Postoperative pain after spine surgery: Comparative efficacy of diclofenac and etoricoxib in combination with tramadol and paracetamol at lower doses.

Garach Bhavikkumar D.*

PhD Research Scholar, Department of Pharmacy, JJT University, Vidyanagari, Churu Jhunjhunu Road, Chudela, District-Jhunjhunu– 333001, Rajasthan, India

ABSTRACT:

Objective:

Study Design: Prospective, single blind, randomized single centre study

The analgesic efficacy and safety of etoricoxib and diclofenac was compared in combination with tramadol and paracetamol at lower doses. Primary outcome measures were Visual Analogue Scale (VAS) and need for rescue analgesics and secondarily, average daily pain relief and patients’ subjective rating of study medication were measured.

Background:

Posterior spinal surgery is a common major orthopedic operation for certain spine disorders, however POP from the wound is unavoidable, which may increase morbidity and incidence of complications and prolong postoperative rehabilitation. It is difficult to achieve effective pain control using a single treatment. Most analgesics cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety and tolerability concerns. Rational combinations of analgesic with different mechanisms of action can improve efficacy and/or tolerability and safety compared with full analgesic dose individually.

Material and methods:

203 patients of spine surgery were divided in to 2 groups: group E (n=103, received etoricoxib 30 mg twice daily orally) and group D (n=100, received diclofenac 12.5 mg i.m. twice daily on the day of surgery and 25 mg thrice daily orally from the next day of surgery). Both groups received tramadol / paracetamol combination. Rescue medication as required were given. POP (post operative pain) was evaluated by VAS every 24 hr for 10 days.

Results:

The POP of both study groups, as measured by VAS showed a significant reduction of pain at rest as well as on movement (p=0.0001) progressively in 10 days. There was no significant difference between the groups, except on day 2 when group D showed higher efficacy in reducing pain at movement. Significant differences were not found in need for rescue analgesic, daily pain relief, patient’s preference and adverse outcomes in the groups.

Conclusion:

Etoricoxib and diclofenac in combination with tramadol and paracetamol at lower doses are effective in reducing spinal POP especially after the first 48 hours.

KEYWORDS: Acute pain/ combination/ low dose/ analgesia/ NSAIDs/ COXIBs

INTRODUCTION:

Postoperative pain (POP) is generated by noxious stimuli from a preexisting disease, surgical incision/complications, inserted tubes/drains, or other invasive measures.^[1]

Posterior spinal surgery is a common major orthopedic operation for certain spine disorders, however POP from the wound is unavoidable, which may increase morbidity and incidence of complications and prolong postoperative rehabilitation.^[2] Pain is related to soft tissue and muscle dissection and to manipulations and removal at the operation site. Most patients complain of severe pain at rest during the first 12 hours after surgery. During the following 48–72 hours, pain is moderate at rest, whereas it is severe on movement, interferes with patient mobilization and delays discharge.^[3] Long-term use of opioid leads to development of tolerance, that is, a loss of opioid receptor-activated function, hyperalgesia and consequent allodynia can occur after short-term use of opioids.^[4]Epidural infusions of local anesthetic alone do not seem to be commonly used due to a significant failure rate due to inadequate analgesia and relatively high incidence of motor block and hypotension with continuous monitoring requirements.^[5] The current practice guidelines for pain management in the perioperative setting specifically suggest “unless contraindicated, all patients should receive around-the-clock NSAIDs (non-steroidal anti-inflammatory drug), COXIBs (Cyclo- oxygenase inhibitors), or acetaminophen”.^[1]

Etoricoxib is a selective COX-2 (enzyme involved in pain and inflammation) inhibitor and effective in treating different surgical pains.^[6,7] Oral diclofenac (NSAID), is effective and relatively safe in treating mild to moderate pain.^[8] Both paracetamol and tramadol are effective against POP. ^[9,10]

It is difficult to achieve effective pain control using a single treatment. Most analgesics cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety and tolerability concerns. Rational combinations of analgesic with different mechanisms of action can improve efficacy and/or tolerability and safety compared with full analgesic dose individually. Increased efficacy is due to synergism.^[11]Other potential benefits of combining include enhanced duration of analgesia and patient compliance.^[12] The synergistic antihyperalgesic effect of etoricoxib and tramadol combination have clinical utility in mechanical hyperalgesia associated with spinal injury.^[13] Paracetamol may be administered with NSAIDs or COXIB , since these add on to improve analgesia.^[14] The combination of paracetamol and tramadol in itself is a rational which clubs paracetamol’s rapid onset of efficacy with tramadol’s prolonged analgesic effect.^[11]

