|Year : 2020 | Volume
| Issue : 2 | Page : 113-117
Intra-articular ultra-low-dose naloxone for postoperative analgesia after knee arthroscopy
Usama I Abotaleb, Ahmad S Abdelrahman, Ismail M Abdelgawad Ahmed
Department of Anesthesia and Intensive Care, Al-Azhar Faculty of Medicine, Cairo, Egypt
|Date of Submission||18-Jan-2020|
|Date of Decision||12-Feb-2020|
|Date of Acceptance||20-Feb-2020|
|Date of Web Publication||29-Jun-2020|
MD Usama I Abotaleb
214, Faisal Street, Alharam, Giza, 12555
Source of Support: None, Conflict of Interest: None
Background Naloxone has been used at low doses to enhance the analgesic effect; however, this application remains less well defined. It was added to local anesthetics for intrapleural, axillary brachial plexus block, and peribulbar anesthesia with good results but was not used before as an adjuvant in intra-articular injection. The aim of this prospective double-blinded randomized controlled study is to assess the effect of intra-articular ultra-low-dose naloxone when added to bupivacaine on postoperative pain after knee arthroscopy, with time to first analgesic request as the primary outcome and total analgesic requirement, severity of pain, and side effects as secondary outcomes.
Patients and methods In all, 80 patients who underwent knee arthroscopic meniscectomy under general anesthesia were randomly allocated into two groups (40 patients each): the naloxone group received 100 ng naloxone added to 20 ml 0.25% bupivacaine, and the control group received 20 ml 0.25% bupivacaine. General anesthesia was standardized for all patients. At the end of surgery, the study solution was injected intra-articularly through the arthroscope. Visual analog scale was recorded at 1, 2, 4, 6, 8, 12, 18, and 24 h. An intravenous dose of 20 mg pethidine was given if visual analog scale greater than or equal to 3 or on patient request. The time to first analgesic request, total analgesic consumption, and side effects were recorded.
Results The time to first analgesic request was significantly longer, and the total analgesic consumption was significantly lower in the naloxone group compared with the control group. Pain score was significantly higher after 6 and 8 h in the control group compared with the naloxone group. No side effects were reported.
Conclusion Intra-articular ultra-low-dose naloxone enhanced postoperative analgesic effect of bupivacaine after knee arthroscopy without adverse effects.
Keywords: intra-articular, knee arthroscopy, meniscectomy, postoperative pain, ultra-low-dose naloxone
|How to cite this article:|
Abotaleb UI, Abdelrahman AS, Abdelgawad Ahmed IM. Intra-articular ultra-low-dose naloxone for postoperative analgesia after knee arthroscopy. Sci J Al-Azhar Med Fac Girls 2020;4:113-7
|How to cite this URL:|
Abotaleb UI, Abdelrahman AS, Abdelgawad Ahmed IM. Intra-articular ultra-low-dose naloxone for postoperative analgesia after knee arthroscopy. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Jul 11];4:113-7. Available from: http://www.sjamf.eg.net/text.asp?2020/4/2/113/288285
| Introduction|| |
Knee arthroscopy is one of day-case surgeries; it may lead to significant postoperative pain, usually in the first 2 days after the operation ,. Uncontrolled postoperative pain can lead to multiple consequences, including decreased patients’ satisfaction, increased risk of thromboembolism, prolonged hospital stay, as well as declined motion range of the joint, and prevent early rehabilitation .
Several methods have been described for postoperative pain control, such as epidural analgesia, peripheral nerve blockade, intra-articular injection, analgesia, and narcotics ,. Among these techniques, the use of narcotics is the most popular practice, but in association with multiple side effects, including respiratory depression, drowsiness, nausea and vomiting, pruritis, reduced intestinal motility, and urinary retention .
Intra-articular injection of local anesthetics (LA) is an effective method for pain relief that avoids adverse effect of epidural injection and systemic side effects . When LA is injected into the intra-articular cavity it can spread into the surrounding soft tissues, so providing satisfactory analgesia is needed in the immediate postoperative period . While levobupivacaine, ropivacaine, and lidocaine were also used ,,, bupivacaine is the most commonly used and studied drug . It is characterized by a relatively prolonged period of active effectiveness. However, some studies suggest a toxic effect of high LA concentration on human chondrocyte cells (0.5% bupivacaine, 0.75% ropivacaine, and 1% lidocaine) .
