Fassoulaki, Argyro MD, PhD, DEAA*,; Patris, Konstantinos MD†,; Sarantopoulos, Costantine MD, DEAA‡,; Hogan, Quinn MD‡
Modified radical mastectomy or lumpectomy with axillary node dissection, combined variably with chemotherapy or radiotherapy, is currently the treatment of choice for breast cancer. However, postoperative pain may be followed by chronic neuropathic pain, particularly after dissection of axillary lymph nodes and injury of the brachial plexus. In fact, postoperative pain may influence the development of chronic postmastectomy pain (1).
In a retrospective cohort study of mastectomies over a 6-yr period, the cumulative prevalence for persisting postmastectomy pain was 43% overall but reached 65% in a subgroup of younger women aged 30 to 49 yr (2). This pain may substantially affect the quality of life of women treated for breast cancer. In previous studies (3–5), we investigated pharmacologic means of reducing the incidence of this condition. An additional goal was improved symptom management, including acute pain control and preventing postoperative nausea and vomiting. Gains in controlling pain and nausea would aid in immediate mobilization and nutrition, improving patient satisfaction and limiting the need for prophylactic heparin for deep vein thrombosis.
We have shown that a eutectic mixture of local anesthetics (EMLA) reduces acute and chronic pain after breast surgery for cancer (4). A modest dose of mexiletine 400 mg/d did not affect acute or chronic pain but enhanced analgesia produced by local anesthetic block (5). To improve the efficacy of our postoperative analgesic techniques, we subsequently selected gabapentin as a possible candidate because of its antihyperalgesic action in chronic pain (6), as well as its favorable side effect profile (7).
Mexiletine, a Class 1b antiarrhythmic, provides analgesia by blocking sodium channels (8). It has been used for alleviating neuropathic pain of various origins such as cancer and diabetes (8,9). However, results from different studies are controversial. A daily dose of 900 mg of mexiletine did not alleviate neuropathic pain with allodynia (10) and had a minimal effect on experimental pain in humans (11). Gabapentin, the second drug evaluated in the present study, is a structural analog of γ-aminobutyric acid and was initially introduced as an adjunctive drug to control small seizures. Because other antiepileptic drugs are used to treat neuropathic pain, gabapentin has been investigated as an analgesic for neuropathic pain in the experimental and clinical setting (6).
The aim of the present study was to compare the effects of gabapentin with an increased dose of mexiletine on acute pain intensity and analgesic consumption in patients operated for breast cancer, as well as the impact of these drugs on long-term pain and sensation abnormalities.
This study was approved by the Hospital Ethics Committee, and written informed consent to participate was obtained from all patients. Seventy-five ASA physical status I or II female patients scheduled for breast surgery for cancer were recruited. Exclusion criteria included body weight exceeding 20% of the ideal body weight, age older than 59 yr, heart block, and preoperative treatment with analgesics other than those determined by the protocol, sedatives, hypnotics, antidepressants, and calcium channel blockers. Patients who received chemotherapy or radiotherapy before surgery were also excluded.
The day before surgery, all patients were visited for assessment and to explain study protocols, including analgesic administration on request and the visual analog scale (VAS) score at rest and after movement. Each patient was randomly assigned to a treatment group, and the first dose was given the evening before surgery.
Premedication was omitted, but analgesic treatment as determined by the study protocol was continued the morning before surgery. In the operating room, after being given an IV lactated Ringer’s solution, patients received 10 mg of metoclopramide and 0.25 mg of droperidol for prevention of gastroesophageal reflux and vomiting. Standard intraoperative monitoring was used. After preoxygenation for 3–4 min, anesthesia was induced with thiopental 3 mg/kg and propofol 1 mg/kg. Intubation of the trachea was facilitated with rocuronium 0.6 mg/kg, and anesthesia was maintained with 2% sevoflurane and 70% nitrous oxide in oxygen. Neuromuscular block was monitored, and incremental rocuronium doses were repeated to maintain a single twitch response at 5%–10% of baseline. At the end of surgery, neuromuscular block was antagonized with neostigmine 2.5 mg and atropine 1.2 mg. After tracheal extubation, patients were transferred to the postanesthesia care unit (PACU). The surgical procedures included either modified radical mastectomy or lumpectomy with axillary lymph node dissection.
The study was conducted in a double-blinded manner. Seventy-five envelopes were prepared, coded as Group 1, Group 2, and Group 3, sealed, and opened for each patient to indicate the group of assignment. Control and/or treatment capsules for each group were packaged in group-specific bottles and coded as Bottle 1, Bottle 2, and Bottle 3 for Groups 1, 2, and 3, respectively. The placebo red and yellow capsules were filled with thin sugar. Envelopes, bottles with capsules, and coding were prepared by an anesthesiologist in cooperation with the hospital’s pharmacy. This anesthesiologist did not participate in the study, evaluation of the patients or data, or in report of the findings. No other medical or nursing staff was aware of the treatment administered to each patient.
