Comparative evaluation of oral flupirtine and oral diclofenac sodium for analgesia and adverse effects in elective abdominal surgeries.

BACKGROUND: Flupirtine is a centrally-acting, nonopioid analgesic that interacts with N-methyl-D-aspartate receptors. AIM: The present study was designed to compare analgesic efficacy and adverse effects of orally administered flupirtine and diclofenac sodium for postoperative pain relief. SETTINGS AND
DESIGN: In a prospective, randomized double-blind study, 100 patients of American Society of Anesthesiologist grade I and II in the age group of 18-65 years of either sex undergoing elective abdominal surgeries were included after taking informed consent.
MATERIALS AND METHODS: The present study started after 12 h of surgery and patients were randomly divided into two groups of 50 each. For postoperative analgesia, group A received flupirtine 100 mg orally and group B received diclofenac sodium 50 mg orally and study drugs were repeated every 6 hourly for 5 days postoperatively. Vital parameters and visual analogue scale (VAS) scores for pain were recorded at 0, 1, 2, 4, 6, 8, 12, 16 and 24 h, and adverse effects were noted for 48 h of the study period. STATISTICAL ANALYSIS: Data were compiled and analyzed statistically using Chi-square test and two-tailed Student's t-test.
RESULTS: Visual analogue scores decreased more rapidly in diclofenac group during 1(st) h, hence there was rapid onset of analgesia in this group as compared to flupirtine group but later on VAS was comparable in both groups at all measured intervals (P > 0.05). Patients in diclofenac group experienced significantly more heartburn (P = 0.00), impaired taste sensation (P < 0.001) and dizziness (P = 0.004) as compared to flupirtine group.
CONCLUSION: Oral flupirtine and diclofenac sodium were equally effective for postoperative analgesia. There was faster onset of analgesia with diclofenac sodium, but flupirtine was better tolerated by the patients because of its minimal adverse effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Abdominal surgeries tend to be the most painful among all types of surgeries and 70% of the patients suffer from severe pain in the postoperative period.[1] Because the pain is a subjective and uniquely individual experience, postoperative pain assessment and management remains one of the major clinical challenges confronting health-care professionals.[23] Pharmacological interventions are the primary source of providing pain relief in today's scenario.[34] Diclofenac sodium a nonsteroidal anti-inflammatory agent (NSAID) is a phenylacetic acid derivative, which has both analgesic and antipyretic actions.[567] The efficacy of NSAIDs in acute pain has been demonstrated in many studies, but these are associated with increased risk of serious gastrointestinal adverse events like inflammation, bleeding, ulceration and perforation of the stomach or intestines.[58] Flupirtine is a centrally-acting, nonopioid analgesic and is the first representative of selective neuronal potassium channel openers (SNEPCO), which interacts with N-methyl-D-aspartate (NMDA) receptors.[910] It is a potent analgesic and muscle-relaxant and also has anticonvulsant and antioxidant properties, without any major adverse effects.[111213] In most of the studies, analgesic efficacy and adverse effects of oral Flupirtine were observed in patients having chronic musculoskeletal pain or cancer pain.[1415161718] Scant literature is available where oral flupirtine was used for postoperative pain relief. So the present study was designed to compare the analgesic efficacy and adverse effects of oral diclofenac sodium and oral flupirtine for the relief of postoperative pain in patients undergoing elective abdominal surgeries.

MATERIALS AND METHODS

This prospective, randomized, double-blind study was conducted from February, 2012 to October, 2013. Totally, 100 patients of American Society of Anesthesiologist (ASA) grade I and II in the age group of 18–65 years of either sex who had undergone elective abdominal surgeries were included after approval from Institutional Ethics Committee (Letter No 92/PHM dated 22/02/2012). Patients with history of allergy to the study drugs, diabetic neuropathy, coagulopathy, acid peptic disease, renal parenchymal disease, unconscious or critically ill patients, patients having epidural analgesia or sedation, unwillingness and those undergoing gastrointestinal surgeries were excluded from the study. Informed and written consent was taken from all the patients. A day before surgery, detailed preanesthetic check-up was carried out in every patient. Interpretation of the visual analogue scale (VAS) was explained to the patients to determine the level of analgesia achieved in the postoperative period. This was carried with a 10 cm line. The first end with mark ‘0’ means no pain and the second end with mark ‘10’ means severe pain. On the day of surgery inj. Glycopyrrolate 0.2 mg I/M and injection midazolam 0.04 mg/kg intravenous was given as a premedication. Abdominal surgeries were performed under spinal anesthesia in all patients. Hemodynamic parameters were monitored and maintained both intraoperatively as well as postoperatively. At the end of surgery, injection paracetamol 1 g intravenously was given to all patients for postoperative pain. If any patient complained of pain in the first 12 h of surgery, then inj. Tramadol 50 mg intramuscular was given as rescue analgesia.

