Arthroscopic surgery is more and more commonly used for the diagnosis and treatment of knee disorders. One of the main complications resulting from knee arthroscopy is intense pain in the postoperative period . Several intra-articular drugs including local anaesthetics, non-steroidal anti-inflammatory analgesics and opioids have been used to decrease postoperative pain, particularly after arthroscopic knee surgery .
Opioid receptors are located at peripheral nerve endings in animals  and human beings . Results of studies concerning postoperative analgesic effects of intra-articular administration of opioids are confusing [4-6]. Combination therapy by using an opioid plus a non-opioid drug has been proposed for alleviating postoperative pain [7,8]. Intra-articular glucocorticoid may also improve pain relief after arthroscopy possibly due to its effect on reducing inflammation [6,9].
The aims of this study were to evaluate the analgesic effectiveness of intra-articular administration of different doses of morphine and morphine with methylprednisolone.
With approval by the Atatürk University, Medical Faculty Ethical Committee, informed patient consent was obtained from all patients. Seventy-two patients, ASA I-II, scheduled for arthroscopic knee surgery either for diagnostic purposes or for partial meniscectomy were recruited to this study. Patients taking steroids, non-steroidal anti-inflammatory drugs or opioids, having relevant drug allergy or needing postoperative articular drainage were excluded.
All operations were performed under general anaesthesia with controlled ventilation. Monitoring included continuous electrocardiogram, pulse oximetry and non-invasive blood pressure every 5 min. General anaesthesia was induced by intravenous (i.v.) administration of fentanyl (1-1.5 μg kg−1) and propofol (2.0 mg kg−1). Tracheal intubation was facilitated with vecuronium (0.1 mg kg−1) and anaesthesia was maintained with propofol 10 mg kg−1 h−1 for 10 min, 8 mg kg−1 h−1 for 10 min and then 6 mg kg−1 h−1 for the remainder of the procedure. Patients breathed N2O (70%) and O2 (30%) through an endotracheal tube. No other opioids were given during the operation. A thigh pneumatic tourniquet was applied during surgery and kept inflated until 10 min after the intra-articular injection of the trial drug into the knee joint at the end of the procedure.
Before the arthroscope was removed, patients were randomly assigned (by a computer-generated randomization sequence) to four groups for double-blind administration of drugs: Group C (n = 18), the control group, received 20 mL of intra-articular isotonic saline and 5 mg morphine in 5 mL of isotonic saline i.v.; Group M5 (n = 17) received 5 mg morphine in 20 mL of isotonic saline intra-articularly and 5 mL isotonic saline i.v.; Group M1 (n = 18) received 1 mg morphine in 20 mL of isotonic saline intra-articularly and 5 mL of isotonic saline i.v.; and Group M1M (n = 19) received 1 mg morphine plus 40 mg methylprednisolone in 20 mL of isotonic saline intra-articularly and 5 mL of isotonic saline i.v. The doses of drugs were chosen on the basis of previous clinical studies [6,8,10]. The test drugs were given to the surgeon who injected the solution through the arthroscope at the end of the procedure without knowing the contents so as to ensure that the drug was delivered into the joint. Postoperative analgesic consumption and pre- and postoperative pain scores (visual analogue scale, VAS, 0-100 mm) at rest and during movement (active flexion of the knee) were measured and recorded by another anaesthetist who was blinded to the group allocation. Eleven patients were instructed preoperatively in the use of the 100-mm VAS. Pain scores were recorded preoperatively (T0), and at 60 min (T1), 120 min (T2), 180 min (T3) and 24 h (T4) relative to the intra-articular injection.
Postoperative analgesia was provided by bolus doses of 50 mg tramadol i.v. if pain score exceeded 5 in the recovery room or 500 mg paracetamol orally at patients request on the ward. The occurrence of side-effects (nausea, vomiting, sedation and pruritus) was noted for each patient.
Sample size was calculated using VAS as the primary variable. Sample size calculation resulted in a requirement for 16 patients per group (SD 20%, 80% power, P < 0.05). Patient characteristics, arthroscopy type, anaesthesia duration and tourniquet time were analysed using analysis of variance (ANOVA) and the χ2-test when appropriate. Pain scores were analysed by ANOVA and group means were compared by linear standard deviation (LSD) post hoc test. Analgesic consumption was analysed by the U-test. Results were considered statistically significant when P < 0.05. All data were presented as mean ± standard error of the mean (SEM).
