Arthroscopic surgery of the knee is common practice, carried out on an ambulatory basis or during a short hospital stay. Post-operative analgesia is of great importance for these patients, because inadequate analgesia may cause undue discomfort and prolong hospital stay.
Thus, it is important to emphasize the simplicity of the technique to be used. Therefore, the regional approach has become increasingly popular because of its adaptation to the technical characteristics of arthroscopy ranging from the intra-articular application of local anaesthesia  to the practice of regional techniques .
Different proposals have been made for the intra-articular (IA) administration of drugs. Intra-articular bupivacaine 0.25-0.5% has been routinely used by surgeons at the end of the arthroscopic procedures. Nevertheless, its effectiveness has been related both to reactive hyperemia after 1 h of ischaemia and the time from bupivacaine injection to tourniquet release. These facts account for the estimated peak plasma concentrations (Cpmax) and effectiveness , perhaps explaining the differences in the results reported in literature [4,5].
Investigations in animal models have shown that the local injection of small doses of opioids at the site of inflammation produces analgesia . Nevertheless, clinical results have not been conclusive (and in some cases even controversial) and achieved with exceedingly variable dosages .
The combination of bupivacaine and morphine has not always led to better results than either of these drugs administered separately [7,8] and it was surprisingly ineffective in other series with no conclusive explanation. This may have been due to changes in the degree of ionization of morphine and bupivacaine induced by mixing them .
The present study was designed to determine the effectiveness of IA bupivacaine and a small dose of IA morphine in the first 24 h after arthroscopic knee surgery, using a placebo control group. Further, we measured the pH of the solutions used during the procedure in order to evaluate its influence.
Following approval by the hospital ethics and clinical trials committee, patients of ASA Grades I-II, and 16-80 years of age, scheduled for elective arthroscopic meniscectomy by a single surgeon, gave informed consent to participate in this randomized double-blind, placebo-controlled trial. The patients were randomly allocated to one of four groups. Exclusion criteria were severe systemic disease, allergy to local anaesthetics and/or morphine, prior history of drug abuse, consumption of analgesics or NSAIDs within 24 h of surgery, arrhythmic heart disease, acute traumatic knee injury, and refusal by the patient.
All groups received general anaesthesia, without premedication. Anaesthesia was induced intravenously (i.v.) with propofol 2-3 mg kg−1, atropine 0.01 mg kg−1, atracurium 0.4 mg kg−1 and alfentanil 10 μg kg−1, and maintained with alfentanil 5 μg kg−1 given each 15 min and 70% nitrous oxide in oxygen. Prior to surgery, a tourniquet was placed on the leg, using insufflation pressures of about 100 mmHg above systolic blood pressure (range, 300-350 mmHg). Standard monitoring was used .
Using a random number table, each patient was randomized to one of four protocols: group 1 patients received 0.25% bupivacaine (50 mg) without adrenaline IA, group 2 1 mg of 0.1% preservative free morphine chloride IA in 19 mL normal saline, group 3 1 mg of 0.1% preservative free morphine chloride in 19 mL 0.25% bupivacaine without adrenaline, and group 4 received normal saline (0.9%).
When surgery was terminated and after the cleaning solution removed, the surgeon injected 20 mL of the appropriate study group solution into the knee joint. The patient, the anaesthesiologist in charge and the surgeon were blind to the solution injected. After 10 min the tourniquet was deflated once the leg was bandaged.
The patient was then transferred to the recovery unit. Follow-up was continuous during this period, and was carried out by nursing staff blind to patient randomization. In the case of inadequate analgesia, patients of all groups received ketorolac (Toradol®, 30 mg i.m.) as rescue medicaction - giving a starting dose once it was requested and at a maximum dose of 90 mg daily.
The Pharmacy Service of this hospital assessed both the stability and physico-chemical properties of the solutions given at four different intervals: T0 immediately after its preparation and T10, T30, T60 at 10, 30 and 60 min, respectively.
Patients were informed pre-operatively by a blinded observer about all pain scores. To assess the quality of analgesia a visual analogue scale(VAS) was carried out at pre-established times. The global measurement of VAS was made in all patients, i.e. the mean of the sum of hourly measurements (VAS, 0 mm=no pain, 10 mm=worst pain imaginable). The daily global assessment of verbal rating scale (VRS), to rate the analgesia provided as 'good', 'adequate', or 'poor' were performed 24 h post-operatively. Supplemental analgesic consumption (SAC) was documented. The presence of side effects, such as nausea, vomiting, pruritus or somnolence were recorded for each patient.
Statistical analysis was computer processed, by putting the data into a Super Base 4 (Windows 'Software Publishing Corporation'), and applying a descriptive and analytical program (SPSS PC−1 + by 'SPSS Inc'). Data analysis was performed by the Kruskal-Wallis test for non-parametric one-way analysis of variance (ANOVA), Bonferroni post-hoc test, χ2 with Mantel-Haenszel or Yates correction when appropiate, and Fisher's test. Statistical significance was assumed for P-values of 0.05 or less.
