ORIGINAL ARTICLE
Thoracic Paravertebral Block and Its Effects on Chronic Pain and Health-Related Quality of Life After Modified Radical Mastectomy Manoj Kumar Karmakar, MD, FRCA, FHKCA, FHKAM,* Winnie Samy, BN,* Jia W. Li, PhD,* Anna Lee, PhD,* Wing Cheong Chan, FRCSE (Gen),† Phoon P. Chen, FANZCA,‡ and Anthony M.-H. Ho, MD* Background and Objectives: Patients undergoing breast cancer surgery frequently experience chronic postoperative pain. The primary objective of this randomized study was to determine if thoracic paravertebral block (TPVB) reduced the incidence of chronic pain after a modified radical mastectomy (MRM) when compared with general anesthesia (GA). Methods: One hundred eighty women undergoing MRM were randomized to 1 of 3 study groups: group 1: standardized GA, group 2: GA with a single-injection TPVB and placebo paravertebral infusion, and group 3: GA with a continuous TPVB. Outcomes assessed postoperatively included acute postoperative pain and analgesic consumption and, at 3 and 6 months, the incidence and severity of chronic pain and physical and mental healthrelated quality of life (HRQOL). Results: There was no significant difference in the incidence of chronic pain at 3 months (P = 0.13) and 6 months (P = 0.79) after the MRM between the study groups. The relative risk of developing chronic pain (P = 0.25) was also similar between the groups. There was no difference in acute pain (P = 0.22) or postoperative analgesic consumption (P = 0.67) between the groups. Nevertheless, differences were observed in chronic pain–related secondary outcome variables. The TPVB groups reported lower chronic pain scores (P < 0.05), exhibited fewer symptoms and signs of chronic pain (P ≤ 0.01), and also experienced better physical and mental HRQOL than did the GA group. Chronic pain scores also decreased with time in all study groups (P < 0.05). Conclusions: There is no significant difference in the incidence or relative risk of chronic pain at 3 and 6 months after an MRM when TPVB is used in conjunction with GA. Nevertheless, patients who receive a TPVB report less severe chronic pain, exhibit fewer symptoms and signs of chronic pain, and also experience better physical and mental HRQOL. From the *Department of Anesthesia & Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin; and Departments of †Surgery and ‡Anaesthesiology and Operating Services, North District Hospital, Sheung Shui, New Territories, Hong Kong, Special Administrative Region, China Accepted for publication April 25, 2014. Address correspondence to: Manoj Kumar Karmakar, MD, Department of Anesthesia & Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, 4th Floor-Main Clinical Block and Trauma Centre, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong, SAR, China (e‐mail: [email protected]). The authors declare no conflict of interest. Dr Ho is now with the Department of Anesthesiology and Perioperative Medicine, Queen’s University, Kingston, Ontario, Canada. Attribute work to the Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China. This research work was fully funded by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (RGC reference no. CUHK4406/05, project code 2140452). Part of this work was presented as a poster discussion at the 36th Annual Regional Anesthesia Meeting and Workshops of the American Society of Regional Anesthesia and Pain Medicine, May 5–8, 2011, Caesars Palace, Las Vegas, Nevada. Institutional review board contact information: Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee, CREC reference no. CRE-2004.376-T. Contact CRE officer: tel.: +852 2632 3935; fax: +852 2646 6653. Copyright © 2014 by American Society of Regional Anesthesia and Pain Medicine ISSN: 1098-7339 DOI: 10.1097/AAP.0000000000000113
(Reg Anesth Pain Med 2014;39: 289–298)
B
reast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related deaths among women.1,2 Surgery followed by chemotherapy and/or radiotherapy are the mainstay of current management. Chronic pain, or persistent postsurgical pain, which until recently was considered infrequent after breast cancer surgery (BCS), affects 60% to 80% of breast cancer survivors.3 It is a difficult clinical condition to treat, has a profound negative impact on health-related quality of life (HRQOL),4 and produces psychological morbidity that includes anxiety and depression.5 The exact cause of chronic pain after BCS is not clear, but there is an association between acute postoperative pain and chronic pain generation after BCS.3 Postoperative pain intensity and analgesic consumption are significantly higher in patients who develop chronic pain after BCS,4,5 and it is suggested that optimizing postoperative pain management may reduce chronic pain.6,7 A single-injection8 or continuous9 thoracic paravertebral block (TPVB) when used in conjunction with general anesthesia (GA) reduces postoperative pain8,9 and analgesic consumption8 in patients undergoing BCS.8,9 Current data also suggest that it reduces the prevalence8,9 and severity of chronic pain after BCS.8 However, patients recruited for these preliminary studies were heterogeneous8,9 and underwent different types of breast surgery,8,9 and the studies were also of small sample sizes.8,9 The primary objective of this study was to determine if TPVB reduced the incidence of chronic pain following modified radical mastectomy (MRM) when compared with GA. Moreover, because there are no data on whether a TPVB affects long-term HRQOL in breast cancer survivors, we also evaluated HRQOL as a secondary outcome measure.