The present study started after 12 h of surgery, where 100 patients were randomly divided into two groups of 50 each as group A (flupirtine) (n = 50) and group B (diclofenac sodium) (n = 50) by a computer-generated table of random numbers by a person blinded to the procedure. Baseline VAS scores, hemodynamic parameters (pulse rate, systolic blood pressure and diastolic blood pressure) were recorded at 12 h postoperatively in both the groups. All durations were calculated considering the 12th h postoperatively as 0 h.

At 0 h (12th h), VAS scores for pain were recorded, and the first dose of analgesic study drug was given to the patients of both groups. Group A (n = 50) received oral Flupirtine100 mg and group B (n = 50) received oral diclofenac sodium 50 mg. The study drugs were given to the patients by a nurse and the observer who noted the VAS scores and adverse effects was not aware of the drug given to the patient. The above mentioned study drugs were then repeated every 6 hourly for 5 days postoperatively. Patients were monitored for vital parameters, postoperative pain using VAS scores and side effects of the study drugs. VAS scores and hemodynamic parameters were recorded at an interval of 1-h for first 2 h, then every 2 hourly for 8 h and then at an interval of 4 h till first 16 h and then at an interval of 8 h at 24 h by an independent observer blinded to the study drug. Patients were not disturbed during sleep and pain score was considered zero at that time. During study period, if any patient had a VAS score of more than 7 then inj. Tramadol 50 mg was given intramuscularly as rescue analgesia. After giving the study drug patients were monitored for adverse effects like nausea, vomiting, heartburn, pain abdomen, headache, dizziness, dry mouth and any rash on the body for 48 h. Statistical analysis: A statistical analysis was carried out using Statistical Package for Social Sciences version 15.0 (SPSS Inc., Chicago, IL, USA). Mean and standard deviation for all parameters was calculated. The nonparametric data (sex, ASA grade and adverse effects were analyzed using the “Chi-square test” and Fischer's exact test while the intergroup comparison of the parametric data (age and VAS score) was done using two-tailed “Student's t-test.” The ‘P’ value was determined to finally evaluate the level of significance. The P < 0.05 was considered significant at 5% significance level; P < 0.01 was considered significant at 1% significance level and a P < 0.001 was considered highly significant. The blinding was disclosed at the end of the study. Power analysis was done to calculate the power of the study by taking alpha error of 0.05, and it was found that power of the study was 99%.

RESULTS

In the present study both groups were comparable with respect to age, sex ratio, body weight and ASA grade as shown in Table 1a. Maximum patients were in the age group of 21–40 years in both the groups. Only four patients in group A and two patients in group B were more than 60 years of age. Type of surgeries and baseline vital parameters were also comparable in both the groups. Most commonly performed surgeries were inguinal hernia and appendectomy in both the groups [Table 1b]. Hemodynamic parameters monitored at various time intervals throughout the study period remained stable and are comparable in both groups as shown in Table 2.

Table 1a

Demographic profile of patients in group A and group B

Table 1b

Type of surgical procedures performed in both groups

Table 2

Hemodynamic parameters at various time intervals in group A (flupirtine) and group B (diclofenac sodium)