Patients were blindly randomized to one of three groups. In the mexiletine group, patients received 200 mg of mexiletine along with placebo capsules (identical in appearance to the gabapentin capsules) three times per day. Patients in the gabapentin group received 400 mg of gabapentin and placebo capsules (identical in appearance to the mexiletine capsules) three times per day. Patients in the placebo group received both placebo capsules three times per day. Administration of the active and/or placebo drugs started the evening before surgery and continued three times a day for the first 10 postoperative days, including the day of surgery.
All subjects stayed in the PACU for at least 1 h where the first analgesic was administered and recorded. We used an analgesic study technique that has proved effective in achieving low pain scores in previous investigations (3,4). The analgesic drugs for the first 24 h were propoxyphene 75 mg and paracetamol 600 mg given intramuscularly (IM) on demand, with a minimal allowed interval of 5 h. Apotel® (Uni-Pharm, Kifissia, Greece) is an injectable solution that contains 600 mg of paracetamol for IM administration and excipients such as edetate disodium, lidocaine, sodium metabisulfite, disodium dibasic phosphate, ethanol, glycerol formal, and water for injections (12). Apotel® injections are not painful because of the presence of lidocaine.
From the second to the tenth postoperative day, subjects had free access to Lonarid® tablets, each tablet containing 400 mg of paracetamol and 10 mg of codeine. Fever or pain other than postoperative pain, such as a headache, were treated with paracetamol alone. Subjects who complained of insomnia were given 75–100 mg of hydroxyzine orally.
Acute postoperative pain at rest and after movement was assessed at 0 (arrival to the PACU), 3, 6, 9, and 24 h after surgery as well each morning from the second to the tenth postoperative day using the VAS score (0 mm = no pain and 100 mm = intolerable pain). Movement consisted of abduction of the arm on the operated side by 90 degrees.
Before discharge from the hospital, all patients were familiarized with a questionnaire assessing chronic pain. They were also instructed to note weekly the pain they experienced subsequently at home and the possible need for analgesics for the next 3 mo. Three months after surgery, patients were interviewed by phone to identify whether they received postoperative chemotherapy, radiotherapy, or both and if they experienced pain or abnormal sensations in the chest, axilla, or the arm of the operated side (Appendix 1). The verbal numeric score for pain (0–10 cm) and the analgesic requirements at home were recorded. Subjects were informed that they had the option of discontinuing participation in the study at any time, after which conventional treatment was continued. This methodology regarding anesthetic technique and pain assessment were similar to those applied in previous studies (4,5).
Initial sample size estimation showed that approximately 25 patients should be included in each group to ensure a power of 0.80 for detecting a clinically relevant reduction of the doses of postoperative analgesics ranging from 35% to 45%. Standard deviations (sd) estimated from initial pilot observations were approximately 122 mg for propoxyphene and 980 mg for paracetamol, 3000 mg for total oral paracetamol, and 65 mg for codeine. The α error was assumed as 0.05. The pilot study included 32 patients: 9, 10, and 13 patients for the mexiletine, gabapentin, and control groups, respectively. The calculations were based on the analgesic requirements to control acute postoperative pain, so these patients were observed for the 10 postoperative days, but no longer.
Demographics among the three groups, duration of surgery, VAS scores at rest and with movement, and the chronic pain intensity were compared with analysis of variance. Scheffé’s test was used for post hoc comparisons between individual groups. We used the Kolmogorov-Smirnov test to check if variables followed normal distribution. Because of skewed, non-normal, or noncontinuous distributions of some variables, the consumption of the analgesics was analyzed by the Kruskal-Wallis test. If overall differences were found, pair-wise comparisons were made using the Mann-Whitney test. Qualitative data regarding chronic pain were compared with the χ2 test or Fisher’s exact test when appropriate.
The groups that received mexiletine, gabapentin, or placebo were similar with regard to age (46 ± 5 yr, 42 ± 7 yr, and 45 ± 9 yr, respectively), body weight (63 ± 9 kg, 65 ± 6 kg, and 62 ± 7 kg, respectively), and height (164 ± 4 cm, 164 ± 5 cm, and 163 ± 6 cm, respectively). Values are mean ± sd. Duration of surgery, the number of patients that had modified radical mastectomy versus lumpectomy with axillary dissection, and the number of patients in each group who received chemotherapy or radiotherapy were similar (Table 1). Patients treated with chemotherapy received cyclophosphamide, methotrexate, and fluorouracil. Those patients treated with radiotherapy, independently of the group they were assigned, received 5000 cGy in the area of the node axillary dissection plus 1000 cGy on the thoracic wall.
