Intra-articular Analgesia with Ketamine and Tramadol; the Effect of the Type of Surgery

Arthroscopies are most commonly performed on day case basis, but postoperative pain remains a problem as more complicated procedures are performed. This study was carried out on 60 adult ASA I-II patients undergoing arthroscopic procedures. Patients were assigned into 2 equal groups; group I underwent low inflammatory surgeries, whereas group II had high inflammatory surgeries. Both groups were further subdivided randomly into 3 equal subgroups. Subgroup K received 0.5 mg kg ketamine intra-articularly, subgroup T received 100 mg tramadol intra-articularly and subgroup S received placebo. The following parameters were recorded; vital signs, first time to ask for analgesia, total rescue i.v pethidine given and VAS scores hourly for the 1 6 hours, then 3-hourly till the end of the first postoperative day. Results: Group I showed significantly delayed onset of pain (p=.009), lower pethidine consumption (p=.036) and lower VAS scores at 1,4,5,6,9,12,15,18,21,and 24 hours. On the other hand, on comparing K, T and S subgroups, both K and T subgroups showed a significant delay in asking for analgesic (p=.001), significantly lower pethidine consumption (p=.001) and significantly lower VAS scores at 1,2,3,6,12,15, and 24 hours as compared to S subgroups. On comparing K and T subgroups, there was no significant difference among them except in the first 2 hours where K subgroups had significantly lower VAS in the first hour (p=.018), while Tsubgroups showed significantly lower VAS in the second hour (p=.004). conclusion: Both ketamine and tramadol proved to be useful and safe analgesic agents when applied intra-articularly particularly in the low inflammatory procedures. INTRODUCTION Elective knee arthroscopy and arthroscopic knee surgery are frequently performed as day case surgery. The problem of postoperative analgesia remains a concern for early discharge of patients.1 Postoperative analgesia is even more highlighted owing to the fact that more and more complex procedures are now performed arthroscopically such as anterior cruciate ligament reconstruction (ACLR).2 Several modalities of pain control are in common use including; parenteral opioids. NSAIDS, regional blocks, intraarticular analgesia, and a multimodal approach employing two or more of the fore-mentioned modalities.3 Intra-articular analgesia is a simple and commonly employed technique. The most commonly used analgesic agents include long acting lacal anaesthetics particularly Bupivacaine and Ropivacaine. Opioids come second as intra-articular analgesics with a large body of research employing morphine and other opioids with various degrees of success. Other intra-articular analgesics employed include α2-adrenergic agonists, particularly clonidine, neostigmine and NSAIDs.1 Recently, Tramadol and Ketamine were put to test as intra-articular analgesics with conflicting results. Tramadol is a weak μ-opioid agonist and a serotonin and noradrenaline reuptake inhibitor is, at least theoretically , capable of producing peripheral analgesic effects as those produced by other μ-opioid and α2adrenergic agonists.4 Ketamine , on the other hand , is a well known NMethyl-d-Aspartate (NMDA) receptor Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (8) No. 2 June 2005 62 blocker, and it is now suggested that peripheral NMDA receptors are present at nerve terminals and may account for a peripheral action of ketamine independent of its central actions.5,6 Finally , a question remains to be answered which is whether the analgesic requirements and the efficacy of the intra-articular analgesic agents varies according to the type of surgery , for instance, does a minor arthroscopic procedure like a diagnostic arthroscopy or partial minescectomy , that is likely to be associated with relatively low surgical inflammatory response , pose a marked impact on the quality of intra-articular analgesia as compared with a high inflammatory procedure like ACLR.7 The purpose of this study was to compare the efficacy and analgesic properties of tramadol and ketamine injected intra-articularly in