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From the *Department of Anesthesia, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris; Department of Outcomes Research, The Cleveland Clinic, Cleveland, Ohio; Outcomes Research Institute, University of Louisville, Louisville, KY; and Department of Anesthesia and INSERM E 332, Hôpital Ambroise Paré.
Address correspondence and reprint requests to Frédéric Adam, MD, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, 9 Ave. Charles de Gaulle, 92100 Boulogne, France. Address e-mail to frederic.adam{at}apr.ap-hop-paris.fr.
Abstract
BACKGROUND: Inadequate analgesia is common after shoulder arthroscopy. Both interscalene blocks and gabapentin are effective methods of pain management under various circumstances. We tested the hypothesis that gabapentin augments postoperative analgesia provided by interscalene brachial plexus block in patients having ambulatory arthroscopic shoulder surgery.
METHODS: Sixty patients were randomly assigned to receive oral gabapentin, 800 mg, or placebo 2 h before surgery. An interscalene brachial plexus block with 0.3 mL/kg of 0.5% ropivacaine was performed. General anesthesia was maintained with sevoflurane and included a single 1-µg/kg dose of remifentanil. Postoperative analgesia was initially provided with morphine and subsequently with ketoprofene (150 mg orally twice daily) and a combination of 400 mg acetaminophen and 30 mg dextropropoxyphene as needed. Pain scores, analgesic requirements, and side effects were assessed in the ambulatory unit and at home for 48 h.
RESULTS: Emergence from general anesthesia was similar in both groups. There were no significant differences in pain scores, first postoperative request for analgesia, or oral analgesic consumption. The incidence of side effects was comparable in both groups, except that headaches were less frequent in the gabapentin group.
CONCLUSION: A single preoperative dose of gabapentin (800 mg) does not augment postoperative analgesia in patients given interscalene brachial plexus blocks for arthroscopic shoulder surgery.
Pain management is often inadequate after ambulatory surgery (1). This is especially the case after arthroscopic shoulder surgery, an especially painful procedure. Supplementing general anesthesia with a single-dose interscalene brachial plexus block reduces pain scores, delays first analgesic use, and decreases overall opioid requirements (2). Effective regional blocks also help prevent surgery-induced central sensitization by suppressing the peripheral nociceptive inputs from injured sites (3).
Supplementing regional anesthesia with antihyperalgesic drugs such as N-methyl-d-aspartate antagonists in a multimodal approach reduces postoperative pain in patients undergoing abdominal or orthopedic surgery (3,4). Gabapentin is an antihyperalgesic drug that is effective for neuropathic pain, diabetic neuropathy, postherpetic neuralgia, and reflex sympathetic dystrophy. It selectively affects the nociceptive process involving central sensitization (5), by presynaptically binding to the 
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subunit of voltage-dependent calcium channels (6), which reduces neurotransmitter release. Gabapentin has been shown to decrease postoperative pain and morphine consumption after surgery (7,8).
Regional anesthesia and gabapentin (as an adjuvant) are thus reasonable choices in the management of postoperative pain. However, the combination has yet to be evaluated. We tested the hypothesis that a single preoperative oral dose of gabapentin improves postoperative pain after ambulatory arthroscopic shoulder surgery in patients with an interscalene brachial plexus block.
METHODS
With approval of the local ethics committee and written informed consent, we studied ASA physical status I–II patients. All were scheduled to undergo elective ambulatory arthroscopic shoulder surgery under general anesthesia. Exclusion criteria included ASA physical status more than II, age younger than 18 yr or older than 60 yr, weight more than 100 kg, contraindications to interscalene brachial plexus block (coagulation defects, infection at puncture site), diabetes, severe respiratory insufficiency, psychiatric disorders, routine use of opioid medications, and history of chronic pain syndromes.
