Intravenous regional anaesthesia (IVRA) is a reliable method of providing anaesthesia for hand surgery expected to last less than 1 h. Inability to provide effective postoperative analgesia and tourniquet pain are the major disadvantages of IVRA. Different additives have been combined with local anaesthetics to improve block quality, prolong postdeflation analgesia and decrease tourniquet pain with limited efficacy [1,2].
Ondansetron, a specific 5-hydroxytryptamine-3 (5-HT3) antagonist, is widely used as an antiemetic drug  and has a well defined and minor side-effect profile. The 5-HT3 antagonists interfere with peripheral serotonin effects on nociception .
Ondansetron exhibits local anaesthetic properties . Ondansetron has demonstrated binding at the opioid μ receptors in humans and exhibits agonist activity . The anti-nociceptive effects of ondansetron have been demonstrated in animals . Ondansetron has been shown to be successful in decreasing pain associated with injection of propofol  and rocuronium , with the added advantage of preventing postoperative nausea and vomiting. A study evaluating the addition of ondansetron to lidocaine for IVRA has not been reported.
The aim of this study was to evaluate the effect of ondansetron on intraoperative and postoperative analgesia, tourniquet pain, sensory and motor block onset and recovery times when added to lidocaine for IVRA.
This prospective, randomized and double-blinded study was performed in 30 ASA physical status I or II patients scheduled for hand or forearm surgery (i.e. carpal tunnel, trigger finger and tendon release). Informed patient consent and ethics committee approval was obtained. Patients with Raynaud disease, sickle cell anaemia or a history of any drug allergy were excluded.
Patients were allocated randomly into two groups according to a sealed envelope technique in a double-blind manner. As premedication, midazolam 0.07 mg kg−1 and atropine 0.01 mg kg−1 was administered intramuscularly (i.m.) before the surgical procedure. After the patients had been taken to the operating room, arterial blood pressure was monitored noninvasively and the mean values were recorded. Peripheral oxygen saturation (SpO2) and heart rate (HR) were monitored. Preoperative assessment of pain and motor function of the operative hand was done by an anaesthesiologist blinded to group assignments. Two cannulae were placed: one in a dorsal vein of the operative hand and the other in the opposite hand for crystalloid infusion. The operative arm was elevated for 2 min and then exsanguinated with an Esmarch bandage; a double cuff pneumatic tourniquet was then placed around the upper arm and the proximal cuff was inflated to 250 mmHg (at least 100 mmHg above the systolic blood pressure for all patients). Circulatory isolation of the arm was verified by inspection, absence of radial pulse and loss of pulse oximetry tracing in the ipsilateral index finger. IVRA was administered with 3 mg kg−1 lidocaine 2% w/v diluted with saline to a total volume of 40 ml in the control group (n = 15) or with 4 mg ondansetron 2 mg ml−1 plus 3 mg kg−1 lidocaine 2% w/v diluted with saline to a total volume of 40 ml in the ondansetron group (n = 15). The solution was injected over 90 s by an anaesthesiologist blinded to group assignments.
The sensory block was assessed by a pinprick performed with a 22-gauge short-bevelled needle every 30 s. Patient response was evaluated in the dermatomal sensory distribution of the medial and lateral antebrachial cutaneous, ulnar, median and radial nerves. The sensory block was defined using a visual analogue scale (VAS) from 0 (no sensation) to 10 (normal sensation). Sensory block onset time was defined as the time elapsed from injection of drug to sensory block achieved in all nerve distributions. The motor block was assessed objectively as follows: finger abduction (ulnar nerve), opposition of thumb to each finger (median nerve) and wrist and hand extension (radial nerve). Motor blockade was assessed on a three-point scale (0 = normal finger motility, 1 = decreased motility, 2 = complete motor blockade). The motor block onset time was the time elapsed from injection of drug to complete motor block.
After sensory and motor blocks were achieved, the distal tourniquet was inflated to 250 mmHg and the proximal tourniquet was released. Mean arterial pressure (MAP), HR, SpO2 and subjective pain assessment using a VAS from 0 cm (no pain) to 10 cm (worst pain) were monitored before and 1, 5, 10, 15, 20 and 30 min after tourniquet inflation. Data were obtained after the release of the tourniquet and 1, 2, 4, 6, 12 and 24 h postoperatively. When pain due to the tourniquet was 4 or more on the VAS, patients were given fentanyl 1 μg kg−1 and the total administered dose and requirement time were recorded. No additional sedative drugs were given during the intraoperative period. At the end of the operation, patients were asked to qualify the operative conditions such as tourniquet pain or incisional pain according to the following numeric scale: excellent (4) = no complaint from pain; good (3) = minor complaint with no need for supplemental analgesics; moderate (2) = complaint that needed a supplemental analgesic; and unsuccessful  patient was given general anaesthesia. At the end of the operation, the surgeon, who was blinded to group assignment, was asked to qualify the operative conditions according to the following numeric scale: 0 = unsuccessful; 1 = poor; 2 = acceptable; 3 = good; and 4 = excellent .