Since NSAIDs have unsafe GI profile whereas COXIBs are associated with adverse cardiovascular events ^[15], current research should be focused on their lowest effective dose. Absolute avoidance of us of such analgesics after major surgery is not possible. We designed this current study for evaluating the effectiveness of multidrug combination of lower doses of analgesics/NSAIDs. Half the recommended doses of etoricoxib, tramadol and paracetamol versus diclofenac, tramadol and paracetamol were compared in postoperative period.

MATERIALS AND METHODS:

This is a single-blinded, randomized, prospective comparative study of etoricoxib versus diclofenac in combination with tramadol/paracetamol in patients undergoing spinal surgery at single centre.

Patients who underwent spinal surgery were included from March 2012 to Dec 2012 and randomly assigned to receive one of the two treatment regimes. Out of 249 patients, 129 patients were randomized to receive etoricoxib/tramdol/paracetamol (group E) and 120 patients to receive diclofenac/tramadol/paracetamol (group D). The inclusion criteria required age between 18 to 70 years, existence of post-operative pain ≥ 4 cm on Visual Analogue Scale (VAS) and American Society of Anesthesiologist physical status I or II. The exclusion criteria included use of analgesics within 6 hours of study medication or concomitant use of sedatives or steroids or anticoagulants, contraindication to opioids or paracetamol, chronic alcohol / substance abuse, or unstable medical disease; major psychiatric disorder, known allergy to NSAIDs/analgesics/COXIBs, history of hepatic/renal/cardiac insufficiency and/or gastrointestinal ulceration, uncontrolled hypertension or asthma, pregnant and lactating women.

On the day of surgery, group E patients were given etoricoxib 30 mg p.o. twice daily whereas patients in group D were given diclofenac 37.5 mg i.m. twice daily. In addition both groups were administered tramadol 25 mg i.m. twice daily and paracetamol 75 mg i.v. thrice daily. On the next day of surgery up to 10^thpostoperative day (POD), group E patients were given etoricoxib 30 mg p.o. twice daily and group D patients were given diclofenac 25 mg p.o. thrice daily. In addition, both groups were received tramadol/paracetamol (18.75/162.50 mg) p.o. thrice daily.

The anesthetic techniques were standardized among the two anesthesiologists. All patients were premedicated with Inj. glycopyrrolate 0.2 mg and Inj. fentanyl (2 mg/Kg). Anesthesia was induced with Inj. propofol (1.5 mg/Kg). Orotracheal intubation was facilitated with Inj. isoflurane (0.1 mg/Kg). Anesthesia was maintained with Inj. isoflurane in a partial mixture nitrous oxide and oxygen and Inj. vacuronium 0.02 mg/Kg when necessary. No local anesthetics or any medications with a possible coanalgesic effect were administered intra- or 48 hours after surgery.

Two spine surgeons did standard operative techniques mentioned for spine surgery. In patients with an isolated disc prolapse, operation was carried out through a laminotomy/fenestration and discectomy. In patients with spinal stenosis, decompression was carried out through a laminectomy and foraminotomy, where there was stenosis. Instability patients were operated pedicle fixation with fusion (Transforaminal Lumbar Interbody Fusion or Inter transverse Process Fusion). Surgery was performed at either single or multiple levels from third lumbar vertebra to sacrum. Local bone graft and/or hydroxyapatite/tricalcium phosphate composite was used for spinal fusion.

Laboratory investigation including CBC, LFT and RFT were performed before and after study. The demographic details, including age, gender, duration of surgery, length of incision and type of surgery were recorded. The efficacy outcome measures included Visual Analogue Scale (VAS), need for rescue analgesic/s within 48 h of surgery and with subsequent days as primary measures and 6- point Likert Scale (6-PLS) and patients’ subjective rating of study medication as secondary measures.

