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AMBULATORY ANESTHESIA

Premedication with Gabapentin: The Effect on Tourniquet Pain and Quality of Intravenous Regional Anesthesia

Alparslan Turan, MD^*, Paul F. White, PhD, MD, Beyhan Karamanliolu, MD^*, and Zafer Pamukçu, MD^*

From the *Department of Anaesthesiology, Trakya University, Turkey; Department of Anesthesiology and Perioperative Medicine and Outcomes Research Institute, University of Louisville, Kentucky; and Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Texas.

Address correspondence and reprint requests to Paul F. White, PhD, MD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu.

	Abstract

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BACKGROUND: Gabapentin, an oral non-opioid analgesic, has been used to decrease pain after a variety of surgical procedures. We hypothesized that premedication with gabapentin would minimize tourniquet-related pain in patients receiving IV regional anesthesia (IVRA).

METHODS: Patients undergoing elective hand surgery with IVRA were randomly assigned to one of two study groups using a double-blind study design. The control group (n = 20) received placebo capsules 1 h before the surgery, and the gabapentin group (n = 20) received gabapentin 1.2 g p.o. before the operation. IVRA was achieved in all patients with lidocaine, 3 mg/kg, diluted with saline to a total volume of 40 mL. Fentanyl, 0.5 µg/kg IV, was administered as a rescue analgesic during surgery. Sensory and motor block onset and recovery times, tourniquet pain, and quality of anesthesia were assessed at specific time intervals during the perioperative period. Visual analog scale pain scores (0–10) were recorded during the 24 h follow-up period, and patients received diclofenac, 75 mg IM, if their pain score was >4.

RESULTS: The onset of the sensory and motor block did not differ between the two study groups. However, tourniquet pain scores at 30, 40, 50, and 60 min after cuff inflation were lower in the gabapentin group (P < 0.05). The time to intraoperative analgesic rescue was prolonged in the gabapentin group (35 ± 10 min vs 21 ± 13 min, P < 0.05), and less supplemental fentanyl was required (35 ± 47 µg vs 83 ± 73 µg, P < 0.05). The quality of anesthesia, as independently assessed by the anesthesiologist and the surgeon, was significantly better in the gabapentin (versus control) group. In the gabapentin group, the time to requesting a rescue analgesic after surgery was prolonged (135 ± 25 min vs 85 ± 19 min, P < 0.05), and postoperative pain scores at 60 min (3.8 ± 0.9 vs 2.2 ± 0.5) and 120 min (3.2 ± 1.4 vs 1.8 ± 0.8), as well as diclofenac consumption (30 ± 38 mg vs 60 ± 63 mg), were reduced after surgery.

CONCLUSIONS: Premedication with oral gabapentin (1.2 g) decreased tourniquet-related pain and improved the quality of anesthesia during hand surgery under IVRA. Gabapentin also reduced pain scores in the early postoperative period.

	Introduction

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IV regional anesthesia (IVRA) is a simple, reliable, and cost-effective anesthetic technique for short surgical procedures involving the hands or feet (1). The major disadvantages of this technique are the occurrence of tourniquet pain, potential for local anesthetic toxicity, and minimal residual postoperative analgesia. Tourniquet pain precludes the use of IVRA techniques for longer procedures involving the upper and lower extremities and decreases patient satisfaction (2). The etiology and neural pathways involved in tourniquet pain are complex (3). Pain associated with nerve compression is mediated by unmyelinated, slow-conducting C-fibers, which are normally inhibited by earlier-arriving fast impulses conducted by myelinated A- fibers because mechanical compression appears to block the large A- fibers (4,5) more effectively. In animal models, both neurophysiological and pathological nerve fiber damage have been found to correlate with the degree of tourniquet pressure applied (6).

Gabapentin is an anticonvulsant drug that is safe and effective for the treatment of neuropathic pain syndrome (7,8), as well as for the prevention of postoperative pain (9–12). In animal models of inflammatory pain (13,14), gabapentin was shown to reduce hyperalgesia and inhibit C-fiber responses to noxious stimuli (15) by modulating both central and peripheral nociceptive response (16).

Therefore, we tested the hypothesis that premedication with gabapentin would reduce tourniquet pain during IVRA and the need for analgesic medication during hand surgery, while improving the overall quality of the intraoperative conditions. The secondary objectives of this study were to evaluate the onset and recovery of the sensory and motor blockade, as well as the severity of postoperative pain.

