The Efficacy of Intrathecal Morphine With or Without Clonidine for Postoperative Analgesia After Radical Prostatectomy

Abstract

BACKGROUND: 

In this randomized study, we compared intrathecal (IT) morphine with or without clonidine and IV postoperative patient-controlled analgesia (PCA) morphine for analgesia after radical retropubic prostatectomy.

METHODS: 

Fifty patients were randomly divided into three groups. They were allocated to receive IT morphine (4 μg/kg) (M group), IT morphine and clonidine (1 μg/kg) (MC group), or PCA (PCA group). Each patient was given morphine PCA for postoperative analgesia. The primary objective was the quantity of morphine required during the first 48 postoperative hours. The first request for morphine, numeric pain score at rest and on coughing, the time of tracheal decannulation and adverse effects (pruritus, postoperative nausea and vomiting, respiratory depression) were recorded.

RESULTS: 

Morphine consumption in the first 48 h was decreased in the M and MC groups. The numeric pain score at rest and on coughing were lower in the M group until the 18th postoperative hour and until the 24th postoperative hour in the MC group. The first requests for PCA were delayed in these two groups. The need for intraoperative sufentanil was significantly lower in the MC group.

CONCLUSION: 

IT morphine provided a significant reduction in morphine requirement during the first 48 postoperative hours after a radical prostatectomy. The addition of clonidine to IT morphine reduced intraoperative sufentanil use, prolonged time until first request for PCA rescue, and further prolonged analgesia at rest and with coughing.

Radical prostatectomy (RP) is the most common treatment for patients with screen-detected prostate carcinoma.¹ This type of surgery involves severe postoperative pain, lasting <48 h. Therefore, intrathecal (IT) analgesia could be useful, because IT morphine is technically simple and is likely to improve analgesia for 24 postoperative hours.²

The α-2 adrenergic agonist clonidine is classically used in conjunction with morphine or local anesthetic to enhance spinal and peripheral nerve blocks. Even though the combination of morphine and clonidine has not been studied frequently, the combination of these two drugs has been effective after knee arthroplasty³ and cardiac surgery.⁴

The aim of this study was to assess the impact of IT morphine with and without clonidine on morphine consumption during the first 48 h after RP.

METHODS

This study obtained the approval of the ethics committee of the Lille University. Written consent was obtained from patients to undergoing retropubic RP for prostate carcinoma.

Eligibility criteria were age older than 18 yr and ASA physical status less than or equal to 3. Exclusion criteria included serious neurological or psychiatric disorders, emergency surgery, coagulation abnormalities, and allergy to narcotic or anesthetic drugs. Patients were randomly assigned to three groups: morphine group (M group) received IT injection of 4 μg/kg morphine with a maximum dose of 300 μg, morphine plus clonidine group (MC group) received IT injection of 4 μg/kg morphine (with a maximum of 300 μg) and 1 μg/kg clonidine with a maximum dose of 75 μg, and a control group (patient-controlled anesthesia (PCA) group) in whom analgesia was provided by IV morphine administered by PCA alone.

All patients received hydroxyzine (1.5 mg/kg orally) 2 h before surgery. In the operating room, standard monitoring was accompanied by Bispectral Index (Medical Aspect Systems, Norwood, MA) and monitoring of myorelaxation. In the M and MC groups, the subarachnoid injection was performed in the sitting position, before induction of anesthesia. The mixture was injected between the second and fifth lumbar vertebral bodies using a standard 25-gauge Whitacre needle.

Anesthesia was standardized. General anesthesia was induced using propofol (2–3 mg/kg) and sufentanil (0.3 μg/kg). Tracheal intubation was facilitated by the administration of atracurium 0.5 mg/kg. General anesthesia was maintained with sevoflurane in oxygen–nitrous oxide mixture. Sevoflurane was adjusted to maintain a Bispectral Index between 40 and 60. Additional doses of sufentanil were administrated for a change in systolic blood pressure and in heart rate over 20% compared with the baseline values measured at rest.

Postoperative pain management included scheduled acetaminophen (1 g IV every 6 h) and PCA morphine (1 mg bolus, 7 min lockout, no continuous infusion). The numeric pain score (NPS) at rest and on coughing was collected regularly during the first 48 postoperative hours. The NPS on coughing was standardized and registered with patients sitting in their beds.