Eight patients failed to complete the study. In the mexiletine group, one discontinued participation herself, one had a vein thrombosis in the axilla treated with aspirin, a third was removed because of nausea and vomiting, and a fourth was eliminated because her frozen section was negative for cancer, so no axillary node dissection was performed. In the gabapentin group, one patient had a migraine after surgery that required additional analgesic treatment, another had frozen section negative for cancer, and a third discontinued participation herself. In the control group, one patient discontinued participation herself. The three patients who decided to discontinue participation 5–7 days after surgery did so because felt they did not need treatment at that time. Data are missing for chronic follow-up of one more patient.
Time to first analgesic requirement (mean ± sd) was 22 ± 15 min, 33 ± 18 min, and 25 ± 19 min in the mexiletine, gabapentin, and control group, respectively, and did not differ among the groups. The analgesic requirements for propoxyphene and paracetamol given IM during the first 24 h were similar in the three groups (Table 2). Codeine and paracetamol consumption given orally from the second to the tenth day was reduced in the mexiletine and gabapentin groups by 50% compared with consumption in the control group (t statistic = 7.11 and P = 0.029;t statistic = 7.11 and P = 0.029 for codeine and paracetamol, respectively). Total paracetamol requirements such as Lonarid® tablets and paracetamol alone also differed among the groups (t statistic = 9.53 and P = 0.0085). Hydroxyzine requirements were similar among the groups.
The VAS scores at rest did not differ among the groups during the first 24 postoperative h. They differed on the third postoperative day, being significantly less in the mexiletine and gabapentin groups (F = 5.978 and P = 0.0042;P < 0.05 for the mexiletine and P < 0.05 for the gabapentin groups) when compared with the control group (Fig. 1).
The VAS scores after movement were similar during the first 24 h but significantly less in the mexiletine and gabapentin groups on the third postoperative day (F = 5.852 and P = 0.0046;P < 0.005 and P < 0.005 for the mexiletine and gabapentin groups, respectively, when compared with the control group). The VAS score after movement was also significantly reduced in the gabapentin group on the second (F = 6.057 and P = 0.0039), third (F = 5.852 and P = 0.0046), fourth (F = 5.689 and P = 0.0053), and fifth (F = 3.372, P = 0.040) days, with P < 0.005 for gabapentin versus the control group for all individual comparisons (Fig. 2).
The VAS scores on Day 1 for the mexiletine, gabapentin, and control groups were 9 ± 12.4 mm, 5 ± 8.2 mm, and 7 ± 8.6 mm at rest and 26 ± 24.3 mm, 20 ± 12.7 mm, and 30 ± 25.7 mm after movement. On Day 10, VAS scores were 6 ± 11.0 mm, 9 ± 12.4 mm, and 10 ± 15.7 mm at rest and 28 ± 16.7 mm, 25 ± 20.8 mm, and 30 ± 25.7 mm after movement for the mexiletine, gabapentin, and control groups, respectively. No significant differences among the groups were found for pain on Day 10.
Three months after surgery, the incidence of pain in the chest, axilla, or arm, the total incidence of chronic pain at any site, and the incidence of abnormal sensation did not differ among the groups (Table 3). However, regarding the types of chronic pain, burning pain was significantly increased in the control group (P = 0.033) (Table 4). There was a trend in the mexiletine group for a less frequent total incidence of chronic pain. The number of patients in each group that required analgesics at home to relieve postsurgical pain was similar. The intensity of chronic pain and the incidence of reduced or absent sensation in the arm or chest also did not differ among the groups.
Our results demonstrate a significant reduction of postoperative analgesic requirements in patients given mexiletine or gabapentin. Mexiletine 600 mg/d or gabapentin 1200 mg/d have equipotent effects in reducing analgesic requirements, although gabapentin is more effective in reducing pain after movement. As demonstrated in the present study, mexiletine reduces pain at rest as well as pain after movement on the third postoperative day, whereas gabapentin reduces postoperative pain after movement from the second to the fifth postoperative day included.
The 50% reduction in cumulative doses of paracetamol and codeine by gabapentin or mexiletine may not be directly cost effective because these drugs, particularly gabapentin, are more expensive than the conventional analgesics. However, reduction of pain after movement, a more consistent finding in the gabapentin group, is important because immobilization of the arm to avoid pain may result in its ankylosis and a patient’s inability to work. Pain after movement, though less over Days 2 to 5 particularly for the gabapentin group, did not differ among the groups on the 10th day. Increased activity of the patients after the fifth or sixth postoperative day, such as exercising of the operated side recommended by the surgeon, may have contributed to similar pain scores by then.