At the preanesthetic visit, patients were instructed about the use of a 100-mm visual analog scale (VAS; 0 = no pain to 100 = worst pain) and a five-point verbal rating scale (VRS; 0 = no pain, 1 = light pain, 2 = moderate pain, 3 = intense pain, 4 = severe pain). They were also instructed in the use of the study questionnaires and were asked to record relevant information for 2 days.
On the day of surgery, patients were randomly assigned to receive gabapentin 800 mg (gabapentin group) or an identical-looking placebo (control group) orally 2 h before surgery (n = 30 per group). Randomization assignments were based on computer-generated codes that were maintained in sequentially numbered opaque envelopes until just before use. Personnel involved in patient management and data collection were unaware of the group assignment.
No sedative premedication other than gabapentin or placebo was given. An interscalene brachial plexus block was performed using the landmarks suggested by Winnie (9). Once contraction of muscles distal to the deltoid could be maintained with a current of 0.5 mA or less, 0.3 mL/kg of ropivacaine 0.5% was injected. Regional block was assessed with ice in the areas of circumflex and musculocutaneous nerves before induction and immediately after the arrival in the postanesthesia care unit (PACU).
Anesthesia was subsequently induced with propofol 2–3 mg/kg, remifentanil 1 µg/kg, and atracurium 0.5 mg/kg. The trachea was intubated, and controlled ventilation began. Anesthesia was maintained with sevoflurane (1%–2%) in a mixture of nitrous oxide (N2O) with oxygen (50%). No additional intraoperative analgesics were administered to patients during surgery.
Sevoflurane and N2O were discontinued at the end of surgery. The lungs were ventilated with 100% O2 at a fresh gas flow rate of 8 L/min. Emergence times (min) from discontinuation of anesthesia to spontaneous breathing, hand pressing, tracheal extubation, and recalling date of birth were assessed at 1-min intervals. The durations of anesthesia and surgery were also recorded.
After extubation, patients were transferred to the PACU until they achieved a modified Aldrete score of 9 on two sequential measurements at 10-min intervals. They were then transferred to the ambulatory unit. They were discharged 6 h later if they met home-readiness criteria that included orientation to time and place, stable vital signs, absence of nausea, control of pain, and ability to void and ambulate.
Analgesia in the PACU was provided by titrating morphine in increments of 3 mg every 5 min until the VAS pain score was 
30 mm or the VRS score was <2. Patients who required morphine titration were excluded from the study on the grounds of musculocutaneous nerve block failure. This criterion was based on the results of a previous study at our institution using the same surgical population (unpublished results).
None of the patients was discharged unless the VAS score was <30. Before discharge from the hospital, patients were instructed to systematically take ketoprofene 150 mg twice daily and two Di-Antalvic® tablets (400 mg acetaminophen and 30 mg dextropropoxyphene; Aventis, Montrouge, France) every 6 h as needed for pain.
In the PACU and in the ambulatory unit we specifically evaluated the potential side effects of gabapentin, including dizziness, drowsiness, headache, decreased coordination, visual disturbances, nausea, and vomiting.
After discharge, patients were asked to complete written questionnaires for 2 days (the day of surgery and the day after). These questionnaires asked patients to record pain intensity at six different time intervals (two times on the day of surgery and four times on the first postoperative day) by marking a VAS consisting of a 100-mm-long horizontal line with the two end points labeled "no pain" and "the worst imaginable pain." Patients also recorded the number of tablets of Di-Antalvic used during the day, the time of the first Di-Antalvic use, frequency and severity of side effects, and sleep quality. The patient's global satisfaction with pain control was marked on a VAS that corresponded to the overall level of satisfaction with the pain control they experienced that day. One of the investigators, also blinded to the group assignment, called each patient on the second postoperative day to remind him or her to complete the questionnaire and return it.
Our primary outcome was the number of Di-Antalvic tablets during the two days. This number was used to calculate the statistical power. A previous study at our institution using the same surgical procedure and the same outcome measure (unpublished results) indicated that Di-Antalvic use over 48 h was 8 ± 4 tablets (mean ± sd). Twenty-five patients per group thus provided an 80% power for detecting a 40% difference in Di-Antalvic consumption at an level of 0.05. We thus made a priori decision to evaluate 30 patients per group.