	METHODS

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After obtaining approval of the Institutional Ethics Committee at Trakya University, and written informed patient consent, 40 ASA physical status I–II patients scheduled for elective hand surgery were enrolled in this double-blind study from October 2004 through December 2005. Patients with Raynaud’s syndrome, sickle cell anemia, chronic pain syndromes, use of opioid analgesics or gabapentin 24 h before surgery, or known allergy to any of the study medications were excluded from participating in this study. The patients were randomized to one of two treatment groups based on a computer-generated randomization sequence. Identical-appearing capsules containing either gabapentin 400 mg or an inert substance (placebo) were prepared by the pharmacy department to insure blinding of the patients and the investigators. The selected dose of gabapentin (1.2 g) was based on earlier premedication studies (10,12).

Patients randomized to the control group (n = 20) received three placebo capsules 1 h before surgery, and the gabapentin group (n = 20) received three gabapentin 400 mg capsules (Neurontin^TM, Pfizer, Goedecke GmbH, Germany) 1 h before surgery with a sip of water. All patients were premedicated with midazolam, 0.4 mg/kg p.o., 45 min before the surgical procedure. Mean arterial blood pressure (MAP), oxygen saturation (Spo₂), and heart rate (HR) values were recorded at 5 min intervals in the operating room. Two IV cannulae were placed, one in a vein on the dorsum of the operative hand for the IVRA, and the second in the opposite hand for administering supplemental medications and fluid during the operation.

After a pneumatic double tourniquet had been placed around the upper arm, the extremity was elevated and exsanguinated with an Esmarch bandage. The proximal cuff was then inflated to 250 mm Hg (or 100 mm Hg above the systolic blood pressure), and circulatory isolation of the arm was verified by inspection, absence of radial pulse, and loss of the pulse oximetry tracing in the ipsilateral index finger. The IVRA was performed using lidocaine, 3 mg/kg, diluted with saline to a total volume of 40 mL and injected over 90 s.

Sensory block was assessed every 30 s after injection of the lidocaine using a standardized pinprick technique with a 22-gauge short-beveled needle. The patient’s response was evaluated in the dermatomal sensory distribution of the medial and lateral antebrachial cutaneous, ulnar, median, and radial nerves. Motor function was assessed by asking the subject to flex and extend their wrist and fingers at 30 s intervals, and complete motor block was recorded when no voluntary movement was present. The onset time for sensory blockade was the time elapsed from injection of the lidocaine until a complete sensory block was achieved in all dermatomes, and the onset time for motor blockade was the time elapsed from injection of lidocaine to achieving a complete motor block.

When an adequate surgical block was achieved, the operative tourniquet (i.e., distal cuff) was inflated to 250 mm Hg and then the proximal cuff was released. The MAP, HR, and Spo₂ values were recorded before and after tourniquet application, at 5, 10, 20, 30, 40, 50, and 60 min after tourniquet inflation, and after release of the tourniquet. Assessments of tourniquet-related pain were performed using an 11-point visual analog scale (VAS), with anchors of 0 = no pain and 10 = worst pain imaginable. These evaluations were performed before and after tourniquet application at 5, 10, 15, 20, 30, 40, and 50 min after the lidocaine injection. When the tourniquet pain score was reported to be >4, the patient was administered fentanyl, 0.5 µg/kg IV boluses, and the total intraoperative fentanyl dose was recorded.

At the end of the operation, the anesthesiologist was asked to quantify the operative conditions according to the following descriptive scale: 4 = excellent (no complaint of pain from patient), 3 = good (patient complained of pain, but supplemental analgesics were not required), 2 = acceptable (patient required supplemental IV analgesia), and 1 = unacceptable (patient required supplemental anesthesia and analgesia). Independently, the operating surgeon was also asked to clinically assess the adequacy of the intraoperative conditions according to the following numeric scale: 4 = excellent, 3 = good, 2 = acceptable, and 1 = poor.

The distal tourniquet was not deflated until a minimum of 30 min after the lidocaine injection. At the end of surgery, tourniquet deflation was performed using a cyclic deflation technique over 1–2 min. Sensory recovery time was noted as the time elapsed after tourniquet deflation until recovery of sensation in all dermatomes as determined using the pinprick technique at 30 s intervals. Motor block recovery time was noted as the time elapsed after tourniquet deflation until return of movement in the fingers. The time until the first analgesic requirement was noted as the time elapsed after tourniquet release until the patient’s initial request for pain-relieving medication.

