A Double-blind Randomized Trial of Wound and Intercostal Space Infiltration with Ropivacaine during Breast Cancer Surgery

Effects on Chronic Postoperative Pain

Aline Albi-Feldzer, M.D.,* Emmanuelle Mouret-Fourme E, M.D., Smail Hamouda, M.D., Cyrus Motamed, M.D., Pierre-Yves Dubois, M.D., Ludivine Jouanneau, Ph.D., Christian Jayr M.D., Ph.D.*

ABSTRACT Background: The efficacy of local anesthetic wound infiltration for the treatment of acute and chronic postoperative pain is controversial and there are no detailed studies. The primary objective of this study was to evaluate the influence of ropivacaine wound infiltration on chronic pain after breast surgery. Methods: In this prospective, randomized, double-blind, parallel-group, placebo-controlled study, 236 patients scheduled for breast cancer surgery were randomized (1:1) to receive ropivacaine or placebo infiltration of the wound, the second and third intercostal spaces and the humeral insertion of major pectoralis. Acute pain, analgesic consumption, nausea and vomiting were assessed every 30 min for 2 h in the postanesthesia care unit and every 6 h for 48 h. Chronic pain was evaluated 3 months, 6 months, and 1 yr after surgery by the brief pain inventory,

What We Already Know about This Topic

There is an association between severity of acute pain after surgery and likelihood of chronic pain, yet whether these are causally related is not known

What This Article Tells Us That Is New

In 236 women undergoing breast surgery for cancer, wound infiltration with ropivacaine reduced postoperative pain for the first 90 min after surgery, but did not reduce the incidence or severity of pain 312 months later

* Professional Staff, Department of Anesthesia and Intensive Care, Institut Curie-Hpital Ren Huguenin, Saint-Cloud, France. Professional Staff, Clinical Epidemiology, Institut Curie-Hpital Ren Huguenin. Professional Staff, Department of Anesthesia and Intensive Care, Paoli Calmette, Marseille, France. Professional Staff, Department of Anesthesia and Intensive Care, Institut Gustave Roussy, Villejuif, France. Professional Staff, Department of Anesthesia and Intensive Care, Institut Godinot, Reims, France. Received from the Department of Anesthesia and Intensive Care, Institut Curie-Hpital Ren Huguenin, Saint-Cloud, France. Submitted for publication December 30, 2011. Accepted for publication October 19, 2012. AstraZeneca (Rueil-Malmaison. France) provided the authors with all information on ropivacaine and paid 5,000 for the civil liability insurance for the study protocol, which is mandatory in France. Support was provided from institutional or departmental sources. Presented at the American Society of Anesthesiologists annual meeting, New Orleans, Louisiana, October 1721, 2009, and at the Socit Franaise dAnesthsie et de Ranimation annual French meeting, Paris, France, September 2326, 2009. Address correspondence to Dr. Jayr: Chairman, Department of Anesthesia and Intensive Care, Institut Curie-Hpital Ren Huguenin, 35, rue Dailly, Saint-Cloud 92210 cedex France. christian.jayr@curie.net. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiol ogy.org.
Copyright 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:318-26

hospital anxiety and depression, and neuropathic pain questionnaires. Results: Ropivacaine wound infiltration significantly decreased immediate postoperative pain for the first 90min, but did not decrease chronic pain at 3 months (primary endpoint), or at 6 and 12 months postoperatively. At 3 months, the incidence of chronic pain was 33% and 27% (P = 0.37) in the ropivacaine and placebo groups, respectively. During follow-up, brief pain inventory, neuropathic pain, and anxiety increased over time in both groups (P < 0.001) while depression remained stable. No complications occurred. Conclusion: This multicenter, prospective study shows that ropivacaine wound infiltration after breast cancer surgery decreased immediate postoperative pain but did not decrease chronic pain at 3, 6, and 12 months postoperatively. reast cancer affects nearly 10% of all women, and is the most common type of cancer identified in women in western countries. Early detection and treatment have led to increased survival. With the increasingly prolonged

This article is featured in This Month in Anesthesiology. Please see this issue of Anesthesiology, page 9A. This article is accompanied by an Editorial View. Please see: Cohen SP, Raja SN: Prevention of chronic postsurgical pain: The ongoing search for the holy grail of anesthesiology. Anesthesiology 2013; 118:2413.

