Efficacy of Adding Dexmedetomidine to Intra-articular Levobupivacaine on Postoperative Pain after Knee Arthroscopy.

BACKGROUND AND AIMS: Intrarticular ingection of local anesthetics in the knee joint decreases postoperative pain after knee arthrosopy. Dexmedetomidine an α2 agonist has sedative and analgesic effects and decreases postoperative pain after knee arthroscopy when injected intraarticulary. Levobubivacaine is a long acting local anesthetic with less toxicity than bubivacaine. We compared the analgesic effects of dexmedetomidine when added to intraarticular levobupivacaine in patients posted for knee arthroscopy.
METHODS: Data were first tested for normality by Kolmogorov-Smirnov test. Study was done on 90 patients. Patients were divided into 3 groups 30 patients each. Group (C) received 50 ml saline only as a control group. Group (L) received 50 ml 0.25% levobupivacaine. Group (L/D) received 50 ml 0.25% levobupivacaine and dexmedetomidine 1μg.kg-1. (VAS) score was used to assess postoperative pain. Time of first pethidine demand and total dose of pethidine in the first 24 h were recorded, also postoperative complications such as pruritis, nausea and vomiting. SPSS version 16 was used for data analysis. P < 0.05 was considered significant.
RESULTS: Postoperative VAS sore at different intervals was less in Group LD than Group L than Group C, time to the first pethedine injection in (min) was longer (39 ± 6, 31 ± 7, 21 ± 6), and total pethedine dose given (mg) was lower (36 ± 9.8, 64 ± 19, 102 ± 24) in Group LD than Group L than Group C respectively.
CONCLUSION: Adding dexmedetomidine to intraarticular levobupivacaine in patients undergoing knee arthroscopy provides more analgesic effect with lower pain scores than levobupivacaine alone with less use of postoperative analgesics during the first 24 h.

INTRODUCTION

Postoperative pain delays discharge after operations and increase postoperative cost. Several methods were tried before to decrease this pain after arthroscopic knee surgery as opioids, nonopioid drugs, central, peripheral nerve blocks, and intra-articular injection of several drugs as local anesthetics and analgesics.[1]

Local anesthetics have short duration of action, so other drugs usually added to increase its duration of action and to decrease the toxicity of large dose of one drug when used alone.[2]

Levobupivacaine is s enantiomer of bupivacaine with less side effects and more duration of action.[3] It reversibly blocks action potential in sensory, motor, and sympathetic nervous fibers by blocking sodium transmission in voltage-sensitive ion channels in nerve cells. It has less depressant action on atrioventricular conduction time[4] and QRS time,[5] and less depressive effect on contractility of the isolated animal heart.[6]

The highly selective α2 adrenoreceptor agonist drug dexmedetomidine causes hypnotic, sedation, anxiolysis, antisympathetic, and analgesic effects.[7] Compared to clonidine, an α2 agonist which was used widely before, dexmedetomidine is more α2 receptors agonist (α2:α1 ratio of 1620:1 vs. 220:1).[8] α1 adrenoceptors counteract α2 sedative effects, so dexmedetomidine is effective than clonidine.[9] Side effects of dexmedetomidine are due to α2 receptors activation include hypertension, bradycardia, and hypotension.[10] Dexmedetomidine delays stress response of surgery.[11] Intra-articular dexmedetomidine injection has been tried to decrease postoperative pain after knee arthroscopy, with more time of first analgesics needed and less use of postoperative analgesics.[12]

We hypothesized that adding dexmedetomidine when added to intra-articular levobupivacaine in patients posted for knee arthroscopy will decrease postoperative pain compared to intra-articular levobupivacaine alone as the primary outcome, and will decrease the use of postoperative analgesics and increase patients’ satisfaction as secondary outcome.

METHODS

After approval of the Institutional Review Board (IRB) of anesthesia and surgical intensive care department (IRB number R/16.03.91), and consents were obtained from all patients, this prospective, randomized, double-blinded study was conducted on 90 patients of the American Society of Anesthesiologists (ASA) physical status Classes I and II of both sexes from 20 to 35 years old. Any patients allergic to drugs or in whom postoperative drain inserted were excluded from the study. Intravenous midazolam 2 mg was used for premedication, before shifting patients to operation rooms, routine monitoring used included pulse oximetry, noninvasive blood pressure cuff, 5-lead electrocardiogram and capnography, induction of general anesthesia by intravenous fentanyl 1–1.5 μg/kg and propofol 1.5–2.0 mg/kg atracuronium 0.5 mg/kg for endotracheal intubation, maintenance of anesthesia with 40% O2 in air and isoflurane 1.0%–2.0%, no more analgesics were used, tourniquet was applied after induction and for 10 min after intraarticular drugs injection into the knee joint after finishing the procedure before removing the arthroscope, patients were randomly allocated to one of three groups (n = 30) for intraarticular injection using sealed envelope method as follows: Group (C), received 50 ml saline only and served as the control group. Group (L) received 50 ml 0.25% levobupivacaine. Group (L/D) received 50 ml 0.25% levobupivacaine and dexmedetomidine 1 μg/kg, the study drugs were injected in the knee joint by the surgeon through the arthroscope after completing the procedure (without knowing the drugs used) to be sure that the drugs injected into the knee joint. All patients were informed before operation about the 100 mm visual analog scale (VAS) for pain (0 = no pain to 100 = the maximum pain).[13] Pain scales at rest and during actively flexed knee movement were recorded. VAS scores were recorded before surgery (baseline), and at 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after the intra-articular drugs administration. VAS scores were recorded in the postanaesthesia care unit by physician blinded to the patient. For postoperative analgesia as meperdine was used intravenously to decrease pain if the VAS score was >50. The time from injection of intra-articular drugs to the first need of meperidine was recorded. The total dose of meperidine given during the first 24 h was recorded. Any adverse effects such as bradycardia (heart rate <50/min), hypotension (mean arterial pressure <60 mm hg), nausea, vomiting, sedation, or pruritis were recorded for 24 h.

