Propofol is a useful agent because of its properties and short-term effects . The initial preparations of propofol (2,6-diisopropyl phenol) used in clinical practice contained Cremophor EL formulation which caused pain on injection and haemodynamic reactions. Because a link between Cremophor EL and the occurrence of anaphylactic reactions was suspected, propofol was subsequently prepared as an emulsion in soy oil. This resulted in a 30% reduction in pain at the site of injection, but not its complete elimination [2,3].
Ondansetron is a commonly used antiemetic drug which, upon the demonstration of its local anaesthetic property, started to be used in the prevention of propofol injection pain [4-6]. Tramadol is a synthetic analgesic which structurally resembles codeine with an analgesic effect equivalent to that of meperidine . It has been argued that the central effect of tramadol is due to an effect on neurons that contribute to the monoaminergic modulation of pain, rather than to its effect on the opioid receptor . We compared the local anaesthetic effects of tramadol and ondansetron administered into an occluded vein when propofol was injected.
Our Hospital Ethics Committee approved the protocol and written informed consent was obtained from the patients. The study was conducted on 100 ASA I-II consenting patients who were to undergo various elective operations (hysteroscopy, arthroscopy). Patients with opioid allergy, Parkinson's disease or those with weak, thin dorsal veins were excluded from the study. The patients included in the study were randomly assigned to two groups of 50 patients each. The study design was randomized and double-blind; patients were randomly allocated by computer. The patients were taken into the operating room and premedication with midazolam 0.06 mg kg−1 and atropine 0.01 mg kg−1 was administered intramuscularly (i.m.). An electrocardiogram (lead II), non-invasive arterial pressure and pulse oximetry (PM 8040 Cato®; Dräger, Lübeck, Germany) were applied. A 20-gauge cannula was inserted into a vein on the dorsum of each hand. In order to keep the test drug in the vein, the forearm was compressed by a tourniquet up to 70 mmHg and the drug was then administered: tramadol 50 mg to the patients in Group 1 and ondansetron 4 mg to the patients in Group 2. The syringes were prepared by an independent anaesthesiologist and the investigator did not know the contents. The tourniquet was released after 20 s and the first 5 mL of the propofol induction dose (2 mg kg−1) was injected. No analgesic drug was given before the propofol. The level of pain was assessed by a second, independent anaesthesiologist who was also unaware of the group to which the patient had been allocated.
The patients were asked standard questions about the comfort of the injection. Verbal response and behavioural signs, such as facial grimacing, arm withdrawal, or tears were noted. A scoring system of 0 to 3. (which corresponded to no pain = 0; mild pain = 1; moderate pain = 2; and severe pain = 3 (Table 1)) was used.
The induction of anaesthesia was then continued with the rest of the calculated dose of propofol. The cannula in the opposite hand was used for infusions or other medication. Atracurium (0.5 mg kg−1) was administered for muscle relaxation and to facilitate oro-tracheal intubation, and anaesthesia was continued with 50% N2O in O2; the lungs were mechanically ventilated (Cato®; Dräger, Lübeck, Germany). Following induction of anaesthesia, all patients were given fentanyl (0.5 μg kg−1 intravenously (i.v.)) and no other opioid analgesics were used during the operation. Patients were extubated without requiring antagonism of muscle relaxation. During the first 24 h after the operation, the injection site was checked for any complications such as pain, swelling or allergic reactions, by an anaesthesiologist who did not know which drug had been administered. Postoperative nausea and vomiting (PONV) were assessed on a four point scale (0 = no nausea or vomiting; 1 = nausea alone; 2 = moderate vomiting; 3 = severe vomiting). If a score of ≥2 was reached, metoclopramide 0.1 mg kg−1 was given i.v. The degree of sedation (0 = alert; 1 = drowsy but rousable to command; 2 = very drowsy, rousable to shaking) was recorded during the first 24 h after operation. Student's t-test was used in the analysis of demographic data, the χ2-test was used for pain scores and side-effects. P < 0.05 was taken as the level of significance.
No significant differences were found in demographic data (Table 2). The distribution of pain scores is shown in Table 3. No pain was reported by 21 of the patients (43%) in Group 1 and by 14 of the patients (28%) in Group 2. Slight pain was seen in 15 of the patients (30%) in Group 1 and in 18 of the patients (36%) in Group 2. Ten patients (20%) of those in Group 1 and 15 of those (30%) in Group 2 reported moderate pain. Severe pain was seen in four of the patients (8%) in Group 1 and three (6%) in Group 2. Statistically, there was no difference between the two groups.
In the Group 1 patients, hyperaemia was observed in three patients after the administration of tramadol. There was no need for further treatment: the hyperaemia resolved spontaneously after 20 to 30 s.
