Severe trauma or surgery may be a cause of chronic pain. Scars and injury of soft tissues and of sensory afferents, which innervate the surgical area, may all contribute to chronic pain. Breast surgery for cancer, thus modified radical mastectomy or lumpectomy plus axillary lymph node dissection, is associated with chronic pain development referred to the area of mastectomy, the axilla, and the proximal medial arm (1).
This chronic pain is persistent and burning or pricking in nature. The incidence of chronic postmastectomy pain reported by several studies varies significantly. In a retrospective cohort study, 43% of the patients suffered from chronic postmastectomy pain, but the incidence in young women was 65% (2). Chronic postmastectomy pain may impair women's professional lives or other activities. This is a major problem considering the number of women operated on for breast cancer.
Acute and chronic pain management after breast cancer surgery has been investigated previously (3–6). Three of the four studies also examined the impact of analgesic regimens on chronic pain development. Although local anesthetics may have some beneficial effect, regimens that provide an efficient postoperative analgesia and reduce analgesic consumption for acute pain relief do not prevent chronic pain development to a satisfactory degree.
We hypothesized that multimodal analgesia may be effective in preventing both acute and chronic postmastectomy pain. We investigated the effect of multimodal analgesia, comprising of local anesthetics applied on the surgical area and gabapentin administered orally, for acute pain and analgesic requirements in patients operated on for breast cancer. We also investigated the impact of these drugs on chronic pain development and sensation abnormalities.
Methods
Approval from the Hospital Ethics Committee and patients' written informed consent were obtained. Fifty women, aged between 32 and 59 yr old and ASA physical status I or II, admitted to St. Savas Hospital for breast cancer surgery were enrolled in the study. Eligibility criteria were age ≤59 yr and body weight not exceeding the 20% of the ideal. Patients with chronic pain of any cause, consuming analgesics, antidepressants, calcium channel blockers, antiepileptics, sedatives, or hypnotics during the last month or radiotherapy or chemotherapy before surgery and those with inoperable breast cancer were not recruited for the study. Operations were performed by two surgeons highly experienced in breast surgery. All patients were assessed the day before surgery. They were informed that some treatment might be helpful in attenuating postoperative discomfort. The visual analog scale (VAS) scoring pain was explained.
Each patient was randomly assigned to a control group (A) or to a treatment group (B). Fifty envelopes, 25 containing odd and 25 containing even numbers, obtained from a computer-generated table, were prepared and sealed. According to the odd or even number obtained after opening a sealed envelope, drawn but not read by a nurse, patients were randomized to Group A (control treated with placebo capsules, placebo cream, and normal saline) or to Group B (treatment with gabapentin, eutectic mixture of local anesthetics [EMLA] cream, and ropivacaine solution), respectively.
The study was conducted in a double-blind manner. Placebo capsules were identical in appearance with the gabapentin capsules. The same number of capsules was packaged in group-specific bottles and coded as bottle A and bottle B for the control and treatment groups, respectively. A white odorless cream was the control treatment corresponding to the EMLA cream. Similarly, cream for each group was kept in boxes labeled as A and B for the control and treatment groups, respectively.
An independent anesthesiologist, who did not participate in the study or data collection, read the number contained in the envelope and made group assignments. She also prepared for the surgeons the envelopes, bottles with capsules, boxes with creams, and the solution of normal saline or ropivacaine in identical syringes. Except for the independent anesthesiologist, no other physician or nursing staff member was aware of the interventions administered to each patient.
To avoid motor impairment and possibly excessive numbness interfering with the blinding of the study, brachial plexus and intercostal nerves were not infiltrated with the local anesthetic but irrigated instead. Regarding EMLA cream and possible interference with blinding, EMLA or placebo was applied in the morning after pain assessment, and patients were instructed to remove it 3–4 h later. By the next morning when pain was assessed again, the effect had worn off.