Postoperative assessments of surgical-related pain were made using the same VAS pain scoring system at 1, 2, 4, 6, 12, and 24 h after surgery. Patients were administered diclofenac, 75 mg i.m., at 8 h intervals if the VAS pain score was >4, and the total diclofenac dosage was recorded. All the evaluations were performed by a blinded observer. The occurrence of nausea, vomiting, skin rash, tachycardia (HR >100 bpm), bradycardia (HR <50 bpm), hypotension (MAP <60 mm Hg), excessive sleepiness, hypertension (MAP >120 mm Hg), headache, dizziness, tinnitus, and hypoxemia (Spo₂ <90%), as well as any surgical complications (e.g., wound hematoma), were noted upon discharge from the recovery room and at the end of the 24 h postoperative observation period on the postsurgical ward.

For purposes of the a priori power calculation, a 25% reduction in the tourniquet VAS pain score in the gabapentin (versus control) group was considered to be significant. Based on this pain reduction estimate (and an average standard deviation of 1.375), we calculated that a sample size of 20 patients would provide a Type I error of = 0.05 and power of 80% (17). Independent samples Student’s t-tests were used for evaluation of the demographic data, intraoperative and postoperative hemodynamic data, the time for the onset and recovery of sensory and motor block, the duration of the operation and tourniquet inflation, analgesic rescue times, and intraoperative and postoperative analgesic requirements. The Mann–Whitney U-test was used for intraoperative and postoperative VAS pain and sedation scores, as well as the quality of anesthesia. The changes in VAS pain and sedation scores over time after study drug administration were assessed using independent samples test with a Bonferroni correction. Summary data are presented as mean (±sd) and median (interquartile ranges) values. Statistical significance was reported when the P value was <0.05.

	RESULTS

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A total of 44 patients were assessed for study eligibility. One patient failed to meet the inclusion criteria due to current use of gabapentin, and three patients refused to sign the consent form. All 40 remaining patients were able to complete the study, and no data were excluded from the analysis due to protocol violations. There were also no significant differences in the demographic characteristics, types of hand surgery (e.g., carpal tunnel release and tendon repair), surgery times, or amount of local anesthetic administered between the two study groups (Table 1). There were also no statistical differences between the two groups with respect to MAP, HR, or Spo₂ values at any of the assessment intervals (data not reported). Sensory and motor block onset and recovery times did not differ between the two study groups (Table 1). However, VAS scores for tourniquet pain were significantly reduced in the gabapentin group at 30, 40, 50, and 60 min after tourniquet inflation (Fig. 1). The time to intraoperative fentanyl rescue was prolonged in the gabapentin group (35 ± 10 min vs 21 ± 13 min, P < 0.05), and the supplemental fentanyl requirement during surgery was also significantly reduced in the gabapentin group (Table 1).

View larger version (10K): [in this window] [in a new window]   Figure 1. Intraoperative tourniquet-related (Intra-Op) and postoperative (Post-Op) pain scores using an 11-point visual analog scale (VAS) in the Control (--) and Gabapentin (--) treatment groups. Values are medians (and interquartile ranges). Visual analog scale: 0 = none to 10 = worst pain imaginable. *P < 0.05, P < 0.001, P < 0.01 compared with the control group. BT = before tourniquet; AT = after tourniquet.

The quality of anesthesia scores [medians (and interquartile ranges)] reported by the anesthesiologist (4 [3–4] vs 2 [1–2]) and the surgeon (3 [3–3] vs 2 ([2–3]), were significantly higher in the gabapentin (versus control) group (P < 0.05). The time to first postoperative analgesic request was prolonged in the gabapentin group when compared with the control group (135 ± 25 min vs 85 ± 19 min, P < 0.05). Postoperative VAS pain scores were significantly lower at both 1 and 2 h after surgery in the gabapentin group (Fig. 1), and the postoperative diclofenac consumption was significantly decreased (30 ± 38 mg vs 60 ± 63 mg, P < 0.05).