As shown in Table 1, experimental groups were homogenous, with respect to patient characteristics data (sex, age, knee operated and weight), anaesthesia duration, tourniquet time and surgery type. Neither complications in relation to drugs administered and their side-effects (nausea, vomiting and pruritus) nor postoperative infection were observed in any group.
Difference of pain scores at rest and during movement among groups by time are shown in Figures 1 (at rest) and 2 (during movement). There were no differences in preoperative pain scores across the groups. Pain scores for all groups were highest 1 h after operation and gradually decreased until 24 h. Postoperative pain scores during rest and movement were significantly lower in the M1, M5 and M1M groups than in the control group at 60, 120 and 180 min (P < 0.05). Pain scores in the M5 and M1M groups were also significantly lower than in the M1 group at these (P < 0.05) times. At 24 h, pain scores for the M5 and M1M groups were significantly lower than for the control and M1 groups although pain scores for the control and M1 groups were similar.
Postoperative supplementary analgesic consumption was significantly less in the M5 and M1M groups as compared with the control and M1 groups at all times (P < 0.05). Analgesic consumption for the control group was the highest. The differences in analgesic consumption between the control and M1 groups were not significant in the recovery room (P < 0.05), but were in the ward (P < 0.05), although postoperative analgesic requirements was lower for the M1 group than that for the control group (Table 2).
Pain scores for patients in the M1M group were slightly higher than for those in the M5 group at 180 min and 24 h. Although consumption of tramadol in both groups in the recovery room was almost the same, consumption of paracetamol in patients in the M1M group was less than in patients in the M5 group during the first 24 h. Consumption of paracetamol between the two groups did not differ.
After knee arthroscopy, patients regularly suffer from pain and are commonly given non-steroidal agents , neostigmine , opioids and/or bupivacaine . Reduction of postoperative pain by injecting opioid into the knee joint is believed to support the hypothesis that peripheral opioid receptors are activated in response to inflammation . The use of opioid drugs such as fentanyl, morphine  and meperidine , or even combination therapy by using an opioid plus a non-opioid drug have also been reported to reduce postoperative pain [7,8].
Despite a number of studies, it has been difficult to determine whether intra-articular injections of opioids provide significant postoperative pain relief. Gupta and colleagues reported that 13 studies showed a beneficial effect of morphine among 27 studies involving 1748 patients undergoing arthroscopic knee surgery . Rosseland and colleagues reported that only 70% of 57 patients had pain at varying degrees of severity (moderate-to-severe) within 1 h after an arthroscopic surgery and that there was a lack of pain relief from 2 mg morphine in 10 mL of saline intra-articularly compared with placebo . Lin Cheng Yang and colleagues also reported no difference in pain score of patients receiving 2 mg morphine and placebo after arthroscopy, but morphine administration decreased analgesic need for 48 h . However, Haynes and colleagues used 1 mg intra-articular morphine vs. saline placebo and observed that the morphine injected group had lower pain scores than the control group at 2 and 4 h postoperatively despite a lack of difference in pain scores at 1 h or at 24 h after recovery . In contrast, studies by Jesus and colleagues , Joshi and colleagues  and Allen and colleagues  consistently demonstrated greater responses to the administration of 5 mg morphine in patients undergoing arthroscopy and anterior cruciate ligament repair. In our study, intra-articular morphine provided a considerable clinical analgesic effect into the postoperative period.
Another issue regarding provision of postoperative analgesia is whether the potential effect of intra-articular morphine is dose dependent or not . The analgesic effects of intra-articular morphine may be related to the dose , which was confirmed by the present study. In a recent meta-analysis investigating efficacy of morphine, Kalso and colleagues  reported that seven studies (one testing 1 mg, one testing 3 mg and five testing 5 mg) showed positive effects and eight studies (seven testing 1 mg and one testing 4 mg) showed negative effects on pain relief during the initial period (0-2 h); eight studies (two testing 1 mg, one testing 3 mg and five testing 5 mg) showed positive effects and four studies (three testing 1 mg and one testing 4 mg) showed negative effects on pain relief during the early period (2-6 h); and ten studies (four testing 1 mg, one testing 4 mg, five testing 5 mg) showed positive effects and three studies (all testing 1 mg) showed negative effects on pain relief during the late period (6-30 h), respectively. Regardless of the period, the authors  concluded that as compared with 1 mg of intra-articular morphine, 5 mg of intra-articular morphine provided better analgesia.