METHODS This prospective, randomized controlled trial was registered with the Centre for Clinical Trials of The Chinese University of Hong Kong, http://www.cct.cuhk.edu.hk/Registry/publictriallist.aspx, under the unique trial number CUHK_CCT00100, date of registration December 4, 2006. After research ethics committee (The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee) approval and written informed consent, of the 288 women who were screened for the study, 180 patients, younger than 70 years, American Society of Anesthesiologists (ASA) physical status 1 to 3, undergoing MRM, which included axillary lymph node clearance, met the inclusion criteria for this study (Fig. 1). The following were the exclusion criteria: history of chronic pain, history of regular analgesic usage, contraindication to the use of a TPVB10 or nonsteroidal anti-inflammatory drugs, known allergy to local anesthetic drugs, preexisting neurological or muscular disorders, history of psychiatric illness, pregnant patients, patients who in the 24 hours before surgery had received opioid drugs, patients who had
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Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014
FIGURE 1. CONSORT E-Flowchart.
received chemotherapy or radiotherapy before surgery, and patients with breast pain before surgery.
Randomization Patients were randomized to 1 of 3 study groups by drawing sequentially numbered, coded, sealed, opaque envelopes each with a computer-generated allocation number: Gp1: standardized GA (control group), Gp2: GA with a single-injection TPVB (ropivacaine 2 mg/kg with 5 μg/mL epinephrine) and a paravertebral infusion of 0.9% saline (0.1 mL/kg per hour), and Gp3: GA with a singleinjection TPVB (ropivacaine 2 mg/kg with 5 μg/mL epinephrine) and a continuous paravertebral infusion of 0.25% ropivacaine at 0.1 mL/kg per hour (CTPVB group). The sealed envelopes for the randomization were prepared by a third party (research assistant) who took no further part in the study.
Blinding Method Patients in Gp1, who had received standardized GA with no paravertebral intervention, could not be blinded for obvious reasons and thus served as the control group. For the other 2 study groups that had a thoracic paravertebral catheter placed, we adopted a double-blind methodology. The principal investigator performed all the thoracic paravertebral catheter placements, collected procedural data, injected the ropivacaine bolus for the TPVB, conducted the GA, and took no further part in data
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collection during the postoperative period. The paravertebral infusion (ropivacaine 0.25% or 0.9% saline) was prepared under strict aseptic precautions by a postanesthetic care unit (PACU) nurse not involved in the study according to instructions placed in a folder. A label reading “study drug” was applied to the infusion bag. A single surgeon, who was also blinded to the group allocation, performed or supervised all the surgical procedures using a standardized technique, which included axillary lymph node removal, without sentinel lymph node sampling, up to level 2, and no attempt was made to spare the intercostobrachial nerve. A research nurse blinded to the group allocation recorded data preoperatively, in the PACU, and at regular intervals in the postoperative ward. For logistical reasons during after-hours (5:00 PM to 8:00 AM), the nurse in the surgical ward assigned to care for the patient, also blinded to group allocation, assisted with postoperative data collection. The telephone interview at 3 and 6 months after surgery was also conducted by the same research nurse (blind to group allocation).
Preoperative Visit All patients were seen the day before surgery, and written informed consent was obtained. Patients were instructed on the use of a 100-mm verbal rating scale (VRS) for postoperative pain (0 = no pain to 100 = worst imaginable pain) assessment. They were © 2014 American Society of Regional Anesthesia and Pain Medicine
Copyright © 2014 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.
Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014
also instructed about pain assessment at rest and on moving the arm (abducting the arm to 90 degrees) ipsilateral to the operated breast. Baseline HRQOL data were measured using the Chinese (HK) version of the Medical Outcomes Study 36-Item ShortForm questionnaire (SF-36),11 which is a HRQOL measure that has been validated in the Chinese population. All patients recruited received midazolam (7.5 mg, per oral) as premedication 30 minutes prior to arrival in the operating room.
Intraoperative Management On arrival in the anesthetic room, baseline electrocardiogram, heart rate, blood pressure, and SaO2 were recorded. An intravenous infusion of 0.9% sodium chloride was then commenced on the hand or forearm contralateral to the side of surgery. Patients randomized to Gp2 and Gp3 then had a thoracic paravertebral catheter placed opposite the third thoracic spine, ipsilateral to the side of surgery, under strict aseptic precautions with the patient in the sitting position using the technique described by Eason and Wyatt.12 An 18-gauge Tuohy needle (Minipack; Portex, Hythe, UK) was used, and loss of resistance to air with a 5-mL glass syringe was used to identify the thoracic paravertebral space. After negative aspiration through the Tuohy needle ropivacaine (2 mg/kg) with freshly added epinephrine (5 μg/mL) in a total volume of 20 mL with normal saline was slowly injected in 3- to 4-mL aliquots over 2 to 3 minutes. An epidural catheter was then inserted through the Tuohy needle into the thoracic paravertebral space, and 3 to 4 cm of the catheter was left in situ after which it was tunneled subcutaneously and secured to the back.