There were no statistically significant differences between groups with respect to adverse effects reported during the 24-h postoperative observation period. Two patients in the gabapentin group and three patients in the control group had nausea that required antiemetic treatment, and two patients in the gabapentin group complained of dizziness. Another postoperative complaint was dry mouth in four patients in the gabapentin group and two patients in the control group. None of the patients in either group reported being excessively drowsy (or sleepy) after surgery.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
The efficacy of gabapentin premedication on intra and postoperative pain scores is controversial (18). Analogous to our earlier findings in patients undergoing general anesthesia (9,11), monitored anesthesia care (10) and central neuroaxis blockade (12), these findings suggest that patients receiving IVRA can benefit from premedication with oral gabapentin (1.2 g). The results of this study revealed that a single oral dose of gabapentin given as preoperative medication decreased tourniquet-related pain during IVRA by up to 50%, supplemental intraoperative opioid usage by 42%, and postoperative analgesic consumption by 50%, without producing clinically significant side effects. Importantly, both the anesthesiologists and the surgeons rated the quality of anesthesia as better in the gabapentin group. The cost of gabapentin 1.2 g (US $5.04) was comparable to celecoxib 400 mg (US $5.22) and significantly less than dexmedetomidine 0.2 mg (US $54) and clonidine 100 µg (US $80). However, all of these non-opioid analgesic adjuvants are more costly than generic opioid analgesics. Therefore, careful cost-benefit analyses are necessary to document the effects of these opioid-sparing compounds on patient outcome (19).

Tourniquet-related pain is an important factor limiting the more widespread use of IVRA techniques during superficial surgical procedures involving the upper and lower extremities. Although, neuropathic pain produced by nerve compression plays an important role in the etiology of this discomfort (4), other factors which may contribute to tourniquet pain include stimulation of the nerve endings in the cutaneous tissue (which can contribute significantly to the superficial component of tourniquet pain) (20), skeletal muscle ischemia (21), and local metabolic changes (22). Although premedication with gabapentin could also theoretically reduce intraoperative incisional pain, patients were specifically questioned about tourniquet-related pain during the operation.

A predominant peripheral action of gabapentin in neuropathic pain has been suggested as a result of the "up-regulation" of ₂ Ca²⁺ channel subunits in the dorsal root ganglia after peripheral nerve injury (23). In addition, gabapentin has the ability to reduce the increased action potentials observed in dorsal root ganglia neurons. In animal models of inflammatory pain, gabapentin was shown to reduce hyperalgesia (11,24–26) and inhibit C-fiber responses to noxious stimuli (15). In addition to its central mode of action, peripheral administration of gabapentin has been shown to reduce local nociception at the site of injury, and this may prove to be beneficial in the treatment of inflammatory pain states (16,25). The present study is the first clinical study to assess the usefulness of gabapentin in preventing tourniquet pain during IVRA and in providing residual analgesia in the early postoperative period.

A deficiency of the current study design relates to the seemingly arbitrarily chosen dosage of the study drug (namely, 1.2 g of gabapentin). However, this is the most commonly used dose of gabapentin in both acute and chronic pain studies (7,9–12). Although a higher dose of gabapentin might provide greater analgesic efficacy, more side effects (e.g., sedation, dizziness) would also be expected. In order to optimize the premedicant dose of gabapentin, a dose-ranging study design would be required. In contrast to the usual clinical practice in the United States, the timing of the switch from the proximal to the distal tourniquet cuff was performed upon achieving an adequate surgical sensory and motor blockade (rather than when the patient first complained of tourniquet-related pain). Another criticism of this preliminary study relates to the fact that the study population involved only patients undergoing minor hand surgery procedures. Further comparative studies are clearly needed in patients undergoing other types of orthopedic surgical procedures. The trend toward a higher incidence of dizziness in studies involving patients receiving gabapentin, 1.2 g, for oral premedication (9–12) suggests that large scale studies are needed in patients undergoing ambulatory surgery.

In conclusion, preoperative administration of a single oral dose of gabapentin (1.2 g) provided a significant clinical benefit by decreasing tourniquet-related pain and improving intraoperative conditions during IVRA. Pain scores, and the need for analgesic medications during and after these elective hand surgery procedures, were also reduced when gabapentin was used for premedication.

	Footnotes

 
Accepted for publication October 3, 2006.