Demographic data and clinical variables were analyzed by using unpaired two-tailed Student's t-test. The VAS pain intensity scores were analyzed by using two-way repeated-measures analysis of variance. Because Di-Antalvic consumption did not follow a normal distribution, we used the Mann-Whitney U-test to compare the doses consumed by the two groups. The 
2 test was used to compare the incidence of side effects, sex distribution, and global satisfaction. Results are expressed as mean ± sd; P < 0.05 was considered significant.
RESULTS
Among the 60 randomized patients, all had a block in the circumflex nerve area. Four in the control group and three in the gabapentin group required morphine titration in the PACU and were excluded from the study. In contrast to the other patients, these seven patients experienced pain in the PACU (VAS > 30 mm or VRS > 1) and they had no demonstrable block in the musculocutaneous nerve area. Patient demographics, type of surgery, and duration of surgery were similar in the remaining patients in each group (Table 1).
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The mean end-tidal concentrations of sevoflurane at the end of anesthesia were 1.3% ± 0.4% and 1.3% ± 0.3%, in the control and gabapentin groups, respectively. The times from the end of anesthesia to spontaneous breathing, following verbal commands (hand grip), tracheal extubation, and orientation were similar in both groups (Table 2). The time to achieve an Aldrete score 
9 was similar in both groups (Table 3).
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There were no statistically significant differences between the two groups in the VAS score at discharge and during the first 48 h (Fig. 1). One patient in the control group and two patients in the gabapentin group did not use Di-Antalvic. Cumulative use of Di-Antalvic at home was similar in each group (control group: 7 ± 3 tablets; gabapentin group: 6 ± 3 tablets). Our results provided an 80% power to detect a 33% difference between the treatment groups. The delay between the interscalene brachial plexus block and use of the first Di-Antalvic tablet was comparable in the two groups (control group: 719 ± 199 min; gabapentin group: 768 ± 218 min).
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The incidence of side effects was comparable in both groups (Table 3), except that headaches were more frequent in the control group (P = 0.034). On the day of surgery, 17 patients (65%) in the control group and 19 patients (70%) in the gabapentin group experienced postoperative sleeping disturbances. Sleep disturbances were predominantly related to pain. About 25%–30% of the patients considered their analgesia insufficient. However, scores for overall satisfaction with pain management were high (about 80 mm in both groups) and did not differ between the two groups.
DISCUSSION
Gabapentin has been shown to be effective for spontaneous (10) and movement-evoked pain (11). It is opioid sparing and accelerates physiological recovery after surgery (8). Preoperative doses as low as 300 mg provide significant analgesia after laparoscopic cholecystectomy (12) or lumbar discoidectomy (13). A recent dose-response study defined gabapentin 600 mg as the optimal preemptive dose for postoperative pain relief. Increasing the dose beyond 600 mg did not improve analgesia, but did increase the risk of side effects (14).
The most common side effects of gabapentin are dizziness and drowsiness (11,15), either of which could delay emergence from general anesthesia or prolong postoperative recovery. Turan et al. (16) observed considerable dizziness when gabapentin 1200 mg was given 1 h before outpatient surgery. Moreover, gabapentin did not prolong early or late recovery end points, all of which were quantitatively similar to those reported previously with sevoflurane (17). We thus empirically chose 800 mg of gabapentin as a reasonable compromise between efficacy and toxicity.
In our patients, 800 mg of gabapentin did not provoke dizziness or other apparent side effects, suggesting that this dose of gabapentin can be used in ambulatory patients without fear of excessive side effects. However, we were unable to demonstrate an analgesic benefit of supplementing interscalene brachial plexus blocks with 800 mg of gabapentin after ambulatory arthroscopic shoulder surgery. Pain scores were comparable in each group, as were the amounts of Di-Antalvic that patients used. (This negative result was not a consequence of inadequate power; we had an 80% power to detect a difference of only 33%.) Our results are thus consistent with those of Radhakrishnan et al. (18) who also failed to identify any beneficial effect of gabapentin 800 mg administered preoperatively on pain after lumbar laminectomy and discectomy. It remains possible that the results would have been better at higher doses, but improved efficacy might have come at the cost of increased toxicity.