There were no significant differences among the groups with regard to demographic variables(age, gender, weight and height), ASA physical status and duration of arthroscopy(Table 1).
No statistical differences were found among the four groups regarding the amount of alfentanil administered peri-operatively.
Table 2 shows the results of the physico-chemical analysis of the different solutions used, with mean value and range given by the drug manufacturer as follows: bupivacaine 0.25%, 6 (4-6.5), morphine 0.1%, 5 (3-6.5).
Table 3 shows the verbal rating scale (VRS) scores. Better pain scores were found only in group 1 vs. groups 3 and 4 (P<0.05). Only in groups 3 and 4 did the patients rate analgesia as 'poor' in a higher percentage (27% and 44%, respectively).
Table 4 shows the VAS results for post-operative analgesia results at hourly intervals. VAS scores were higher at all times in the control group; lowest VAS scores were seen in group 1 for the first 20 min after surgery, and in groups 1 and 2 for 4 h and 10 h after surgery, as well as in the total study period (Global VAS). Each group was assessed against placebo applying Mann-Whitney U-Wilcoxon Rank Sum W test. Significant differences were obtained after 20 min and 4 h in group 1 (P<0.01), after 10 h in groups 1 and 2 (P<0.05), and after 24 h in the three active treatment groups.
Supplementary analgesic consumption measured in terms of the number of ketorolac doses requested was studied regarding the influence of the global VAS for each group. Patients in groups 2 and 4 requested analgesics post-operatively earlier than those in groups 1 and 3 (P<0.05) (Table 5).
Side effects occurred in 13.7% of the patients, with urinary retention being the most common (n=8, 10%). In this regard there were no significant differences between the groups. A multifactorial analysis was performed to study the influence of various factors (group, duration of surgery, peri-operative opioid consumption and post-operative analgesia requirements) on the occurrence of side effects; no significant differences among groups or a specific causative factor was identified.
These results show no significant differences in the level of analgesia achieved with bupivacaine or morphine in patients undergoing arthroscopic meniscal knee surgery. These findings are consistent with those previously reported , the efficacy being better when administered separately than when given together. After analysis of the present results, we believe that though all arthroscopy is therapeutic, the nociceptive input appears to be low or that there is a significant pain tolerance in the patient population studied.
Intra-articular bupivacaine may cause transient inhibition of sulphate uptake by articular cartilage. However, there is no evidence of ultrastructural damage occurring to chondrocytes. This had been previously explained by the rapid onset of analgesia corresponding to peak plasma concentrations .
Some authors, who assessed the efficacy of bupivacaine 0.25% and 0.5%  using a post-operative VAS and the need for supplementary analgesia, concluded that no benefit was obtained. The present data suggest that 50 mg of bupivacaine IA produces an immediate analgesic effect with the maximum pain relief occurring 4 h after surgery and that it is as effective as morphine between 10 and 24 h post-surgery.
Opioid receptors are present on sensory nerve terminals before the inflammatory response, but when this begins the perineurium disrupts the number of peripheral sensory nerve terminals and the number of opioid receptors increased stimulating the axonal transport of opioid receptors . These changes may account for the differences between the results reported in separate clinical studies.
Previous studies regarding the dosage of IA administered morphine and its analgesic effect are not conclusive. The minimum dose given was 1 mg, with 10 , 20 [8,11,14], 30 , 40 , and 45  mL volumes leading to different clinical results. Dierking et al. failed to demonstrate specific local analgesic effect with a dose of 2 mg of morphine in 40 mL of normal saline. The administration of 3 mg in 20 mL volume resulted in no obvious analgesic effect , and, surprisingly, 5 mg may lead to either excellent local analgesia  or a limited effect . It is difficult to conclude whether there is an ideal relation between dosage and volume because we found no conclusive results in the literature reviewed.
During the first hours after surgery, the lack of effect of IA administered morphine has been reported [8,9,11], possibly reflecting the occurrence of local inflamation and the resulting inactivation of peripheral opioid receptors. The present results are consistent with this finding as the patients reached maximum comfort within 10 h and 24 h after administration.
The combination of bupivacaine and morphine should theoretically improve analgesia, but in the present series no decrease in demand for the rescue analgesic was recorded and pain scores were no better than with either solution used on its own. These results are consistent with those reported by Haynes et al. and Joshi et al. which show that the use of 1 mg of morphine leads to better results and the addition of bupivacaine is less effective and uneconomical; Kern et al. reports the greatest comfort in the group who received 20 mL of bupivacaine 0.5%. These results conflict with those of Allen et al. and Khouryet al. who showed better results using morphine 1 mg in a volume of 30 and 20 mL of bupivacaine 0.25%, respectively, compared with the use of both substances separately.