the knee following high and low inflammatory arthroscopic procedures. PATIENTS AND METHODS After obtaining the institution ethics committee approval and informed consent from patients, 60 adult ASA I-II patients were enrolled in this study. All patients were scheduled for elective knee arthroscopy under general anaesthesia with a standard technique using Fentanyl 2μg.kg -1 , Propofol induction, Atracurium 0.5mg.kg and endotracheal intubation, anaesthesia was maintained using sevoflorane with N2O in O2 (60:40). According to the type of surgery patients were divided into two equal groups each of 30 patients : Group 1: low inflammatory surgery group including diagnostic arthroscopy and arthroscopic minescectomy Group 2: high inflammatory surgery group as ACLR Each group was further randomly subdivided into 3 equal subgroups each of 10 patients. Subgroups K: in whom 0.5mg.kg Ketamine in 25ml normal saline were injected intra-articularly. Subgroups T: in whom 200mg Tramadol in 25ml normal saline were injected intra-articularly. Subgroups S: in whom 25ml normal saline were injected intra-articularly as a control subgroup. Intra-articular injection was carried out at the end of arthroscopy by a surgeon who was blinded to the drug given. All patients received postoperative analgesia upon their request in the form of pethidine intravenously in a dose of 0.5mg/kg -1 and if pain persists after 5 minutes incremental doses of 5 mg were given at five minute intervals till pain is acceptable ( VAS of 3 or less) then no further doses were given for 4 hours, or the patient asks for more analgesia whichever comes later. For the purpose of the study, the following parameters were recorded: • The duration of surgery in minutes • First time to ask for analgesic in minutes • Total dose of pethidine administered in mg • Heart rate (HR), MABP in mmHg, respiratory rate (RR), O2 saturation (SpO2),all these parameters were recorded every hour postoperatively and an average value at 6 and 18 hours was recorded. • Visual analog scale score (VAS) which was recorded every hour postoperatively in the first 6 hours, and every 3 hours thereafter for the first 24 hours postoperatively. • Side effects if present were also recorded. RESULTS There was no difference among both groups as regards age and weight whereas duration of surgery was signifycantly higher in group II (table 1). Patients of group I first asked for analgesia after a mean time of 78.66 Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (8) No. 2 June 2005 63 min ± 48.83 which was significantly longer than that in patients of group II who first asked for analgesia after a mean time of 49.166 min ± 34.066. The mean total dose of pethidine administered in group I was 120.166 mg ± 48.83 which was significantly less than that in group II which was 146.5 mg ± 46.88 (table 2). Both HR and MABP were significantly higher in group II as compared to group I at 6 and 18 hours. RR and SpO2, on the other hand, showed no statistical significant difference between both groups except at 18 hour measurement were the respiratory rate was significantly higher in group I ( table 3 and 4). As regards VAS scores, they were significantly higher in group II as compared with group I at 1,4,5,6,9,12,15,18,21, and 24 hours while they were insignificantly higher at the 2, and 3 hour measurements (table 5). On comparing subgroups using analysis of variance (ANOVA) test, the first time to ask for analgesia was significantly higher in the S subgroups as compared with both the K and T subgroups, On the other hand, there was no significant difference between the K and T subgroups. Similarly, the total dose of pethidine was significantly higher in the S subgroups as compared to the K and T subgroups with no significant difference between the latter subgroups.