Analgesic Effect of Intraarticular Tramadol with Morphine after Arthroscopic Knee Surgery

Introduction: Post-operative improved pain control of patients has made arthroscopy as a day care procedure, reducing patient’s expenses and hospital staffs work load. Various analgesic drugs have been administered into the joint following Arthroscopy. Intra-articular injection of morphine has been practiced in many centres all over the world. We aimed to compare the effi cacy of intra-articular tramadol and morphine. Tramadol is an opioid drug with similar analgesic properties like morphine. Tramadol unlike morphine is readily available over the counter not being abused and has more favourable side effects. Methods: It was a prospectively randomized double-blind study in which sixty patients having elective arthroscopic surgery of the knee were randomized into two groups. Group A (Tramadol Group) received intra-articular tramadol 50mg and Group B (Morphine Group) received morphine 5mg in equivalent volumes. Post-operative pain using Visual Analogue Score (VAS) between 0 and 10, (0 no pain to 10 worst pain) requirement of fi rst analgesic, and incidence of side effects were recorded postoperatively at intervals of 3,4,5,6 and 24 hours. Results: The assessment of VAS score among the two groups in 3,4,5,6 and 24 hours of IA injection showed a p value of 0.349, 0.807, 0.676, 0.271 and 0.163 respectively, suggesting non signifi cant difference in two groups. There was statistically signifi cant result (p=0.005) for request of fi rst analgesia (Ibuprofen 400mg+ Paracetalmol 500mg) at 6 hours of IA injection with tramadol group, requiring less analgesics. There are no other clinically important differences between the groups, including preoperative duration of symptoms, postoperative pain scores and side effects irrespective of the diagnosis and the procedure performed. Conclusion: 50 mg IA tramadol provides analgesia equivalent to 5 mg IA morphine.


INTRODUCTION
Arthroscopic knee surgery is one of the most common surgical procedures done in an outpatient basis.Postoperatively improved pain control of patients has made this surgery as a day care procedure, reducing patient's expenses and hospital staffs work load 1 .Various analgesic drugs have been administered into the joint following this type of surgery.Intra-articular injection of morphine following knee arthroscopy has been practiced in many centres all over the world.Morphine is an opioid agonist drug and it has long been known to relieve severe pain with remarkable effi cacy 2 .Tramadol is a synthetic codeine analog that is a weak opioid receptor agonist.Generally opioids also can produce analgesia when administered peripherally, since these receptors are present on peripheral nerves and will respond to peripherally applied opioids and locally released endogenous opioid compounds when up-regulated during infl ammatory pain states 3 .Part of tramadols analgesic effect is produced by inhibition of uptake of norepinephrine and serotonin, which are neurotransmitters in neuronal circuit responsible for pain and many other actions. 4] Tramadol's analgesic effect has been equated with that of morphine, with a more favorable side-effect profi le for tramadol including less respiratory depression, nausea and vomitting 7 .Whether opioid and nonopioid actions of tramadol would provide superior peripheral analgesia compared with opioid morphine needs to be explored.The aim of the study was to compare the analgesic effect of intra-articular (IA) tramadol with IA morphine.

