European Journal of Cardiovascular Medicine

Pain is an extraordinary complex sensation which is difficult to define and equally difficult to measure in an accurate objective manner. In 1979 the International Association for the study of pain (IASP) proposed a definition of pain, as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in s of such a damage) terms

Serfce the earliest times men have tried to alleviate pain. Opium (juice obtained by Papaversomniferum) has been used for centuries to allay anxiety and to reduce pain associated with surgery. Morphine was isolated from opium in 1803 and it became a drug for relief of pain.

During the nineteenth century however a real onslaught against pain was launched mainly through the development of pain-killing drugs. Initially it was the use of anaesthetics to prevent pain by acting locally on the painful area, or on the nerves conducting the pain, or by making patients unconscious through action on the brain cells. Later in the century various analgesics, or pain-killers, which work on the brain's pain centres, without causing unconsciousness were developed. Such drugs were useful but not very effective against severe pain for which morphine and heroin were employed. They act on the brain and reduce pain sensation. In addition they produce an intensive feeling of well-being which allow people to tolerate pain quite well. Unfortunately, morphine and similar drugs (pethidine) have undesirable side effects including addiction. Opiates (natural alkaloids of opium: Morphine and Codeine and semisynthetic preparations dimorphine, dihydrocodeine and oxymorphine) act on opiate receptors and induce their pharmacologic effect as agonists.

The modern pharmaceutical industry has made, and continues to make great efforts to find a perfect analgesic a powerful pain killer which dees not lead to addiction and which has no unpleasant side effects.

Nalorphine was synthesized in 1941 and was used as an antidote for morphine. Apart from antagonising the analgesic effects of morphine, it was shown to be an effective analgesic when administered postoperatively". However its diaphoretic effects have made it unsuitable for clinical use. This led to the discovery of compounds, agonist antagonist opioid analgesics. These are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as morphine and codeine. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (Pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine -like. Meptazinol does not fit into either classification

Post-operative pain differs from other types of pain which is usually transitory with progressive improvement persuing a relatively short time course. Affective component tends towards anxiety state, associated with the diagnosis of the condition and fear of delay in provision of analgesic therapy by attendants

This study was undertaken at Government General Hospital and Basaveshwara Teaching and General Hospital, Gulbarga which are attached to M.R. Medical College. Gulbarga. A clinical comparative study was made using Diclofenac sodium, Pentazocine and Ketorolac through intra-muscular (IM) route for post-operative pain relief.

The study included 150 patients who had come to the hospital for surgery below the umbilicus either abdominal or non-abdominal.

After taking consent, all patients had a thorough pre-operative check up and those who came under ASA-1" were included in the study. Any patient with a systemic disorder pertaining to cardiovascular, respiratory or central nervous system was excluded from the study. All the patients were made familiar with pain scoring.

50 patients were assigned randomly to one of the three drugs namely, diclofenac sodium, pentazocine and ketorolac as group I, group II and group III respectively.

All the surgeries were performed under spinal or epidural anaesthesia. Intra operatively all patients were monitored for their vital signs. No premedication was administered to the patients. No analgesics were administered during surgery.

Operations performed in each group are as shown in table I.

Table I. : Type of operation

Patients were randomly assigned to receive a single intramuscular dose of either 75mg doclofenac sodium, 30mg Pentazocine or 30mg Ketorolac when they requested medication for relief of pain. Concomittant analgesics, sedatives or hypnotics were not allowed during the study period. The baseline sensitivity of pain.vital signs and injection site were assessed. The drug was administered by a nurse who was not the observer to maintain the study design.

Patients were interviewed every 1/2, 2, 6, 10, 16 and 24 hours following injection or until patients requested rescue analgesic for relief of pain. Patients were asked to assess pain intensity on a visual analogue scale with no pain (0%) and worst pain imaginable (100%) at the extremes and verbally as either none, mild, moderate or severe. The vital signs by PRST scale that is, blood pressure, heart rate, sweating and tears were assessed along with the examination of the injection site. The patients were also observed for side effects like nausea, vomiting, drowziness, sedation, diarrhoea, constipation and pain at the injection site.

The study was conducted on a total of 150 patients, 108 males and 42 females all of whom were of ASA grade 1. The operations were performed under spinal or epidural anaesthesia. All the patients were adults with age ranging from 20 to 60 years. These patients were divided into 3 groups of 50 each.

Of the 150 patients included, the abdominal surgical procedures were 60%, orthopaedic 20% and obstetric and gynaecology 20%. There was no significant differences in age or sex distribution between the various treatment groups.

After surgery, patients were observed for development of pain. The pain score was assessed with the help of the visual analogue scale (VAS) and PRST scale before giving the drug.

Onset of analgesia:

After drug administration onset of analgesic action was observed every 5 minutes until patients noticed pain relief as shown in table II.

