Laparoscopic cholecystectomy is a common procedure. Compared with open cholecystectomy, it leads to more rapid convalescence, and return to normal activity and discharge is earlier. However, these patients experience significant postoperative pain, frequently in the abdomen or shoulder region, which is often maximal on the first postoperative day. Pain is the dominating complaint and the primary reason for prolonged convalescence. It has been hypothesized that intense pain may predict the development of chronic pain after laparoscopic cholecystectomy [1–5].
Pain after laparoscopic cholecystectomy has three major components: parietal, visceral and shoulder pain . Overstretching, persistent presence of gas in the peritoneum, or irritation due to bile, pus or blood in the peritoneal cavity may cause peritoneal or diaphragmatic irritation, and thus cause pain. The peritoneal origin of the pain suggests that analgesia delivered locally to the peritoneal cavity may be of benefit postoperatively . After laparoscopy, shoulder pain secondary to diaphragmatic irritation as a result of CO2 pneumoperitoneum is a frequent postoperative observation (35–60%) . Different local anaesthetic infiltration techniques have been tried for the relief of post-laparoscopic cholecystectomy pain [3–5].
Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It has an affinity for μ-opioid receptors and inhibits the neuronal reuptake of serotonin and norepinephrine . Tramadol has central analgesic effects due to monoaminergic and μ-receptor agonistic activities. It also has local anaesthetic properties, and the risk of serious adverse effects is limited [7–9]. Local administration of tramadol has been found to be an effective analgesic when given intra-articularly or when added to local anaesthetics for nerve blocks [7,10,11].
The aim of this study was to compare the postoperative analgesic efficacy of intraperitoneal (i.p.) with intravenous (i.v.) tramadol in patients undergoing laparoscopic cholecystectomy.
After approval of the local Ethics Committee, and consent by the involved patients, 69 patients with ASA I-II physical status scheduled for laparoscopic cholecystectomy were informed about the different components of postoperative pain that they would experience, and were trained for differentiating these components and using the numeric pain-rating scale. Patients with acute cholecystitis, history of analgesic or narcotic use, previous abdominal surgery, hypersensitivity to study drugs, or those who needed conversion to open cholecystectomy or postoperative drains were excluded.
Patients received a standard anaesthetic. They were premedicated with 5 mg diazepam orally. Anaesthesia was induced with propofol 2.5 mg kg−1 and vecuronium 0.8 mg kg−1 i.v. Anaesthesia was maintained with 2% sevoflurane in 50% N2O/O2. Ventilation was adjusted to maintain end-tidal carbon dioxide (etCO2) between 34 and 40 mmHg. During laparoscopy, intra-abdominal pressure was kept at 10–14 mmHg. At the end of surgery, metoclopramide 0.5 mg kg−1 was administered to minimize postoperative nausea and vomiting. For reversal of neuromuscular blockage, neostigmine 0.05 mg kg−1 combined with atropine 0.01 mg kg−1 was administered.
Patients were randomized to one of three groups in a double-blind manner using a computerized allocation schedule and coded syringes. After randomization, an anaesthesiologist not involved in patient care and data collection prepared the coded syringes. All patients received two sets of syringes filled with the study drugs at two different times: first, immediately after installation of the pneumoperitoneum but before dissection of the gall bladder, and second, after control of haemostasis but before removal of the trocars (Table 1). The anaesthesiologist injected the drugs i.v. the surgeon injected the drugs i.p. In all groups, 10 mL of the study drug was injected into the hepatodiaphragmatic space, 5 mL into the area of the gallbladder and 5 mL was injected into the space between the liver and the kidney under direct vision by the surgeon. At the end of surgery, the surgeon injected an additional 20 mL of the study solution into the same areas.
Parietal pain (defined as a superficial pain located on the abdominal wall) and visceral pain (defined as deep, dull pain deep inside the abdomen) were assessed using a numeric rating scale (NRS, 0 = no pain to 10 = the worst imaginable pain) at rest (supine, 10°–15° head up), on coughing and during mobilization (rising from supine to the sitting position). Shoulder pain was also recorded. In the recovery room, patient-controlled analgesia with morphine (bolus 1 mg, lock-out interval 7 min, 4 h limit 20 mg, no background infusion) was started if NRS ≥ 4. A blinded observer recorded pain, delay unit first morphine dose, cumulative morphine consumption and adverse effects (nausea, vomiting, shivering, sedation and muscular rigidity) at 0, 15 and 30 min and at 1 and 24 h postoperatively. Sedation was defined as no sedation (alert) or sedated (drowsy but responsive to verbal numeric pain rating only after called loudly and/or repeatedly). The patients were discharged from the recovery room according to Aldrete criteria .
