Antinociceptive Effect of (α₂-Adrenoceptor Agonist) Dexmedetomidine vs Meperidine, Topically, after Laparoscopic Gynecologic Surgery

MATERIALS AND METHODS

After approval of Local Ethical and Research Committee in Dar Alshifa hospital (in The State of Kuwait) during the period from January 2007 to December 2007, the informed written consents were obtained from sixty female patients (25-40 yeas old), ASA physical status 1 and 2 undergoing elective laparoscopic gynecologic surgery (e.g., diagnostic laparoscopy, adhesolysis, tubal ligation, ovarian cystectomy, etc.). Patients with previous abdominal surgery, hypertension, diabetic and cardiac patients were excluded from the study. Leaving intra-abdominal drain at the end of surgery was also a ground cause for exclusion. All patients were premedicated with oral midazolam 5 mg, approximately 60-90 min prior to surgery. Upon arrival to an operating room, a wide bore intravenous cannula was inserted and 8 mL kg^-1 normal saline was infused intravenously. Electrocardiogram (lead 2 and 5 with ST segment analysis), pulse oximetry and non-invasive arterial blood pressure were monitored. Anesthesia was induced in all patients with intravenous 1.5 μg kg^-1 fentanyl, 3-4 mg kg^-1 propofol and 0.6 mg kg^-1 rocuronium. The trachea was intubated with oral cuffed tube lubricated with lidocaine jelly 2%, 1-2 min after rocuronium administration guided by peripheral nerve stimulator. Intravenous lidocaine 2% (1 mg kg^-1) was injected one minute before endotracheal intubation. Ventilation was controlled using O₂/N₂O (50%:50%) with sevoflurane 1-1.5%. Nasogastric tube was inserted and end-tidal (Et) CO₂ was monitored after intubation. Ventilation was adjusted to maintain normocapnic (EtCO₂ around 36 mm Hg). Additional doses of rocuronium were given guided by peripheral nerve stimulation. Intravenous 10 mg metoclopramide, as well as intramuscular 75 mg diclofenac sodium were given following intubation in all patients. Diagnostic laparoscopy was done prior to proceeding to the surgical procedure. Surgery was conducted in the lithotomy and Trendelenberg position. Complete revision of hemostasis was done. Patients were randomly allocated (using table of randomization) into one of three equal sized groups (n = 20):

The drugs were prepared and given to the investigator who was blinded to the identity of drugs.

In the three studied groups, at the end of surgery, intraperitoneal injection was guided by the camera on the surgical site and under both copulae of the diaphragm. Pain was assessed using Visual Analogue Scale (VAS), where zero score corresponds to no pain and 10 to the maximum or worst pain. Postoperative pain (VAS>3) was initially managed with a bolus of 1 mg i.v. morphine. Patients were then instructed to start using intravenous Patient-Controlled Analgesia (PCA) morphine pump (IVAC 5000). The PCA pump was adjusted to deliver morphine boluses in 1 mg increments with a lockout interval of 10 min and a maximum hourly dose of 5 mg. The PCA regimen was reviewed if analgesia proved to be inadequate.

The following parameters were evaluated in all studied groups:

Statistical analysis: All data were presented as mean (SD) or as median and range, comparison among groups was done using Analysis of Variance test (ANOVA) and post hoc test was performed in case of significant difference. Significance was considered where (p>0.05.) Statistical analysis was performed using the statistical computer program SPSS version 2.

RESULTS

Patient characteristics and operative details showed no significant differences among the three studied groups (Table 1).

Times to first request of postoperative analgesia were 45(10) min, 116 (20) min and 120 (18) min in groups (B), (B+M) and (B+D), respectively. It was significantly shorter in group (B) compared to the other 2 groups (p<0.05) with non significant difference between the later two groups ((B+M) and (B+D) ) (Table 2).

Doses of intravenous PCA morphine consumed at 0-6, 6-12, 12-18, 18-24 and 0-24 h were significantly less in groups (B+M) and (B+D) compared to group (B) (p<0.05), with no significant difference between groups (B+M) and (B+D) (Table 2).

The incidence of shoulder pain were less in groups (B+M) and (B+D)) compared to group (B) (p<0.05) with no significant difference between groups (B+M) and (B+D) (Table 2).

The severity of shoulder pain measured at 1, 6, 12, 18 and 24 h were significantly less in groups (B+M) and (B+D) compared to group (B) (p<0.05) with no significant difference between groups (B+M) and (B+D) (Table 3).