Table II : Onset of Analgesic action

The onset of analgesia in group 1 was 5 to 15 minutes in 20 patients and 15-30 minutes in 30 patients. In group 11 20 patients noticed onset of analgesia in 15-30 minutes and 15 patients in 30-45 minutes while 10 patients had the onset in 5-15 minutes. In group III the onset of analgesia was 5-15 minutes in 40 patients and 10 patients had it between 15 and 30 minutes. Thus the onset of analgesia was faster in group III.

Duration of analgesia:

Duration of analgesia and mean duration of analgesia in different groups are shown in table III and table IV respectively

Table III. Duration of analgesia

The onset of analgesia in group 1 was 5 to 15 minutes in 20 patients and 15-30 minutes in 30 patients. In group 11 20 patients noticed onset of analgesia in 15-30 minutes and 15 patients in 30-45 minutes while 10 patients had the onset in 5-15 minutes. In group III the onset of analgesia was 5-15 minutes in 40 patients and 10 patients had it between 15 and 30 minutes. Thus the onset of analgesia was faster in group III.

Table IV: Comparison of mean duration of analgesia in different groups

Table IV shows longer duration of action of analgesia in group 1 compared to group II and group III which was statistically significant (<0.001). And when groups II and III were compared very minimal difference was noted.

Effect on cardiovascular system:

Variation of systolic blood pressure within each group was studied and its significance is noted as in table V.

Table V. Mean systolic blood pressure in the study groups

In the above table, systolic blood pressure in group II was significantly increased when compred to group 1 and group III which were not very significant.

Variation in diastolic blood pressure in each group was studied and the significance was calculated and is shown as in table VI.

Table VI: Mean diastolic BP in all three groups

The mean diastolic blood pressure in group II though showed an increase it was not significant.

Variation in heart rate within each group was studied and its significance noted is shown in the table VII.

Table VII: Mean heart rate in all three groups

The mean heart rate in group II was significantly increased when compared with group 1 and group III.

Sweating and tears:

The presence of sweating and tears was asked in each patient and also monitored. The sweating was graded as 0, 1, 2 for nil, moist to touch and visible beads of sweat respectively.

Comparative study of analgesic effect of 3 drugs such as Diclofenac sodium, Portazocine and Ketorolac was done on 150 patients who underwent surgery below the umbilicus either abdominal or non-abdominal. All the patients belonged to ASA-1 category.

The onset of analgesa was fast in Ketorolac wherein 80% of patients exhibited the onset within 15 minutes following administration of the drug. The onset of analgesia within 15 minutes was seen in 20% and 40% of patients in the groups of pentazocine and diclofenac respectively.

Ketorolac has been studied in a number of single-dose trials in patients with moderate to severe surgical pain. Ketorolac acts by inhibiting prostaglandin synthesis and possesses greater systemic analgesic activity than anti-inflammatory potency¹ In a dose of 30 to 90mg intramuscularly, ketorolac has shown analgesic efficacy superior to that of opioid analgesics including 30mg pentazocine²

Estenne et al compared the analgesic activity of ketorolac with pentazocine which is an antagonist at morphine receptors and an agonist or partial agonist at other opioid receptors² They administered double-blind single intramuscular doses of ketorolac 10 to 30mg, pentazocine 30mg or placebo to 160 patients with moderate to severe post-operative pain following abdominal including gynaecological and urological surgery. A higher dose of ketorolac demonstrated efficacy superior to either of the other active medications or to placebo. ketorolac 10mg was at least as effective as pentazocine 30mg in terms of summed pain intensity differences or total pain relief at 8 hours. Of the patients treated with ketorolac 30mg, 8% withdrew from the study prematurely because of inadequate pain relief as did 18% of patients receiving ketorolac 10mg, while the proportion of patients receiving pentazocine who withdrew because of inefficacy was identical with that seen with placebo as 29%

Ketorolac 30mg has been shown in dose response studies to be as effective as ketorolac 10mg when given 4 times daily intramuscularly for upto 5 days to the patients with moderate to very severe pain associated with orthopaedic surgery and to be more effective than the lower dosage when administered in upto 5 doses after major or general surgery³

Kumar et al compared the effect of a single dose of intramuscular ketorolac 30mg with pentazocine and diclofenac sodium in moderate to severe postoperative pain⁴. They found ketorolac had a rapid onset of analgesia. In our study ketorolac had an onset of analgesia faster compared to that of pentazocine and diclofenac. Forbes et al while evaluating ketorolac in Postoperative oral surgery found ketorolac 10mg provided greater pain relief than aspirin 650mg. The results were based on patients self-rating records⁵

The duration of analgesic action of ketorolac was not long in the present study. It was of short duration for a period of 3 to 6 hours in 80% of cases who received ketorolac. The duration of analgesia action was longer in diclofenac group wherein 50% of cases exhibited analgesic for 6 to 9 hours and in 20% of cases analgesic effect lasted for 9 to 12 hours. In pentozocine group though analgesic effect was for 3 to 6 hours in 60% cases, 30% of cases exhibited relief of pain for 6 to 9 hours and 10% of cases for 9 to 12 hours. A comparative study shows that the duration of relief of pain noted in diclofenac was statistically significant when compared to pentozocine and ketorolac.