After randomization to Group A or B, patients were treated as follows: Group A received placebo capsules identical to capsules of gabapentin, every 6 h, starting the evening before surgery (18:00) and continued until the eighth postoperative day. Twenty grams of placebo cream was applied in the wound area, starting the day of surgery until the third postoperative day. Intraoperatively, the brachial plexus in the axilla was irrigated with 10 mL of normal saline and irrigation of the third, fourth, and fifth intercostal spaces was performed with a total of 3 mL of the same solution.
Patients of Group B received 400 mg of gabapentin with the same time points and of the same duration as the control group. Also, 20 g of EMLA cream (2.5% of lidocaine and 2.5% of prilocaine) was applied from the day of surgery until the third postoperative day. As previously described, 5 g of EMLA was applied over the sternal area, 5 g close to the wound, and 10 g around the incision in the axilla (4). Intraoperatively, irrigation of the brachial plexus block in the axilla with 10 mL of 0.75% ropivacaine and irrigation of the third, fourth, and fifth intercostal spaces with 3 mL of the same solution was performed by the surgeon.
Premedication was omitted. Intraoperatively, noninvasive monitoring was used (electrocardiogram, heart rate, arterial blood pressure, Spo2, and capnography). All patients received 10 mg of metoclopramide and 0.25 mg of droperidol and were administered oxygen for 3–4 min. Anesthesia was induced with thiopental 2 mg/kg and propofol 2 mg/kg. Intubation of the trachea was facilitated with rocuronium 0.6 mg/kg, and anesthesia was maintained with 2% of sevoflurane end-tidal concentration and 70% nitrous oxide in oxygen. At the end of surgery, neuromuscular block was antagonized with neostigmine 2.5 mg and atropine 1.2 mg, the trachea was extubated, and patients were transferred to the postanesthesia care unit (PACU). The operation performed was either a modified radical mastectomy or lumpectomy plus axillary lymph node dissection.
All patients remained in the PACU for at least 1 h. Those who complained of pain in the PACU received 1.2 g of paracetamol IM. In the ward, Lonalgal® tablets (Boehringer Ingelheim, Italy) were given, with each tablet containing 500 mg of paracetamol and 30 mg of codeine. Acute postoperative pain at rest and after movement was assessed using the VAS by an anesthesiologist blinded to group assignment. The scale consists of a 100-mm horizontal line with 0 representing no pain and 100 represented the worst unbearable pain. Patients were asked to draw a line vertical to the horizontal line showing the intensity of their pain. Movement consisted of the operated side arm abduction by 90 degrees. Pain was recorded at time 0 (arrival to the PACU), 3, 6, and 9 h after surgery and each morning from the first to the eighth postoperative day.
Before discharge from the hospital, all patients were instructed to note the pain they might have at home and analgesic needs. We defined chronic pain as the presence of pain 3 mo after surgery, independent of its intensity or analgesic requirements. Three and 6 mo after surgery, patients were interviewed by a blinded anesthesiologist as to whether they received postoperative chemotherapy or radiotherapy and if they experienced pain and or abnormal sensations in the chest, axilla, or the arm of the operated side. The presence of pain (yes versus no pain), the pain intensity (no pain = 0, mild pain = 1, moderate pain = 2, or severe pain = 3), and the analgesic requirements at home, if any, were recorded. The methodology regarding anesthetic technique, postoperative analgesia protocol, and acute and chronic pain assessment were similar to those in our previous studies (2–4).
Initial sample size estimation showed that approximately 24 patients should be included in each group to ensure a power of 0.80 for detecting a 50% difference in analgesic consumption (reduction of Lonalgal® tablets use) between the two groups during the first 8 postoperative days and a reduction in the incidence of chronic pain by 50%. The standard deviation of numbers of Lonalgal® tablets consumed during the first 8 postoperative days, estimated from initial pilot observations, was approximately 3.5. The incidence of chronic pain, estimated also from initial pilot observations and previous studies (2–4), was approximately 70% in the control group. The α error was assumed to be 0.05.