Some authors have recommended multimodal intra-articular cocktails instead of multimodal pain management . Since the intra-articular LA injection technique was described in 1989, various adjuvants have been used (e.g. morphine, fentanyl, tramadol, ketorolac, hyaluronic acid, magnesium, dexmedetomidine, and dexamethasone) with variable results, but no agreement about the most effective one was reached ,,,,, and still there is a need to search for an effective adjuvant that prolong the action and increase the effectiveness of pain control without side effects.
Naloxone, an opioid receptor antagonist, frequently used in clinical practice to antagonize the effects of opioid overdosage, has also been used at low doses in combination with opioids to decrease opioid-induced side effects, block the development of acute opioid tolerance, and enhance the analgesic effect; however, these applications remain less well defined .
Naloxone has proved to have paradoxical effects as it antagonizes the opioid analgesia if delivered in microgram range (high doses) and produces anti-nociceptive effects if delivered in the nanogram range (low doses). It has been used safely with epidural and intrathecal opioids for the reduction of their side effects or enhancing analgesia. Also, it was added to LA for intrapleural, axillary brachial plexus block, and peribulbar anesthesia and to prolong the duration of postoperative analgesia without side effects ,,,.
Ultra-low-dose naloxone was not used before as adjuvant to LA in intra-articular injection. So, the aim of this study was to evaluate the effect of addition of ultra-low-dose of naloxone to bupivacaine for intra-articular injection after knee arthroscopic meniscectomy on the quality and duration of postoperative analgesia. Our primary outcome is the time to first analgesic request, while total analgesic requirement, severity of pain, and side effects are the secondary outcomes.
Our sample size was calculated using G*Power 18.104.22.168 program (Kiel, Kiel University, Kiel, Germany); depending on our primary outcome (time to first analgesic request). In a previous study the time to first analgesic request in bupivacaine-treated patients was 230±85 min. We planned our study in order to detect at least 30% increase in the time to first analgesic request and a power of 90% (1−β), at 5% significance level (α). The minimum sample size was to study 33 patients in each group [and increase 10% (≈four patients) for dropout]; we investigated 40 patients in each group.
| Patients and methods|| |
After local Ethic Committee approval, this prospective double-blinded randomized controlled study was conducted from April 1, 2018 to March 31, 2019 in Al-Hussein University Hospital. In all, 80 patients, American Society of Anesthesiologists physical status I or II, aged from 21 to 60 years and weighing from 60 to 90 kg underwent elective knee arthroscopic meniscectomy under general anesthesia, were included in the study after obtaining written informed consent. Patients with a history of impaired renal or hepatic functions, chronic pain, drug abuse, patients who used analgesics the day before the surgery, patients who did not want to be operated under general anesthesia, and the patients requiring postoperative intra-articular drainage were excluded from the study. Before operation, informed written consent was obtained and the patient received instructions for using the visual analog scale (VAS) with 0=no pain and 10=severe intolerable pain. Using computer-generated randomization and sealed opaque envelope, the patients were randomly divided into two groups (40 patients each) according to the intra-articular drug given. The naloxone group received 100 nanograms naloxone added to 20 ml 0.25% bupivacaine, and the control group received 20 ml 0.25% bupivacaine. No premedication before induction or other analgesic medication was given. After application of standard monitoring, general anesthesia was induced with fentanyl 2 μg/kg and 2 mg/kg propofol, then laryngeal mask airway was inserted after loss of consciousness and anesthesia was maintained with isoflurane 1.2–1.5% inhaled by spontaneous ventilation. Before surgical incision, a pneumatic tourniquet was applied to all patients. Paracetamol 1 g intravenous infusion was given to all patients after induction of anesthesia and was repeated every 6 h. At the end of the surgery and 15 min before the release of the tourniquet, a coded 20 ml syringe containing one of the study drugs was injected intra-articularly. The surgeon and observer were unaware of the nature of drug in each syringe and master codes were stored by personnel who did not participate in the observation. VAS for pain was recorded at 1, 2, 4, 6, 8, 12, 18, and 24 h postoperative. Pethidine 20 mg was administered intravenously as rescue analgesic if the VAS pain score was 3 or more, or if the patient asked for analgesia and can be repeated after 20 min till VAS less than or equal to 3. The time to first analgesic request and total analgesic requirement during first 24 h postoperatively were recorded. Adverse systemic effects were also recorded.