General Anesthesia (Total Intravenous Anesthesia) All patients then had standardized GA. This included intravenous fentanyl (100 μg) and propofol (target plasma concentration 3–5 μg/mL) for induction. Once patients were unresponsive, rocuronium (0.5 mg/kg) was administered to facilitate endotracheal intubation. Anesthesia was maintained using a target controlled infusion of propofol (target plasma concentration, 3–4 μg/mL) titrated to maintain a BIS (Bispectral Index) value of 40 to 60. Mechanical ventilation of the lung was commenced with an airO2 mixture (fraction of inspired oxygen concentration of 33%) and adjusted to maintain an end-tidal CO2 concentration between 32 and 34 mm Hg. Morphine (0.1 mg/kg) was also administered intravenously to every patient irrespective of group allocation for intraoperative analgesia. Once hemodynamic parameters were stable, a continuous infusion of the blinded “study drug” (Gp2: 0.9% saline and Gp3: ropivacaine 0.25%) was commenced at a rate of 0.10 mL/kg per hour via the indwelling paravertebral catheter. This infusion rate was maintained constant intraoperatively and for 72 hours after surgery, and additional rescue analgesia was administered if necessary. During the intraoperative period, additional doses of morphine (1 mg intravenous therapy [IV] bolus) was administered to obtund increases in heart rate and/or blood pressure greater than 20% of preincisional baseline. Ondansetron (4 mg IV) was administered 30 minutes before the end of surgery as prophylaxis against postoperative nausea and vomiting. On completion of surgery, the propofol infusion was discontinued, neuromuscular blockade was reversed using neostigmine (50 μg/kg) and atropine (20 μg/kg), and patient’s trachea was extubated when awake.
TPVB and Breast Cancer Surgery
maximum 10 mg) if the VRS pain score at rest was greater than 40 mm, or the patient demands additional analgesia. A research nurse, blind to group allocation, performed postoperative data collection while patients were nursed in the PACU.
Postoperative Ward Once the patients returned to the surgical ward, they were allowed to drink and eat as tolerated and also actively encouraged to mobilize out of bed. Diclofenac (75 mg) was administered every 12 hours (twice a day) orally as regular analgesia for the next 72 hours. Morphine (0.1 mg/kg, PRN every 3 hours) intramuscularly or Dologesic (paracetamol 325 mg and dextropropoxyphene 32.5 mg, 2 tablet, PRN every 6 hours) orally was administered as rescue analgesia if VRS pain score at rest was greater than 40 mm, or if the patient demanded additional analgesia. The thoracic paravertebral infusion was discontinued after 72 hours, and the catheter was removed. On completion of data collection, patients were asked to rate their overall satisfaction with the quality of their postoperative pain relief using a VRS (0-100: 0 = totally dissatisfied to 100 = totally satisfied). On the day of discharge from hospital, usually on day 4 or 5, the research nurse briefed the patients about the telephone interview that would take place at 3 and 6 months after surgery, and envelopes containing copies of the Chinese-Cantonese versions of the data forms (SF-36 Health Survey Questionnaire11) that would be used during the interview were given to the patients.
Postoperative Follow-up (3 and 6 Months) Patients underwent a telephone interview at 3 and 6 months after surgery. The main objective of this follow-up was to record data on the incidence and severity of chronic pain and its effects on HRQOL. We defined chronic pain as defined by the International Association for the Study of Pain (IASP),13 that is, pain that persisted beyond the time of normal tissue healing (usually taken as 3 months) and that was not related to other causes (eg, recurrence of disease or inflammation). The interview was conducted by a research nurse, unaware of group allocation, and data outlined in Appendix 1 were obtained. The HRQOL (Chinese-HK version of the SF-36 Health Survey)11 data were also obtained.
Statistical Analysis Sample Size Estimation Sample size was calculated using nQuery Advisor software (version 6.0; Janet D Elashoff 2005, Los Angeles, California) and based on the incidence of chronic pain after BCS, which was our primary outcome variable. Published data showed that the incidence of chronic pain after BCS varied from 50% to 80%.3 Because there were no comparable data from the Hong Kong Chinese patients, we conducted a pilot study on 23 patients who had undergone GA for BCS under our care. We found that 17 of the 23 patients (74%) reported chronic pain when they were interviewed at 3 months after surgery. With a baseline incidence of 74%, using 2 proportions sample test, we estimated that 58 patients per study group would provide 80% power (α = 0.05) to detect a 25% reduction in the incidence of chronic pain in the study groups (groups that will receive the TPVB).