Thirty patients in each group were calculated enough to get a power of 0.8 to detect a 15% or more reduction in VAS score and 15% increase in the duration of postoperative analgesia in the dexmedetomidine group compared to levobupivacaine group.

SPSS 16 SPSS Inc., Released 2007. SPSS for Windows, Version 16 (Armonk, NY, USA: IBM Corp) was used for data analysis. Mean ± standard was used for continuous variables, number, and percentages (%) were used for categorical variables. One-way ANOVA was the test for comparing continuous variables, Kruskal–Wallis test was used to compare continuous normal variables and ordinal variables, and categorical data were compared using the Chi-square. P < 0.05 was considered statistically significant.

RESULTS

One hundred and four patients began the study, 14 patients were excluded from the study due to the use of surgical drain, and 90 patients were included in the study; the sample size was 90 patients.

Considering age, sex, and weight and the ASA classification, time of surgery, and anesthesia time, there were no significant differences between groups [Table 1].

Table 1

Patients’ characteristics data (mean±standard deviation) or number

	Group C	Group L	Group LD	P value
Age (years)	24.9±4.6	25.5±4.5	25.6±74.7	1*
				0.18†
				0.66‡
Weight (kg)	70.2±5.8	70.7±6	67.6±6.4	1*
				0.21†
				0.1‡
Sex (female/male)	7/23	6/24	9/21
Duration of surgery (min)	54±7.3	55±7	53±6.3	0.13*
				0.21†
				1‡
ASA
I	25	24	26
II	10	11	12

C=Control, L=Levobupivacaine, LD=Levobupivacaine dexmedetomidine group, ASA=American Society of Anesthesiologist. *Level of significance between Group C and Group L, †Level of significance between Group C and Group LD, ‡Level of significance between Group L and Group LD

Postoperative median VAS scores were higher in Group C than Group L at 1, 2, 4, and 6 h postoperatively P < 0.05 and it were significantly lower in Group LD than Group C and Group LD at 1, 2, 4, 6, and 12 h postoperatively P < 0.05 [Table 2].

Table 2

Postoperative pain (data are in mean±standard deviation)

	Group C	Group L	Group LD	P value
VAS30rest	54.9±16.7	41.8±9.8	36.2±8.4	0.001*
				<0.001†
				0.022‡
VAS30mov	58.3±16.4	44.7±10	39.2±8.3	<0.001*
				<0.001†
				0.024‡
VAS1rest	52.6±16.7	40.4±9.2	34.6±8.4	0.001*
				<0.001†
				0.014‡
VAS1mov	56.9±17.1	43.5±9.6	37.6±8.6	0.001*
				<0.001†
				0.016‡
VAS2rest	41.7±12.1	33.8±6.8	32.4±6.	0.001*
				0.001†
				0.427‡
VAS2mov	46±11.1	38.3±6.5	37.43±6.1	0.002*
				0.001†
				0.601‡
VAS4rest	34.1±8.1	28.6±6.1	27.5±5.5	0.004*
				0.001†
				0.495‡
VAS4mov	40.±6.8	35.5±5.9	35.3±5.6	0.008*
				0.005†
				0.93‡
VAS6rest	27.6±5.4	24.9±4.9	18.5±4.7	0.049*
				<0.001†
				<0.001‡
VAS6mov	31.2±5.5	28±5.3	21.7±5.5	0.028*
				<0.001†
				<0.001‡
VAS12rest	19.8±5.9	18.4±3.8	14.2±4.6	0.28*
				<0.001†
				<0.001‡
VAS12mov	23.8±6	21.7±4.3	17.5±4.3	0.32*
				<0.001†
				<0.001‡
VAS24rest	13.9±3.9	13.2±2.7	11.9±2.9	0.413*
				0.035†
				0.105‡
VAS24mov	16.8±4.2	15.9±2.8	14.8±2.9	0.357*
				0.024†
				0.077‡

*Level of significance between Group C and Group L, †Level of significance between Group C and Group LD, ‡Level of significance between Group L and Group LD. C=Control, L=Levobupivacaine, LD=Levobupivacaine dexmedetomidine group

The total dose of pethidine used was lower in Group LD compared to Group C and Group L (P < 0.001 and 0.004), respectively, and first time to need pethidine was significantly longer in Group LD than Group C and Group L (P < 0.001 and 0.011) [Table 3].

