Effect of Karamardādi Yoga versus diclofenac sodium in post-operative pain management: A randomized comparative clinical trial.

INTRODUCTION: Post-operative pain is Nociceptive i.e., anticipated unavoidable physiological pain which is caused due to tissue trauma. Drugs such as NSAIDs (Non Steroidal Anti Inflammatory Drugs) and Opioids are used for post-operative pain management but are associated with their own drawbacks. Karamardādi Yoga has been in use in Ayurvedic practice for analgesia. It is known to relieve pain and can be used to supplement anaesthesia and also get rid of adverse effect of modern analgesic drugs. AIMS AND
OBJECTIVE: To study the comparative effect of Karamardādi Yoga and Diclofenac sodium in post-operative pain management.
MATERIALS AND METHODS: Randomized clinical trial with Group A (Control Group: Tab Diclofenac sodium 50 mg as a single dose) and Group B (Trial Group: Cap Karamardādi Yoga 500 mg as a single dose). Those who had undergone haemorrhoidectomy operation under local anaesthesia were selected as per inclusion criteria. Vitals, desirable effect and undesirable effect, total surgical time, requirement of 1(st) dose of analgesic, requirement of rescue analgesic and pain determined by VAS (Visual Analog Scale) were the assessment criteria and were observed and recorded.
RESULTS: Karamardādi Yoga does not show any undesirable or serious ill effects and altered values of vitals as per statistical analysis. As per VAS scale, pain felt by Trial group was earlier than control group.
CONCLUSIONS: Karamardādi Yoga has analgesic property but its analgesic property and pain threshold capacity is lesser than those of Diclofenac sodium.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Pain is derived from the Latin word ‘ponea’. Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage mainly due to tissue trauma.[1]

Post-operative pain is not avoidable in surgery. The treatment of post-operative pain results in real benefits to the patients and surgical units. Although pain has a purpose in the wider evolutionary sense, it is a largely inappropriate maladaptive response in the post-operative period, which is associated with stress and systemic complications that include pulmonary, cardiovascular and gastrointestinal ones.[2] Uncontrolled pain may cause struggling, crying, and restlessness and may result in hematoma formation and thereby delay wound healing. Adequate pain control leads to decreased manipulation of the surgical site and thus reduces swelling, hematoma formation, and infection.[3]

Some of the analgesics are tested to pacify surgical pain namely anaesthetics and analgesic. Whereas others, to pacify post-operative pain and its complications. All these drugs are categorised under opioids, NSAIDs and other synthetic and semi synthetic groups. Most of them produce a potent analgesic action but none of them are devoid of their known systemic untoward effects and hence are used with certain limitations.

In the texts of Ayurveda a large number of drugs are mentioned under the heading vedanasthāpana (~ analgesic), śothahara (anti inflammatory), vātaśāmaka (controlling of vāta) and śūlapraśamana (pain reliever) groups and at different places with their specific analgesic actions.[4] According to Ayurveda, vitiation of vāta is the prime factor producing pain perception along with other systemic consequences such as palpitation, depression, insomnia, vomiting, irritation, alerted sensorium, hypertension, excitement etc.

Analgesia is a component of anaesthesia. Ayurveda drugs which relieve pain could be used to supplement anaesthesia as well as get rid of adverse effects of modern drugs.[5] Some Ayurvedic physicians use herbal preparations for analgesia. One such preparation is Karamardādi Yoga which is a combination of jāti (Jasminum officinilas Linn.), karamarda (Carissa carandas Linn.) and kāñji (sour gruel). According to Ayurvedic literature, jāti is tridoṣahara and indicated in śiras (head), mukha (mouth) and danta (dental) diseases. Karamarda is vātahara[6] and kāñji is also vātahara and kaphahara.[7] Chemically jāti and karamarda contain salicylic acid. Kāñji which is one of sandhāna kalpanās i.e., fermented preparation whose contents are similar to vinegar (mainly acetic acid).[89] By combining salicylic acid and acetic anhydride one can get acetylsalicylic acid (Aspirin) which is one of the NSAIDs.[9] Therefore, on the basis of Ayurveda references indicating vātahara properties of these drugs and reverse pharmacology of these drugs, this study has been taken up to provide clinical evidence of analgesic property fof Karamardādi yoga comparing it with Diclofenac sodium. In the present study, Karamardādi yoga is prepared in the form of a capsule combination of jāti and karamarda cūrṇa which has been treated with a bhāvanā of kāñji.

MATERIALS AND METHODS

60 patients who were to undergo haemorrhoidectomy operation under local anaesthesia were randomly selected using a random number table. They were of either sex with A.S.A (American Society of Anaesthesiologists) grade I or II from the IPD of Shalyatantra ward. They were divided in to two groups using sequentially numbered opaque envelopes i.e group A and group B each consisting of 30 patients of either sex. Group A (Control) was given Diclofenac sodium and group B (Trial) is given Karamardādi Yoga. Both control drug and trial drug was given preoperatively one day before operation and 60-90 min preoperatively and postoperatively after appearance of pain at 8 hr intervals for three days. SOS medicine was also given per group. Assessment was done using subjective and objective parameters.

Collection and preparation of drugs

Ingredients of Karamardādi Yoga are Jāti pañcāṅga, Karamarda unripe fruit and rice gruel (kāñji). Jāti plant and unripe fruit of Karamarda were collected from their respective natural habitats and were autheticated. Jāti pañcāṅga and unripe fruit of Karamarda were dried, powdered and mixed in equal proportions. Kāñji was procured from a GMP certified vendor. The powder is given eleven bhāvanās using kāñji. The resultant powder was filled in 500 mg capsules and preserved in an air tight container. Thus, Karamardādi Yoga capsule (cūrṇa) was prepared with the standard preparatory methods as mentioned in the texts of Ayurveda.