(table 2) VAS scores in the S subgroups were significantly higher at 1, 2, 3, 6, 12, 15, and 24 hours as compare with both the K and T subgroups, whereas on the 4, 5, 9, 18, and 21 hours there was no significant difference between the three subgroups. On comparing the K and T subgroups, on the other hand, using unpaired t-test; there was no significant difference between them at all times except at the first and second hour where in the first hour VAS was significantly lower in the K subgroups, while at the second hour, it was significantly lower in the T subgroup (table 5). No complications were reported in all patients pertaining to the drugs used, and no psychomimetic manifestations were reported in the K subgroups. DISCUSSION In the present work, more sophisticated, high inflammatory arthroscopic procedures (ACLR) resulted in more severe postoperative pain, earlier demand of analgesia and higher pethidine consumption than low inflammatory arthroscopies. Meanwhile, both ketamine and tramadol, when injected intra-articularly produced a clear analgesic effect in terms of VAS scores, first time to demand analgesics, and total parenteral analgesia administered, yet the efficacy of both agents was more pronounced in the low inflammatory category. It may be a tentative assumption that a drug administered locally is capable of blocking pain sensation. However, this does not seem to be the case here. Marchal et al reported that even such a potent local anaesthetic like bupivacaine, when administered intra-articularly, after high inflammatory procedures like ACLR were less effective than in low inflammatory procedures.7 But, on the other hand, several authors reported the increased expression of opioid receptors especially μ-receptors with increased inflammation, a fact that renders these tissues more responsive to the analgesic effects of opioids and perhaps to local steroids and NSAIDs.8-10 In the present study, ketamine injected intra-articularly proved to be effective analgesic. This analgesic effect was more pronounced in patients who underwent less inflammatory procedures. Peripheral effects of ketamine were proposed by several researchers who reported the presence of inhibitory NMDA mediating analgesia in peripheral neural tissues and thus opening the way for utilizing ketamine, the potent central Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (8) No. 2 June 2005 64 Table 1: Demographic data in different studied groups. Group I Low inflammatory Group II High inflammatory Gp. Ia Ketamine Gp. Ib Tramadol Gp. Ic Saline Gp. IIa Ketamine Gp. IIb Tramadol Gp. IIc Saline Age (years) 29.5±8.2 30.1±7.2 27.9±8.22 30.3±7.21 31.2±5.6 28.5±7.32 F, p 2.33, 0.32 Weight (kg) 70.5±8.65 71.3±9.2 74.3±8.9 69.8±10.5 72.6±9.65 73.8±10.3 F, p 1.98, 0.45 Duration (min). 52.3±10.3 58.6±9.65 62.3±11.25 100.3±14.3 105.3±10.3 112.3±14.3 F, p 28.98, 0.001* Ia, Ib, Ic # IIa, IIb, IIc Table 2: Time to first analgesic and total analgesic in different studied groups. Group I Low inflammatory Group II High inflammatory Gp. Ia Ketamine Gp. Ib Tramadol Gp. Ic Saline Gp. IIa Ketamine Gp. IIb Tramadol Gp. IIc Saline Time to analge (min). 80.3±15.3 65.3±10.8 11.3±3.69 97.75±24.99 84.0±27.4 10.0±5.61 F, p LSD 25.65, 0.0001* Ic, IIc # Ia, Ib, IIa, IIb Total analg (mg) 85.3±11.3 92.3±20.6 132.2±16.5 111.7±24.9 105.3±24.2 190.0±32.5 F, p LSD 23.9, 0.002* Ia, Ib # Ic, IIa, IIb, IIc Table 3: Heart rate and mean arterial blood pressure in both groups. Group I Low inflammatory Group II High inflammatory Gp. Ia Ketamine Gp. Ib Tramadol Gp. Ic Saline Gp. IIa Ketamine Gp. IIb Tramadol Gp. IIc Saline Heart rate After 6 hr 85.6±6.89 82.6±10.25 86.6±6.25 87.3±9.25 92.6±11.3 96.6±10.8 F, p LSD 19.95, 0.002* Ia, Ib # other gp; Ib, Ic # IIb, IIc After 18 hr 82.3±10.6 82.3±11.2 84.3±8.25 85.6±11.23 91.3±10.9 95.3±11.4 F, p LSD 24.3, 0.001* Ia, Ib # other gp; Ib, Ic # IIb, IIc MABP After 6 hr 85.6±8.9 86.9±11.2 87.9±10.8 91.3±14.3 92.8±11.9 96.6±16.2 F, p LSD 23.3, 0.001* Ia, Ib # other gp; Ib, Ic # IIb, IIc After 18 hr 89.6±9.61 90.3±11.3 93.2±18.8 95.9±15.6 96.5±16.2 97.5±11.3 F, p LSD 18.98, 0.003* Ia, Ib, Ic, IIa # IIb, IIc Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (8) No. 2 June 2005 65 Table (4): Respiratory rate and O2 saturation in both groups. Group I Low inflammatory Group II High inflammatory Gp. Ia Ketamine Gp. Ib Tramadol Gp. Ic Saline Gp. IIa Ketamine Gp. IIb Tramadol Gp. IIc Saline RR After 6 hr 15.6±3.2 14.5±1.58 18.3±3.65 18.2±2.98 16.2±3.25 14.6±2.85 F, p LSD 9.88, 