PACU Management
Data Analysis
Postoperative pain was scored once on arrival and then prior to discharge from the PACU. Pain at rest and on movement was assessed using a VRS (0- to 100-mm scale) All patients had access to nurse-administered IV morphine for rescue analgesia as per a standardized regimen (1-mg bolus, every 3 minutes,
The primary analyses were performed on a modified intentionto-treat basis (ie, patients were analyzed according to their randomized allocated groups but were excluded from the analysis if they did not adhere to the protocol after randomization). Patients who reported pain at rest over the operated site, axilla, or arm
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TABLE 1. Demographic Data GA + Single-shot GA Group TPVB + Placebo (Gp1) Infusion (Gp2) GA + CTPVB (n = 60) (n = 57) (Gp3) (n = 60) Age, y 51 (9) BMI, kg/m 24.2 (3.7) ASA (I:II:III) 39:20:1
54 (9) 24.0 (3.7) 23:33:1
53 (8) 24.2 (3.9) 35:24:1
P* 0.12 0.94 0.10
Data are presented as mean (SD) except ASA physical status, which is presented as frequency (n). *Gp1 vs Gp2 vs Gp3. BMI indicates body mass index.
(ie, reported yes to any of the 3 questions 4, 6, and 8 of Appendix 1) and that was related to the surgery were defined as having chronic pain after the MRM, and the data were used to calculate the incidence of chronic pain at 3 and 6 months (Table 3). A generalized estimating equation (GEE) model using a Poisson distribution and log link function was used to obtain a common relative risk of postoperative chronic pain associated with treatment groups. This model takes into account the correlation between chronic pain measurements at 3 and 6 months within a patient. As none of the baseline characteristics were significant at P < 0.05 level, we did not adjust for covariates in the GEE model. Separate GEE models were performed for chronic pain at all sites and over the operative site, with GA (group 1) as the reference group. In estimating the effect of treatment on HRQOL, the 8 subscales of the Chinese-HK SF-36 were added to form the SF-36 physical and mental health summary (PCS and MCS) scores using the HK-specific scoring algorithm.14 Severity (intensity) of chronic pain was compared between the study groups by comparing the VRS pain scores reported by patients at 3 and 6 months. Also in order to quantify and statistically compare the total number of chronic pain symptoms and signs reported by the patients, a score of 1 was given to a response “yes,” and a score of 0 was given to a response “no” to any of the following
15 questions, that is, pain in the operated site at rest and on movement; pain in the axilla at rest and on movement; pain in the arm at rest and on movement; any phantom breast sensation; any painful response to a normally innocuous stimulus (allodynia); if they were taking regular oral analgesics at home, sensory loss over the chest wall, axilla and arm; and decreased sensation over the chest wall, axilla, and arm (Appendix 1, Chronic Pain Symptom and Sign Score, maximum score possible was 15). Questions in Appendix 1 were partly sourced from a previous publication by Fassoulaki and colleagues.15 Difference was defined as GA outcome measure minus CTPVB (placebo or infusion) outcome. We used analysis of variance (ANOVA), Kruskal-Wallis test, and χ2 test to compare demographic characteristics between groups. Repeated-measures ANOVA was used to examine pain scores and HRQOL measures. When differences were found in the repeatedmeasures ANOVA, Bonferroni correction for between-groups multiple comparisons was applied. One-way ANOVA was performed to assess differences in patient satisfaction between groups. As the homogeneity assumption was violated, a Kruskal-Wallis test was done. Data are reported as mean and SD or 95% confidence interval (CI) if the data were normally distributed or median and interquartile range (IQR) if the data were not normally distributed. All statistical analyses were performed using SPSS Windows 15.0 (SPSS Inc, Chicago, Illinois). P ≤ 0.05 was considered statistically significant.
RESULTS Three patients were excluded after randomization (Fig. 1). There were no major complications directly relating to the technique of thoracic paravertebral catheter placement or the paravertebral infusion. The 3 study groups were comparable with respect to age, body mass index, ASA physical status, baseline SF-36 PCS and SF-36 MCS scores, total dose of morphine used in the PACU, duration of PACU and hospital stay, number of patients who received rescue oral analgesia in the ward, patient satisfaction score, and the number of patients who had radiotherapy or chemotherapy during the study (Tables 1 and 2). The median supplementary morphine requirement during surgery in Gp1 (1.5 [IQR,
TABLE 2. Clinical Parameters and Secondary Outcome Variables
Baseline SF-36 PCS Baseline SF-36 MCS Supplementary morphine used during surgery, mg Total morphine used in PACU, mg Total duration of PACU stay, min No. patients (%) who received oral Dologesic for rescue analgesia in the ward at any time on day 1:2:3 Patient satisfaction score Duration of hospital stay No. patients who had chemotherapy at 3 mo No. patients who had radiotherapy at 3 mo No. patients who had chemotherapy at 6 mo No. patients who had radiotherapy at 6 mo
GA Group (Gp1) (n = 60)
GA + Single-shot TPVB + Placebo Infusion (Gp2) (n = 57)
GA + CTPVB (Gp3) (n = 60)
P*
53.6 (5.4) 43.4 (17.7) 1.5 (0–3) 0.25 (0.70) 38 (14) 4 (7)
53.4 (6.2) 49.3 (12.9) 0 (0–1.0) 0.21 (0.53) 38 (11) 6 (11)
54.5 (5.5) 47.4 (13.8) 0 (0–1) 0.22 (0.58) 38 (10) 4 (7)