METHODS
After ethical committee approval, informed written consent was obtained from 60 patients who fulfi ll the inclusion criteria to undergo elective knee arthroscopic surgery.Standard general anaesthesia was given to all the cases.A short-acting opioids (fentanyl) was used and general anesthesia was maintained with halothane and oxygen at the beginning of the operation.No nonsteroidal anti-infl ammatory drugs or additional pain medications were administered.All the arthroscopies were performed under tourniquet application on thigh and by two orthopaedic surgeons trained in arthroscopic surgery in department of orthopaedics and trauma, TUTH.Two standard portals (anteromedial and anterolateral) or more was_used.
Patients aged between 15 to 70 years, who under went diagnostic arthroscopies, Arthroscopic meniscal excision or repair, Arthroscopic removal of loose bodies, Arthroscopic debridement or combination of these procedure were included in the study.Those who required Epidural or spinal anaesthesia, Allergies to local anaesthetic or opioids, Ligament reconstruction and articular cartilage procedures, Cases of extensive arthroscopic synovectomy, Severe cardiovascular, respiratory, metabolic or neurological diseases, Postoperative splinting and pregnant were excluded from this study.
At the conclusion of surgery, patients were randomized to a particular group, Group A (Tramadol Group -30 patients) and Group B (Morphine Group -30 patients) and the appropriate study drug was injected into the knee by the surgeon, who was blinded to its contents.The study drug prepared by the scrub nurse, who keeps the record of injection, was injected before the release of tourniquet.All cases were observed by the author who was also blinded and recorded pain, supplemental analgesic requirements, and incidence of side effects at 3,4,5,6 and 24 hours post-operatively.Post-operative pain was assessed using Visual Analogue Score (VAS) between 0 and 10, (0 no pain to 10 worst pain).Pain score was assessed in the recovery room for 6 hours.In case of need of supplementary analgesics, Ibuprofen 400 mg plus 500mg paracetamol was administered orally.In the event that there was no pain relief, 75 mg diclofenac was injected intramuscular.The time to the fi rst request for analgesia and the total analgesic consumption was recorded for 24 hours duration at intervals of 3,4,5,6, and 24 hours.At the time of discharge the patients were instructed to take oral analgesic combination of Ibuprofen 400mg + paracetamol 500mg, as required for a maximum of 8 hourly intervals.The patients were discharged from the recovery room after 6 hours with a copy of VAS to record pain at home at 24 hours of intra-articular injection.The fi nal VAS recording was taken when the patient returns to OPD on the 4 th or 5 th day of surgery.
Demographic data, distribution of sex, preoperative symptoms and post-operative analgesic consumption in two groups were analyzed by analysis of variance and compared by applying chi-square test.Comparison of mean VAS in two groups was done by applying independent ttest.The Fisher's Exact test was used to compare analgesic requirements and side effects.A probability of P <.05 was considered statistically signifi cant.

RESULT
There were no signifi cant differences among the two groups with respect to age, sex, duration of pre-operative, VAS score for pain at the specifi ed intervals, Table1.Post-operative VAS for both groups at 3,4,5 and 6 hours of intra-articular injection range from 3.00 to 4.13 (moderate pain) and their p values were statistically not signifi cant.The post-operative VAS for both groups at 24 hours range from 2.07 to 2.67 (mild pain).This is also not signifi cant statistically for both groups, Table 2 Two patients (6.7%) required fi rst oral analgesic (Ibuprofen400mg + paracetamol 500mg) in Group A (Tramadol) at six hours of intra-articular injection while eleven patients (36.7%) requested from Group B (Morphine) during the same interval, Table 3.These results are statistically signifi cant.P=0.005.All other intervals of analgesic consumption are not signifi cant including oral and injectible analgesic.
When postoperative VAS at interval of 3,4,5,6 and 24 hours of intra-articular injection was correlated with duration of pre-operative symptoms within the two groups all the results were not signifi cant among the groups.This shows that there is no signifi cant difference of analgesia with tramadol or morphine at these hours of intra-articular injection irrespective of preoperative symptom.

