Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03090776 |
| Other study ID # |
2016P002521 |
| Secondary ID |
K23GM110540 |
| Status |
Active, not recruiting |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2017 |
| Est. completion date |
December 1, 2025 |
Study information
| Verified date |
October 2023 |
| Source |
Brigham and Women's Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Aim 1: To determine the effectiveness of perioperatively administered ketamine to decrease
acute and persistent postmastectomy pain (PPMP).
Hypothesis 1.1: Patients undergoing partial or total mastectomy treated with a bolus and
perioperative infusion of the NMDA-receptor antagonist ketamine will have decreased
postoperative pain and opioid utilization compared to those receiving saline control.
Hypothesis 1.2: Patients undergoing partial or total mastectomy treated with a bolus and
perioperative infusion of the NMDA-receptor antagonist ketamine will have decreased
persistent postoperative pain measured at one year after surgery.
Aim 2: To determine whether there is increased power to detect therapeutic effectiveness in
an interventional preventive trial, by enrichment with patients at high risk of PPMP.
Hypothesis 2.1: Ketamine will have a greater analgesic and opioid sparing effect on pain
scores in high-risk patients than non-high risk patients, compared to placebo.
Hypothesis 2.2: Ketamine will have a greater preventive effect on pain burden scores at one
year after surgery in high-risk patients than non-high risk patients, compared to placebo.
Description:
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:
1. 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.
2. 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.
Subject and investigator blinding of screening and treatment: As part of informed consent,
subjects will be appraised of the fact that the study investigates risk of short- and
long-term pain and whether people in different risk groups respond to a treatment, but will
not be told whether they are considered high- or low- risk, or whether they received ketamine
or placebo. Effectiveness of blinding will be assessed by querying patients about which group
they think they are in on POD1. Investigator and hands-on provider will be blind to treatment
(ketamine vs placebo). Nursing staff in PACU will be appraised of the fact that patients are
in a study, but also blinded to the treatment. Effectiveness of blinding of study staff who
is asking patient to rate perioperative pain will be achieved by having this study staff
record their impression of group on a single item questionnaire in the Redcap system.
Responses of patient and study staff as to their impression of group will be compared to
actual group at the end of the study.
3. Perioperative data collection
1. Surgical, Anesthetic, and analgesic data collection: Using the Weiner preoperative
evaluation center email alert system, the hands-on anesthetist and/or anesthesiologist
will be contacted to inform them on the patient's participation in the study, and given
instructions about the volume of bolus and rate of infusion. The total time and volume
of infusion will be recorded will be recorded in the anesthetic record, so that a total
dose of ketamine can be calculated. In order to adjust for potential impact of other
anesthetic techniques or pharmacological agents on PPMP, the following data will be
extracted from the electronic anesthesia record: Primary anesthetic method (volatile vs.
IV propanol vs. regional/paravertebral vs. combined PVB/GA), amount and type of local
anesthetic administered, and opioid analgesic used (the latter expressed as morphine
equivalent units/hr). In addition, information about other relevant analgesic
preoperative, intraoperative, and postoperative medications such as Oxycontin,
gabapentin, pregabalin, and dexmedetomidine will be gathered from the electronic record.
Other potentially confounding intraoperative factors such as vasopressor use/amount,
fluids or blood administered, total anesthesia time, and airway management (LMA, ETT, or
native) will be recorded. Among this group of breast surgeons, there is relative
homogeneity in anatomical technique and tissue disturbance, although there is some
variation in dissection technique. Detailed assessment of surgical technique will
include primary surgeon, duration of surgery, presence of bilateral surgery, type of
surgery (total mastectomy, segmental mastectomy), performance of nodal dissection
(axillary or sentinel node), and presence and type of concurrent reconstruction.
2. Acute postoperative pain assessment: Initial pain score upon arrival will be assessed by
PACU nursing staff and/or anesthetist. One hour and 24 hours after PACU arrival, patient
will be assessed by research study personnel, being asked to rate pain at rest, with arm
movement, and with maximal deep inspiration using the pain verbal rating scale (VRS).
Presence of nausea and treatment with supplemental antiemetics in recovery area will be
recorded. In addition, opioid consumption and adjuvant analgesic use will be ascertained
from the patient's medication administration record. Upon discharge, which is typically
on POD1 or 2 for mastectomy patients, total postoperative opioid use/hours of
postoperative time as inpatient will be calculated and expressed in morphine equivalent
units/hr. On postoperative day 1, mastectomy patients will undergo brief bedside QST (as
at preoperative evaluation, described above).
3. Persistent pain, long term psychosocial and psychophysical assessment: Follow up
assessments of persistent pain using the BCPQ, BPI, VAS, and pain coping questionnaires
will be made at 2 weeks, 3 mo, 6 mo, 12, and 24 mo, with follow-up either via secure
link to the REDcap electronic data capture system. Patients are seen at visits with the
surgical team, or oncologists at these times. The brief QST and psychosocial
questionnaires will be re-administered at 2 weeks and 1 year postoperatively during one
of the patient's follow-up visits.