Although gabapentin suppresses opioid tolerance (19) and interacts synergistically with opioids (20), it has effects that are independent from those of opioids. Gabapentin reduces pain and nonopioid analgesic requirement in patients who did not receive opioids (10). Furthermore, gabapentin reduces central nervous system sensitization (5,15), thus preventing development of surgery-induced central excitability that contributes to postoperative pain hypersensitivity (21). It is thus unlikely that our negative results are entirely a consequence of restricting opioid administration.
Peripheral neural blockade maintains effective postoperative analgesia in shoulder arthroscopy (2), and reduces central sensitization (22). The interscalene brachial plexus block provided intraoperative anesthesia in our patients, and also provided analgesia through peripheral blockade of nociceptive input in the early postoperative period. It is thus likely that injured surgical tissue was unable to initiate central hypersensitivity during the first hours after surgery. This is a critical point because gabapentin has no antinociceptive effects per se. Gabapentin is analgesic by virtue of substantial antiallodynic and antihyperalgesic effects (23). A possible explanation for our negative results is that the interscalene brachial plexus block prevented central sensitization, precluding gabapentin's mechanism of analgesic action.
A limitation of the current study design is that we did not administer gabapentin throughout the postoperative period. Multiple doses extending beyond the time that the local anesthetic worked might have provided benefit. Two studies showed that gabapentin might be a useful adjuvant for postoperative analgesia in patients with regional analgesia (24) or local application of EMLA cream (25). These investigators administered gabapentin before, and two (24) or eight (25) days after surgery. However, in Turan et al.'s study (24) patients in the control group experienced severe pain during the first postoperative day. Moreover, patients receiving gabapentin had increased dizziness (24) or sedation (25), which may limit the use of gabapentin postoperatively in ambulatory patients.
In summary, our results indicate that oral gabapentin at the dose of 800 mg does not prolong recovery or cause other apparent side effects. It may thus have a role in ambulatory surgery. However, a single preoperative dose of 800 mg of gabapentin did not augment postoperative analgesia in patients with interscalene nerve blocks. The lack of efficacy is likely related to the nerve block preventing central sensitization. Since gabapentin acts by preventing allodynia and hyperalgesia, the lack of central sensitization precluded gabapentin's analgesic action. Larger doses, or repeated doses, might have demonstrated analgesic activity, as well as increased adverse effects.
Footnotes
Accepted for publication June 20, 2006.
None of the authors has a personal financial interest in this research.
Supported by NIH Grant GM 061655 (Bethesda, MD), the Gheens Foundation (Louisville, KY), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).
REFERENCES
This article has been cited by other articles:
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  V. K. F. Kong and M. G. Irwin Gabapentin: a multimodal perioperative drug? Br. J. Anaesth., December 1, 2007; 99(6): 775 - 786. [Abstract] [Full Text] [PDF]
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 N. M. Gajraj Pregabalin: Its Pharmacology and Use in Pain Management Anesth. Analg., December 1, 2007; 105(6): 1805 - 1815. [Abstract] [Full Text] [PDF]
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F. Adam, D. I. Sessler, and M. Chauvin Single-Dose Gabapentin Does Not Augment Postoperative Analgesia in Ambulatory Arthroscopic Shoulder Surgery Anesth. Analg., July 1, 2007; 105(1): 281 - 281. [Full Text] [PDF]
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S. R. Clendenen and B. A. Harrison Single-Dose Gabapentin Does Not Augment Postoperative Analgesia in Ambulatory Arthroscopic Shoulder Surgery Anesth. Analg., July 1, 2007; 105(1): 280 - 281. [Full Text] [PDF]
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