DISCUSSION
][9][10] Analgesics with different doses and different combinations have been applied to provide optimum analgesia to patients undergoing knee arthroscopy. 7,11Out of those combinations an ideal drug with properties of good analgesic control, less systemic side effect is to be identifi ed.Further more, requirement of additional analgesic is to be explored.Morphine has good analgesic control when injected intra-articularly following knee arthroscopy. 8,11However nausea vomiting and respiratory depression are common side effects of morphine.Tramadol is an opioid drug with similar properties of morphine but causes less side effects like nausea, vomiting and respiratory depression. 12ntra-articular local anaesthetics are often used for the management and prevention of pain after arthroscopic knee surgery, with bupivacaine most commonly used.However, because of their high systemic absorption, short duration of effect, their uses are of limited bennefi t. 7,13,15 Stein et al. 9 reported the intra-articular morphine-induced analgesia in patients after arthroscopic knee surgery.Since then many workers established that intra-articular opioids produce a profound anti-nociceptive effect and it has been widely used intra-articularly with or without local anaesthetics for the management of pain after arthroscopic knee surgery. 6,8,157][18][19][20] Stein and his colleagues 9 provided the fi rst clinical evidence of the peripheral action of opioids, showing that anti-nociceptive effect of intra-articular morphine was blocked by intra-articular naloxone.The peripheral opioid action involves a number of mechanisms, including inhibition of action potentials in pain fi bres 16,21 and inhibition of the release of excitatory substance P. 16,22 Action on Post-ganglionic nerve terminals blocks the release of several sensitizing prostanoids, which may be important in sympathetically maintained pain syndrome. 23 did not use control case because tramdol is an opioid drug with similar actions like morphine and several studies has shown analgesic effect of morphine when injected intra-articularly.Mahara DP et al 10 concluded that low dose (2mg) intra-articular morphine injection is a good alternative to other pain management modalities especially for day care patients following arthroscopic knee surgery.
In a similar study like our study by S. B. Akinci et al 11 , conclude that tramadol 50mg and morphine 5mg provide similar analgesia when given intra-articularly.
We did not observe signifi cant differences in results between intra-articular tramadol 50mg and 5 mg morphine with respect to pain using VAS system, and side effects.
There was less analgesic requirement in tramadol group with signifi cant result for patients who required fi rst analgesic (Ibuprofen 400mg + Paracetamol 500mg) at 6 hours postoperatively, P = 0.005, Table 3.This may be due to longer half life of the tramadol, more potent effi cacy of The average duration of symptoms was 14.15 months.Most symptomatic knees, 48 (80%) were within one year of duration.Within this duration we expected patients to have increased opioid receptors as well as infl ammation signifi cantly.We observed that all patients in both groups had VAS range 3 -4.13(moderate pain), till six hours of post operatively and at 24 hours mean VAS range was 2.07 -2.67 (mild pain).This persisting pain could be due to chronic infl ammatory mediators which have built up within the knee joint.
Injury to the sensitive structures in the knee joint and infl ammation cause C and A-δ fi bers to undergo changes such as sensitization, increased activity in normally silent nociceptors. 2Likar et al 25 mentioned increasing duration of symptoms increases the number of receptors in the infl amed tissues.Several workers 26.27 have demonstrated that increased duration increase number of receptors in the synovium.Most severe acute pain can usually be well controlled with signifi cant but tolerable adverse effects with currently available opioid analgesics.However, chronic pain is not very satisfactorily managed with opioids. 2 The moderate pain which persisted till 6 hours in both groups and the mild pain which persisted at 24 hours in both groups could be due to pain from the infl ammatory mediators.
Three patients in each group had severe pain at three hours of intra-articular injection and received fi rst analgesic i.m diclofenac 75mg injection, P= 1, and it was statistically not signifi cant.Out of these six patients, three patients did not take any other analgesic during the 24 hours.One patient consumed further three doses of oral analgesic during the 24 hours duration.This could be due to the infl ammatory pain which either persisted from the preoperative symptoms or after the arthroscopic procedure, in which the opioid drugs has limited action.
Despite the combination of different analgesic mechanism of tramadol, we could not fi nd any superiority between intra-articular tramadol and intra-articular morphine with respect to VAS score, preoperative symptoms and side effects.However tramadol, unlike morphine is readily available over the counter, not being abused and have more favourable side effects.In future further studies, with larger number of patients are needed to compare the side effects of intra-articular administered morphine and tramadol.We believe that intra-articular tramadol can be an alternative to intra-articular morphine for postoperative analgesia after arthroscopic knee surgery.

CONCLUSION
We conclude that 50 mg intra-articular tramadol provides analgesia equivalent to 5 mg intra-articular morphine.

Table 2 .
Visual Analogue Score at different time period

Table 3 .
Comparative characteristics of Both the Groups.