This study was conducted in the postoperative period (i.e. after 12 h of surgery). Baseline VAS scores were recorded in all the patients of both groups before giving study drugs, to evaluate postoperative pain. At the start of the study, mean baseline VAS score in group A at 0 h was 6.64 ± 1.65 and in group B was 6.28 ± 1.37. The difference in the baseline VAS scores of both the groups was statistically nonsignificant (P = 0.238). First dose of the study drugs was given to the patients in both groups, and VAS scores were noted after 1-h. The mean VAS scores in group A decreased to 5.80 ± 1.52 and in group B, VAS score decreased to 4.87 ± 1.46. At this interval difference in the VAS score of two groups was statistically significant (P = 0.018). At 2nd h, mean VAS in group A was 4.67 ± 0.06 and mean VAS in group B was 4.63 ± 0.67 and the difference in the two groups was nonsignificant (P = 0.847). Difference in the mean VAS score in group A and group B at 4th h was also nonsignificant (P = 0.23). Second dose of the study drug was given at 6th h when the again the mean VAS score in group A and in group B was comparable (P = 0.665). VAS score was then recorded at 8th h and 12th h and the difference in the mean VAS score of both groups was nonsignificant (P = 0.689 and P = 0.744 respectively) at both intervals. The third dose of study drug was given and again VAS was recorded at 16th h and 24th h and the mean VAS score in group A and in group B remained comparable (P = 0.587 and 0.652 respectively) [Table 3]. Rescue analgesia in the form of injection Tramadol was given to eight patients in group A and to ten patients in group B during the first 6 h of the study period. Later on, none of the patients required rescue analgesia for pain.

Table 3

Mean VAS scores at various time intervals in group A and group B

Patients were monitored for adverse effects of the study drugs for 48 h. In group A (flupirtine), most common adverse effects were nausea, vomiting, pain abdomen and dry mouth, which occurred in 20 (40%), 6 (12%), 7 (14%) and 7 (14%) patients respectively. In group B (diclofenac) most common side effects were heartburn, nausea, vomiting, dizziness, dry mouth and impaired taste sensation, which occurred in 31 (62%), 25 (50%), 9 (18%), 10 (20%), 13 (26%) and 29 (58%) patients respectively. Pain abdomen as a side effect was significantly more with flupirtine (P = 0.006) but dizziness (P = 0.004), Heartburn and Impaired taste sensation (P < 0.001) was observed more with diclofenac sodium as shown in Table 4. Injection ondansetron was given for vomiting and tablet ranitidine150 mg was given for heartburn to the patients in both groups.

Table 4

Adverse effects of the study drugs in group A and group B

DISCUSSION

A surgical procedure causes tissue damage at the operated site, which further releases chemical mediators like protons, ATP, serotonin, histamine, bradykinin and arachidonic acid from injured cells. Arachidonic acid is further converted into prostaglandins and leukotrienes via lipoxygenase pathway, which stimulates the peripheral sensory neurons causing neuronal sensitization and hyperalgesia.[1920] Diclofenac sodium competes with arachidonic acid for binding to cyclooxygenase thus leading to decreased formation of prostaglandins and leukotrienes, hence produces analgesia.[567] The spectrum of action of flupirtine was reviewed in 1999 by Kornhuber et al.[9] Over the past few years, however, evidence has accumulated that flupirtine interacts with the glutamatergic NMDA receptor. Although it was not possible to demonstrate a direct effect on the NMDA receptor, all of the findings pointed to an indirect influence on the NMDA receptor in the sense of a functional NMDA antagonism. Such a site of action proved to be the G-protein-activated inwardly rectifying K+ channels, the opening of which leads to stabilization of the resting membrane potential of neuronal cells and thus causes an indirect inhibition of the NMDA receptor. At therapeutically relevant concentrations, flupirtine is a neuronal potassium channel opener. This mechanism may explain the spectrum of action of flupirtine. SNEPCO thus proves to be a new principle of action, making Flupirtine the prototype of a new substance class with analgesic, muscle-relaxant and neuroprotective properties.[21]

Comparison of two groups with respect to post operative analgesia, side effects and complications

In the present study, both groups were comparable with respect to the demographic profile of the patients. Number of patients under each type of surgery was comparable in both groups to avoid any bias. Elderly patients more than 60 years of age were also comparable in both the groups (four in group A and two in group B). Hemodynamic parameters were comparable at all measured intervals during study period in both groups.

According to principal criteria for an accurate pain measurement, method should be valid, reliable and yield consistent results over the time.[2223] Most commonly used method for the evaluation of pain severity and relief, is the VAS because of its practicality, reproducibility, sensitivity to treatment effects and ease of analysis.[2425] We have also used VAS for evaluating the severity of pain.