Anesthesiology, V 118 No 2

318

February 2013

PERIOPERATIVE MEDICINE

survival of breast cancer patients, chronic postoperative pain has therefore become an important issue. Acute pain after breast surgery is moderate and depends on the type of surgery, ranging from simple lumpectomy to mastectomy with axillary node dissection. However, the estimated prevalence of chronic pain in the literature is between 20 and 65%.16 Chronic pain has a neuropathic component and has been reported to occur in various areas: the chest wall, breast, scar, axilla, and medial upper arm or shoulder. Several predictive factors, related to both the patient and surgical factors, have been identified for chronic postoperative pain. Preoperative pain sensitivity, the presence of pain before surgery, acute postoperative pain, and analgesic consumption are strong predictors of persistent pain after surgery.79 Other predictive factors include anxiety, psychosocial factors, young age (< 40 yr), type of surgery, intercostobrachial nerve damage, adjuvant radiation therapy, or chemotherapy.6,1017 Adequate and effective pain relief during the perioperative period may prevent and reduce chronic pain.1820 Postoperative loco-regional analgesia is one of the multimodal pain relief strategies used to prevent chronic pain and reduce opioid consumption and side effects.1820 However, the efficacy of local anesthetic wound infiltration for the treatment of acute pain after breast surgery is controversial.5,2124 The effect of local anesthetic instillation on chronic pain has been evaluated, and seems to be significantly effective at 3 months but not at 6 months.25 The authors suggested that larger clinical trials were necessary. Therefore, we conducted an extensive study in a homogenous population on the effect of deep wound infiltration with ropivacaine on acute and chronic pain as well as on factors of comorbidity, such as anxiety and depression after breast cancer surgery. The primary objective of this study was to address the question: Does wound infiltration influence the incidence of chronic pain evaluated by a score of three or more on item five (average pain) of the brief pain inventory (BPI) at 3 months after breast surgery? The secondary objectives were to assess the following: acute postoperative pain at rest or during mobilization, the consumption of analgesics, nausea and vomiting every 30min for 2 h in the postanesthesia care unit (PACU) and every 6h for 48h after surgery. Chronic pain was evaluated 3 months, 6 months, and 1 yr after surgery by the BPI, hospital anxiety and depression (HAD), and neuropathic pain (DN4) questionnaires.

placebo-controlled study to evaluate the effect of ropivacaine infiltration on postoperative pain in patients undergoing breast cancer surgery. Patients were recruited from a surgical ward during the preoperative visit. Inclusion Criteria. Women between the ages of 18 and 85 yr with an American Society of Anesthesiologists physical status I, II, and III and a minimum life expectancy of 2 yr, treated by conservative breast surgery with axillary lymph node dissection or radical modified mastectomy with either sentinel lymph node dissection or axillary lymph node dissection or no axillary lymph node dissection were included. Exclusion Criteria. An occurrence of any previous cancer other than breast cancer, allergy to local anesthetics and morphine, reported history of substance abuse, pregnancy, ipsilateral breast surgery in the past 3 yr, preoperative analgesic use (12h), severe renal, pulmonary, or hepatic dysfunction, active malignant disease, and those unable to comply with the protocol for any reason were excluded. All patients gave their written informed consent, and the protocol (Eudra CT N 2005-005691-32; ClinicalTrials. gov NCT N NCT00370240) was approved by the institutional review board (Institut Curie, Saint-Cloud, France) and the study ethics review committee (Hpital Ambroise Par, Boulogne, France). Randomization A balanced block stratified randomization scheme was used for patient allocation. Stratification was performed on the basis of hospital and type of surgery (conservative or not). Patients were randomized in randomly permuted blocks of four or six patients in each stratum. Assignments were computer-generated and maintained in sequentially numbered, opaque, sealed envelopes. Patients were enrolled and informed consent was obtained at least 1 day before surgery. The study was performed under double-blind conditions. The envelope was opened in an isolated room on the day of surgery, and patients were assigned to either the placebo group or the ropivacaine group. Treatment On the morning of surgery and before induction of anesthesia, an operating room nurse read the results of randomization to prepare the solution of normal saline or ropivacaine in identical syringes, to be infiltrated by the surgeon. The solution was prepared in an isolated room and the nurse did not have any further contact with the patient. No other physician or nursing staff member was aware of the contents of the solution administered to each patient. Patients were premedicated with hydroxyzine (2mg/kg) administered orally 1h before surgery. General anesthesia was induced with propofol (2.5mg/kg), sufentanil (0.2 g/kg), and atracurium or cisatracurium to facilitate orotracheal intubation. Anesthesia was maintained with 50% nitrous oxide in oxygen, sevoflurane (12% end-tidal concentration)
319 Albi-Feldzer et al.