After surgery, on recovery from GA, the pain intensity was measured at rest and with movement using VAS and this was considered as baseline score. The pain with movement was assessed after patient performed a 90 degree logroll while in bed. The subsequent pain intensity at rest / with movement, and pain relief (6-PLS) measurements were performed 24 h, 48 h, 96 h and 240 h after surgery, i.e., at POD1, POD2, POD5 and POD10 respectively. All patients were routinely monitored for adverse drug reaction/s. The intensity of adverse reaction was reported by investigators as mild, moderate or severe.

The VAS is 0-10 cm non-graduated scale, stretching from “no pain” to “pain as bad as it could be” and commonly used tool in research and clinical practice, and its reliability and validity in pain assessment has been clearly demonstrated.^[16]

Within 48 h of surgery, patients who complained of sustained severe POP of ≥ 8 on VAS were administered pentazocine 15 mg (half dose) intravenously as a rescue analgesic as required. At discharge all patients were provided with paracetamol 650 mg, tablet twice daily as a primary rescue medication and as a secondary rescue, if needed, piroxicam 40 mg i.m. once daily. The need for rescue medication, occurrence of adverse reaction and pain grading were recorded.

6-PLS was used to identify amount of the average daily pain relief, the patient had experienced since the last assessment compared with the pain the patient had experienced before the initiation of the study medications.^[17]It comprises of six verbal terms, “worse, none, slight, moderate, a lot and complete relief” which were assigned to individual numerical value, “-1”, “0”, “1”, “2”, “3” and “4” indicates worse, none, slight, moderate, a lot and complete relief respectively. Patients reported the term that best suited to their pain relief at POD1, POD2, POD5 and POD10.

Patient’s opinion for analgesic therapy was determined by a verbal scale,using the verbal terms, “poor, fair, good and excellent”^[17] at POD10. Statistical analysis was carried out using software, SPSS and PRISM. Statistical significance was assessed using the two-tailed t test for all comparisons. A p value less than 0.05 was considered as statically significant.

RESULTS:

46 patients were excluded due to loss to adequate follow up. Finally, 103 patients were in group E and 100 in group D. There were no differences between the groups in terms of age, weight, gender, duration of surgery, length of incision and types of operation (Table 1).

DISCUSSION:

The results from this study shows the similar adequate analgesic effects of etoricoxib and diclofenac with tramadol/paracetamol combination in reducing spinal POP both at rest and with movement (intra group p value on successive measured days significant, Table 1 & 2). On day 1, group D patients had a significantly lower VAS than group E. However, the standard error for these findings overlaps between both the groups. On 0-10 cm VAS, which showed a 1-point difference, this overlap is of limited clinical significance.

Patients in both groups had equivalent pain relief during the 10 postoperative days. Within 48 h of surgery, greater number patients in both groups required rescue analgesics. However after 48hrs, very few patients required rescue analgesics.

PGE₂ is the predominant prostanoid associated with inflammatory responses and is responsible for reducing the pain threshold at the site of injury (primary hyperalgesia), resulting in central sensitization and a lower pain threshold in the surrounding uninjured tissue (secondary hyperalgesia).^[18] NSAIDs are thought to reduce POP by suppressing COX-2-mediated production of PGE₂. The primary site of action of NSAIDs is believed to be in the periphery, although recent research indicates that central inhibition of COX-2 may also play an important role in modulating nociception. NSAIDs inhibit the synthesis of prostaglandins both in the spinal cord and at the periphery, thus diminishing the hyperalgesic state after surgical trauma.^[19]

Tramadol is a weak μ opioid receptor agonist centrally and an inhibitor of norepinephrine and serotonin reuptake. The 2 enantiomers of racemic tramadol function in a complementary manner to enhance the analgesic efficacy, (+)-tramadol and (-)-tramadol inhibits serotonin reuptake and norepinephrine reuptake respectively.^[20]

Paracetamol acts centrally via activation of descending serotonergic pathways to provide analgesic effect, but its primary action may still be inhibition of PG synthesis.^[21]

The primary reason for combining different analgesics are to gain efficacy and to reduce toxicity, provided that such analgesic combinations may act pharmacokinetically, or pharmacodynamically, or both in positive terms and the individual analgesic should exihibit synergism to allow lower doses of each drug to be used in combination ^[11] and to enhance efficacy in complex pain state that involves multiple causes.^[12] Centrally acting analgesics such as tramadol or paracetamol may be combined with peripherally acting NSAIDs/COXIBs, in order to gain appropriate efficacy/toxicity ratio by reducing the NSAID dosage. ^[22]