Perhaps physical or biochemical modifications developing after local administration might explain the results. The pH of local anaesthetics is moderately acidic (pH 4-6) and following injection, may be increased by tissue buffers altering the binding of opiates to their receptors. Raja et al. when using solutions with adrenaline, failed to demonstrate the analgesic effects of morphine administered IA. Taking into account reports of a possible modification in the pH resulting from the combination of bupivacaine and morphine, affecting ionization of both . We studied this experimentally, reproducing the temperature and preservation conditions of the operating room; no changes in the pH range compared with those of the base-line pH of the substances used was found. The degradation of morphine sulphate is pH and oxygen dependent, having relative stability at acidic pH, especially at pH below 4, but degradation increases greatly at neutral or basic pH. In plastic syringes, morphine is stated to remain stable at room temperature, for at least 69 days .
The present results showed that the pH variations in the groups are not significant and unlikely to contribute to analgesia efficacy.
We conclude that the combination of morphine and bupivacaine in a volume of 20 mL was superior to placebo at the IA level; however, it is less effective than 50 mg of bupivacaine 0.25% or 1 mg of morphine in normal saline 0.9%, both providing satisfactory analgesia for post-arthroscopic pain.
The authors wish to thank Ana Minguez (Pharmacist) for her help determining the stability and physicochemical properties of the solutions, and the nursing staff of the Trauma and Orthopedics Service, Valencia General University Hospital.
1 Dahl MR, Dasta JF, Zuelzer W, McSweeney ThD. Lidocaine local anesthesia for arthroscopic knee surgery. Anesth Analg
2 Patel NJ, Flashburg MH, Paskin S, Grossman R. A regional anesthetic technique compared to general anesthesia for outpatient knee arthroscopy. Anesth Analg
3 Katz JA, Kaeding CS, Hill JR, Henthorn TK. The pharmacokinetics of bupivacaine when injected intraarticularly after knee arthroscopy. Anesth Analg
4 Milligan KA, Mowbray MJ, Mulrooney L, Standen PJ. Intraarticular bupivacaine for pain relief after arthroscopic surgery of the knee joint in daycase patients. Anaesthesia
5Kaeding ChC, Hill JA, Katz J, Benson L. Bupivacaine use after knee arthroscopy: Pharmacokinetics and pain control study. Arthroscopy
6 Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg
7Raja SN, Dickstein RE, Johnson CA. Comparison of post-operative analgesic effects of intraarticular bupivacaine and morphine following arthroscopic knee surgery. Anesthesiology
8Khoury GF, Chen ACN, Garland DE, Stein C. Intraarticular morphine, bupivacaine, bupivacaine, and morphine/bupivacaine for pain control after knee videoarthroscopy. Anesthesiology
9Haynes TK, Appadurai IR, Power I, Rosen M, Grant A. Intraarticular morphine and bupivacaine analgesia after arthroscopic knee surgery. Anaesthesia
10 Eichhorn JH, Cooper JB, Cullen DJ, Maier WR, Philip JH, Seeman RG. Standards for patient monitoring during anesthesia at Harvard Medical School. JAMA
11 De Andres J, Bellver J, Barrera L, Febre E, Bolinches R. A comparative study of analgesia after knee surgery with intraarticular bupivacaine, intraarticular morphine and lumbar plexus block. Anesth Analg
12 Stein C, Hassan AHS, Przewlocki R, Gramasch C, Peter K, Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA
13 Niemi L, Pitkänen M, Tuominen M, Björkenheim JM, Rosenberg PH. Intraarticular morphine for pain relief after knee arthroscopy performed under regional anaesthesia. Acta Anaesthesiol Scand
14 Kern C, Glisson SN, Hess I, Fletcher E, Sites T. Pain control following knee arthroscopy. Intraarticular morphine, bupivacaine or both. Anesth Analg
15 Allen GC, St Amand MA, Lui ACP, Johnson DH, Lindsay P. Postarthroscopy analgesia with intraarticular bupivacaine/morphine. Anesthesiology
16Joshi GP, McCarroll?, Brady OH, Hurson BJ, Walsh G. Intraarticular morphine for pain relief after anterior cruciate ligament repair. Br J Anaesth
17 Dierking GW, Ostergaard HT, Dissing CK, Kristensen JE. Analgesic effect of intra-articular morphine after arthroscopic meniscectomy. Anaesthesia
18 Newton PT, Moote CA. Intravenous vs. intraarticular analgesia for outpatient anterior cruciate ligament repair. Anesthesiology
19 Joshi GP, McCarroll SM, O'Brien TM, Lenane P. Intraarticular analgesia following knee arthroscopy. Anesth Analg
20 Gove LF, Gordon NH, Miller J. Pre-filled syringes for self-administration of epidural opiates. Pharm J