Materials and Methods

Population Four hospitals (cancer centers) participated in this prospective, randomized (1:1), double-blind, parallel-group,
Anesthesiology 2013; 118:318-26

Ropivacaine Wound Infiltration and Chronic Pain

or desflurane (34%), and boluses of sufentanil 0.1 g/kg as required. The patient was extubated at the end of surgery after reversal of the neuromuscular block, if necessary. At the end of surgery, before skin suturing, the wound was completely infiltrated under blind conditions with repeated injections of the solution (34 ml for each injection), 3cm along the subcutaneous and deep layers of the breast and axilla surgical incisions. Infiltrations were also performed in the second and third intercostal spaces and in the humeral insertion of the major pectoralis. Intercostal infiltrations were performed under visual control by the surgeon (34 ml for each injection) on the anterior edge of the serratus anterior muscle and the upper edge of the second and third rib. The ropivacaine group received 3mg/kg of 0.375% ropivacaine (0.75% ropivacaine [Astra Zeneca, London, United Kingdom] mixed with saline). All patients received the same per kilogram dose of ropivacaine regardless of the type of surgery. The placebo group received an equal volume of saline solution (0.8 ml/kg). One hour before the end of surgery, the patient received an intravenous injection of 1 g of paracetamol and 100 mg of ketoprofen omeprazole. All patients were transferred to the PACU for 2h. Consumption of analgesics (paracetamol, ketoprofen, and morphine), and nausea and vomiting were assessed at the time of transfer to the PACU, every 30min for 2h in the PACU and every 6h for the first 48h postoperatively. Pain was scored by a visual analog scale (VAS) anchored by no pain at all (score 0cm) and worst possible pain (score 10 cm). Pain was evaluated by a nurse who was blinded to the treatment group. Acute postoperative pain at rest and after movement (elevation of the arm on the operated side) was assessed every 30min for 2h in the PACU and every 6h for 48 h. All patients were administered oral analgesics for postoperative pain (paracetamol 1g and ketoprofen 50 mg) every 6 h and rescue morphine with a patient-controlled analgesia pump for 24h (bolus dose 1mg on demand, lockout interval of 5min). Ondansetron 4mg was administered for nausea and vomiting droperidol 1.25mg every 8h. Evaluation Patients were asked to fill in questionnaires at inclusion, and at 3 months, 6 months, and 1 yr after surgery evaluating chronic pain (BPI),26 anxiety-depression (HAD),27 neuropathic pain (DN4),28 consumption of analgesics, and comorbidities (lymphedema). The BPI is a multidimensional pain assessment tool which includes, pain intensity, pains interference with functions (seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep), and finally the experience of pain which is the consequence of pain intensity and pain interference. Data on demographics and the history of cancer included age, body mass index, patient satisfaction, breast cancer site, adjuvant therapy, and cancer status at follow-up.
Anesthesiology 2013; 118:318-26 320

Because toxicity was not expected with ropivacaine in this study (Phase 4 study with safe doses of ropivacaine), the trial was not assessed by an independent data safety monitoring board.

Statistical Analysis
At 3 months, the estimated incidence of chronic pain was 40% in the control group. The number of patients included was calculated to obtain a 20% difference between the two groups (50% reduction of the incidence of chronic pain from 40 to 20%). A population of 216 patients were required to demonstrate a 20% difference between the two groups at 3 months, with 90% power and a 5% alpha risk. It was decided to include 230 patients to take into account patients who could not be evaluated. Patient characteristics were compared by the Chi-square test or Fishers exact test, when necessary, for qualitative variables, and the independent Student t-test or Wilcoxon rank sum test for quantitative variables. VAS, BPI, DN4, and HAD scores were analyzed with mixed models for repeated data with an unstructured variance-covariance matrix. The time group interaction was tested for each score. Logistic regression tested the interaction between confounding factors which could influence the incidence of pain at 3 months among the two groups. The Woolf test was used to evaluate the interaction between the incidence of chronic pain and the study centers among the two treatment groups. All analyses were based on the intent-to-treat principle and used R, version 2.12.0 for Windows software (R foundation for statistical computing, Vienna, Austria). The R nlme package was used for linear and nonlinear mixed effect models. Two-tailed P values were calculated and significance was set at 5%.

Results
Two hundred sixty women aged 1885 yr with an American Society of Anesthesiologists physical status of I, II, or III, admitted for breast surgery were enrolled between September 2006 and July 2007. Finally, 236 patients were treated (fig. 1). Final assessments had to be completed by July 2008, when all patients had a follow-up of at least 12 months (fig. 1). The two groups were not statistically different for demographic data (table 1), type of surgery, or preoperative VAS. Measurement of pain on the VAS showed lower scores at rest and during mobilization in the first 90min after the end of surgery in the ropivacaine group than in the control group (P < 0.001) (figs 2, A and B). Ropivacaine wound infiltration decreased immediate postoperative pain in the PACU and increased the percentage of pain-free patients (VAS = 0) for the first 48 h. A higher percentage of pain-free patients was observed in the ropivacaine group than in the placebo group during the first postoperative 48h at rest and during
Albi-Feldzer et al.