0.01* Ia, Ib # Ic; IIa # IIb, IIc After 18 hr 14.5±3.22 13.9±4.1 16.9±2.65 17.3±2.14 14.5±2.54 13.6±2.45 F, p LSD 20.6, 0.002* Ic, IIa # Ia, Ib, IIb, IIc SpO2 After 6 hr 98.5±2.15 98.6±1.85 97.3±2.65 96.8±1.85 95.6±2.65 96.5±1.85 F, p LSD 3.22, 0.13 N.S. After 18 hr 97.6±2.85 96.8±3.21 97.5±1.65 95.9±2.54 94.6±1.36 95.6±2.3 F, p LSD 2.65, 0.21 N.S. Table (5): VAS scores in different studied groups at different period of follow up. VAS Group I Low inflammatory Group II High inflammatory Gp. Ia Ketamine Gp. Ib Tramadol Gp. Ic Saline Gp. IIa Ketamine Gp. IIb Tramadol Gp. IIc Saline V1 3.12±1.23 4.03±1.25 4.22±1.65 3.25±1.85 4.5±1.33 4.85±1.47 F, p 14.6, 0.01* V2 4.21±1.85 3.65±1.65 4.22±1.52 4.95±1.52 4.1±1.98 5.2±2.1 F, p 18.36, 0.001* V3 3.1±2.01 2.36±1.98 2.85±1.84 3.0±1.24 2.65±1.22 3.9±1.42 F, p 16.52, 0.001* V4 2.98±1.42 2.45±1.25 3.01±1.32 3.2±1.22 3.1±1.04 3.35±1.42 F, p 18.25, 0.003* V5 3.25±1.47 3.01±0.98 3.12±1.11 3.95±1.42 3.7±1.32 3.85±1.42 F, p 8.25, 0.04* V6 3.98±1.52 4.25±1.65 4.85±1.65 4.8±1.74 4.7±2.01 5.05±1.98 F, p 12.3, 0.032* V9 3.21±1.42 3.12±1.65 4.01±2.06 3.45±1.66 4.1±1.52 4.4±2.01 F, p 22.3, 0.001* V12 3.65±1.98 3.21±1.62 3.98±1.42 4.0±2.05 3.8±1.36 4.3±2.52 F, p 12.3, 0.0021* V15 3.22±1.52 2.98±0.95 3.22±1.52 3.35±1.72 3.5±1.62 3.85±1.36 F, p 9.52, 0.03* V18 3.6±0.95 3.25±0.89 3.41±0.74 4.0±1.003 4.15±1.08 4.45±1.21 F, p 16.5, 0.008* V21 3.02±1.42 3.1±1.22 3.12±0.98 3.25±1.03 3.4±1.1 3.55±1.09 F, p 18.25, 0.003* V24 2.98±0.98 3.02±1.25 3.1±1.21 3.2±0.98 3.25±0.98 3.7±1.04 F, p 21.3, 0.002* Alexandria Journal of Anaesthesia and Intensive Care AJAIC-Vol. (8) No. 2 June 2005 66 Huang et al used 0.5 mg kg ketamine intra-articularly following knee arthroscopies, however, they failed to produce analgesia superior to placebo, but this can be explained by the fact that these procedures were carried out under spinal anaesthesia which may mask analgesia by ketamine.14 Contrary to this, Dal et al used ketamine intraarticularly and reported a significant analgesic effect that was comparable to intra-articular neostgmine.15 Tramadol, on the other hand, is hypothesized to possess a peripheral analgesic effect owing to its μ-opioid and α2-adrenergic agonist activity. In the present study, tramadol produced significant analgesic effect over placebo. In agreement to our findings, Alagol et al demonstrated such intra-articular analgesic effect in patients who underwent arthroscopies.16 This is also supported by Akinci et al who demonstrated a similar analgesic effect that was even comparable to intra-articular morphine.4 Both ketamine and tramadol demonstrated a significant efficacy as analgesics over placebo, there was no significant difference between both drugs except during the first 2 hours, where ketamine was superior during the first hour whereas tramadol was superior during the second suggesting a more rapid onset of action for ketamine though there is no evidence in literature to support or deny this finding. In this study, both ketamine and tramadol did not exhibit any of their common side effects (psychomimetic and sympathetic for ketamine and nausea, vomiting and hypotension for tramadol) and this finding gives a clear advantage to the intra-articular route of administration. This finding agrees with those reported by Dal et al who reported no side effects with intra-articular ketamine of the same dose used in the present study.15 Whereas Alagol et al using 100 mg tramadol intra-articularly reported significantly less nausea attributable to tramadol as compared to the same dose administered systemically.16 Finally, dose dependency of intraarticular analgesia was once and again demonstrated with local anaesthetics and morphine, consequently, the use of larger doses of ketamine and tramadol may be more effective even in high inflammatory procedures.17 In conclusion: Both ketamine and tramadol proved to produce a clear peripheral analgesic effect when injected intra-articularly in the knee following arthroscopic surgeries. Both agents reduced pain scores and opioid consumption and had no systemic side effects. However, both seem to be less effective in high inflammatory procedures like ACLR.