The results of the present study elucidated no statistically significant difference in the mean visual linear analogue scores observed on the basis of age, sex and cause of pain. There was no significant difference in the residual analgesic effect of injection paracetamol or injection tramadol given in the first 12 h of surgery, as the mean VAS scores at the start of this study were comparable in both groups. Hence, the severity of pain in both groups at 12th h was almost same as the VAS score was 6.64 ± 1.65 in group A and 6.28 ± 1.37 in group B, when the first dose of study drug was given. After 1-h of giving the study drugs, although there was not much decrease in the pain scores in both groups. But VAS was significantly on the lower side in the diclofenac group as compared to flupirtine group. This might be related to the fact that peak plasma concentration of flupirtine is achieved at about 2–3 h after oral administration.[26] After 2 h of giving the study drugs, VAS scores started decreasing in both the groups and were now comparable. Thus onset of analgesia was more rapid in diclofenac group as compared to flupirtine group but later on analgesic efficacy of both drugs was comparable as after 4 h, VAS score decreased to 2.62 ± 0.90 in group A and 3.00 ± 0.94 in group B (P = 0.23). At 6 h, VAS scores were recorded, and the second dose of study drug was given to the patients of two groups. After 2 h of giving second dose, VAS decreased from 4.12 ± 1.49 to 2.00 ± 0.64 in group A and from 4.00 ± 1.26 to 2.07 ± 0.63 in group B. So after second dose of oral diclofenac and oral flupirtine, pain scores decreased more rapidly in both groups, and there was no significant difference in the analgesic efficacy of the two drugs. After that, there was not much difference in the VAS scores of both the groups till the end of the study. Similar results were reported by a study conducted by Mastronardi et al.,[27] where analgesic efficacy of oral flupirtine 100 mg was compared with diclofenac sodium 50 mg in 40 orthopedic patients for postoperative pain relief. They observed that initially there was no significant decrease in pain scores with both the drug during first 2 h of giving the first dose. After giving the second dose, there was a significant reduction in pain scores in both the groups, but pain scores remained comparable in both groups at all intervals. Marczyk evaluated the analgesic efficacy of diclofenac and flupirtine in treating pain of musculoskeletal origin and concluded that, both flupirtine and diclofenac treatment resulted in significant improvement in pain scores as compared to baseline scores.[16] Even perioperative administration of two doses of 100 mg flupirtine was efficacious in reducing morphine requirements in 48 h postoperative period after carcinoma breast surgery.[26]

Yadav et al. compared the analgesic potential of diclofenac 50 mg and flupirtine 100 mg for postcraniotomy pain relief. There was a significant reduction in VAS scores in flupirtine and diclofenac groups as compared to the placebo group (P < 0.0001) Pain relief was 90.2% in flupirtine and 90.5% in the diclofenac group.[28] Hence, the results of the present study are in accordance with the above studies.

The present study revealed heartburn, impaired taste sensation and dizziness as the major adverse effects experienced by the patients who received diclofenac sodium. These adverse effects were significantly less in flupirtine group. Rest of the adverse effects like nausea, vomiting, headache, dry mouth and any bodily rash were comparable in both the groups. These results are in accordance with the findings of Mueller-Schwefe[29] and Ringe[30] where they observed that oral Flupirtine was effective in controlling pain and was well tolerated. There were no serious adverse events reported. Other studies also observed that oral flupirtine is an effective analgesic with advantage of fewer central nervous system side-effects as compared to opioids.[1431] Naser et al.[32] evaluated the efficacy and safety of flupirtine 100 mg for postoperative pain management. It was observed that there was a significant reduction in pain scores and the incidence of adverse effects was much less (7.4%).

To conclude, the onset of analgesia was faster with diclofenac sodium but later on both drugs were equally effective in relieving postoperative pain in abdominal surgeries. Flupirtine was well tolerated by patients because of its minimal adverse effects as compared to diclofenac sodium.

Limitation of our study was that, we have not observed the severity of adverse effects in both groups, only the incidence of adverse effects was studied. Further causality assessment of adverse effects was not done. They were managed symptomatically using appropriate measures. Within the limitations of this study, flupirtine can be considered as an effective analgesic for the treatment of acute pain states such as postoperative pain.