PERIOPERATIVE MEDICINE

Randomization n = 260

Excluded n = 24 Withdrawal of consent n=6 Failed to meet inclusion criteria n = 18

Patients included n = 236

Allocated to the Ropivacaine group, n = 117 Tumorectomy with ALDN Mastectomy alone Mastectomy with either SLDN or ALDN n = 53 n = 11 n = 53

Allocated to the Placebo group, n = 119 Tumorectomy with ALDN n = 62 n=9 n = 48

Allocation

Mastectomy alone Mastectomy with either SLDN or ALDN

Analyzed for chronic pain at 3 months Intent-to-treat Lost to follow-up Missing data (BPI) n = 111 n=3 n=3

Analyzed for chronic pain at 3 months

Analysis

Intent-to-treat Lost of follow-up Missing data (BPI)

n = 108 n=3 n=8

Fig. 1. Patient flow chart. ALND = axillary lymph node dissection; BPI = Brief Pain Inventory; n = number of patients; SLND = sentinel lymph node dissection.

mobilization. In the ropivacaine group, 73 and 53% of patients reported no pain at all at rest or during movement, respectively, compared to 53 and 48% of patients in the placebo group (P < 0.001 and P = 0.005 for each comparison,

respectively). The level of pain was lower than expected in the placebo group. Morphine consumption with the controlled analgesia pump was very low in both groups: 2.95mg (median) (021)

Table 1. Demographic Data and Characteristics of the 236 Patients Treated for the Study Ropivacaine Group n = 117 Age (yr) Mean (SD) Range Body weight (kg) Mean (SD) Range BMI (kg/m2) Mean (SD) Range Visual analog scale (VAS) before surgery Mean (SD) Median Range ASA physical status (%) I II III Surgery (%) Breast-conserving surgery with ALND Mastectomy with ALND or SLND Mastectomy without ALND or SLND Sufentanil during surgery (g/kg) Mean (SD) Range 56 (12) 4765 67 (13) 40105 25 (6) 16.945.5 0.33 (0.77) 0 05 66 (56.4) 48 (41.0) 3 (2.6) 53 (45.3) 53 (45.3) 11 (9.4) 0.34 (0.11) 0.170.83 Saline Group n = 119 57 (13) 4868 67 (12) 45109 25 (4) 17.737.2 0.32 (0.93) 0 07 62 (52.1) 55 (46.2) 2 (1.7) 62 (52.1) 48 (40.3) 9 (7.6) 0.33 (0.11) 0.070.83

ALND = axillary lymph node dissection; ASA = American Society of Anesthesiologists; BMI = body mass index; SLND = sentinel lymph node dissection. Anesthesiology 2013; 118:318-26 321 Albi-Feldzer et al.

Ropivacaine Wound Infiltration and Chronic Pain

Fig. 2.(A) VAS at rest during the first 48 postoperative hours. (B) VAS on mobilization during the first 48 postoperative hours. VAS showed lower scores at rest and during mobilization in the first 90 min after the end of surgery in the ropivacaine group than those in the control group (P < 0.001). In addition to wound infiltration, patients in the two treatment groups received the same quantities of intravenous analgesics. The time group interaction was tested. P value is associated with the test of group time effect. VAS = visual analog scale.

variable ( 3 over 10) (P = 0.37 and 0.42, respectively) (table 2). No statistically significant difference was observed between the two groups in relation to potential confounding factors, such as adjuvant therapy (chemotherapy or radiotherapy), age, body mass index, type of surgery, or anxiety and depression scores (table 3). Pain severity and pain interference on the BPI were not statistically different between groups but increased significantly in both groups over time (P < 0.0001 and 0.001, respectively) (fig. 3). The maximum percentage of missing data for each point (0, 3, 6, and 12 months) in both arms was less than 5% (range: 05%). A statistically significant increase was observed in the mean BPI scores (severity and interference) compared to baseline during the study in both groups (P < 0.0001 and P < 0.001, respectively) (fig. 3). The mean DN4 scores also increased over time (P < 0.001) and this increase was not statistically different between the two groups (P = 0.058) (fig. 4). A statistically significant improvement was observed in the anxiety score during the study (P < 0.0001) in both groups, whereas depression scores remained stable compared to baseline in both groups (fig. 5). No adverse effects were observed during or just after ropivacaine wound infiltration. No statistically significant interaction was observed between the incidence of chronic pain and study centers in the two treatment groups (Woolf test).

and 2.96 mg (018) for the first 48 postoperative hours in the ropivacaine and placebo groups, respectively. Following the protocol, the amount of paracetamol and ketoprofen consumed during the postoperative period was not different between the two groups. The incidence of nausea and vomiting (Apfel score > 2) was 4% in the ropivacaine and 6% in the control group. The statistical difference was not tested because the incidence was low. No treatment-related complication was observed. No statistically significant difference was observed between the two groups for the primary outcome (BPI average pain) evaluated 3 months after breast surgery, whether it was measured as a continuous score or as a categorical

Discussion
This multicenter, prospective, randomized, double-blind, placebo-controlled study shows that ropivacaine wound infiltration after breast surgery 1. decreased immediate postoperative pain for the first 90min in the PACU, 2. increased the percentage of pain-free patients for the first 48h postoperatively, 3. did not decrease chronic pain at 3 months (primary objective of the study), 6 and 12 months postoperatively, and 4. did not decrease neuropathic pain at 3, 6, and 12 months postoperatively (P = 0.058).