Supported by institutional funds.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

1. Chan VW, Peng PW, Kaszas Z, et al. A comparative study of general anesthesia, intravenous regional anesthesia, and axillary block for outpatient hand surgery: clinical outcome and cost analysis. Anesth Analg 2001;93:1181–4.[Abstract/Free Full Text]
2. Perlas A, Peng PW, Plaza MB, et al. Forearm rescue cuff improves tourniquet tolerance during intravenous regional anesthesia. Reg Anesth Pain Med 2003;28:98–102.[Web of Science][Medline]
3. Estebe JP, Le Naoures A, Chemaly L, Ecoffey C. Tourniquet pain in a volunteer study: effect of changes in cuff width and pressure. Anaesthesia 2000;55:21–6.[Web of Science][Medline]
4. Gielen MJM, Stienstra R. Tourniquet hypertension and its prevention: a review. Reg Anesth 1991;16:191–4.[Web of Science][Medline]
5. Hodgson AJ. A proposed etiology for tourniquet-induced neuropathies. J Biomed Engl 1994;116:224–7.
6. Pedowitz RA. Tourniquet-induced neuromuscular injury: a recent review of rabbit and clinical experiments. Acta Orthop Scand Suppl 1991;245:1–33.[Medline]
7. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352:1324–34.[Abstract/Free Full Text]
8. Vinik A. Clinical review: use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 2005;90:4936–45.[Abstract/Free Full Text]
9. Turan A, Karamanlioglu B, Memis D, et al. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:1370–3.[Abstract/Free Full Text]
10. Turan A, Memis D, Karamanlioglu B, et al. The analgesic effects of gabapentin in monitored anesthesia care for ear-nose-throat surgery. Anesth Analg 2004;99:375–8.[Abstract/Free Full Text]
11. Turan A, White PF, Karamanlioglu B, et al. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg 2006;102:175–81.[Abstract/Free Full Text]
12. Turan A, Kaya G, Karamanlioglu B, et al. Effect of oral gabapentin on postoperative epidural analgesia. Br J Anaesth 2006;96:242–6.[Abstract/Free Full Text]
13. Lu Y, Westlund KN. Gabapentin attenuates nociceptive behaviours in an acute arthritis model in rats. J Pharmacol Exp Ther 1999;290:214–19.[Abstract/Free Full Text]
14. Singh L, Field MJ, Ferris P, et al. The antiepileptic agent gabapentin (neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by d-serine. Psychopharmacology 1996;127:1–9.[Medline]
15. Stanfa LC, Singh L, Williams RG, Dickenson AH. Gabapentin, ineffective in normal rats, markedly reduces C-fiber evoked responses after inflammation. NeuroReport 1997;8:587–90.[Web of Science][Medline]
16. Carlton SM, Zhou S. Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. Pain 1998;76:201–7.[Web of Science][Medline]
17. Memis D, Turan A, Karamanloglu B, et al. Adding dexmedetomidine to lidocaine for intravenous regional anesthesia. Anesth Analg 2004;98:835–40.[Abstract/Free Full Text]
18. Hurley RW, Cohen SP, Williams KA, et al. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med 2006;31:237–47.[Web of Science][Medline]
19. White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg 2005;101:5–22.[Free Full Text]
20. Lowrie A, Jones MJ, Eastley RJ. Effect of a eutectic mixture of local anaesthetic agents (EMLA) on tourniquet pain in volunteers. Br J Anaesth 1989;63:751–3.[Abstract/Free Full Text]
21. Mense S. Nociception from skeletal muscle in relation to clinical muscle pain. Pain 1993;54:241–89.[Web of Science][Medline]
22. Kokki HV, Väätäinen U, Penttilä I. Metabolic effects of a low-pressure tourniquet system compared with a high-pressure tourniquet system in arthroscopic anterior crucial ligament reconstruction. Acta Anaesthesiol Scand 1998;42:418–24.[Web of Science][Medline]
23. Luo ZD, Chaplan SR, Higuera ES, et al. Upregulation of dorsal root ganglion ₂ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 2001;21:1868–75.[Abstract/Free Full Text]
24. Kanai A, Sarantopoulos C, McCallum JB, Hogan Q. Painful neuropathy alters the effect of gabapentin on sensory neuron excitability in rats. Acta Anaesthesiol Scand 2004;48:507–12.[Web of Science][Medline]
25. Field MJ, Holloman EF, McCleary S, et al. Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther 1997;282:1242–6.[Abstract/Free Full Text]
26. Hanesch U, Pawlak M, McDougall JJ. Gabapentin reduces the mechanosensitivity of fine afferent nerve fibers in normal and inflamed rat knee joints. Pain 2003;104:363–6.[Web of Science][Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Turan, A. Articles by Pamukçu, Z. Search for Related Content PubMed PubMed Citation Articles by Turan, A. Articles by Pamukçu, Z. Related Collections Ambulatory Regional Anesthesia Pharmacology