The primary outcome measure was PCA morphine consumption. The secondary outcomes were the evaluation of pain at rest and on coughing by NPS, duration of surgery, intraoperative sufentanil requirement, delay before tracheal decannulation, the first request of PCA, sedation score range between 0 and 3 (0 = eyes open spontaneously, 1 = eyes open to speech, 2 = eyes open when shaken, 3 = unrousable),⁵ length of hospital stay and morphine adverse effects (postoperative nauseas and vomiting (PONV) and pruritus). Respiratory depression was defined by one of the following variables: respiratory frequency <8/min, Spo₂ <90% or Paco₂ >70 mm Hg.

The number of patients to be included in the study was calculated at 18 patients per group, based on a reduction of 50% of morphine consumption in the first 48 postoperative hours (α = 0.05 and β = 0.15), according to data from the Snijedelaar et al.⁶ study. The quantitative variables were compared by Kruskal-Wallis and Mann-Whitney’s tests. The qualitative variables were compared by the Fischer exact test. Post hoc testing was performed according to the Bonferroni correction for multiple comparisons. A corrected value of P < 0.05 was considered statistically significant. The data are expressed as median (range). All statistical tests were performed using the software Statview® 5.0 (SAS Institute, Cary, NC).

RESULTS

Fifty-four patients were included in this study. Four patients were excluded because of incomplete pain data. Fifty files were analyzed, 16 in the PCA group, 17 in the M group and 17 in the MC group. Patient characteristics were similar for all groups (Table 1).

Table 1: Patient Demographics and Duration of Surgery

The intraoperative sufentanil requirement was significantly lower in the MC group compared with the M and PCA groups. No difference was observed for time until tracheal extubation, intraoperative epinephrine requirement, or postoperative median arterial blood pressure. The period before the first request for PCA morphine was significantly longer in group M and MC (Table 2).

Table 2: Intra and Postoperative Analgesic Consumption

NPS at rest were significantly lower between H0 and H18 in group M compared to group PCA. This difference lasted until the 24th h in group MC (Fig. 1). On coughing, NPS decreased by 3 in the 15th h in group M and after arrival in the postanesthesia care unit until the 24th h in group MC (Fig. 2). Thereafter, no difference was observed for all the groups until the end of the study. No difference between M and MC groups was observed throughout the study.

Figure 1.: Numeric Pain Scores at rest during the 48 postoperative hours. Results are expressed as median. The top and bottom of each box indicate the 75th and 25th percentiles, and the error bars the 10th and 90th percentiles.

Figure 2.: Numeric Pain Scores on coughing during the 48 postoperative hours. Results are expressed as median. The top and bottom of each box indicate the 75th and 25th percentiles, and the error bars the 10th and 90th percentiles.

Consumption of morphine during the 48 h decreased significantly in the M and MC groups (Table 2). All patients used their PCA morphine. No respiratory depression was reported. At the 24th postoperative hour, no patient had Paco₂ more than 70 mm Hg. The sedation scores were similar in both groups. Only two patients in the M group suffered from PONV (P = 0.9). No patient had pruritus during the study. Finally, the hospital length of stay was not different among groups.

DISCUSSION

This study shows the effectiveness of IT injection of morphine with or without clonidine for analgesia after RP. The decrease in postoperative morphine consumption induced by IT analgesia was related to a significant reduction of static and dynamic pain intensity whereas the addition of clonidine prolonged analgesic efficacy. Thus, single-shot IT morphine may be an effective and simple method for managing the short duration of postoperative pain after RP, as the average duration of analgesia after IT morphine injection is approximately 24 h.⁷

The dose of IT morphine of 300 μg was chosen based on previous studies with IT morphine with doses ranging from 500 to 1000 μg, in which heavy sedation and respiratory depression were frequent.⁸ The optimal dose seems to be between 100 to 300 μg for pelvic surgery.⁹ Our dose also seems nearly optimal, as the NPS in the M group was significantly lower during the first 18 postoperative hours compared with the control group. With our dose, side effects were infrequent as only two patients experienced PONV and none had respiratory depression. Clonidine enhances and prolongs the effects of morphine in proportion to the dose.^4,10 The addition of clonidine to IT morphine reduced intraoperative sufentanil consumption and prolonged postoperative analgesia by 6 h at rest and by 12 h when coughing.

In conclusion, our prospective randomized study showed a reduction in IV morphine consumption and pain intensity with the administration of IT morphine with or without clonidine. The increase in the duration of analgesia by clonidine and the absence of major side effects make IT morphine plus clonidine an useful technique for the management of pain after RP.