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A Dose-Ranging Study of Intraarticular Midazolam for Pain Relief After Knee Arthroscopy

Batra, Yatindra Kumar MD, MNAMS, FAMS*; Mahajan, Rajesh MD*; Kumar, Sushil MD*; Rajeev, Subramanyam MD, DNB*; Singh Dhillon, Mandeep MS

doi: 10.1213/ane.0b013e3181770f95
Analgesia: Brief Report

BACKGROUND: A variety of analgesic techniques have been used to manage postoperative pain after arthroscopic knee surgery. Intraarticular midazolam may have an analgesic effect similar to that seen when midazolam is used in a centroneuraxial fashion.

METHODS: Sixty ASA status I or II patients undergoing knee arthroscopy with general anesthesia were randomized to receive intraarticular midazolam 50 μg/kg, 75 μg/kg, or isotonic saline. We assessed the efficacy of the analgesic technique with visual analog scale pain scores, time until first request for analgesics, and cumulative analgesic consumption. Patients were observed for 48 h.

RESULTS: The addition of intraarticular midazolam significantly reduced visual analog pain scores in the early postoperative period compared with saline. Both doses similarly prolonged duration until first request for analgesic compared with saline (4.7 and 4.6 vs 0.7 h). There was no statistically significant difference between the two doses of midazolam or cumulative 48 h analgesic consumption.

CONCLUSIONS: We conclude that when intraarticular midazolam was compared with placebo there was a reduction in pain after day-case arthroscopic knee surgery; however, this pain relief was of relatively short duration.

IMPLICATIONS: Intraarticular midazolam provides pain relief of short duration after arthroscopic knee surgery.

From the Departments of *Anaesthesia and Intensive Care and †Orthopaedic Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India.

Accepted for publication March 20, 2008.

Address correspondence and reprint requests to Dr. Yatindra Kumar Batra, Professor, Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India. Address e-mail to

Local anesthetics, opioids, nonsteroidal antiinflammatory drugs, ketamine, and neostigmine have been used via the intraarticular (IA) route either alone or in combination to prevent pain after arthroscopy surgery,1–4 with variable results. Midazolam, a benzodiazepine (BDZ) agonist, is effective in the pediatric, adult, and obstetric population when administered by the centroneuraxial route.5,6 Midazolam has analgesic properties mediated via the γ-aminobutyric acid (GABA)A receptor in the spinal cord.7 Furthermore, both human and animal models have shown ubiquitous distribution of peripheral BDZ receptors in various organs and in joints,8 which promoted us to examine whether midazolam had an analgesic effect via IA delivery. We performed a double blinded, randomized study in patients undergoing knee arthroscopy. In this study, the hypothesis was that IA midazolam may result in the reduction of postoperative pain when compared with placebo, and this was tested by evaluating pain using a visual analog scale scoring system (VAS). The secondary end-point was the time to first analgesic consumption as well as the total dose of analgesics used over 48 h in the postoperative period.

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After obtaining local ethics committee approval and written informed consent, 60 unpremedicated ASA, physical status I and II patients scheduled for outpatient arthroscopic knee surgery were enrolled in the study. Patients <18 yr of age, those with relevant drug allergy, use of oral narcotics preoperatively, or concurrent use of nonsteroidal antiinflammatory drugs/opioid therapy, and those requiring knee drainage were excluded from the study.

All procedures were standardized. Anesthesia was induced with 2 μg/kg IV fentanyl, 2 mg/kg IV propofol, and maintained with 66% N2O in O2, 1%–2% inspired isoflurane, and patients breathed spontaneously via a laryngeal mask airway. No other supplementary analgesic medication was given. At the end of the operation, using a random number table and a sealed envelope technique, patients were randomly assigned to receive in a double-blind fashion normal saline (group S), midazolam 50 μg/kg (group ML), or midazolam 75 μg/kg (group MH). The volume of injectate was standardized at 20 mL. The study solutions (preservative free) were prepared aseptically by an anesthesiologist not directly involved in the study and were supplied in a coded syringe in identical packs. The attending anesthesiologist and the patients were blind to the study drug. Each group consisted of 20 patients. The solution was injected into the knee joint through an arthroscope at the end of surgery, 10 min before the tourniquet release. After termination of anesthesia, patients were returned to the recovery room, and were discharged home according to normal clinical criteria. No postoperative IA drainage was used for any patient.

We recorded the VAS Pain 0–10 score (0 = no pain, 10 = worst pain imaginable), cumulative ibuprofen dose at 48 h (brufen 400 mg PO; Abbot laboratories, Auckland, NZ) and morphine 0.15 mg/kg IM if no response after 30 min in the first 4 h, the duration of effective analgesia measured from time of completion of surgery to first dose analgesic requirement and severity of side effects {Nausea/vomiting (0 = none, 1 = mild, 2 = moderate and 3 = severe), and sedation (1 = responds readily to name spoken in normal tone, 2 = lethargic response to name spoken in normal tone, 3 = responds only after name is called loudly, 4 = responds only after mild prodding or shaking)}. All patients were contacted by the anesthesiologist on postoperative day 1 and 2 for an interview to evaluate postoperative pain and adverse effects such as nausea and vomiting. Using a 3-point satisfaction score (1—bad, 2—good, 3—excellent), orthopedic surgeons assessed the efficacy of the analgesic technique for knee mobility in the patient follow-up.