Stein and colleagues showed a reduction in pain and supplementary analgesic need in subjects receiving 1 and 0.5 mg of morphine intra-articularly following arthroscopic knee surgery. Although these parameters did not differ with morphine doses, the pain scores decreased slightly with increasing morphine dose . In another study, although the pain score for 1-6 h postoperation was reported to be inversely related to morphine dose, pain scores at 24 h were similar for patients who received 1 and 2 mg morphine . Moreover, patients who received 1 mg morphine required less analgesic than those who received 2 mg morphine . Brandsson and colleagues observed that the pain scores were lower for intra-articular morphine treatment groups (both 1 and 5 mg) as compared with placebo after 24 h. The pain score during the whole postoperative period (from 24 h to 1 week after surgery) was also significantly lower for the morphine 5 mg group than for placebo . Alvarez-Cabo and colleagues reported that patients treated with a morphine dose of 5 mg had less intense pain than those patients treated with a morphine dose of 1 mg. In addition, supplementary analgesic requirement after arthroscopy with spinal anaesthesia was lower in the 5 mg morphine groups than the 1 mg morphine groups . Drosos and colleagues found that neither the low (5 mg) nor the high dose (15 mg) of morphine solution administered intra-articularly, provided significantly better analgesia and achieved lower pain scores compared to the control group . Meta-analysis performed by Gupta and colleagues  showed that 1 mg morphine had no benefit in two studies and less pain in four studies as compared to placebo. When the dose-response relationship of intra-articular morphine was evaluated, it was shown that 5 mg morphine provided better analgesia as compared to 1 mg morphine but there were no differences among other doses compared.
Synovial cellular inflammation is associated with oedema and inflammation which may lead to a greater postoperative pain score and greater demand for analgesic depending upon the kind of arthroscopic surgery . In this study, to decrease pain scores and analgesic requirements during the postoperative period, we administered methylprednisolone plus a low-dose opioid. Our results consistently showed that the combination of 40 mg methylprednisolone with 1 mg morphine was more effective at reducing postoperative pain score and analgesic requirement than 1 mg morphine alone.
There was no difference between pain scores (at rest and movement) of patients administered 1 mg morphine plus 40 mg methylprednisolone and patients administered 5 mg morphine at 60 and 120 min. However, pain scores in the M1M group were slightly higher than those of the M5 group at 180 min and 24 h. Although consumption of tramadol of patients in both groups in the recovery room was almost the same, consumption of paracetamol in the M1M group (78 mg) was less than that in the M5 group (117 mg) during the first 24 h (not statistically significant). Moreover it was observed that the ability of the former group to walk and manage stairs was better than that of the latter group, indicating better postoperative comfort.
In our study, intra-articular 5 mg morphine administration provided better analgesia and necessitated less postoperative analgesia than 1 mg morphine. Moreover, the analgesic effect of 1 mg morphine was similar to that of 5 mg morphine when 40 mg methylprednisolone was added. As an indirect indicator of the intensity of pain, the need for supplemental analgesic medication was significantly lower in the 5 mg morphine and 1 mg morphine plus methylprednisolone groups than in the control and 1 mg morphine groups, suggesting that this combination was effective in reducing pain and supplementary analgesic use. Due to greater postoperative analgesic intake for the control group than for the M1 group, the pain scores at 24 h did not differ.
The volume of the intra-articular injection may be important to intra-articular opioid action with respect to intra-articular pressure which may facilitate systemic absorption of drugs . Khoury and colleagues reported that a 20 mL volume produced satisfactory analgesia . The application of a tourniquet and an interval between intra-articular injection and tourniquet release may have an effect of the duration of the local action of the drugs and the rate of opioid absorption from the joint . Due to these points, drugs were prepared at a similar volume and a tourniquet was applied in the present study. In our study, 5 mg morphine was administered i.v. to the control group. A systemic analgesic effect of intra-articular morphine could be excluded because the control group had less pain relief postoperatively. To obtain accurate recording of pain scores and the required supplementary analgesia, our patients stayed in hospital during the entire study period. Infection is a potential complication in the use of intra-articular glucocorticoid administration. Montgomery and Campbell reported that incidence of septic arthritis to be 0.2% among patients treated with glucocorticoids . In our study, postoperative infection was not seen in any patient.
In conclusion, the combination of intra-articular low dose morphine (1 mg) plus methylprednisolone (40 mg) provides good analgesia after knee arthroscopy.
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