In the tramadol group, 28 patients (56%) were without PONV, 16 patients (32%) complained of nausea (score = 1), three patients (6%) had moderate vomiting (score = 2) and three patients (6%) vomited repeatedly (score = 3). In the ondansetron group, 39 patients (78%) were without PONV, eight patients (16%) complained of nausea (score = 1), two patients (4%) complained of moderate vomiting (score = 2), and one patient (2%) vomited repeatedly (score = 3). We found that ondansetron reduced PONV significantly compared with tramadol (P = 0.033) and that the percentage of patients without PONV was significantly higher in the ondansetron group (P = 0.019). Six patients (12%) in the tramadol group and three patients (6%) in the ondansetron group had a PONV score of ≥2 and were given metoclopramide 0.1 mg kg−1 i.v. (P > 0.05).
During the postoperative 24-h period, two patients (4%) in Group 1 experienced sedation, rated 1 in severity, and four patients (8%) in Group 2 experienced headache that did not require treatment. No statistically significant differences were found (P > 0.05).
Propofol causes injection pain in 45-75% of all patients, particularly when administered into the small veins on the back of the hand [10,11]. This is higher than the incidence reported in the patients of this study who had been given one of the study drugs. Although it is not a serious complication, efforts are underway to reduce the severity of the pain or discomfort. Various studies have recommended using larger veins ; pre-treatment with lidocaine, alfentanil, fentanyl or some premedication drugs [10,11,13]; diluting it with glucose 5% or Intralipid® (Kabi Pharmacia AB, Stockholm, Sweden) 10% [14,15]; cooling the propofol to 4°C ; injecting cold saline with the propofol or discontinuing fluid during the injection .
Scott and colleagues  speculated that the pain is caused by activation of the kallikrein-kinin system in plasma by contact with propofol, consequently generating kinins, probably bradykinin. Activation of the kallikrein-kinin system in plasma involves activation of coagulation factor XII that converts to prekallikrein, which in turn cleaves high-molecular weight kininogen to release bradykinin . Studies have revealed a potential mechanism for propofol-induced pain in which the lipid solvent for propofol activates the plasma kallikrein-kinin system and produces bradykinin that in turn modifies the local vein by its vasodilatory and hyperpermeability actions. This modification in the local vein increases contact between the aqueous phase propofol and free nerve endings resulting in aggravation of pain on injection .
In animal experiments, ondansetron administered intrathecally reduces the nociceptive responses of dorsal horn neurons . Ye and colleagues  demonstrated that ondansetron, a specific 5-HT3 antagonist, blocks sodium channels in rat brain neurons. They also found that ondansetron is 15 times more potent than lidocaine in causing numbness when injected under the skin. Recently it has been shown that ondansetron attaches to opioid mu receptors, with agonist activity  but some investigators have shown that ondansetron acts indirectly as an opioid receptor antagonist .
In previous studies it was shown that ondansetron 4 mg is effective in alleviating, but not totally eliminating, the pain of injection caused by propofol [6,20]. Memiş and colleagues , in a study in which they administered ondansetron (4 mg) and lidocaine 1% (2 mL) to reduce the pain of injection, demonstrated that the ondansetron and lidocaine applications were more effective compared to controls. In the present study we have also demonstrated that the same amount of ondansetron eliminated the pain of injection linked to propofol.
Ondansetron has a well-known prophylactic antiemetic effect on cancer chemotherapy protocols, which frequently cause nausea and vomiting [4,21], and its effectiveness in postoperative nausea and vomiting has been demonstrated in various studies . The side-effects of ondansetron include headache, constipation and elevated liver enzymes [23,24]. Thirty-nine patients (78%) who had been given ondansetron had no PONV and only three patients (6%) vomited. Four patients (8%) complained of headache.
Tramadol has been found both in vivo and in vitro to have a low but preferential activity at mu opioid receptors, to inhibit both norepinephrine and 5-HT neuronal reuptake, and to facilitate 5-HT release [7,25,26]. Pang and colleagues  demonstrated that tramadol (25 mg i.m.) has local anaesthetic effects. Taking this local anaesthetic property of tramadol into account, Pang and colleagues , administered tramadol (50 mg) i.v. to prevent the pain of injection of propofol and compared it to lidocaine. They observed that both drugs reduced the pain significantly, but did not totally eliminate it. There were more local skin reactions in the tramadol group than in the lidocaine group. In our study, we also administered tramadol 50 mg i.v. according to the study of Pang and colleagues  and expected a similar effect; however, the incidence of local skin reactions was higher in our study.
Tramadol produces a significant incidence of nausea [29,30]. Other side-effects include vomiting, dizziness, sedation, dry mouth, sweating, headache and some mild effects on the cardiovascular system resulting in hypertension [29,31,32]. In the patients receiving tramadol, PONV occurred in 22 patients (44%). Sedation was observed in two patients (4%).
There was no difference between the effectiveness of ondansetron and tramadol in preventing the pain of injection of propofol. Ondansetron had the added benefit of a lower incidence of PONV and this could be an argument for choosing this drug. In addition, if the use of ondansetron is anticipated its administration could be timed to exploit its local anaesthetic properties.
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