Effect of Perioperative CBT on Chronic Persistent Postsurgical Pain Among Breast Cancer Patients
Condition: Breast Cancer; Chronic Pain; Chronic Postsurgical Pain; Quality of Life
MeSH terms: Breast Neoplasms; Chronic Pain; Pain, Postoperative
Study type: Interventional

Summary: 
      Chronic persistent post-surgical pain (CPSP) is defined as pain at or near the site of
      surgery persisting for 3 months or more after the date of surgery. The incidence CPSP in
      Europe is up to 50% at 3 months and 12% at 12 months, but the incidence varies depending on
      surgical procedure [Fletcher D et al]. In Breast surgery, one of the most commonly performed
      surgical procedures for cancer [Kehlet H et al], CPSP has been observed in 20-30% of patients
      at 6 months after surgery, making this group among the highest risk of developing CPSP
      [Spivey TL et al & Weiser TG et al]. Clinical developments that could mitigate the
      development of CPSP after breast cancer surgery would potentially yield multiple benefits in
      terms of reducing future healthcare utilization, associated costs [Spivey Tl et al], and
      improving their physical and mental health.

      Several predictive factors for CPSP have been identified, the most important being chronic
      pre-operative pain, high intensity of acute postoperative pain, and several psychological
      factors [Vranceanu A-M et al]. Of these psychological factors, pain catastrophizing has
      emerged as one of the strongest predictors of pain severity and disability among individuals
      with a range of pain presentations and CPSP [Leung L & Wade Jb & Wildeman TH].
      Catastrophizing is described as a maladaptive psychological coping strategy involving an
      exaggerated reaction to anticipated or actual pain. It can involve mental rumination,
      magnification of the perceived danger or threat associated with pain, and feelings of
      helplessness in relation to what can be done [Leung L et al]. A recent systematic review on
      psychological interventions undergoing major elective abdominal surgery concluded
      catastrophization can have a direct influence on the neuropathophysiological mechanisms
      underlying pain experiences and can improve pain and psychological outcomes, after surgery
      [Villa G et al].

      In recent years, there has been a growing number of studies investigating the potential
      impact of perioperative psychological interventions in a variety of patient groups. A recent
      systematic review and meta-analysis of observational studies concluded that psychological
      predictors may have a significant association with chronic postsurgical pain, including
      catastrophization, although this conclusion is limited by the heterogeneity of study designs
      and methods used [Giusti et al]. To our knowledge, no randomized controlled trial has been
      done to date, investigating the influence of perioperative psychological interventions on
      CPSP in patients undergoing breast cancer surgery.
    

Detailed description: 
      This will be a single-center, prospective, double-blinded, randomized controlled trial. The
      study will randomize breast cancer surgery patients into two groups: one that receives
      perioperative cognitive-behavioral therapy (CBT) in addition to usual care and the other
      receives an educational program. The estimated duration for the main investigational plan
      (e.g. from the start of screening of the first participant to the last participant processed
      and finishing the study) is one year.

      Aims and objectives:

      The primary objective is to examine whether a perioperative CBT-based psychological
      intervention is effective at reducing pain intensity at three-month follow-up, in high
      catastrophizing patients undergoing breast cancer surgery, compared to an education program.

      Secondary objectives of the study include examining whether perioperative CBT has a
      demonstrable impact on patients, compared to a time-matched education program, with regard to
      additional self-reported secondary outcomes, including quality-of-recovery, pain
      catastrophizing, pain interference, depression, and anxiety.

      Participants and recruitment:

      Adult patients who are undergoing breast surgery (defined as wide excision with magseed
      surgery or full mastectomy patients with or without axillary clearance) who are proficient in
      the English language will be eligible for inclusion. Patients will be enrolled at the
      outpatient clinic of the Department of Anaesthesiology and the Breast Health Department at
      the Mater Misericordiae University Hospital. All patients entering the screening phase of the
      study will be registered on a Study Patient Registration Log and a unique registration number
      will be assigned. Clinical data will be assessed to evaluate a subject's eligibility.

      Patients eligible for participation will be evaluated approximately two weeks before surgery
      and asked for informed consent, and then asked to complete the Pain Catastrophizing Scale
      (PCS) [Sullivan M et al] by a member of the research team. Patients with high pain
      catastrophizing, defined as a score of ≥24 on the PCS, will be eligible for randomization to
      perioperative treatment with CBT or the education and mindfulness program. This cut-off is
      based on a previous study that showed a pre-treatment score of 24 or higher on the PCS
      best-predicted follow-up chronic pain ratings and work status after multidisciplinary
      treatment[Scott W et al] and has since been selected as an appropriate score cut-off in a
      perioperative CBT intervention in lumbar surgery patients [Scarone P et al]. More recently,
      this cut-off was also suggested to obtain the highest sensitivity and specificity to predict
      unfavorable outcomes after spinal surgery [Tuna T et al].