Levene's test was performed for equality of variances. Demographics, duration of surgery, and time until the first analgesic requirement were compared between the groups with two-tailed unpaired Student's t-test. Paracetamol consumed in the PACU, the number of Lonalgal® tablets consumed by each group of patients during the 8 days after surgery, and the VAS scores at rest and after movement were compared between the groups using the Mann-Whitney U-test. The number of patients who had modified radical mastectomy, received chemotherapy, radiotherapy, analgesics in PACU, developed chronic pain in the chest, axilla, or arm, absent or decreased sensation, and developed chronic pain overall and the intensity of chronic pain were compared between the groups with Pearson χ2 test with continuity correction. The number of patients in each group who required analgesics for chronic pain 3 and 6 mo after surgery was compared with Fisher's exact test. The intensity of chronic pain between the two groups 3 and 6 mo after surgery was compared with χ2 test. The effect of the type of surgery, i.e., modified radical mastectomy versus lumpectomy plus axillary dissection on chronic pain development, was compared within each group with Fisher's exact test. The SPSS 11 software for Macintosh was used for statistical analysis (SPSS Base 10.0 for Macintosh; SPSS Inc, Chicago, IL).
Results
Figure 1 illustrates the flow diagram of the study. Patient recruitment began March 15, 2001, and was completed on January 20, 2004. Exit assessments were to be completed by July 2004 when all patients had a 6-mo follow-up. Two of the patients in the control group developed local inflammation and thrombosis in the axilla in the early postoperative period and received nonsteroidal antiinflammatory drugs (NSAIDS). A third patient in the control group developed depression within the first month after surgery and was treated with tricyclic antidepressants. These side effects are not related to the interventions applied.
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Figure 1.:
The flow of patients studied. EMLA = eutectic mixture of local anesthetics; NSAIDS = nonsteroid antiinflammatory drugs; 3 M = 3 mo.
Demographics, duration of surgery, the number of patients who had modified radical mastectomy versus lumpectomy plus axillary dissection, and the number of patients who received chemotherapy or radiotherapy did not differ between the two groups (Table 1).
Table 1: Demographics and Characteristics of the 50 Patients Recruited for the Study
The results for acute pain assessment are shown in Table 1. The number and percent of patients in each group who required analgesia in PACU, the time to first analgesic requirement, paracetamol requirements in the PACU, and Lonalgal® tablet requirements for the first 8 postoperative days in each group are shown in Table 1 (Fig. 2). The VAS scores at rest and after movement in each group are shown in Figures 3 and 4, respectively.
Figure 2.:
The daily consumption of Lonalgal® tablets in the control and treatment group.
Figure 3.:
The visual analog scale (VAS) scores at rest in the treatment and in the control groups 0, 3, 6, and 9 h after surgery and from the first to the eighth postoperative day.
Figure 4.:
The visual analog scale (VAS) scores after movement in the treatment and in the control groups 0, 3, 6, and 9 h after surgery and from the first to the eighth postoperative day.
Chronic pain assessment 3 and 6 months after surgery in patients treated with analgesics versus the controls are shown in Table 2. The incidence of total chronic pain 3 mo after surgery was equally distributed between the controls who underwent lumpectomy (82%) or mastectomy (80%) and those in the treatment group who underwent lumpectomy (46%) or mastectomy (44%).
Table 2: Patients with Chest, Axillary, Upper Arm, and Overall Chronic Pain, Absent or Decreased Sensation, and Patients who Required Analgesics at Home 3 and 6 mo After Surgery
Discussion
Our results demonstrate that the analgesic drugs administered per protocol of the study significantly reduced the analgesic consumption after surgery and the development of chronic pain three months after breast surgery for cancer. The difference in chronic pain between the groups became less evident six months after surgery.
Previous studies assessing acute pain after breast surgery for cancer have shown a beneficial effect of regional block, of local application of local anesthetics (3,4), and of drugs, such as mexiletine, stabilizing the neural membrane (5). Brachial plexus block with local anesthetic during surgery provides satisfactory analgesia, but arm movement is temporarily impaired, which is undesirable, particularly for fast-track interventions (3). Local application of EMLA cream, a mixture of lidocaine and prilocaine, effectively reduced postoperative analgesic requirements associated with breast surgery for cancer and the incidence of long-term pain (4).