Data were analyzed using SPSS version 17 statistical software (SPSS Inc., Chicago, USA). Data were presented as mean±SD and number. Student’s t-test was used for comparison of parametric data. Mann–Whitney test was used to compare nonparametric data. Fischer’s exact test was used for comparison between frequencies. P less than 0.05 was considered significant.
| Results|| |
Patients’ characteristics and duration of surgery were comparable among the two groups ([Table 1]).
Time to first analgesic request was significantly longer, and the total analgesic consumption was significantly less in the naloxone group compared with the control group ([Table 2]).
Pain score was significantly lower after 6 and 8 h postoperatively in the naloxone group; otherwise both groups were comparable ([Table 3]).
No side effects were reported during the first 24 h after surgery.
| Discussion|| |
Knee arthroscopic surgeries are associated with variable amounts of postoperative pain, but it may be quite considerable. The pain is caused by an irritation of free nerve endings of the synovial tissue, anterior fat pad, and joint capsule due to surgical excision and resection .
This study was conducted to assess the efficacy and safety of adding ultra-low-dose naloxone to bupivacaine after knee arthroscopic meniscectomy, in comparison with bupivacaine alone. The main finding in this study was the longer duration of action after intra-articular injection of low-dose naloxone at the end of arthroscopic knee meniscectomy procedures. This study also showed a significant analgesic benefit; the patients who received naloxone had reduced postoperative pain score, and lower consumption of analgesia without side effects compared with intra-articular bupivacaine alone.
Some variables may affect pain control capacity of the LA, including timing of the application, dose of LA, and the insertion of a suction drain at the end of the operation as the efficacy of LA applied into the knee joint might decrease due to absorption of the agent by the suction drain .
In our study, we used 20 ml of 0.25% bupivacaine, at the end of surgery and 15 min before the tourniquet release and patients needing suction drain were excluded.
Many investigators have suggested the instillation of LA into the knee joint at the end of arthroscopic surgery, whereas others have recommended the application at the beginning of the surgery (preemptive). Cansü et al.  showed that 20 min was sufficient for tissue binding of LA and they recommended the administration of intra-articular bupivacaine 20 min before the start of the operation to produce a significant reduction in pain after the operation. The second choice is to delay instillation of LA till the end of arthroscopic surgery, followed by closing the suction drain (if used) for 1 hour.
Although the toxic effect of high LA concentration (e.g. 0.5% bupivacaine) on cartilage was not proved in clinical practice, we used 0.25% bupivacaine; 20 ml of 0.25% bupivacaine was accepted for analgesia after knee arthroscopy in many studies .
Toxic effect is one of the major concerns; evidence on the chondrotoxic effect of bupivacaine has been obtained mainly from in-vitro studies and/or animal subjects, and the authors concluded that their results should not be interpreted to mean that 0.5% bupivacaine has harmful clinical effects. Not all studies have reported a relationship between bupivacaine and chondrotoxicity. Also, there was no permanent impairment of cartilage function after 3 months in an in-vivo experiment on rabbits , and in spite of the laboratory evidence for chondrotoxicity; clinically, there is a low incidence of chondrolysis after intra-articular bupivacaine administration. Bupivacaine, as can be seen in the literature, is still one of the most commonly used intra-articular agents for postoperative pain management following arthroscopic surgery ,.
Kızılcık et al.  recommended the use of adjuvants to decrease the LA concentration.
In our study, there was a significant prolongation of the time to first analgesic request in the naloxone group. Evidence has indicated that ultra-low doses of naloxone have some analgesic properties. It reveals a biphasic dose-dependent effect on pain; low doses of naloxone enhances opioids’ analgesic effects, while high doses reverse the analgesia and produce hyperalgesia . The exact mechanism of this analgesic effect of low doses of naloxone is not fully understood ; however, different mechanisms have explained this effect including blocking the excitatory opioid receptor pathway and release of enkephalin . Peripheral opioid receptors have been found in the joint and involved in mediating this effect .
Previous studies have used low doses of opioid antagonists, along with an opioid to prevent some of the opioids’ side effects. At the same time they enhanced the analgesic effect of opioid agonists ,. Intravenous infusion of naloxone was used to decrease post-hysterectomy pain and analgesic consumption .
