Clinical Trial Details
— Status: Suspended
Administrative data
NCT number |
NCT02729805 |
Other study ID # |
UW15-079 |
Secondary ID |
|
Status |
Suspended |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
August 18, 2015 |
Est. completion date |
June 2024 |
Study information
Verified date |
May 2023 |
Source |
The University of Hong Kong |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Preventive analgesia is when an administered analgesic drug provides reduction in pain beyond
its duration of action. This can be used to reduce acute postoperative pain and prevent
occurrence of chronic post-surgical pain.
According to the International Association for the Study of Pain (IASP), chronic pain can be
defined as pain that persisted beyond the time of normal tissue healing (usually 3 months)
and that was not related to other causes. Mastectomy is associated with a high incidence of
chronic post-surgical pain. Breast cancer is the most common malignancy affecting females
around the world. Many undergo mastectomy as part of curative treatment. However, a
significant proportion of patients experience chronic post-surgical pain. This results in
significant negative impact on physical, psychological and social wellbeing.
Ketamine is an intravenous anaesthetic drug with analgesic effects. It can be used to treat
both acute and chronic pain. A recent meta-analysis of different surgeries showed that
patients receiving ketamine had a modest but statistically significant reduction in incidence
of chronic post-surgical pain. In a small sample single dose pilot study, patients given low
dose intravenous ketamine intraoperatively had a statistically non-significant reduction in
incidence of pain around the surgical scar at three months after radical mastectomy.
Randomized control trials with larger sample sizes are needed to determine the effectiveness
and optimal dosing regime of ketamine for reduction of chronic post-mastectomy pain. It is
therefore hypothesized that intravenous ketamine given intraoperatively will reduce the
incidence and severity of chronic pain after modified radical mastectomy. A double blind
randomized controlled trial comparing placebo group with two different doses of ketamine is
proposed.
The mechanism of action of ketamine in reducing pain is complex and multiple. How ketamine
can prevent and reduce chronic pain is unknown. Ketamine has been shown to reduce immediate
gene expression at site of mechanical injury. Transient Receptor Potential Vanilloid 1
(TRPV1) and Transient Receptor Ankyrin 1 (TRPA1) are receptors shown to mediate acute and
chronic pain. Ketamine, shown to affect gene expression, may alter the expression of TRPV1
and TRPA1 via epigenetic mechanisms.
Description:
Procedures Patients will be approached at the preadmission clinic or in the general ward
before operation. The analgesic methods will be explained and s/he will be recruited into the
study if s/he agrees. The patient will be randomized into one of three groups. The patients
in the first group (C) will receive intraoperative morphine, local wound infiltration with
local anaesthetic, cyclooxygenase-2 (COX-2) inhibitor post-operatively, and post operative
Patient Controlled Analgesia (PCA) morphine. Patients in the second (K1) and third groups
(K2) will receive different doses of intraoperative intravenous ketamine in addition to
intraoperative morphine, local wound infiltration with local anaesthetic, COX-2 inhibitor,
and PCA morphine.
Randomization and blinding Patients recruited for mastectomy will be stratified in
randomization. To ensure equal distribution of patients between each type of operation
(modified radical mastectomy with axillary dissection and mastectomy with sentinel lymph node
without axillary dissection) block randomization will be used. There will be 9 blocks of 15
patients for each type of operation. The allocation order will be selected by a computer
generated random sequence.
This is a double blind randomized control trial. Both the patients and the investigators will
be blinded to the allocated analgesic modalities: ie the administration of ketamine. Ketamine
or normal saline (placebo) will be prepared by clinical staff who will not participate in
observation and data analysis.
Data collection
The following data will be collected during the perioperative period:
- Demographics
- Time of admission
- Intraoperative vital signs (blood pressure, heart rate, oxygen saturation)
- Estimated intraoperative blood loss
- Volume of intraoperative fluid/blood infusion
- Duration of anaesthetic or analgesic procedures before surgical procedure
- Duration of surgical procedures
- Time from end of surgical procedure to extubation
- Demands and goods of PCA morphine use
- Cumulative morphine consumption
- Vital signs and NRS pain scores at rest and during cough/ipsilateral arm movement upon
recovery every hour for 4 hours, and then once every 4 hours for up to 5 days during the
time that PCA morphine is used. Afterwards, these data will be collected daily until
discharge
- Dose and frequency of rescues analgesics (Intra muscular injection of morphine) used
- Side effects of analgesics (pruritus, dizziness, nausea, vomiting, psychomimetic effects
etc.)
- Time to recovery of food intake (fluid, semisolid and solid diet)
- Time to ambulation (bed rest, sit up, sit out of bed, walk with aid, walk without aid)
- Surgical and anaesthetic complications, if any (wound infection, urinary retention,
etc.)
- Time to discharge
- Patient satisfaction upon discharge
The following data would be obtained at 3 and 6 months after surgery:
- The presence of chronic pain
- The location of pain
- Pain severity (Numerical Rating scale (NRS) score): at rest, during cough/movement of
the ipsilateral arm
- Any analgesic consumption
- Nature of pain: nociceptive, neuropathic
- Timing of pain occurrence: continuous, related to movement, intermittent.
- Any abnormal sensation or loss of sensation over operated side.
- Health related quality of life (HRQOL) data obtained with the Chinese (Hong Kong)
version of Short Form-12 version 2 (SF12v2) Health Survey.
- Patient's psychological condition will be assessed with the Hospital Anxiety and
Depression Scale (HADS) questionnaire.
- Physical examination to check for any brush allodynia and pinprick hyperalgesia
Other data:
- Survival status at 6 and 12 months after operation
- Any recurrence of disease
- Treatment with radiotherapy or chemotherapy
- If, at certain time point after operation, patient cannot be managed according to the
protocol due to any reason such as development of complication, no further data will be
collected.
Blood taking for assessment of genetic, epigenetic factors and biomarkers Blood (10mls in
tubes with Ethylenediaminetetraacetic acid (EDTA) as preservative) will be taken immediately
pre-surgery, immediately post-surgery, one day post-surgery, three days post-surgery, and at
3 and 6-months after surgery.
Data analysis Intention-to-treat will be used. Patients will remain in their initial
designated groups for data analysis even if there is a change in surgical or
anaesthetic/analgesic management, as long as they have had a laparoscopic incision during the
operation.
Statistical methods used:
- Incidence of chronic post mastectomy pain: Chi-Square test
- NRS pain scores at 3 and 6 months after surgery, estimated blood loss, duration of
anaesthetic, analgesic and surgical procedures, time to extubation, tries and goods of
PCA morphine used, cumulative morphine consumption, dose and frequency of rescue
analgesic used, time to food intake and ambulation, time to discharge, patient
satisfaction: Kruskal-Wallis test
- Acute NRS pain scores over 48 hours: Expressed as area under the curve (AUC) using the
trapezoid rule and compared using Kruskal-Wallis test.
- Patient demographic data: One way Analysis of Variance (ANOVA) and chi-square test.
- Intraoperative vital signs, HRQOL, HADS: Repeated measures ANOVA (with Bonferroni
correction when appropriate)
- Side effects and postoperative complications: Chi Square test
- Binary logistic regression will be used to assess the relationship between development
(or non-development) of chronic pain and DNA methylation status of TRPV1 and TRPA1.
- When a significant result was obtained, t-test or Mann-Whitney test for numerical values
and Chi-square test for categorical data will be applied for post hoc pairwise
comparisons.