Table 2. Chronic Pain: Primary Outcome 3 Months after Surgery. Intention to Treat Analysis Primary Pain Outcome: BPI at 3 Months Score 3: n (%) CI 95% (Score 3, %) Mean score (SD) Range Ropivacaine Group n = 117 37/111 (33.3%) 24.542 1.97 (2.3) 09 Saline Group n = 119 29/108 (26.9%) 18.435.2 1.7 (2.2) 09 P Value 0.37 0.41

BPI = brief pain inventory; n = number of patients; % = percentage of patients. Anesthesiology 2013; 118:318-26 322 Albi-Feldzer et al.

PERIOPERATIVE MEDICINE

Table 3. Potential Confounding Factors which May Interact with the Incidence of Chronic Pain at 3 Months among the Two Groups Factors Breast-conserving surgery with ALND Mastectomy without ALND or SLND Mastectomy with ALND or SLND Age BMI Axillary lymphedema: yes/no Radiation therapy: yes/no Chemotherapy: yes/no Hormonal treatment: yes/no Postoperative nausea and vomiting score > 2 Patient satisfaction HAD score at 3 mo Anxiety score at 3 mo Anxiety score 11 at 3 mo Depression score at 3 mo Depression score 11 at 3 mo P Value* 0.24 0.42 0.77 0.54 0.93 0.87 0.62 0.94 0.99 0.37 0.98 0.62 0.45 0.92 0.80 0.33

* P value for logistic regression to test the interaction between confounding factors which may influence the incidence of pain at 3 months, and the two treatment groups. No significant difference was observed between the two groups. ALND = axillary lymph node dissection; BMI = body mass index; HAD = hospital anxiety and depression; SLND = sentinel lymph node dissection.

No difference in anxiety and depression (HAD scores) was observed between the two groups, but anxiety decreased significantly with time. Multivariate analysis failed to identify any risk factors for chronic pain in this study. The various types of surgery included breast tumor resection with axillary lymph node dissection, mastectomy with or without axillary lymph node dissection, and mastectomy with sentinel lymph node dissection.

In this study, the overall incidence of chronic pain at 3 months on the BPI (27 and 33% in the ropivacaine and placebo groups, respectively) was low compared to certain other published studies (2065%), and the estimated prevalence of sensory disturbances ranges between 20 and 80%.3 This wide range of prevalence of pain reported in the literature is probably because of differences in the definitions of persistent pain, the frequency and period of monitoring, the methods used to measure pain, types of surgery, adjuvant therapy, number of patients studied, time to surgery, and finally the type of analgesia. However, the incidence of neuropathic pain on the DN4 (24 and 30% in the ropivacaine and placebo groups, respectively) in our patients was in the middle range compared to that reported in other studies (1750%).13,19,29,30 The intensity of acute postoperative pain was always less than 25mm on the VAS, both at rest and during mobilization, which is similar to the results reported in the literature.18,31 A statistically significant difference between the two groups was only observed for the first 90min, which is also in line with the literature and shows that local anesthetic infiltration is a potent adjuvant as part of the multimodal management of pain after breast surgery. Patients received optimal postoperative treatment with nonsteroidal antiinflammatory drug, acetaminophen and rescue morphine (Patient-controlled Analgesia). Morphine consumption was also very low for the first 48h in both groups (2.9mg/48h). Because the management of acute postoperative pain was optimal in the two groups, ropivacaine infiltration could not decrease the pain score further after the first 90min and the pharmacokinetics of ropivacaine do not allow a sustained effect for more than 90min. No statistically significant difference in the incidence of chronic pain was observed on the BPI 3, 6, and 12 months after surgery. The incidence of chronic pain was low in this

Fig. 3.BPI scores before surgery and 3, 6, and 12 months after surgery. Pain severity and pain interference (BPI scores) increased significantly over time in both groups (P < 0.001 and P < 0.001, respectively). The increase in pain severity was statistically significant from the preoperative period until the third month, and then from the third to sixth months, while the increase in pain severity from the sixth to twelfth months was not statistically significant. The increase in pain interference was statistically significant from the preoperative period until the third month only. The time group interaction was tested. P value is associated with the test of group time effect. BPI = brief pain inventory.
Anesthesiology 2013; 118:318-26 323 Albi-Feldzer et al.