Analysis of variance was used to compare pain scores in three different groups and the least significant difference method used for pair-wise comparisons of mean at each time. The time to first analgesic dose and the 48 h analgesic requirement was analyzed using a one-way analysis of variance. Post-hoc comparisons were made using the Newman–Keuls test. The χ2 analysis of contingency table was used for comparison of categorized data. Data are presented as mean ± sd. A P value of <0.05 was considered significant. Based on a sd of 20 mm (estimated from previous VAS after knee arthroscopy in patients given IA analgesia),4 a group size of 20 patients would be sufficient to detect a difference of 20 mm of the VAS at 0.5 h postoperatively with 80% power.

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All patients completed the study protocol. There were no statistically significant differences among groups with regard to gender, age, weight, tourniquet time, and preoperative VAS scores (Table 1). Pain scores were significantly higher in group S when compared with groups ML and MH from 1 to 4 h postoperatively (P < 0.05), but these were not statistically significant between group ML and MH (P > 0.05) (Fig. 1). Thereafter, VAS pain scores were not significantly different during the remainder of study period among the three groups. Median time to rescue analgesic drug was 4 h in group S and 8 h in both group ML and group MH (P < 0.001) (Fig. 2). There was no statistically significant difference among the three treatment groups in consumption of analgesic drugs (Table 2). Complications included hemarthrosis in one patient in group MH that resolved after conservative treatment. Two patients in group S and ML and three patients in group MH reported nausea. There was no difference in the mobility of the knee joint as assessed by orthopedic surgeons (P > 0.05).

Table 1

Table 1

Figure 1

Figure 1

Figure 2

Figure 2

Table 2

Table 2

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This study demonstrates that IA administration of midazolam decreases postoperative pain after arthroscopic knee surgery, when compared with placebo. This observation suggests that midazolam may act at a peripheral site in the joint, to produce analgesia. This is supported by a significant decrease in VAS scores during the first four postoperative hours and by a prolonged delay between the IA administration and additional analgesic requirement. We did not demonstrate a dose dependent effect with our selected doses, although it is possible that our doses were both too large to produce differing effects.

Antinociceptive effects of neuraxial midazolam occur from agonism at the BDZ binding site on a subunit of pentameric GABA-A receptor, which serves paradoxically to decrease the transmitter release, a form of presynaptic inhibition.5,6 Consistent with this effect and from BDZ subunit expression in dorsal root ganglion and on spinal nerves, BDZ tend to suppress afferent evoked excitation in substantia gelatinosa and motor horn, leading to an antinociceptive effect.6,9,10 Various authors have also demonstrated the presence of these GABA-A receptors in peripheral nerves, which may have served as the mechanism of action for IA midazolam. In addition to GABA effects, spinal midazolam activates the opioid system through Δ or κ receptors.11In vitro studies have demonstrated that midazolam displaced [3H]-deprenorphione binding from cloned human κ and Δ receptors, and this effect of midazolam was prevented by selective κ and Δ agonists.12 Peripheral opioid receptors present in the peripheral joint and their activation is responsible for IA analgesia with opioids. Further, concomitant local tissue inflammation may lead to up-regulation or activation of peripheral opioid receptors.13 Activation of these opioid receptors by midazolam may be responsible for its analgesic effect. The action of midazolam on peripheral receptors has been substantiated by its efficacy in enhancing the duration of analgesia when used in conjunction with bupivacaine for brachial plexus block.14 A similar action of midazolam on GABA-A receptors in afferent nerve endings in the knee joint may be responsible for its analgesic action, albeit limited in the postoperative period. In addition to neuronal GABA-A receptors, peripheral BDZ receptors are present in the outer mitochondrial membranes8 and bind with a varying affinity to various BDZ.

Three patients experienced mild nausea after 0.75 μg/kg IA midazolam, and two patients each after 0.5 μg/kg midazolam or placebo, none of them requiring treatment. Partial vascular uptake and subsequent transport to the central nervous system may account for the side effects caused by midazolam.15 The side effects are short-lived due to the high lipophilicity, rapid clearance (6–11 mL · kg−1 · min−1), and short half-life (1.7–2.6 h) of midazolam.14,15 There were no worrisome complications with midazolam, probably because it was injected in a relatively avascular area.

Our study is limited by the lack of a systemic midazolam control group and an active analgesic comparator such as IA opioid or local anesthetic. Thus, further studies comparing groups receiving IA midazolam with IV saline, IA saline with IV midazolam, IA saline with IV saline, and the addition of a standard analgesic are still needed to determine the utility of IA midazolam. In conclusion, IA midazolam provides pain relief of short duration after day care arthroscopic knee surgery.

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