Most recently, gabapentin has been shown to reduce analgesic requirements for acute postoperative pain (6,7). Gabapentin was introduced as an antiepileptic and is extensively used in the treatment of neuropathic pain (8–11). The drug at clinically relevant concentrations reduces the membrane voltage-gated calcium currents in dorsal root ganglia neurons of neuropathic rats and, to a lesser degree, in nonneuropathic rats (12). It may produce analgesia by decreasing neurotransmitter release by sensory neurons, a calcium-dependent process (12).
Side effects reported for gabapentin were somnolence, confusion, dizziness, and ataxia. However, the drug was given for 8 weeks to doses titrated up to 3600 mg/d, unless severe adverse effects were developed (10). We did not observe intolerable side effects for the daily dose and the duration of treatment, as determined by the protocol of the study. Some sedation that our patients exhibited, particularly in the beginning of treatment, is desirable before and immediately after surgery. This analgesic treatment was not associated with adverse effects and may be appropriate not only for those patients who suffer, but also prophylactically to all patients who are potential candidates for developing chronic pain.
The effective treatment of acute pain usually is not associated with prevention of chronic pain (4–6). We found that mexiletine 600 mg/d or gabapentin 1200 mg/d reduced postoperative analgesic requirements but did not significantly affect the development of chronic pain (6). In this study, gabapentin 1600 mg/d and local anesthetic to the surgical area, in the forms of solution and cream, proved as effective as previous analgesic regimens to prevent acute postoperative pain but superior in preventing chronic pain after breast surgery for cancer. Unlike opioids, neither local anesthetics nor gabapentin are associated with nausea and vomiting, nor do they enhance bleeding, like NSAIDs. In addition, local application of EMLA is simple, noninvasive, and produces minimal side effects. Oral gabapentin and application of EMLA are preferable over parenteral analgesia and can be continued after hospital discharge. This multimodal analgesic technique is considered particularly advantageous in the ambulatory setting.
Prevention of chronic pain development is difficult and seems to require prolonged and probably multimodal treatment. Also, although several studies assess acute postoperative pain and analgesic techniques and drugs, the issue of chronic pain development has been largely ignored. Chronic pain may be resistant to opioids, and when these are used, adverse outcome can be more serious than in short-term use for acute pain (13).
Local anesthetics suppressing the afferent nociceptive traffic and inflammatory reaction may prevent the development of chronic pain. Peripheral neural block, by nerve sheath local anesthetic infusion, reduces the incidence of chronic pain up to 12 months after lower limb amputation (14). Intraoperative and postoperative epidural block with mepivacaine reduces long-term postthoracotomy pain (15). Mechanisms of prevention of chronic pain after injury by gabapentin are not clear. With regard to neurogenic processes, in the rat, gabapentin suppresses the ectopic discharge activity from injured peripheral nerves (16) and blocks the injury-induced neuronal hyperactivity (17). Excitatory transmission in the spinal cord was inhibited by gabapentin only in preparations from neuropathic animals showing hyperalgesia and not from normal animals (18). Local application of EMLA cream had a beneficial effect on the incidence of chronic pain (4). However, our results demonstrate that the multimodal analgesic regimen of local anesthetics and gabapentin is the most effective in preventing chronic pain development after breast surgery for cancer.
The incidence of chronic pain six months after surgery was 30% in the treatment group and 57% in the control group. Although multimodal analgesia seems to prevent chronic pain, even six months after surgery, this difference was not statistically significant. Our study was not powered for chronic pain assessment six months after surgery, but a larger clinical trial may show a significant difference in chronic pain between treatment and control groups at this time point.
In conclusion, multimodal analgesia with local anesthetics and gabapentin reduced analgesic consumption after breast surgery for cancer without side effects. The incidence of chronic pain development, the intensity of chronic pain, and the long-term analgesic requirements associated with breast surgery were also less three months after surgery. More studies are required to investigate chronic pain for longer periods of time because for some women, chronic pain may persist in duration and intensity beyond the six-month period.
We thank Dr. Anteia Paraskeva, who acted as the independent anesthesiologist, helping with randomization and blinding of the study.
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