Table 3

Analgesic requirements (mean±standard deviation) in studied groups

	Group C	Group L	Group LD	P value
Total pethidie dose	102±24	64±19	36±9.8	<0.001*<0.001†0.004‡
Time of first dose pethidine	21±6	31±7	39±6	<0.001*<0.001†0.011‡

*Level of significance between Group C and Group L, †Level of significance between Group C and Group LD, ‡Level of significance between Group L and Group LD. C=Control, L=Levobupivacaine, LD=Levobupivacaine dexmedetomidine group

More patients expressed their analgesia as excellent and good in Group L and LD than Group C [Table 4]. Side effects as nausea, vomiting, and itching had no significant differences between Groups [Table 5].

Table 4

Patient satisfaction in the studied groups (numbers)

	Group C	Group L	Group LD	P value
Fair	8	0	0	0.001*
Poor	19	2	1	0.001†
Good	3	18	17	1‡
Excellent	0	10	12

*Level of significance between Group C and Group L, †Level of significance between Group C and Group LD, ‡Level of significance between Group L and Group LD. C=control, L=Levobupivacaine, LD=Levobupivacaine dexmedetomidine group

Table 5

Postoperative adverse/side effects (%) in the studied groups

	Group C	Group L	Group LD
Nausea	1	1	1
Vomiting	2	1	0
Itching	0	0	0

C=Control, L=Levobupivacaine, LD=Levobupivacaine dexmedetomidine group

DISCUSSION

Arthroscopic surgery is a minimally invasive orthopedic surgical procedure. However, postoperative pain can be underestimated. Al-Metwalli et al. showed that patients treated with intra-articular and intravenous saline reported pain intensity of 50 points on a VAS up to 12 h postoperatively.[12] This pain, if left untreated, delays patient discharge and postoperative rehabilitation. Considering the adverse effects associated with systemic opioid use, intra-articular analgesia administration is simple and may provide a better alternative. Intra-articular application of local anesthetics produces good but for short duration for 4 h.[1415] Therefore, various synergistic drugs are added to the local anesthetics.[16]

Due to its long duration of action bupivacaine is commonly used for postoperative analgesia in knee arthroscopy.[16] However, it may cause toxicity, especially at large doses, as cardiac and central nervous systems complications as ventricular arrhythmia, cardiac depression, and seizures.[17] Fortunately, levobupivacaine is a safe drug for local nerve block with prolonged duration of action, with less cardiac and central nervous systems toxicity than bupivacaine.[1819] Karaman et al. compared intraarticular levobupivacaine and bupivacaine in knee arthroscopy and found that 20 ml of 0.5% levobupivacaine better than bupivacaine in postoperative analgesia with less side effects.[20]

Intra-articular α2 adrenoreceptor has proved the analgesic effect. Clonidine injected before into the knee joint in many clinical trials in arthroscopic knee surgery, and it enhanced the analgesic effect of bupivacaine.[21] In one study, Joshi et al.[22] reported this analgesic benefit and found that clonidine, when added to bupivacaine and morphine, increased their analgesic effects. Recently, intraarticularly dexmedetomidine, which has high potency and more selective α2 adrenoreceptor actions than clonidine found to be more effective in increasing postoperative analgesia in arthroscopic knee surgery, the time to first analgesic need was high and the need for postoperative analgesics was less,[12] Al-Metwalli et al. 2008 found that the time to first analgesic need was 312.0 ± 120.7 min in the dexmedetomidine group.

The mechanism of action of intraarticular dexmedetomidine is unknown, maybe by direct peripheral action, but the central action due to systemic absorption cannot be rolled out. A recent study showed that perineural clonidine and dexmedetomidine increased sensory and motor blockade of local anesthetics.[2324] Supraspinal, spinal, and peripheral mechanisms may play a role in analgesic effects of α2 adrenergic receptor agonists.[25] As clonidine, dexmedetomidine inhibits the release of norepinephrine at peripheral afferent nociceptors in presynaptic receptors.[26] There are evidence that analgesics effect of α2 adrenoceptors is by facilitating inhibitory synaptic transmission in the superficial dorsal horn.[27] Besides, the effects of dexmedetomidine on α2 adrenergic receptors. It directly inhibits tetrodotoxin-resistant Na+ channels this may explain the antinociceptive effects of dexmedetomidine when added to local anesthetics.[28] Furthermore, dexmedetomidine inhibits potassium and sodium currents which delay neuronal rectifier of local anesthetic agents.[29]

The limitations of this study are medium size sample, so larger sample size may be used, and that we did not add opioids to study drugs which can prolong the duration of postoperative analgesia. Future studies can use larger sample size.

CONCLUSION

Adding dexmedetomidine to intraarticular levobupivacaine in patients undergoing knee arthroscopy provides more analgesic effect with lower pain scores than levobupivacaine alone with less use of postoperative analgesics during the first 24 h.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.