The incidence of adverse events was lower in both groups. The majority adverse events were reported by the patients during immediate postoperative period. Adverse events reported, were consistent with the occurrence of general symptoms during acute postoperative period, and cannot be attributed to studied combination only. At recommended or higher doses NASIDs causes variety of adverse reactions ranging from most commonest GI events (i.e., nausea, diarrhea, dyspepsia, anorexia, heartburn and abdominal pain), perforation or bleeding from gastric or duodenal ulcer, skin rashes, mouth ulcers, headaches, tinnitus to cardiovascular and renal events ^[23]

The most common frequent adverse events associated with recommended dose of tramadol includes dizziness, drowsiness, nausea, vomiting, fatigue, sweating and dry mouth.^[20]Paracetamol is associated with a low incidence of adverse events and hepatotoxicity only at higher doses.^[21]

One patient in group E reported a frequent incidence of hiccup following acute postoperative period. The incidence of hiccup is associated with tramadol.^[24]That alleviated on stopping tramadol. The bleeding related complications do occur with full dose and do not differ between COX-1 NASIDs and placebo or COX-2 NSAIDs.^[25] In present study, we did not find an evidence of postoperative bleeding effects. Furthermore, NSAIDs can possibly cause side effects such as, anemia, and liver and kidney metabolic alterations.^[26]None of these side effects were found in this study. This may be due to the fact that the dose and duration of analgesics were less.

However, opioids remain the first choice of drugs for controlling POP, the associated adverse events limit their use (i.e., nausea/vomiting, respiratory depression, urinary retention, pruritus and sedation).^[27] So, it is wiser to use opioid as a rescue analgesic rather than using it as standard treatment protocol, in order to minimize incidence of opioid related side effects. Nonetheless, Patient-Controlled Analgesia (PCA) with opioids provides better analgesia and satisfaction, the cost of PCA devices and material per patient is quite high and PCA requires a cooperating patient too.^[27] Since India is developing country and the level of literacy is quite low, the use of PCA devices is not favored.

Recent data revealed that short-term administration of COXIBs had no clinically significant effect on bone healing. ^[28] In contrast, higher dose of ketorolac, history of smoking, and 2 level vertebral fusions resulted in a marked rate of nonunion after spinal fusion surgery. Since in the current study, the dose of etoricoxib used was 60 mg/day which is half the recommended dose for surgical patient, the risk of nonunion is probably nil. In contrast, NSAID affect bone osteogenesis during bone healing.^[29]Patients who administered NSAIDs for more than 3 months after surgery showed lower rate of bone union than control subjects after spinal fusion.^[30] However in present study, we used diclofenac with dose of 75 mg/day, which is half the dose prescribed after surgery and duration of treatment was only 10 days after surgery, so the possibility of bone non-union could be checked. Further long term clinic-radiological investigation is required to evaluate this.

Though our study is randomized prospective analysis it has many limitations also. Though, side effects reported in our study are very less, to exactly pin point them to be because of analgesics can’t be justified as antibiotics were given for whole study period concomitantly. The postoperative baseline pain intensity measurement may have overlapped with general anesthesia and there side effects may also be present. However, above stated two factors are inevitable in any postoperative study. Some of medications used, injection/tablets were manually divided half doses of full dose market preparations, there could be errors in dividing the preparations however the total daily dose of individual preparations remains the same. On the day of surgery, injectable diclofenac and oral etoricoxib were given in the two groups. The bioavailability of injection could be better. But there is no injectable formulation of etoricoxib available. Furthermore, the interaction of these drug combinations needs to be studied, if any.

The present study demonstrates the good equivalent analgesic efficacy of etoricoxib and diclofenac in combination with tramadol and paracetamol in reducing spinal POP as defined by lower pain scores, appropriate pain relief scores, reduction in rescue analgesic requirement and higher patients’ subjective evaluation rating. Patients experience severe pain in the acute postoperative period following spinal surgery where the use of opioids should be considered. Further, multicenter double blind randomized control study is required to evaluate our hypothesis.

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Received on 29.01.2013

Modified on 12.02.2013

Accepted on 22.02.2013

Research J. Pharmacology and Pharmacodynamics. 5(1): January –February 2013, 62-68