Table 1:	Patient characteristics and operative data in the studied groups (mean±SD)
B: Bupivacaine, D: Dexmedetomidine, M: Meperidine, No significant differences among the studied groups

Table 2:	Postoperative analgesic requirements, time to first request of analgesia (mean±SD) and incidence of postoperative shoulder pain (number (%) of patients)
B: Bupivacaine, D: Dexmedetomidine, M: Meperidine, *Significantly different (p<0.05) compared to group (B)

Table 3:	Postoperative Visual Analogue Scale (VAS from 0 to 10) for patients in the studied groups (median (range)
B: Bupivacaine, D: Dexmedetomidine, M: Meperidine, *Significant difference (p>0.05) compared to group (B)

DISCUSSION

Patients undergoing laparoscopic surgery tend to expect a painless postoperative period because of common beliefs about this type of surgery. However, pain after laparoscopic surgery is still one of the important postoperative problems. Almost 80% of patients need opioid analgesia in the postoperative period (Karadas et al., 2007; Colbert et al., 2000) The rationale for intraperitoneal administration of drugs for treatment of the pain which follows laparoscopic surgery is that the small incisions at the abdominal wall cause the visceral component of the pain to be more prominent. With this in mind, many authors have tried to diminish pain via the peritoneal route. The intraperitoneal technique using bupivacaine or meperidine in laparoscopic surgery is deemed to be safe, improve patient comfort, shorten the length of stay in the postoperative care unit and decrease the requirement for nursing care in the ward (Karadas et al., 2007; Colbert et al., 2000).

In the present study, the results has shown that combination of meperidine 1 mg kg^-1 and bupivacaine (0.25%) was superior to bupivacaine (0.25%) alone when installed intraperitoneally as regards the time to first request for analgesia, the dose of morphine consumed and the postoperative pain.

These results were in agreement with those of the study done by Colbert et al. (2000), who studied the analgesic effect of adding 50 mg meperidine to intraperitoneal bupivacaine in post-laparoscopic tubal ligation.

In disagreement with results of present study, the study done by Michael et al. (2008), concluded that; Compared with systemic opioid, IP meperidine and ropivacaine, alone or in combination, did not produce better pain relief or opioid dose-sparing after laparoscopic surgery.

The discrepancy between their results and the present study may be attributed to the population of the study as regards the type of laparoscopic surgery which was not confined to gynaecologic (lower abdominal) surgery.

To our knowledge, there was no clinical study in the literature examined the analgesic effect of dexmedetomidine intraperitoneally in human but intraperitoneal clonidine (another an α-2 agonist) was studied by Memis et al. (2005).

The present study demonstrated that intraperitoneal administration of dexmedetomidine (1 μ kg^-1) in combination with bupivacaine 0.25% (125 mg) compared to bupivacaine 0.25% (125 mg) alone was associated with reduction of shoulder pain, values of postoperative VAS, postoperative analgesic requirements and increased time to the first request of postoperative morphine.

In agreement with the results of the present study was study done by Memis et al. (2005) which has shown that combination of intraperitoneal bupivacaine 0.5% with either clonidine 1 μ kg^-1 or tramadol 100 mg gave more effective analgesia than bupivacaine alone in the early postoperative period in total abdominal hysterectomy patients and the study done by Karadas et al. (2007), on rats, who found that combination of topical COX-2 inhibitors with intraperitoneal dexmedetomidine yielded additive analgesic effect and The antinociceptive effect of dexmedetomidine was blocked by systemic pretreatment of selective α²-adrenoceptor antagonist, atipamezole.

In disagreement with results of the present study, the study done by Schulte Steinberg et al. (1995), who found intraperitoneal bupivacaine (0.25%) was ineffective as analgesic after laparoscopic cholecystectomy and attributed the lack of effect of intraperitoneal injections to the small dose and to a rapid dilution within the peritoneal cavity.

The discrepancy between these results and present study may explained by the big difference in the volume of local anesthetic injected in the peritoneal cavity being 50 mL in the present study and only 20 mL in the study of Schulte Steinberg et al. (1995).

Regarding the postoperative analgesic requirement, the present study has shown statistically significant higher doses of postoperative morphine requirement in Bupivacaine Group (B) compared to the other two groups, which were comparable (p>0.05).

But the results of the study done by Memis et al. (2005), found that, when tramadol or clonidine was added to intaperitoneal bupivacaine, compared to bupivacaine alone, a higher statistically significance postoperative analgesic requirement with tramadol than clonidine, but still the postoperative analgesic requirement in bupivacaine alone group was higher than the other two groups. The more prominent effect of the α-2 agonist in the present study may be attributed to the difference in potency of the drug generation (Dexmedetomidine) in the present study and (Clonidine) in Memis et al. (2005), study.

The results of the present study has shown a statistically significant delayed time for the first postoperative analgesic requirement in (Bupivacaine + Meperidine) groups and (Bupivacaine +Dexmedetomidine) group compared to (Bupivacaine) group, (110 (20) min, 120 (18) min and 45 (10) min, respectively).

This was also in agreement with the study done by Memis et al. (2005) where their results were close to the results of the present study.

Esmaoglu et al. (2005) studied the addition of dexmedetomidine to lidocaine for intravenous regional anesthesia and their results were in parallel with those of the present study regarding the intensity of analgesia, the time for the first postoperative analgesic requirement and its total dose. Meanwhile they noticed no significant difference between the groups with respect to sensory and motor blocks (onset and regression time), which may attributed to the rapid onset of lidocaine.

We conclude that intraperitoneal instillation of dexmedetomidine (1 μ kg^-1) or meperidine (1 mg kg^-1) in combination with bupivacaine 0.25% (125 mg) in female patients undergoing laparoscopic gynecologic surgery significantly decreases the postoperative analgesic requirements of intravenous morphine and decreased the incidence of shoulder pain compared to intraperitoneal bupivacaine 0.25% (125 mg) alone.