0.50 0.09
Thoracic Paravertebral Block and Its Effects on Chronic Pain and Health-Related Quality of Life After Modified Radical Mastectomy Manoj Kumar Karmakar, MD, FRCA, FHKCA, FHKAM,* Winnie Samy, BN,* Jia W. Li, PhD,* Anna Lee, PhD,* Wing Cheong Chan, FRCSE (Gen),† Phoon P. Chen, FANZCA,‡ and Anthony M.-H. Ho, MD* Background and Objectives: Patients undergoing breast cancer surgery frequently experience chronic postoperative pain. The primary objective of this randomized study was to determine if thoracic paravertebral block (TPVB) reduced the incidence of chronic pain after a modified radical mastectomy (MRM) when compared with general anesthesia (GA). Methods: One hundred eighty women undergoing MRM were randomized to 1 of 3 study groups: group 1: standardized GA, group 2: GA with a single-injection TPVB and placebo paravertebral infusion, and group 3: GA with a continuous TPVB. Outcomes assessed postoperatively included acute postoperative pain and analgesic consumption and, at 3 and 6 months, the incidence and severity of chronic pain and physical and mental healthrelated quality of life (HRQOL). Results: There was no significant difference in the incidence of chronic pain at 3 months (P = 0.13) and 6 months (P = 0.79) after the MRM between the study groups. The relative risk of developing chronic pain (P = 0.25) was also similar between the groups. There was no difference in acute pain (P = 0.22) or postoperative analgesic consumption (P = 0.67) between the groups. Nevertheless, differences were observed in chronic pain–related secondary outcome variables. The TPVB groups reported lower chronic pain scores (P < 0.05), exhibited fewer symptoms and signs of chronic pain (P ≤ 0.01), and also experienced better physical and mental HRQOL than did the GA group. Chronic pain scores also decreased with time in all study groups (P < 0.05). Conclusions: There is no significant difference in the incidence or relative risk of chronic pain at 3 and 6 months after an MRM when TPVB is used in conjunction with GA. Nevertheless, patients who receive a TPVB report less severe chronic pain, exhibit fewer symptoms and signs of chronic pain, and also experience better physical and mental HRQOL. From the *Department of Anesthesia & Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin; and Departments of †Surgery and ‡Anaesthesiology and Operating Services, North District Hospital, Sheung Shui, New Territories, Hong Kong, Special Administrative Region, China Accepted for publication April 25, 2014. Address correspondence to: Manoj Kumar Karmakar, MD, Department of Anesthesia & Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, 4th Floor-Main Clinical Block and Trauma Centre, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong, SAR, China (e‐mail: [email protected]). The authors declare no conflict of interest. Dr Ho is now with the Department of Anesthesiology and Perioperative Medicine, Queen’s University, Kingston, Ontario, Canada. Attribute work to the Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China. This research work was fully funded by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (RGC reference no. CUHK4406/05, project code 2140452). Part of this work was presented as a poster discussion at the 36th Annual Regional Anesthesia Meeting and Workshops of the American Society of Regional Anesthesia and Pain Medicine, May 5–8, 2011, Caesars Palace, Las Vegas, Nevada. Institutional review board contact information: Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee, CREC reference no. CRE-2004.376-T. Contact CRE officer: tel.: +852 2632 3935; fax: +852 2646 6653. Copyright © 2014 by American Society of Regional Anesthesia and Pain Medicine ISSN: 1098-7339 DOI: 10.1097/AAP.0000000000000113
(Reg Anesth Pain Med 2014;39: 289–298)
B
reast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related deaths among women.1,2 Surgery followed by chemotherapy and/or radiotherapy are the mainstay of current management. Chronic pain, or persistent postsurgical pain, which until recently was considered infrequent after breast cancer surgery (BCS), affects 60% to 80% of breast cancer survivors.3 It is a difficult clinical condition to treat, has a profound negative impact on health-related quality of life (HRQOL),4 and produces psychological morbidity that includes anxiety and depression.5 The exact cause of chronic pain after BCS is not clear, but there is an association between acute postoperative pain and chronic pain generation after BCS.3 Postoperative pain intensity and analgesic consumption are significantly higher in patients who develop chronic pain after BCS,4,5 and it is suggested that optimizing postoperative pain management may reduce chronic pain.6,7 A single-injection8 or continuous9 thoracic paravertebral block (TPVB) when used in conjunction with general anesthesia (GA) reduces postoperative pain8,9 and analgesic consumption8 in patients undergoing BCS.8,9 Current data also suggest that it reduces the prevalence8,9 and severity of chronic pain after BCS.8 However, patients recruited for these preliminary studies were heterogeneous8,9 and underwent different types of breast surgery,8,9 and the studies were also of small sample sizes.8,9 The primary objective of this study was to determine if TPVB reduced the incidence of chronic pain following modified radical mastectomy (MRM) when compared with GA. Moreover, because there are no data on whether a TPVB affects long-term HRQOL in breast cancer survivors, we also evaluated HRQOL as a secondary outcome measure.
