significantly lower in the ketamine group at 3 months (86.9% in the control group vs 69.0% in the ketamine group, P = .005) postoperatively. However, the NRSr and NRSd did not differ between the groups throughout the follow-up. Limitations: There were no postoperative low-dose ketamine infusion groups to compare due to hospital regulations. Dosage of ketamine was too low to reduce the severity of PPSP. And by using propofol and remifentanil for anesthesia, different results can be deduced with volatile anesthetics. Data from written questionnaires would have been more specific than telephone interviews for long-term assessment. Conclusions: Though intraoperative low-dose ketamine without postoperative infusion significantly reduced the incidence of PPSP up to 3 months after breast cancer surgery, it failed to reduce clinically significant PPSP and improve patients’ quality of life. Key words: Analgesia, breast cancer, chronic pain, ketamine, mastectomy, morphine, pain, postoperative, propofol

Practical strategies for the prevention and management of chronic postsurgical pain

“…Aggressive pharmacological interventions to prevent CPSP seem promising; however, evidence in this field has shown somewhat disappointing results. Intraoperative ketamine appears to be beneficial for the control of acute postoperative pain; however, its impact on chronic pain remains controversial [4,28,79,80]. Recently, a large multicenter randomized controlled trial regarding the effectiveness of ketamine on CPSP has been actively conducted in Australia, and the results are expected soon [81].…”

“…Its prevalence varies depending on the type of surgery, but estimates suggest that up to more than 50% of patients may experience some degree of CPSP following certain procedures, such as thoracotomy, amputation, mastectomy, and hernia repair [3]. Moreover, while CPSP prevalence has been reported mainly in North America and some European countries, recent studies have shown its high prevalence in several East Asian countries [2,[4][5][6].…”

Single-Dose of Postoperative Ketamine for Postoperative Pain After Mastectomy: A Pilot Randomized Controlled Trial

“…37 A 2020 study found that intraoperative ketamine infusion did not improve acute pain control but reduced chronic post-mastectomy pain at 3 months. 38 A recent meta-analysis and systematic review article analyzed 13 randomized control trials on the effect of ketamine on pain control in women undergoing breast surgery and found that perioperative ketamine was effective at reducing pain and reducing opioid requirements during the first 24 hours after surgery. 39 Notably, in none of these studies was the ketamine administered as a single dose after surgery.…”

Individualized multidisciplinary analgesia to prevent persistent postsurgical pain

“…Quite a few studies have investigated the effect of intensified perioperative analgesia to prevent PPBCT by presumed reduction of nociceptive sensitization through reducing acute postoperative pain. So far, neither (preventive) medication [34][35][36][37][38][39] nor regional anaesthesia techniques [40][41][42][43][44] have been shown to consistently reduce the prevalence of PPBCT [45][46] despite successfully reducing acute postoperative pain. Interestingly regional anesthesia seems more effective in reducing the severity and duration of acute postoperative pain after breast cancer surgery in patients scoring higher for pain catastrophizing before surgery [47] again emphasizing the importance of psychological factors for pain processing.…”