Ropivacaine Wound Infiltration and Chronic Pain

Fig. 4. DN4 scores before surgery and 3, 6, and 12 months after surgery. The mean DN4 scores increased over time (P < 0.001) and this increase was not statistically different between the two groups (P = 0.058). Only a trend for decreasing was observed in the ropivacaine group compared to control group between the sixth and the twelfth postoperative month. The time group interaction was tested. P value is associated with the test of group time effect. DN = neuropathic pain.

study compared to the literature.6,8,32 If severe acute postoperative pain is associated with a higher incidence of chronic pain,33,34 the low incidence of chronic and neuropathic pain observed in our study could, therefore, be due to the effective control of acute postoperative pain in the two groups (30% of all patients were pain-free at rest for the first 48h). Postoperative morphine consumption was also low, associated with a low incidence of nausea and vomiting, with no significant differences between the two groups. Neuropathic pain was also globally identical in the two groups. Based on the results of previous studies,3 chronic pain after breast cancer surgery and adjuvant therapy is predominantly characterized by neuropathic pain, partially related to intraoperative nerve injury. Nerve-sparing techniques may reduce the incidence of neuropathic pain without totally eliminating this complication.3 Various types of pain may

also coexist after breast surgery.35 In a review of neuropathic pain after breast surgery, Jung proposed four distinct pain syndromes: phantom breast pain, intercostobrachial neuralgia, neuroma pain, and other nerve injury pain.13 One hypothesis is that local or loco-regional analgesia decreased the incidence of neuropathic pain. For instance, postthoracotomy pain correspond to neuropathic characteristics.36,37 Epidural analgesia with local anesthetics decreases chronic pain 3, 6, or 12 months after thoracotomy.38 After posterior spinal arthrodesis, local anesthetic infusion at the iliac crest bone graft donor site decreased donor site pain and increased patient satisfaction at a minimum of 4 yr after surgery. In addition, none of the patients in the treatment group developed chronic iliac crest dysesthesia (0 vs. 70% in each group, respectively).39 Better control of acute postoperative pain, the antiproinflammatory properties of local anesthetics, and interruption of the nociceptive signal are the most frequent explanations proposed for this phenomenon. Recent data show that chronic pain and other surgical, psychosocial, and socio-environmental factors are major comorbid and confounding factors.29,4042 These results are in accordance with our results; in the current study, high anxiety scores were more frequent (70 vs. 37%) in patients with chronic pain than in the other patients. However, we did not detect any differences for the HAD scores between the two groups, which is concordant with the absence of difference in terms of chronic pain. Similarly, 3 months after breast surgery, Fassoulaki failed to demonstrate a difference in the incidence of chronic pain with gabapentin or mexiletine, but the incidence of burning pain was statistically lower in the two active treatments groups compared to the placebo group.31 Few published studies have evaluated the prevention of chronic pain after breast surgery. Fasssoulaki25 randomized 50 patients who underwent breast cancer surgery to one of two groups. Patients in the multimodal treatment group received gabapentin, topical local anesthetic and intraoperative irrigation of the brachial plexus and several intercostal

Fig. 5. HAD scores before surgery and 3, 6, and 12 months after surgery over time, anxiety scores decreased (P < 0.001) but depression scores remained stable over time. The time group interaction was tested. P value is associated with the test of group time effect. HAD = hospital anxiety and depression.
Anesthesiology 2013; 118:318-26 324 Albi-Feldzer et al.

PERIOPERATIVE MEDICINE

spaces with ropivacaine, while the control group received a placebo instead of the three active agents. Patients in the multimodal treatment group had a lower incidence of axilla pain (14 vs. 45%), arm pain (23 vs. 59%), and analgesic use (0 vs. 23%) 3 months, but not 6 months after surgery. Although previous studies have failed to demonstrate the analgesic effects of wound infiltration with local anesthetic solutions after abdominal surgery, this treatment seems to be more effective when used during minor surgery, such as inguinal hernia repair or breast surgery.25 Two other studies compared a control group with multimodal analgesia or with multimodal analgesia plus paravertebral block.18,19 Postoperative pain intensity and chronic pain at 3, 6, and 12 months were statistically lower in the paravertebral block group.18,19 In addition to providing acute postoperative pain relief, loco-regional analgesia reduces the incidence and intensity of chronic pain. Our study has limitations. The chronic pain and neuropathic pain increased significantly over time in both groups (fig. 4). Several confounding factors were probably present in the first year after surgery delaying the resolution of persistent postoperative pain and increasing neuropathic pain: adjuvant chemotherapy and radiotherapy, anxiety, living with a diagnosis of cancer, and posttraumatic stress disorder. No statistically significant difference in the incidence of neuropathic pain on the basis of DN4 scores was observed after surgery. To test for a statistically significant difference between the two groups, an alpha risk less than 5% was accepted (type I error: inappropriately rejecting a true null hypothesis). After testing the difference between the DN4 scores of the two groups (fig. 4), the P value was 0.058 which although close to 0.05, it still is not sufficient to consider the difference to be statistically significant. It is possible that the number of patients was not sufficient (type II error). In fact, the number of patients for this study was calculated for the main outcome (BPI scores at 3 months) and does allow a robust conclusion concerning this outcome. We did not conduct a post hoc power analysis for DN4 score comparison, but interestingly the incidence of chronic and neuropathic pain is similar as well in the published literature as in our study. The number of patients may, therefore, be sufficient for comparison of neuropathic pain allowing valid conclusions concerning this endpoint. The absence of a statistically significant reduction in the severity and incidence of chronic pain despite the better control of acute pain in the current study could have been due to the short duration or to an insufficient analgesic potency of the local anesthetic compared to the potent prolonged multimodal analgesia given to both groups. Analgesia is probably obtained with paracetamol and ketoprofen in most patients making the combination with wound infiltration less effective. As a result other authors have used continuous wound infiltration after mastectomy to prolong analgesia.43,44 Also, thoracic paravertebral block provides better pain control than infiltration after breast surgery and comparisons of
Anesthesiology 2013; 118:318-26 325

