Swiss Multi-centre, Randomized, Placebo Controlled Trial of Pregabalin for Prevention of Persistent Pain in High Risk Patients Undergoing Breast Cancer Surgery (PREVENT)

Swiss Multi-centre, Randomized, Placebo Controlled Trial of Pregabalin for Prevention of Persistent Pain in High Risk Patients Undergoing Breast Cancer Surgery

Swiss Multi-centre, Randomized, Placebo Controlled Trial of Pregabalin for Prevention of Persistent Pain in High Risk Patients Undergoing Breast Cancer Surgery

University Hospital, Geneva, Centre Hospitalier Universitaire Vaudois, Insel Gruppe AG, University Hospital Bern

This study will test the benefits and risks of using pregabalin perioperatively to prevent persistent postoperative pain in patients at high risk (>30%) of developing such pain after breast cancer surgery.

BACKGROUND Persistent postsurgical pain occurs in more than 30% of patients undergoing breast cancer surgery. Evidence that gabapentinoids such as pregabalin may reduce the incidence of persistent postsurgical pain is ambiguous, potentially because in previous trials prophylactic treatment was administered to every patient undergoing surgery. The patients at low risk of long term pain, were exposed to side effects without much benefit to expect. AIM Validating or refuting the utility of pregabalin to prevent long term post-operative pain in patients at high risk of persistent pain after breast cancer surgery. METHODS Randomized, double-blind, placebo-controlled trial of pregabalin (2*150mg from the day before breast cancer surgery until 2 weeks after surgery) in patients at high risk of persistent pain (>30%). High-risk patients are identified by a risk score derived from a previous observational study. The main outcome is the incidence of clinically important pain (necessitating analgesic treatment, or having an intensity of >3 at rest or >5 on movement) at 3 months after surgery. Secondary outcomes are: incidence of neuropathic pain, pain interference, and incidences at 6 and 12 months of follow-up. In addition, side effects of pregabalin and the retention rate during the treatment period will be monitored, as well as patient expectancies. RELEVANCE This is the first study for prevention of persistent postoperative pain which targets only high-risk patients, thus lowering a false negative outcome and averting the risk of side effects for patients at low risk. The study is powered to show a reduction of the incidence of clinically important pain at 3 months of 20%. In the case the study shows that this can be achieved and pregabalin is well tolerated, the preventive use of pregabalin for breast cancer surgery would be justified at least in high-risk patients. On the other hand, a negative result would indicate the futility of pregabalin prevention, which is already in routine use in many hospitals.

study drugs (including identical placebos) and randomisation lists are prepared by the hospital pharmacy and are kept secret from the investigators until the end of the study and the "freezing" of the electronic data base (an interim analysis will be performed when data for the primary outcome are available for 60 patients per arm. Stopping rules are a difference in the incidence of the primary outcome of less than 8.2% (futility) or more than 19.9% (superiority)).

Pregabalin 150 mg twice daily, starting from the evening before surgery, continuing with two times 150mg per day for 12 days, and ending with one 150mg capsule every evening for the final 3 days.

Identical placebo capsules twice daily, starting from the evening before surgery, continuing with two capsules per day for 12 days, and ending with one capsule every evening for the final 3 days.

"Clinically important pain" is defined by: taking analgesics for pain at the surgical site OR average resting pain at the surgical site >3/10 OR average movement-induced pain at the surgical site >5/10.

blurred vision or diplopia, somnolence or sleepiness, abnormal thinking, confusional state, disturbed attention, and falls, as well as the effects noted in the "generic assessment of side effects" GASE questionnaire

response to the question "In retrospect, do you consider the preventive treatment worthwhile, given your pain outcome and your experience of taking the medication?")

responses to the questions: "How much pain do you expect 3 months from now?"" "How efficient do you think the study treatment is against the long-term pain (i.e. what is the success rate in %)?" "How well do you think it will work for you? (i.e. reduction in pain score 0-10)". Beliefs about treatment attribution after 10 days of treatment (question: "Do you think that you received the real drug or the placebo?")

Inclusion Criteria: patients scheduled for breast surgery for cancer, either breast-conserving (tumorectomy/ quadrantectomy) or mastectomy, with or without immediate reconstruction, and with or without axillary dissection. patients of 18 years or more scheduled for above mentioned type of surgery ability to speak and read French, English or German high (>30%) risk of clinically important persistent pain: identified with 2 or more points of a risk score including the items: pre-existing pain at surgical site (2 points), history of depression (1 point), age < 50 years (1 point), and high expected acute pain (>6/10, 1 point). Informed Consent as documented by signature. Exclusion Criteria: Inability to understand the consent form and to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant Participation in another study with investigational drug within the 30 days preceding and during the present study, Previous enrolment into the current study, Enrolment of the investigator, his/her family members, employees and other dependent persons Pregnancy or lactation - Renal insufficiency (creatinine clearance < 60 ml/min) Allergy to pregabalin or the ingredients of the capsules Long-term preoperative therapy with gabapentinoids or high-dose opioids (more than 60 mg of morphine equivalents) Symptomatic cardiac insufficiency (peripheral oedema, NYHA class III - marked limitation of physical activity) Suicidal ideation, identified by the question: "have you been bothered by thoughts that you would be better off dead, or of killing yourself?" Planned fertility preservation immediately after surgery before a planned chemotherapy Known or suspected non-compliance, or substance-use disorder with impact on medication adherence