In previous studies, we have identified pharmacologic measures that assist in pain management after breast surgery. Brachial plexus block with local anesthetic produces substantial postoperative analgesia, but motor block limits arm-free movement (3), which is undesirable particularly in ambulatory patients. Local application of EMLA cream effectively reduces postoperative analgesic requirements associated with breast surgery for cancer (4). EMLA cream also reduces the incidence of long-term pain (4). The mechanism of EMLA action in this context is unknown, but a potential systemic action suggested to us the possibility of analgesia by a systemic sodium channel blocker such as mexiletine.
In contrast to invasive analgesic interventions, oral treatment is more convenient and agreeable to the patient provided the type of surgery allows oral intake of fluids. Also, delivery of analgesics by the oral route can be prolonged as required and be continued when the patient is discharged from the hospital. This is a further incentive to develop mexiletine as a perioperative analgesic. In a previous study, we showed that mexiletine in a smaller dose, 400 mg/d, is not effective in reducing acute pain after breast surgery, although it does enhance the analgesic effect produced by brachial plexus block with local anesthetic. The dose of 600 mg/d tested in this study proved safe and effective in reducing the analgesic requirements for acute postoperative pain.
Gabapentin, given as a single subcutaneous dose in a rat model of incisional pain, blocks the development of allodynia and hyperalgesia (13). When intrathecally administered, a single dose of gabapentin in the same rat model is even more potent in reducing postoperative allodynia than when given systemically (14). Regarding acute pain , gabapentin had no analgesic effect on its own when given as a single oral dose of 600 mg in volunteers, although it enhances the analgesic effect of morphine (15). A single dose of 300 mg of the drug given one hour before laparoscopic cholecystectomy failed to attenuate acute postoperative pain (16).
Our results are in agreement with these studies, as gabapentin did not affect analgesic requirements for postoperative pain during the first 24 hours after surgery. Despite starting treatment the evening before surgery, the effects of gabapentin assessed by analgesic requirements become apparent only during and after the second postoperative day. Also, pain after movement was significantly reduced in the gabapentin group on the second to fifth postoperative days, but not earlier. Mexiletine similarly reduces analgesic requirements only after the first 24 postoperative hours and attenuates pain at rest and after movement only on the third postoperative day. Thus, in contrast to experimental studies, in humans, a single perioperative dose of these drugs will not be effective (15,16). Because acute pain after movement was reduced by gabapentin on the second postoperative day, initiating treatment two days before surgery may produce analgesia immediately after the operation. Alternatively, gabapentin and mexiletine may only impede the component of postoperative pain produced by central changes in the spinal cord that lead to hyperalgesia (17). In this case, an effect would only be apparent once this condition evolved after a time of several days.
In a multicenter study for treatment of postherpetic neuralgia, side effects reported for gabapentin were somnolence, dizziness, confusion, and ataxia. However, these patients were treated for eight weeks, and the dose was titrated up to 3600 mg/d unless intolerable adverse effects were developed (18). We did not observe any of these side effects for the daily dose of 1200 mg of gabapentin and the duration of treatment that was limited from the day before surgery up to the tenth postoperative day. Except for one subject in the mexiletine group who had to discontinue treatment because of nausea and vomiting, we observed no side effects in any of the three groups treated. In contrast to nonsteroid antiinflammatory drugs, mexiletine and gabapentin do not enhance bleeding, are not associated with severe nausea and vomiting like opioids, produce mild sedation compared with the opioids, and are given by mouth, all of which are particular advantages for ambulatory anesthesia and surgery.
Preventing chronic pain related to surgery is difficult (19). The drug doses and duration of treatment used in the present study may be insufficient to reduce the incidence of chronic pain, and a more prolonged or multimodal treatment might be effective. However, when analyzing each type of chronic pain individually, we found a more frequent incidence of burning pain in the control group. Because adequate treatment of acute postoperative pain may be associated with better control of chronic pain, we based the sample size estimation on the results obtained from the acute pain. Therefore, the sample size we studied may be inadequate for the chronic pain statistical evaluation. A better understanding of pathophysiologic mechanisms will be required to adequately prevent postsurgical chronic pain.
In conclusion, mexiletine 600 mg/d or gabapentin 1200 mg/d reduce analgesic requirements by 50% during the week after breast surgery for cancer, and gabapentin is also effective in attenuating pain after movement. For the doses given and the duration of administration, both drugs are almost entirely free of adverse effects. However, neither of these drugs in the doses given for 10 days attenuated the development of chronic pain. Further studies are required with multimodal and perhaps longer lasting treatments to assess their effect on chronic pain associated with breast surgery for cancer.
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