Movafegh et al.  observed prolongation of the time to first analgesic request when low dose of naloxone was added to lidocaine with or without fentanyl in axillary brachial plexus block.
Also, low-dose intrathecal naloxone was studied in patients with severe chronic low back pain (post-laminectomy) with good results .
Ezz and Elkala  used naloxone with lidocaine 2% in peribulbar anesthesia and found significant prolongation of the time to first request for analgesic. Amer and Omara  added low-dose naloxone to bupivacaine in intrapleural regional analgesia and they noted significantly prolonged pain relief after thoracotomy and delayed the first analgesic rescue.
On comparing our results with other intra-articular adjuvants that have been used, we found that; Magnesium sulfate an NMDA (N-Methyl-D-Aspartate) receptor antagonist has been used (500–1500 mg) alone or as a combination with LA for postoperative analgesia ,. Kızılcık et al.  found that a lower dose of LA can act more efficiently with a combination of magnesium sulfate in decreasing VAS, analgesic consumption, and prolongation of time to rescue analgesia.
Magnesium sulfate also has anti-inflammatory effect and it can be another cause for the lower analgesic required and lower pain scores. Also, magnesium sulfate can enhance chondral regeneration and inhibits chondrocyte apoptosis thus preventing chondral injury .
Dexmedetomidine, a selective α2 adrenergic agonist, provides postoperative analgesia, when used alone or combined with LA ,. Perritt et al. in their meta-analysis demonstrated that the addition of dexmedetomidine (1 μg/kg, 2 μg/kg, or 10 μg) to LA prolongs the duration of analgesia in the early postoperative period up to 8 h, with reduced pain intensity without significant adverse effects in many studies .The intra-articular opioids as a therapeutic option began when experimental studies identified opioid receptor mobilization in peripheral tissues induced by inflammatory stimuli. The analgesic efficacy of intra-articular morphine when added to LA has been demonstrated, but side effects are a concern . Gupta et al.  compared three doses (1, 3, and 5 mg) and found increase in the effect with the increase in the dose, but with systemic side effects which may be due to systemic absorption.
Diab et al.  observed that both morphine and dexmedetomidine when added to bupivacaine intraarticularly improved postoperative analgesia; both drugs were comparable. Also, Devi et al.  concluded that both magnesium and dexmedetomidine are equally effective when added to bupivacaine and may be used as an alternative for better analgesic effect after knee arthroscopic surgeries.
Magnesium and dexmedetomidine have the advantage that they can be used alone without LA. Our study added one to the list of safe intraarticular drugs that may be used as an alternative or in combinations; however, the ideal adjuvant after knee arthroscopic surgery is still under research and we need further clinical trials to compare these drugs with naloxone.
No side effects were reported in our study or previous studies used low-dose naloxone locally ,,.
Limitations of our study are that we did not compare with a higher or lower dose of naloxone. Also, we did not compare with an i.v. dose of naloxone. Future studies are suggested to determine the optimal dose of intra-articular naloxone.
| Conclusion|| |
To conclude, intra-articular administration of 100 ng of naloxone prolongs pain relief and enhances postoperative analgesic effect of 20 ml of bupivacaine 0.25% after knee arthroscopic surgery without additive side effects.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Nasr HM, Metwalii OS, Amer GF, Abotaleb UI. Intra-articular magnesium versus dexmedetomidine for postoperative analgesia after knee arthroscopic meniscectomy. JESMP
Cansü E, Balıkçı T, Aşansu M, Ergün S, Yıldırım Y. Do timing of injection and status of the suction drain effect postoperative pain scores after intra-articular bupivacaine injection in arthroscopic ACL reconstruction? Acta Orthop Traumatol Turc
Cui Y, Yang T, Zeng C, Wei J, Xie X, Li L et al.
Intra-articular bupivacaine after joint arthroplasty: a systematic review and meta-analysis of randomised placebo-controlled studies. BMJ open
Beaussier M, Sciard D, Sautet A. New modalities of pain treatment after outpatient orthopaedic surgery. Orthop Traumatol Surg Res
2016; 102 (1 Suppl):S121–S124.