SPSS 13.0 for Windows statistical package (SPSS Inc., Chicago, IL, USA) was used for all analyses. Patient characteristics, duration of the procedure and of the stay in the recovery room, delay until first analgesic, pain scores and postoperative morphine consumption were analysed using analysis of variance, Kruskal–Wallis test and χ 2-test. Generalized linear model for repeated measures was used to analyse pain scores to test for differences between and within groups. Significance was determined at the P < 0.05 level. A Bonferroni adjustment was made for multiple comparisons. Results are given as medians (range) for non-parametric data and as mean ± standard deviation (SD) for continuous data. The number of patients (19 patients per group) was based on a power calculation; a power of 0.80 was assumed to detect a 2-point difference in NRS scores (mean pain score of 6 and assuming an SD of ±2.5 in all groups) between the tramadol groups and the control group.
We recruited 69 patients; eight were excluded. Reasons for exclusion were use of intra-abdominal drain in one, incomplete administration of drugs in three and conversion to open cholecystectomy in four patients. Twenty patients were enrolled in the control group, 20 in the i.p. tramadol group and 21 in the i.v. tramadol group.
Patient characteristics, duration of surgery and duration of stay in the recovery room were similar between groups (Table 2). Parietal pain at rest, during cough and during movement were lowest in the i.v. tramadol group during the first postoperative hour (P < 0.016 compared with control). Although i.p. tramadol decreased parietal pain scores, this effect did not reach statistical significance when compared with saline. There were no differences between the three groups at and after the first postoperative hour (###Fig. 1, Table 3).
The analgesic effects of tramadol were more prominent on visceral pain scores (###Fig. 2). The lowest visceral pain scores were recorded with i.v. tramadol (P < 0.016 compared with control during the first postoperative hour). The difference between i.p. tramadol and control was significant only at the 15th minute (P < 0.016). There were no differences between the three groups regarding visceral pain scores after the first postoperative hour (Table 4).
The delay until the first analgesic administration was similar in the i.v. tramadol group (median 23 min, range 1–45) compared with the i.p. tramadol group (median 10 min, range 1–120), P = 0.263, but was shorter compared with the control group (median 1 min, range 1–30), P = 0.015. When the i.p. tramadol group was compared with the control group, the difference was not significant (P = 0.027).
The cumulative 1-h dose of morphine was significantly lower in the i.v. tramadol group (mean ± SD; 3.4 ± 2.5 mg) and in the i.p. tramadol group (4.4 ± 4.3 mg) compared with the control group (6 ± 2 mg) (P = 0.044). Morphine consumption during 24 h was similar in all three groups (control 24 ± 18 mg, i.v. tramadol group 16 ± 15 mg, i.p. tramadol group 16 ± 15 mg).
There were no differences in the incidence of shoulder pain, nausea, vomiting, sedation, itching and shivering (Table 5). No patient experienced muscle rigidity. Two patients in the control group and one each in the i.v. and the i.p. tramadol groups each complained of itching.
Administration of i.v. tramadol resulted in slightly lower pain scores, a shorter time interval to the first analgesic administration and less morphine consumption compared with normal saline during the first postoperative hour after laparoscopic cholecystectomy. I.p. tramadol was not as effective as the equivalent dose of tramadol i.v.
Clinical trials that were designed to determine the analgesic efficacy of the peripheral administration of tramadol have yielded contradictory results [7,10,11,13]. Intra-articular administration of tramadol provided better analgesia in patients with a history of preoperative pain that lasted for more than 6 months . It was suggested that the efficacy of tramadol depended in part on the duration of nerve injury-evoked nociception, and that its antinociceptive mechanism may change over time . It might be of interest to evaluate the relation between the duration of preoperative symptoms and the postoperative analgesic efficacy of i.p. tramadol after laparoscopic cholecystectomy. While tramadol provides better analgesia in patients with chronic pain or inflammatory processes having had enough time to develop peripheral opioid and non-opioid receptors compared to acute pain situations, it is more difficult to explain the discrepancy between different nerve blocks. The lack of uniform anatomy of the peripheral nervous system and different susceptibilities to local anaesthetic blockade of different types of fibres may explain the contradictory results obtained with the peripheral administration of tramadol .
