Prevention of Post-Mastectomy Pain With Perioperative Ketamine Administration: A Randomized, Placebo-controlled Trial

V. STUDY PROCEDURES

1. Preoperative evaluation

1. Psychosocial Assessment: After the patient gives informed consent, preoperative demographic, medical, psychosocial and pain questionnaires will be completed by the patient during their preoperative office visit. Questionnaires assessing psychosocial factors have been chosen based upon previous retrospective association with PPMP, and preliminary evidence from our prospective study in the same population, strong psychometric validation characteristics, and brevity. The Pain Catastrophizing Scale (PCS), which has been validated in pain patients and controls, will be used to measure catastrophic thinking associated with pain. Depressive symptoms, anxiety and sleep disturbance will be assessed using short-form instruments from the NIH roadmap initiative, Patient Reported Outcome Measurement Information System (PROMIS). The PROMIS instruments have been extensively validated in studies comparing results with established scales, and have been calibrated on over 20,000 persons.The Brief Symptom Index 18-Somatization Scale, also previously validated in chronic pain patients, will be used to measure somatization. The Positive Affect/Negative Affect Scale (PANAS) measures affective stance.

2. Pain assessment: The primary pain outcome measure will be Pain Burden Index as measured by the Breast Cancer Pain Questionnaire (BCPQ), which was originally developed by Gartner et al and used in over 600 patients in our previous studies. The BCPQ includes assessment of average pain, pain frequency (how many days/week), and specific assessment of pain at 4 body areas (breast, arm, side, axilla), from which a Pain Burden Index (PBI) can be calculated. A later iteration of the BCPQ also includes questions about other body pain, seeking medical help for pain, painkiller use, neuropathic/sensory symptoms, and functional impairment due to pain, and has been successfully employed in our current prospective observational study. We will also use the Brief Pain Inventory, a well-validated general measure of pain and disability worst pain, least pain, and interference. We will supplement this with a standard VAS assessing pain with and without arm movement and deep inspiration. The Pain Coping Questionnaire will be administered to prospectively assay for effective coping strategies used by patients and we will use a 2 item version of this questionnaire to assess the use of these strategies.

3. Quantitative sensory testing:

4. Pressure pain testing methods: Pressure pain threshold and tolerance will be assessed in a similar manner to our previous studies using a digital pressure algometer (Wagner FDX, Greenwich, CT, USA) with a flat round transducer, probe area 0.785 cm2. Testing sites will be bilateral on the dorsal aspect of the proximal forearm (extremity site) and over the trapezius muscle at the upper back (truncal site). For pressure threshold determination, pressure is increased at a steady rate of approximately 1 lb/second until subject indicates that the pressure is first perceived as painful. Pressure Pain Tolerance will be determined by instructing patients to indicate the pressure at which the pain was no longer tolerable. Two trials will be performed at each site.

5. Temporal Summation testing methods: Mechanical pinprick pain will be assessed in a similar manner to our previous studies using standardized weighted pinprick applicators similar to those described by Rolke et al using a range of forces (128 mN, 256mN and 512mN) which result in a painful sensation in most subjects. First, a single stimulation of the lower force pinprick will be applied to the dorsal aspect of the index finger between the first and second interphalangeal joints of the each hand while resting palm down on the armrest, and then rated by the subject on a scale of 0-10. Next, after a break of at least 10 seconds, a train of 10 stimuli will be applied at the same premarked spot, at a rate of 1 stimulation/second. The subject will rate pain on a scale of 0-10 after the first, fifth and tenth stimulus, then rate any ongoing pain 15 seconds after cessation of the last stimulus. The same procedure will be repeated on the third finger of the each hand. Subjects will undergo two trials at each force, with a break of at least one minute between trials.

2. Perioperative intervention Patients will receive a 0.5 mg/kg dose of IV ketamine (max dose 50 mg) or the same volume of saline 15 minutes after induction of general anesthesia. Thereafter, a continuous infusion of 0.15 mg/kg/hr ketamine with a maximum dose of 15 mg/hr or saline will be administered until the end of surgery (when the surgical closure has begun, approximately 30-60 minutes prior to emergence from general anesthesia). The investigational drug service will prepare blinded solutions (2 mg/mL ketamine or saline) and deliver to OR pharmacy before the beginning of each case to hands-on providers. Cost of ketamine is $12 per 200 mg vial, and will be covered by the NIH K23 budget. General anesthesia will be provided by the hands-on anesthetist, who will be free to use at their discretion the following anesthetic drugs, which are typically used in this population, and are all compatible in solution with ketamine: Midazolam 2 mg, Fentanyl <500 mcg, Dilaudid <5 mg total, Propofol 1-2 mg/kg, Lidocaine 50-100 mg, Vecuronium, Rocuronium, succinylcholine or Cisatracurium as needed, Zofran 4 mg, Decadron 4 mg, Cefazolin, Glycopyrrolate and Neostigmine as needed for reversal, as well as inhalational agents other than nitrous oxide.