Kızılcık N, Özler T, Menda F, Uluçay Ç, Köner Ö, Altıntaş F. The effects of intra-articular levobupivacain versus levobupivacain plus magnesium sulfate on postoperative analgesia in patients undergoing arthroscopic meniscectomy: a prospective randomized controlled study. Acta Orthop Traumatol Turc
Ersan Ö, Akkaya T, Arık E, Ateş Y. Intra-articular levobupivacaine, lornoxicam and morphine analgesia after knee arthroscopy: a randomized, controlled trial. Acta Orthop Traumatol Turc
Tian J, Li Y. Comparative effects of vitamin C on the effects of local anesthetics ropivacaine, bupivacaine, and lidocaine on human chondrocytes. Braz J Anesthesiol
Xie DX, Zeng C, Wang YL, Li YS, Wei J, Li H et al.
Single-dose intra-articular morphine plus bupivacaine versus morphine alone following knee arthroscopy: a systematic review and meta-analysis. PLoS One
Moeen SM, Ramadan IK, Elkady HA. Dexamethasone and dexmedetomidine as an adjuvant to intraarticular bupivacaine for postoperative pain relief in knee arthroscopic surgery: a randomized trial. Pain Physician
Xiao Y, Wu L, Zhou Q, Xiong W, Duan X, Huang X. A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery. Acta Anaesthesiol Scand
Amer AF, Omara AF. Small dose of naloxone as an adjuvant to bupivacaine in intrapleural infiltration after thoracotomy surgery: a prospective, controlled study. Korean J Pain
Movafegh A, Nouralishahi B, Sadeghi M, Nabavian O. An ultra-low dose of naloxone added to lidocaine or lidocaine-fentanyl mixture prolongs axillary brachial plexus blockade. Anesth Analg
Ezz HA, Elkala RS. Ultra-low-dose naloxone added to fentanyl and lidocaine for peribulbar anesthesia: a randomized controlled trial. Egypt J Anaesth
Wael E-S, Riham H. A randomized controlled study of the effects of adding ultra-low dose naloxone to lidocaine for intravenous regional anesthesia. Egypt J Anaesth
Iwasaki K, Sudo H, Kasahara Y, Yamada K, Ohnishi T, Tsujimoto T, Iwasaki N. Effects of multiple intra-articular injections of 0.5% bupivacaine on normal and osteoarthritic joints in rats. Arthroscopy
Shen SJ, Peng PY, Chen HP, Lin JR, Lee MS, Yu HP. Analgesic effects of intra-articular bupivacaine/intravenous parecoxib combination therapy versus intravenous parecoxib monotherapy in patients receiving total knee arthroplasty: a randomized, double-blind trial. Biomed Res Int
Movafegh A, Shoeibi G, Ansari M, Sadeghi M, Azimaraghi O, Aghajani Y. Naloxone infusion and post-hysterectomy morphine consumption: a double-blind, placebo-controlled study. Acta Anaesthesiol Scand
Yeh YC, Lin TF, Wang CH, Wang YP, Lin CJ, Sun WZ. Effect of combining ultralow-dose naloxone with morphine in intravenous patient-controlled analgesia: the cut-off ratio of naloxone to morphine for antiemesis after gynecologic surgery. J Formos Med Assoc
Tarlika P, Dalwadi D, Thakkar K, Singh P. Effectiveness of intra-articular dexmedetomidine as postoperative analgesia in arthroscopic knee surgery (A comparative study). IOSR J Pharm
Perritt E, Wallace H, Singh S, Banerjee A. Effect of intra-articular alpha-agonists on post-operative outcomes following arthroscopic knee surgery: a systematic review and meta-analysis, Egypt J Anaesth
Gupta B, Banerjee S, Prasad A, Farooque K, Sharma V, Trikha V. Analgesic efficacy of three different dosages of intra-articular morphine in arthroscopic knee surgeries: Randomised double-blind trial. Indian J Anaesth
Diab DG, Elmaddawy AA, Elganainy A. Intra-articular morphine versus dexmedetomedine for knee arthroscopy under local anesthesia. Anesth Essays Res
Devi MM, Gupta S, Amaravathi R, Udupa S, Hegde A, Ghosh S. Comparison of efficacy of intra-articular plain bupivacaine and bupivacaine with adjuvants (dexmedetomidine and magnesium sulfate) for postoperative analgesia in arthroscopic knee surgeries: a prospective, randomized controlled trial. Anesth Essays Res
[Table 1], [Table 2], [Table 3]