The tourniquet was not deflated before 30 min and was not inflated for more than 1 h. At the end of surgery, tourniquet deflation was performed by the cyclic deflation technique. Sensory recovery time was noted (time elapsed after tourniquet deflation up to recovery of pinprick in all nerve distributions determined by the pinprick test). Motor block recovery time was noted (the time elapsed after tourniquet deflation up to movement of fingers).
Patients were administered diclofenac, 75 mg i.m., at 8 h intervals if the VAS pain score was higher than 4. First analgesic requirement time (the time elapsed after tourniquet release to the first request by the patient for analgesic) and total diclofenac consumption were recorded. All evaluations were performed by an anaesthesiology resident blinded to the study group assignments. Nausea, vomiting, allergic reaction, headache, dizziness, tinnitus, extra-pyramidal symptoms, cardiac arrhythmia and other side effects were noted if encountered 24 h postoperatively.
A 15% reduction in the tourniquet (VAS) pain score in the ondansetron group compared with the lidocaine control group was considered to be clinically significant. On the basis of pain reduction estimate (and an average standard deviation of 1.4), it was calculated that a sample size of 15 patients in each group would be sufficient to permit a type I error of α = 0.05 and a power of 80% . Independent samples Student's t-test was used for the evaluation of the demographic data, intraoperative and postoperative haemodynamic data, the time of the onset and recovery of sensory and motor block, the duration of the operation and tourniquet and the duration of analgesia. Analysis of variance for repeated measures was performed on VAS pain scores followed by the Bonferroni test for multiple comparisons. The Mann–Whitney U-test was used for intraoperative and postoperative VAS pain scores, analgesic use and the quality of anaesthesia. Complications and operation type were compared with Fisher's exact test. A P value less than 0.05 was considered statistically significant.
The two groups were similar as regards age, weight, sex distribution, duration of surgery, tourniquet time and types of surgical procedures (Table 1). There was no exclusion from the study because of technical failure. There was also no significant difference between groups as regards MAP, HR and SpO2 at any intraoperative and postoperative period.
The sensory and motor block onset times were slightly but significantly shorter [1.4 min (95% confidence interval (CI) 0.5–2.3) and 1.5 min (95% CI 0.45–2.55), respectively] in the ondansetron group than in the control group (overall P = 0.007 and P = 0.008, respectively). The sensory and motor block recovery times were slightly but significantly prolonged [2.6 min (95% CI 1.66–3.54) and 2.8 min (95% CI 1.83–3.78), respectively] in the ondansetron group compared with the control group (overall P = 0.0001) (Table 2). No patient suffered from incisional pain during the intraoperative period in either group.
VAS scores for tourniquet pain were slightly but significantly lower in the ondansetron group at 10 min (P = 0.026), 15 min (P = 0.016), 20 min (P = 0.026) and 30 min (P = 0.016) after the tourniquet inflation compared with the control group (overall P = 0.027) (Table 3). The time of fentanyl requirement for tourniquet pain was significantly prolonged (P = 0.043) in the ondansetron group (35.0 ± 7.1 min) compared with the control group (18.9 ± 8.9 min). Two patients in the ondansetron group required fentanyl for tourniquet pain compared with nine patients in the control group (P = 0.019). Intraoperative fentanyl requirements (median [interquartile range]) were significantly lower in the ondansetron group (0 μg [0–0] vs. 59 μg [0–76]) than in the control group [33.47 μg (95% CI 8.48–58.45), P = 0.015].
Quality of anaesthesia (median [interquartile range]), as determined by the patient (4 [3–4]) vs. 3 [3–4]) and the surgeon (4 [3–4]) vs. 3 [3–4]), was significantly better in the ondansetron group than in the control group (P = 0.029 and P = 0.004, respectively). Postoperative VAS scores were significantly lower for the first postoperative 4 h in the ondansetron group than in the control group (overall P = 0.026) (Table 3). The time to first postoperative analgesic request was significantly prolonged in the ondansetron group (172 ± 51 min) compared with the control group (85 ± 35 min) (P = 0.0001). Total diclofenac consumption over the 24 h study period was significantly less in the ondansetron group (0 mg [0–75]) than in the control group (75 mg [75–150]) (P = 0.002). Seven patients in the ondansetron group and 15 in the control group required diclofenac for postoperative pain (P = 0.002). Except for two patients in the control group who had nausea that required metoclopramide 10 mg intravenous (i.v.) injection, no other postoperative complications or adverse effects occurred in the studied patients.