METHODS This prospective, randomized controlled trial was registered with the Centre for Clinical Trials of The Chinese University of Hong Kong, http://www.cct.cuhk.edu.hk/Registry/publictriallist.aspx, under the unique trial number CUHK_CCT00100, date of registration December 4, 2006. After research ethics committee (The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee) approval and written informed consent, of the 288 women who were screened for the study, 180 patients, younger than 70 years, American Society of Anesthesiologists (ASA) physical status 1 to 3, undergoing MRM, which included axillary lymph node clearance, met the inclusion criteria for this study (Fig. 1). The following were the exclusion criteria: history of chronic pain, history of regular analgesic usage, contraindication to the use of a TPVB10 or nonsteroidal anti-inflammatory drugs, known allergy to local anesthetic drugs, preexisting neurological or muscular disorders, history of psychiatric illness, pregnant patients, patients who in the 24 hours before surgery had received opioid drugs, patients who had
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Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014
FIGURE 1. CONSORT E-Flowchart.
received chemotherapy or radiotherapy before surgery, and patients with breast pain before surgery.
Randomization Patients were randomized to 1 of 3 study groups by drawing sequentially numbered, coded, sealed, opaque envelopes each with a computer-generated allocation number: Gp1: standardized GA (control group), Gp2: GA with a single-injection TPVB (ropivacaine 2 mg/kg with 5 μg/mL epinephrine) and a paravertebral infusion of 0.9% saline (0.1 mL/kg per hour), and Gp3: GA with a singleinjection TPVB (ropivacaine 2 mg/kg with 5 μg/mL epinephrine) and a continuous paravertebral infusion of 0.25% ropivacaine at 0.1 mL/kg per hour (CTPVB group). The sealed envelopes for the randomization were prepared by a third party (research assistant) who took no further part in the study.
Blinding Method Patients in Gp1, who had received standardized GA with no paravertebral intervention, could not be blinded for obvious reasons and thus served as the control group. For the other 2 study groups that had a thoracic paravertebral catheter placed, we adopted a double-blind methodology. The principal investigator performed all the thoracic paravertebral catheter placements, collected procedural data, injected the ropivacaine bolus for the TPVB, conducted the GA, and took no further part in data
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collection during the postoperative period. The paravertebral infusion (ropivacaine 0.25% or 0.9% saline) was prepared under strict aseptic precautions by a postanesthetic care unit (PACU) nurse not involved in the study according to instructions placed in a folder. A label reading “study drug” was applied to the infusion bag. A single surgeon, who was also blinded to the group allocation, performed or supervised all the surgical procedures using a standardized technique, which included axillary lymph node removal, without sentinel lymph node sampling, up to level 2, and no attempt was made to spare the intercostobrachial nerve. A research nurse blinded to the group allocation recorded data preoperatively, in the PACU, and at regular intervals in the postoperative ward. For logistical reasons during after-hours (5:00 PM to 8:00 AM), the nurse in the surgical ward assigned to care for the patient, also blinded to group allocation, assisted with postoperative data collection. The telephone interview at 3 and 6 months after surgery was also conducted by the same research nurse (blind to group allocation).
Preoperative Visit All patients were seen the day before surgery, and written informed consent was obtained. Patients were instructed on the use of a 100-mm verbal rating scale (VRS) for postoperative pain (0 = no pain to 100 = worst imaginable pain) assessment. They were © 2014 American Society of Regional Anesthesia and Pain Medicine
Copyright © 2014 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.
Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014
also instructed about pain assessment at rest and on moving the arm (abducting the arm to 90 degrees) ipsilateral to the operated breast. Baseline HRQOL data were measured using the Chinese (HK) version of the Medical Outcomes Study 36-Item ShortForm questionnaire (SF-36),11 which is a HRQOL measure that has been validated in the Chinese population. All patients recruited received midazolam (7.5 mg, per oral) as premedication 30 minutes prior to arrival in the operating room.
Intraoperative Management On arrival in the anesthetic room, baseline electrocardiogram, heart rate, blood pressure, and SaO2 were recorded. An intravenous infusion of 0.9% sodium chloride was then commenced on the hand or forearm contralateral to the side of surgery. Patients randomized to Gp2 and Gp3 then had a thoracic paravertebral catheter placed opposite the third thoracic spine, ipsilateral to the side of surgery, under strict aseptic precautions with the patient in the sitting position using the technique described by Eason and Wyatt.12 An 18-gauge Tuohy needle (Minipack; Portex, Hythe, UK) was used, and loss of resistance to air with a 5-mL glass syringe was used to identify the thoracic paravertebral space. After negative aspiration through the Tuohy needle ropivacaine (2 mg/kg) with freshly added epinephrine (5 μg/mL) in a total volume of 20 mL with normal saline was slowly injected in 3- to 4-mL aliquots over 2 to 3 minutes. An epidural catheter was then inserted through the Tuohy needle into the thoracic paravertebral space, and 3 to 4 cm of the catheter was left in situ after which it was tunneled subcutaneously and secured to the back.