these techniques may be an area of future research in chronic pain and also in cancer free-recurrence survival.20,45,46

Conclusion
Ropivacaine wound infiltration after breast surgery increases the incidence of pain-free patients by one half in the first 48h after surgery and decreases the pain scores in the PACU. Although the incidence of chronic pain was lower than that reported in the literature, wound infiltration does not decrease the incidence of chronic pain in the two groups.

References
1. Aasvang E, Kehlet H: Surgical management of chronic pain after inguinal hernia repair. Br J Surg 2005; 92:795801 2. Aasvang E, Kehlet H: Chronic postoperative pain: The case of inguinal herniorrhaphy. Br J Anaesth 2005; 95:6976 3. Grtner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet H: Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA 2009; 302:198592 4. Macrae WA: Chronic pain after surgery. Br J Anaesth 2001; 87:8898 5. Macrae WA: Chronic post-surgical pain: 10 years on. Br J Anaesth 2008; 101:7786 6. Perkins FM, Kehlet H: Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology 2000; 93:112333 7. Abrishami A, Chan J, Chung F, Wong J: Preoperative pain sensitivity and its correlation with postoperative pain and analgesic consumption: A qualitative systematic review. Anesthesiology 2011; 114:44557 8. Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: Risk factors and prevention. Lancet 2006; 367:161825 9. Kehlet H: Perioperative analgesia to prevent chronic postmastectomy pain. Anesth Analg 2006; 103:494; author reply 4945 10. Carpenter JS, Andrykowski MA, Sloan P, Cunningham L, Cordova MJ, Studts JL, McGrath PC, Sloan D, Kenady DE: Postmastectomy/postlumpectomy pain in breast cancer survivors. J Clin Epidemiol 1998; 51:128592 11. De Kock M: Expanding our horizons: Transition of acute postoperative pain to persistent pain and establishment of chronic postsurgical pain services. Anesthesiology 2009; 111:4613 12. Ip HY, Abrishami A, Peng PW, Wong J, Chung F: Predictors of postoperative pain and analgesic consumption: A qualitative systematic review. Anesthesiology 2009; 111:65777 13. Jung BF, Ahrendt GM, Oaklander AL, Dworkin RH: Neuropathic pain following breast cancer surgery: Proposed classification and research update. Pain 2003; 104:113 14. Smith WC, Bourne D, Squair J, Phillips DO, Chambers WA: A retrospective cohort study of post mastectomy pain syndrome. Pain 1999; 83:915 15. Stevens PE, Dibble SL, Miaskowski C: Prevalence, charac teristics, and impact of postmastectomy pain syndrome: An investigation of womens experiences. Pain 1995; 61:618 16. Wicksell RK, Olsson GL: Predicting and preventing chronic postsurgical pain and disability. Anesthesiology 2010; 113: 12601 17. Wilder-Smith OH, Arendt-Nielsen L: Postoperative hyperal gesia: Its clinical importance and relevance. Anesthesiology 2006; 104:6017 18. Iohom G, Abdalla H, OBrien J, Szarvas S, Larney V, Buckley E, Butler M, Shorten GD: The associations between severity of early postoperative pain, chronic postsurgical pain and Albi-Feldzer et al.