Although tramadol has been known to have central and peripheral effects, these effects are not fully explained [7,15]. Tramadol promotes serotonin and norepinephrine release . The monoaminergic activity of tramadol enhances the inhibitory activity of the descending pain pathways, resulting in a suppression of nociceptive transmission at the spinal level . These effects are partially reversed by the antagonists ritanserin and yohimbine at α2-receptors and also by the competitive antagonist ondansetron at serotonin subtype 3(5-HT3) receptors .
Early pain after laparoscopic cholecystectomy has a complex mechanism including several components secondary to different pain mechanisms, such as abdominal wall trauma, intra-abdominal trauma secondary to gall bladder removal, abdominal or peritoneal distension, pneumoperitoneum using CO2, etc. Therefore, optimal pain treatment should be multimodal [2,4,5].
Factors that may influence the degree of pain after laparoscopic procedures include the volume of residual gas, the type of gas used for pneumoperitoneum, the pressure created by the pneumoperitoneum and the temperature of the insufflated gas . The rate of insufflation of CO2 also influences the incidence of postoperative pain, with lower rates of insufflations resulting in lower rates of shoulder pain . We kept the insufflation pressures below 14 mmHg. We believe that this led to a low incidence of shoulder pain.
I.p. acidosis has also been documented in humans after CO2 pneumoperitoneum . The benefit of saline may have been in the dilution of this acid, which in turn may have decreased the pain scores in the control group. I.p. tramadol was not as effective as i.v. tramadol when used during CO2 insufflation; this can probably be explained by the fact that tramadol is decomposed in acidic and basic environments . Another explanation has been suggested by Parasprampuria and colleagues . They have shown that in rats the route of administration of tramadol affected the stereoselective pharmacokinetics of this drug; after i.v. administration of the racemate, the pharmacokinetics of tramadol were shown to be non-stereoselective. After i.p. administration of tramadol, the blood concentration of the enantiomers, although lower than that after the i.v. injection, was substantial and stereoselective in favour of the (+)-enantiomer . The manufactured tramadol is a racemic mixture of two complementary and synergistic enantiomers . The effects of the two enantiomers complement each other as the (+)-enantiomer is the main opioid component and also enhances serotonin release, whereas the (−)-enantiomer inhibits norepinephrine uptake. The combination of the actions of the racemic compound produces effective analgesia. The different routes of administration (i.p. vs. i.v.) may result in different enantiomer ratios and therefore in different analgesic efficacies as observed in our study.
The timing of the i.p. tramadol administration may be an issue. Pre-emptive analgesia with i.p. instillation of local anaesthetics before pneumoperitoneum was shown to be more effective for pain relief . Unlike our results, the administration of i.p. meperidine resulted in significantly lower pain scores (both at rest and on movement) when compared with an equivalent dose of meperidine administered intramuscularly in patients undergoing laparoscopic cholecystectomy .
Although we hypothesized that i.p. tramadol would provide multi-action analgesia due to its opioid and non-opioid properties and also due to the local and systemic action, the i.p. administration was not superior to the i.v. administration. As in a similar trial in patients undergoing laparoscopic cholecystectomy , the analgesic effect of i.v. tramadol was extremely short-lived in our study.
A multimodal or step-up therapeutic approach has been recommended for postoperative pain following laparoscopic cholecystectomy due to the complex nature of pain after this specific procedure [4,5]. We believe that tramadol could have a role in this multimodality treatment plan. There are many more options to investigate the role of this atypical opioid. Local wound infiltration of tramadol together with systemic administration may enhance the analgesic efficacy of tramadol. Indeed, one study suggested a dual-site synergism of tramadol following intraplantar (local) and i.p. (systemic) administration of the drug .
In our study, i.v. tramadol increased the delay until the first analgesic administration, and slightly decreased parietal and visceral pain scores and morphine consumption during the first postoperative hour compared with the control group. Adverse effects were similar to normal saline. Thus, tramadol when used at the same doses as in our study does not seem to carry the risks that are associated with potent opioids. I.v. tramadol provides superior postoperative analgesia after laparoscopic cholecystectomy compared with i.p. tramadol or saline. I.v. tramadol may be incorporated into a multimodality pain therapy after laparoscopic cholecystectomy.
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Keywords:© 2008 European Society of Anaesthesiology
LAPAROSCOPIC CHOLECYSTECTOMY; TRAMADOL; PAIN ACUTE AND POSTOPERATIVE