General Anesthesia (Total Intravenous Anesthesia) All patients then had standardized GA. This included intravenous fentanyl (100 μg) and propofol (target plasma concentration 3–5 μg/mL) for induction. Once patients were unresponsive, rocuronium (0.5 mg/kg) was administered to facilitate endotracheal intubation. Anesthesia was maintained using a target controlled infusion of propofol (target plasma concentration, 3–4 μg/mL) titrated to maintain a BIS (Bispectral Index) value of 40 to 60. Mechanical ventilation of the lung was commenced with an airO2 mixture (fraction of inspired oxygen concentration of 33%) and adjusted to maintain an end-tidal CO2 concentration between 32 and 34 mm Hg. Morphine (0.1 mg/kg) was also administered intravenously to every patient irrespective of group allocation for intraoperative analgesia. Once hemodynamic parameters were stable, a continuous infusion of the blinded “study drug” (Gp2: 0.9% saline and Gp3: ropivacaine 0.25%) was commenced at a rate of 0.10 mL/kg per hour via the indwelling paravertebral catheter. This infusion rate was maintained constant intraoperatively and for 72 hours after surgery, and additional rescue analgesia was administered if necessary. During the intraoperative period, additional doses of morphine (1 mg intravenous therapy [IV] bolus) was administered to obtund increases in heart rate and/or blood pressure greater than 20% of preincisional baseline. Ondansetron (4 mg IV) was administered 30 minutes before the end of surgery as prophylaxis against postoperative nausea and vomiting. On completion of surgery, the propofol infusion was discontinued, neuromuscular blockade was reversed using neostigmine (50 μg/kg) and atropine (20 μg/kg), and patient’s trachea was extubated when awake.
TPVB and Breast Cancer Surgery
maximum 10 mg) if the VRS pain score at rest was greater than 40 mm, or the patient demands additional analgesia. A research nurse, blind to group allocation, performed postoperative data collection while patients were nursed in the PACU.
Postoperative Ward Once the patients returned to the surgical ward, they were allowed to drink and eat as tolerated and also actively encouraged to mobilize out of bed. Diclofenac (75 mg) was administered every 12 hours (twice a day) orally as regular analgesia for the next 72 hours. Morphine (0.1 mg/kg, PRN every 3 hours) intramuscularly or Dologesic (paracetamol 325 mg and dextropropoxyphene 32.5 mg, 2 tablet, PRN every 6 hours) orally was administered as rescue analgesia if VRS pain score at rest was greater than 40 mm, or if the patient demanded additional analgesia. The thoracic paravertebral infusion was discontinued after 72 hours, and the catheter was removed. On completion of data collection, patients were asked to rate their overall satisfaction with the quality of their postoperative pain relief using a VRS (0-100: 0 = totally dissatisfied to 100 = totally satisfied). On the day of discharge from hospital, usually on day 4 or 5, the research nurse briefed the patients about the telephone interview that would take place at 3 and 6 months after surgery, and envelopes containing copies of the Chinese-Cantonese versions of the data forms (SF-36 Health Survey Questionnaire11) that would be used during the interview were given to the patients.
Postoperative Follow-up (3 and 6 Months) Patients underwent a telephone interview at 3 and 6 months after surgery. The main objective of this follow-up was to record data on the incidence and severity of chronic pain and its effects on HRQOL. We defined chronic pain as defined by the International Association for the Study of Pain (IASP),13 that is, pain that persisted beyond the time of normal tissue healing (usually taken as 3 months) and that was not related to other causes (eg, recurrence of disease or inflammation). The interview was conducted by a research nurse, unaware of group allocation, and data outlined in Appendix 1 were obtained. The HRQOL (Chinese-HK version of the SF-36 Health Survey)11 data were also obtained.
Statistical Analysis Sample Size Estimation Sample size was calculated using nQuery Advisor software (version 6.0; Janet D Elashoff 2005, Los Angeles, California) and based on the incidence of chronic pain after BCS, which was our primary outcome variable. Published data showed that the incidence of chronic pain after BCS varied from 50% to 80%.3 Because there were no comparable data from the Hong Kong Chinese patients, we conducted a pilot study on 23 patients who had undergone GA for BCS under our care. We found that 17 of the 23 patients (74%) reported chronic pain when they were interviewed at 3 months after surgery. With a baseline incidence of 74%, using 2 proportions sample test, we estimated that 58 patients per study group would provide 80% power (α = 0.05) to detect a 25% reduction in the incidence of chronic pain in the study groups (groups that will receive the TPVB).