      Randomization:

      Patients will be randomized after they are included in the study, having consented and
      completed the PCS (and scoring scored ≥24), and two preoperative appointments will be
      scheduled with the patients in the intervention and control groups. Patients will be
      randomized to either 'CBT' or 'Education' group by using an online computer-generated block
      randomization. The patient study number and group allocation will be typed onto separate
      pages and concealed in sequentially numbered sealed envelopes. Block randomization will occur
      as follows; 12 subjects per block to ensure even numbers of participants in each arm of the
      study and the number of blocks that will be used is 4. Randomization will be performed by an
      independent third party. The randomization key/seed will also be held by an independent third
      party and investigators will not have access to this key/seed until the study has been
      completed.

      The envelope will be opened by the treating psychologist to reveal the group allocation.
      Patients and members of the research team involved in data collection and analyzing the data
      will be masked to group allocation. The treating psychologist will not be blinded. Group
      allocations will be revealed immediately if there was a clinical concern.

      All patients in both interventional arms:

      All patients, irrespective of group allocation, will be routinely prescribed medications for
      pain control and will be referred for physical therapy on an out-patient basis, or other
      services, depending on clinical indications and personal needs.

      Sample size, power considerations, and statistical analysis:

      The primary outcome is the difference in the BPI average pain severity score and average pain
      interference score between the study groups, three months after surgery. A clinically
      important difference on the BPI is a 2 raw score reduction on the 11-point NRS [Wong K et al
      & Marcus J et al & Mease PJ etl al]. The standard deviation (SD) of BPI scores after breast
      surgery is in the order of 2.3 on this scale (Burckhardt CS et al). Taking a BPI score
      reduction of 2 as being clinically significant, then n=21 patients would be required each arm
      if Type I error=0.05 and Type II error is 0.2 (power 80%). Taking into account a 10%
      drop-outs rate, we propose to enroll 24 eligible patients in each group (N=48 total).

      Baseline patient characteristics will be stratified by group and presented as mean and
      standard deviation (SD), median and first and third quartile, and count and percentage, as
      appropriate. Differences in baseline characteristics between randomized groups will not be
      statistically tested, whereas differences with the separate control cohort will be tested
      using the independent-samples t-test for continuous variables, and Pearson's chi-square test
      for categorical variables. In case of expected cell counts of less than 5, Fisher's Exact
      test will be used instead.

      All patients randomized (i.e. those with a PCS score > 24) will be analyzed in an
      intention-to-treat analysis. To test for a difference between the CBT and control group in
      the BPI 'average' pain intensity scale at three months, linear regression will be used.
      Adjustment for the type of surgery, age, and education will be made and, if necessary, for
      other prognostic variables significantly associated with the outcome (i.e., acute
      postoperative pain intensity, the severity of catastrophizing, preoperative depression,
      preoperative surgical fear, length of current sick leave, pain duration).

      Secondary outcome variables will be analyzed similarly to the primary outcome. For these,
      logistic regression analysis will be used to test for differences in proportions at three
      months postoperatively. For exploratory purposes, we will compare the outcomes of the
      patients in the two intervention groups with the outcomes of patients with low pain
      catastrophizing scores (i.e. those with a PCS score < 24) undergoing care as usual. Linear
      mixed-effects regression for the three groups will be performed with primary and secondary
      outcomes at the three postoperative assessment periods and controlling for preoperative
      values. This analysis will indicate whether high catastrophizing patients follow a similar
      trajectory of pain and functioning after breast surgery compared to non-catastrophizing
      patients.
    

Intervention name(s): Cognitive Behavioural Therapy (CBT); Education and Mindfulness
Intervention type(s): Behavioral; Behavioral
Intervention description(s): The CBT intervention will be delivered by a Senior Psychologist with seventeen years of hospital psychology experience, six in the treatment of chronic pain patients. Sessions are delivered in one hour, individual therapy appointments to patients, and there is an emphasis on relaxation training, cognitive restructuring, exercise and pacing, behavioral activation, improving sleep, and anger management. Standardized worksheets and homework assignments are an important part of CBT-CP and these will be given (post or email) to patients who will be asked to read and complete in terms of complementing the consultations. This intervention has been developed with reference to two sources: A successful national implementation of CBT for chronic pain (CBT-CP) using video teleconferencing format [Connolly KS et al] AND an evidence-based CBT manual specifically designed to treat chronic pain [Murphy JL et al].; To control for differences in attention between the two interventions, patients in the mindfulness group will also have two meetings before the surgery and two meetings afterward. As the same person will be providing the CBT-CP and educational interventions, this confounding factor will be controlled for. The control intervention consists of discussing pain education, as derived from the self-management section of the chronic pain Ireland website (https://www.chronicpain.ie/our-services/self-management) and the persistent pain section of the pain toolkit website (https://www.paintoolkit.org/persistent-pain). Four mindfulness-based stress reduction exercises will be completed including an introductory session on mindful breathing, a guided meditation, progressive muscle relaxation, and a body scan. These sessions will last about half an hour.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Breast Surgery; Chronic PostSurgical Pain (CPSP); Mastectomy; Wide Local Excision; Cognitive Behavioural Therapy (CBT); Psychological factors; Perioperative; Pain catastrophizing; Anxiety