But Kumar et al in their study found ketorolac 30mg had a rapid onset and longer duration of analgesic effect Unlike the present study they found significantly higher analgesia with both pentazocine and ketorolac than diclofenac sodium. In the present study diclofenac provided significantly higher analgesic effect between sixth and twelfth hours than both pentozocine and ketorolac.

Various non-controlled studies and comparisons with placebo have shown that diclofenac is an effective analgesic agent in diverse acute painful conditions such as dental or minor surgical pain, postpartum pain and anorectal surgery pain^6,7

Nuutinen et al found the effect of a single intramuscular injection of diclofenac 75mg similar to oxycodone 10mg in pain resulting from various minor surgical procedures, while oxycodone had a faster onset, diclofenac had a longer duration In a cross over study in 20 patients with chronic cancer pain, Tonachella et al. found intramuscular diclofenac 75mg every 12 hours for 3 days produced greater pain reduction than intramuscular pentozocine 30mg every 12 hours⁸

A single intramuscular injection of 75mg diclofenac was found to be more effective than 100mg pethidine in patients undergoing major elective surgery⁹ Lindgen and Djupsjo found single injection of 75mg of diclofenac to be more effective than 50mg pethidine in patients undergoing total hip replacement¹⁰

Two randomised double-blind studies have analysed the prophylactic effect of diclofenac 75mg versus placebo administered intramuscularly immediately after surgery against subsequent narcotic analgesic consumption. Hodaman et al found that diclofenac reduced significantly morphine consumption in 24-hour postoperative period by 36% compared with placebo in 62 patients undergoing abdominal surgical procedure¹¹. Tigersted et al found that oxycodone consumption in the 2 hour postoperative period tended to be reduced by diclofenac compared with placebo in 2 groups of patients undergoing abdominal and superficial surgery¹²

In our study the pain was assessed by visual analogue scale¹³ which has been found to be more sensitive, accurate and consistent than fixed interval scales where the patient was asked to assess the pain as absent, mild, moderate or severe. In the visual analogue scale the patient is shown a 10cm line which represents at one end 'no pain and at the other end 'worst pain impossible' and is asked to mark the point on the line where his pain lies.

Evans considering the various autonomic changes in response to surgical stimulus set up a table of variables such as systolic blood pressure, heart rate, sweating and tears referred as PRST score¹⁴.  Though this has been used as an index of anaesthetic depth, an attempt was made in the present study to find out the changes following the administration of different analgesics in post-operative conditions in the present study.

Pentazocine was the one of first drugs to be widely available for analgetic use. A dese of 30 to 60 mg pentazocine administered in single dose by intramuscular injection produces similar analgesia to 10mg morphine¹⁵ and 100mg pethidine¹⁶ but with a slightly shorter overall duration of action. While reviewing the effect of nalorphine-like agonists and antagonists Hoskin and Hanks have concluded pentazocine is a moderate analgesic in post-operative particles. ¹⁷

Our study there was mild increase in systolic blood pressure(5mm Hg)) in case of pentazocine while there was no change in ketorolac and diclofenac. The score remained zero in all cases. Similarly there was an increase by Smm Hg in diastolic blood pressure in pentozocine group only. However the score remained zero in all cases

In case of heart rate there was mild increase (8 beats/min.) following administration of pehtozocine, whereas there was not much change in ketorolac and diclofenac. Hence the score remained zero. None of the cases exhibited sweating or tears thus the score remained zero. Thus PRST scale did not reveal any alteration insther autonomic functions. The scale thus was found of not much value in the study. Thus there was no single variable which could reliably indicate the depth of anaesthesia.

Kumar et al did not find any significant change in the vital parameters, but found sweating in 4% of cases who received ketorolac, in 4% of cases who received pentozocine and in 8% of cases who received diclofenac. Yee et al in 48 cases who received 30mg ketorolac did not find any sweating¹⁸

The side effects were more frequent with pentazocine and they were in the form of nausea (40%), vomiting (20%), drowsiness (24%) and somnolence (16%). Kumar et al did not find nausea and dizziness to be frequent with pentazocine and they were noted in 16% and 14% of cases respectively ⁴

The occurrence of pain at the site of injection was noted frequently in and it was 60% of cases on diclofenac. Kumar et al found 29% of patients complaining of pain at the site of injection of diclofenac⁴ Pain at the site of injection of ketorolac was noted in 8% of cases. Kumar et al found pain on injection of ketorolac in 13% of cases⁴

Onset of analgesia was faster in case of ketorolac when compared with diclofenac sodium and pentazocine. Duration of analgesia was longer in case of diclofenac sodium when compared to pentazocine and ketorolac. The vital parameters blood pressure and heart rate increased mildly in case of pentazocine. The PRST scale did not reveal any change in autonomic function. The scale was not of much utility.  Side effects such as nausea, vomiting and drowziness were more in case of pentazocine and pain at the injection site was more common in case of diclofenac sodium. In case of ketorolac side effects were very minimal.

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