PACU Management
Data Analysis
Postoperative pain was scored once on arrival and then prior to discharge from the PACU. Pain at rest and on movement was assessed using a VRS (0- to 100-mm scale) All patients had access to nurse-administered IV morphine for rescue analgesia as per a standardized regimen (1-mg bolus, every 3 minutes,
The primary analyses were performed on a modified intentionto-treat basis (ie, patients were analyzed according to their randomized allocated groups but were excluded from the analysis if they did not adhere to the protocol after randomization). Patients who reported pain at rest over the operated site, axilla, or arm
© 2014 American Society of Regional Anesthesia and Pain Medicine
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Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014
Karmakar et al
TABLE 1. Demographic Data GA + Single-shot GA Group TPVB + Placebo (Gp1) Infusion (Gp2) GA + CTPVB (n = 60) (n = 57) (Gp3) (n = 60) Age, y 51 (9) BMI, kg/m 24.2 (3.7) ASA (I:II:III) 39:20:1
54 (9) 24.0 (3.7) 23:33:1
53 (8) 24.2 (3.9) 35:24:1
P* 0.12 0.94 0.10
Data are presented as mean (SD) except ASA physical status, which is presented as frequency (n). *Gp1 vs Gp2 vs Gp3. BMI indicates body mass index.
(ie, reported yes to any of the 3 questions 4, 6, and 8 of Appendix 1) and that was related to the surgery were defined as having chronic pain after the MRM, and the data were used to calculate the incidence of chronic pain at 3 and 6 months (Table 3). A generalized estimating equation (GEE) model using a Poisson distribution and log link function was used to obtain a common relative risk of postoperative chronic pain associated with treatment groups. This model takes into account the correlation between chronic pain measurements at 3 and 6 months within a patient. As none of the baseline characteristics were significant at P < 0.05 level, we did not adjust for covariates in the GEE model. Separate GEE models were performed for chronic pain at all sites and over the operative site, with GA (group 1) as the reference group. In estimating the effect of treatment on HRQOL, the 8 subscales of the Chinese-HK SF-36 were added to form the SF-36 physical and mental health summary (PCS and MCS) scores using the HK-specific scoring algorithm.14 Severity (intensity) of chronic pain was compared between the study groups by comparing the VRS pain scores reported by patients at 3 and 6 months. Also in order to quantify and statistically compare the total number of chronic pain symptoms and signs reported by the patients, a score of 1 was given to a response “yes,” and a score of 0 was given to a response “no” to any of the following
15 questions, that is, pain in the operated site at rest and on movement; pain in the axilla at rest and on movement; pain in the arm at rest and on movement; any phantom breast sensation; any painful response to a normally innocuous stimulus (allodynia); if they were taking regular oral analgesics at home, sensory loss over the chest wall, axilla and arm; and decreased sensation over the chest wall, axilla, and arm (Appendix 1, Chronic Pain Symptom and Sign Score, maximum score possible was 15). Questions in Appendix 1 were partly sourced from a previous publication by Fassoulaki and colleagues.15 Difference was defined as GA outcome measure minus CTPVB (placebo or infusion) outcome. We used analysis of variance (ANOVA), Kruskal-Wallis test, and χ2 test to compare demographic characteristics between groups. Repeated-measures ANOVA was used to examine pain scores and HRQOL measures. When differences were found in the repeatedmeasures ANOVA, Bonferroni correction for between-groups multiple comparisons was applied. One-way ANOVA was performed to assess differences in patient satisfaction between groups. As the homogeneity assumption was violated, a Kruskal-Wallis test was done. Data are reported as mean and SD or 95% confidence interval (CI) if the data were normally distributed or median and interquartile range (IQR) if the data were not normally distributed. All statistical analyses were performed using SPSS Windows 15.0 (SPSS Inc, Chicago, Illinois). P ≤ 0.05 was considered statistically significant.
RESULTS Three patients were excluded after randomization (Fig. 1). There were no major complications directly relating to the technique of thoracic paravertebral catheter placement or the paravertebral infusion. The 3 study groups were comparable with respect to age, body mass index, ASA physical status, baseline SF-36 PCS and SF-36 MCS scores, total dose of morphine used in the PACU, duration of PACU and hospital stay, number of patients who received rescue oral analgesia in the ward, patient satisfaction score, and the number of patients who had radiotherapy or chemotherapy during the study (Tables 1 and 2). The median supplementary morphine requirement during surgery in Gp1 (1.5 [IQR,
TABLE 2. Clinical Parameters and Secondary Outcome Variables
Baseline SF-36 PCS Baseline SF-36 MCS Supplementary morphine used during surgery, mg Total morphine used in PACU, mg Total duration of PACU stay, min No. patients (%) who received oral Dologesic for rescue analgesia in the ward at any time on day 1:2:3 Patient satisfaction score Duration of hospital stay No. patients who had chemotherapy at 3 mo No. patients who had radiotherapy at 3 mo No. patients who had chemotherapy at 6 mo No. patients who had radiotherapy at 6 mo
GA Group (Gp1) (n = 60)
GA + Single-shot TPVB + Placebo Infusion (Gp2) (n = 57)
GA + CTPVB (Gp3) (n = 60)
P*
53.6 (5.4) 43.4 (17.7) 1.5 (0–3) 0.25 (0.70) 38 (14) 4 (7)
53.4 (6.2) 49.3 (12.9) 0 (0–1.0) 0.21 (0.53) 38 (11) 6 (11)
54.5 (5.5) 47.4 (13.8) 0 (0–1) 0.22 (0.58) 38 (10) 4 (7)
0.50 0.09