The results of the present study demonstrated that the addition of ondansetron to lidocaine for IVRA decreases intraoperative and postoperative analgesic requirements, improves sensory and motor block, decreases tourniquet pain and improves the quality of anaesthesia without causing side effects. The differences in pain scores and onset times are small, but the time to first postoperative analgesic request, intraoperative fentanyl requirements and the total diclofenac consumption over the 24 h study period are of more clinical importance. Ondansetron has the added advantage of reducing the incidence of postoperative nausea and vomiting.
Ondansetron is a relatively old drug, extensively used, with a proven antiemetic effect  and a well defined and minor side-effect profile. Ye et al. showed that ondansetron blocks sodium channels in neurons of the rat brain and demonstrated that ondansetron is a potent local anaesthetic and its local anaesthetic properties may contribute to its antiemetic action. Ondansetron applied intrathecally to rats has been found to reduce the nociceptive response of dorsal horn neurons .
Similar to local anaesthetics, ondansetron can block sodium channels; peripheral 5-HT3 receptor are also involved in nociceptive pathways and have demonstrated binding at opioid μ receptors exhibiting agonist activity, thus resulting in a peripheral nociceptive effect [5,6]. Acute inflammation from tissue injury has an important role in the formation of surgical pain, and 5-HT3 antagonists may be useful for their anti-inflammatory effect. 5-HT3 receptor antagonists could supplement or replace the locally administered corticosteroids .
Ambesh et al. showed that ondansetron 4 mg provides a simple and well tolerated method of reducing the incidence of pain on injection of propofol. Ondansetron 4 mg or tramadol 50 mg is equally effective in preventing pain from propofol injection . Reddy et al. found that pain from rocuronium and propofol was significantly reduced in the ondansetron 4 mg and lidocaine 50 mg groups compared with the placebo group. Memis et al. found that ondansetron 4 mg is effective in decreasing the level of rocuronium injection pain.
The results of the present study showed that the addition of ondansetron to lidocaine may improve the quality of IVRA. The finding of an antinociceptive effect of ondansetron is in keeping with the finding of an analgesic effect of other 5-HT3 antagonists: tropisetron can produce analgesia in patients with fibromyalgia pain [13,14] and alosetron in female patients with diarrhoea-predominant irritable bowel syndrome . Muller et al. reported that local injections of 5-HT3 receptor antagonists in various rheumatic diseases have rapid analgesic effect. This effect matches that of local anaesthetics, but lasts considerably longer and is comparable to that of local injections of local anaesthetics combined with corticosteroids.
Fassoulaki et al. found that ondansetron antagonizes the sensory block produced by subarachnoid lidocaine anaesthesia. Stimulation of the periaqueductal grey increases the release of 5- HT in the dorsal horns of the spinal cord, which, along with other neurotransmitters, may inhibit the nociception of dorsal horn neurons . Arcioni et al. concluded that ondansetron reduces the overall analgesic effect of tramadol, probably blocking spinal 5-HT3 receptors, and reported that increasing doses and concentrations of ondansetron allows the onset of analgesic effects acting on peripheral 5-HT3 receptors and/or blocking the sodium channels. 5-HT3 receptors are expressed by the nociceptive primary afferent fibres (PAFs) either on the peripheral free terminal or centrally on their spinal terminal, and by the neurons of the superficial laminae of the dorsal horn [20,21]. 5-HT3 receptors located on PAFs – from the nociceptors up to the dorsal horn – mediate a pronociceptive action and only those postsynaptically located in regard to PAFs allow the antinociceptive effect of endogenous (5-HT) or administered agonists [22,23]. Zeitz et al. concluded that the contribution of peripheral 5-HT3 receptors involves a novel complement of primary afferent nociceptors. The present study provides information about the clinical use of ondansetron 4 mg as an adjunct in IVRA; in addition, it may also be a useful model for studying the peripheral action of ondansetron, as the tourniquet placement prevents whole body distribution of ondansetron through the bloodstream. The majority of differences between the groups showed a slight clinical advantage of ondansetron.
Tourniquet pain is generally considered the main factor limiting the time IVRA can be used for upper limb surgery. Neuropathic pain produced by nerve compression plays an important role in the aetiology of this discomfort . The 5-HT3 receptor antagonist ondansetron has been demonstrated to have potential benefit in neuropathic pain . Pain associated with nerve compression is mediated by unmyelinated, slow-conducting C fibres . 5-HT3 receptor antagonists diminish serotonin-induced release of substance P from C fibres . It has been suggested that compounds with a local anaesthetic activity like meperidine  or clonidine  added to local anaesthetic solutions in IVRA may be of benefit in reducing tourniquet and postoperative pain. Ondansetron has a potent local anaesthetic action . Further studies should evaluate the effect of different doses of ondansetron in other types of orthopaedic surgical procedures and different peripheral techniques.
In conclusion, the addition of ondansetron 4 mg to lidocaine may improve the quality of IVRA and prolong the postoperative analgesia in patients undergoing hand surgery.
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