Ropivacaine Wound Infiltration and Chronic Pain

plasma concentration of stable nitric oxide products after breast surgery. Anesth Analg 2006; 103:9951000 19. Kairaluoma PM, Bachmann MS, Rosenberg PH, Pere PJ: Preincisional paravertebral block reduces the prevalence of chronic pain after breast surgery. Anesth Analg 2006; 103:7038 20. Thavaneswaran P, Rudkin GE, Cooter RD, Moyes DG, Perera CL, Maddern GJ: Brief reports: Paravertebral block for anesthesia: a systematic review. Anesth Analg 2010; 110:17404 21. Johansson A, Axelson J, Ingvar C, Luttropp H-H, Lundberg J: Preoperative ropivacaine infiltration in breast surgery. Acta Anaesthesiol Scand 2000; 44:10938 22. Johansson A, Kornflt J, Nordin L, Svensson L, Ingvar C, Lundberg J: Wound infiltration with ropivacaine and fentanyl: Effects on postoperative pain and PONV after breast surgery. J Clin Anesth 2003; 15:1138 23. Pettersson N, Perbeck L, Hahn RG: Efficacy of subcutaneous and topical local anaesthesia for pain relief after resection of malignant breast tumours. Eur J Surg 2001; 167:82530 24. Rosaeg OP, Bell M, Cicutti NJ, Dennehy KC, Lui AC, Krepski B: Pre-incision infiltration with lidocaine reduces pain and opioid consumption after reduction mammoplasty. Reg Anesth Pain Med 1998; 23:5759 25. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C: Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg 2005; 101:142732 26. Guirimand F, Buyck JF, Lauwers-Allot E, Revnik J, Kerguen T, Aegerter P, Brasseur L, Cleeland CS: Cancer-related symptom assessment in France: Validation of the French M. D. Anderson Symptom Inventory. J Pain Symptom Manage 2010; 39:72133 27. Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:36170 28. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F: Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004; 108:24857 29. Tasmuth T, von Smitten K, Kalso E: Pain and other symptoms during the first year after radical and conservative surgery for breast cancer. Br J Cancer 1996; 74:202431 30. Tasmuth T, Estlanderb AM, Kalso E: Effect of present pain and mood on the memory of past postoperative pain in women treated surgically for breast cancer. Pain 1996; 68:3437 31. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q: The anal gesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002; 95:98591 32. Eisenach JC: Preventing chronic pain after surgery: Who, how, and when? Reg Anesth Pain Med 2006; 31:13 33. Fassoulaki A, Melemeni A, Staikou C, Triga A, Sarantopoulos C: Acute postoperative pain predicts chronic pain and longterm analgesic requirements after breast surgery for cancer. Acta Anaesthesiol Belg 2008; 59:2418

34. Tasmuth T, Kataja M, Blomqvist C, von Smitten K, Kalso E: Treatment-related factors predisposing to chronic pain in patients with breast cancera multivariate approach. Acta Oncol 1997; 36:62530 35. Blunt C, Schmiedel A: Some cases of severe post-mastectomy pain syndrome may be caused by an axillary haematoma. Pain 2004; 108:2946 36. Salengros JC, Huybrechts I, Ducart A, Faraoni D, Marsala C, Barvais L, Cappello M, Engelman E: Different anesthetic techniques associated with different incidences of chronic post-thoracotomy pain: Low-dose remifentanil plus presurgical epidural analgesia is preferable to high-dose remifentanil with postsurgical epidural analgesia. J Cardiothorac Vasc Anesth 2010; 24:60816 37. Steegers MA, Snik DM, Verhagen AF, van der Drift MA, Wilder-Smith OH: Only half of the chronic pain after thoracic surgery shows a neuropathic component. J Pain 2008; 9:95561 38. Sentrk M, Ozcan PE, Talu GK, Kiyan E, Camci E, Ozyalin S, Dilege S, Pembeci K: The effects of three different analgesia techniques on long-term postthoracotomy pain. Anesth Analg 2002; 94:115 39. Singh K, Phillips FM, Kuo E, Campbell M: A prospective, ran domized, double-blind study of the efficacy of postoperative continuous local anesthetic infusion at the iliac crest bone graft site after posterior spinal arthrodesis: A minimum of 4-year follow-up. Spine 2007; 32:27906 40. Ericsson M, Poston WS, Linder J, Taylor JE, Haddock CK, Foreyt JP: Depression predicts disability in long-term chronic pain patients. Disabil Rehabil 2002; 24:33440 41. Katz J, Seltzer Z: Transition from acute to chronic postsur gical pain: Risk factors and protective factors. Expert Rev Neurother 2009; 9:72344 42. Mossey JM, Gallagher RM: The longitudinal occurrence and impact of comorbid chronic pain and chronic depression over two years in continuing care retirement community residents. Pain Med 2004; 5:33548 43. Schell SR: Patient outcomes after axillary lymph node dissec tion for breast cancer: Use of postoperative continuous local anesthesia infusion. J Surg Res 2006; 134:12432 44. Sidiropoulou T, Buonomo O, Fabbi E, Silvi MB, Kostopanagiotou G, Sabato AF, Dauri M: A prospective comparison of continuous wound infiltration with ropivacaine versus single-injection paravertebral block after modified radical mastectomy. Anesth Analg 2008; 106:9971001 45. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ: Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology 2008; 109:1807 46. Boughey JC, Goravanchi F, Parris RN, Kee SS, Kowalski AM, Frenzel JC, Bedrosian I, Meric-Bernstam F, Hunt KK, Ames FC, Kuerer HM, Lucci A: Prospective randomized trial of paravertebral block for patients undergoing breast cancer surgery. Am J Surg 2009; 198:7205

Anesthesiology 2013; 118:318-26

326

Albi-Feldzer et al.