Grouping of patients

After obtaining Institutional Ethical committee approval (ref. IEC/11/PG-KC/19), the trial was registered the Clinical Trial Registry of India, CTRI (ref. CTRI-REF/2013/07/005362). All 60 patients were randomly divided in two equal and identical groups consisting of 30 patients by using sequential numbering using opaque envelopes [Table 1].

Table 1

Grouping and posology

Study design

Randomized Control Trial.

Group A (Control Group)

Patients were given tablet Diclofenac sodium 50 mg as single dose orally with an ounce of plain water pre and post operatively in a haemorrhoidectomy operation under local anaesthesia as per the following schedule: One tablet the night before operation with 10 – 20 ml of water; one tab 60 to 90 min before operation with 10-20 ml of water. Post-operative follow up was as follows: Day 1: 50 mg Diclofenac sodium given when patient complains of pain and the drug is repeated at 8 hour intervals; Day 2 and 3: 50 mg Diclofenac sodium given at 8 hour intervals.

Group B (Trial Group)

Patients were given 3 capsules of 500 mg each Karamardādi Yoga as a single dose orally with an ounce of plain water pre and post operatively in haemorrhoidectomy operation under local anaesthesia as per the following schedule: three capsules of 500 mg each with 10 – 20 ml of water the night before operation, three capsules of 500 mg each with 10-20 ml of water 60-90 min before operation. Post operative follow up was as follows Day 1: three capsules of 500 mg as one dose given when patient complains of pain and the drug is repeated at 8 hour intervals, Day 2 and 3: 500 mg three capsules one dose given at 8 hour intervals.

Preoperative preparation and premeditation

All the patients were assessed thoroughly and consent was taken about the proposed research work. Their age (years), weight (kg) and vital signs viz. pulse rate, blood pressure, respiratory rate, oxygen-saturation and axillary temperature were recorded. General condition, physiological and psychological conditions were also recorded. After complete satisfaction, the grouping was done as discussed earlier.

A patent intravenous line with Ringer lactate solution was maintained by identical size intravenous cannula (Venflan – 18G). After intravenous line, the patients were transferred to operation table and lithotomy position was given. After all aseptic and antiseptic precautions, painting and draping was done. The local anaesthesia infiltration was done using hypodermic needle No. 25 G with drug lignocaine 2%. Intra-operatively, patients were re-evaluated thoroughly regarding their vital signs and physiology etc., Observations were recorded on the standard proforma for the study.

Post operatively time for first analgesic and pain before administration of first analgesic was recorded as per case proforma. Three days follow up was done according to case proforma. During this follow up, capsules Karamardādi Yoga and tablets Diclofenac sodium were given to respective groups as per drug dosage schedule. Pain assessment was done using VAS (Visual Analog Scale) before every dose of control and study group medication. Effects such as sedation, apprehension, excitement, dizziness, nausea etc., were observed and recorded as per case proforma.

RESULTS

All the data collected viz. age, blood pressure, pulse rate, respiratory rate, total surgical time, difference of VAS 1 of first post operative day with VAS 1 of third post operative day and VAS 3 of first post operative day with VAS3 of third post operative day between groups etc., were also recorded [Tables 2–4]. Mean, standard deviation (SD), applying unpaired t-test, t-value, standard error, P value, using percentage of incidence and degree of freedom etc., were calculated. Requirement of Rescue Analgesic in both Groups are depicted in Figure 1.

Table 2

Result of different parameters

Table 4

Difference of visual analog scales on post operative days between groups

Figure 1

Requirement of Rescue Analgesic in Both Groups

DISCUSSION

In Ayurveda, analgesia is achieved by drugs mentioned in Sāṅgyasthāpana gaṇa, Vedanāsthāpana gaṇa, Vātahara dravya, Vātānulomana and Śūlapraśamana dravya. Mode of actions of these drugs are mainly based on rasa, vīrya, vipāka and prabhāva. Vaidyas use different herbal drugs in combinations for the purpose of analgesia. In the present study, a combination of Jāti and Karamarda was selected which is used for analgesia by vaidyas. Capsule containing Jātipañcāṅga cūrṇa and the cūrṇa of Karamarda unripe fruit which is given bhāvanā in kāñji is used to evaluate post-operative pain relief in haemorrhoidectomy operation under local anaesthesia.

Diclofenac Sodium, one of the widely used NSAIDs agent, is an insoluble compound in acidic solution (pKa = 4.0), but dissolves in intestinal fluid and water. In order to eliminate the gastrointestinal adverse effects of this drug, several swellable controlled-release pharmaceutical dosage forms have been developed.[11]

In Control group, altered mean blood pressure intra-operatively returned to basal sooner than study group. Therefore it can be said that both drugs decrease pain and stress response preoperatively with the control drug being more effective. On the basis of these findings it can be concluded that the study drug Karamardādi Yoga has no serious ill effects on cardio vascular system and it does not alter Mean Blood Pressure (MBP).

Mean pulse rate during the course of the observations before premedication and after recovery from anaesthesia within the group is significant in group B and insignificant in group A. In In Group A, there is no change of pulse rate at the time of observation before premedication and post operatively. Hence the altered mean pulse rate during operation is treated to be basal for post operative readings. In Group B postoperative mean pulse rate decreased compared to preoperative but still it was more than the basal pulse rate. Hence, in the Control group altered mean heart rate intra-operatively reverts to basal sooner than the study group.

Mean respiratory rate/min within both groups before premedication versus after premedication, before premedication versus intra-operative and before premedication versus after recovery from anaesthesia were identical. The observations prove that there is no untoward effect of either the study or control drugs on the respiratory rate.

The response of analgesic premedication plays a definite role during post operative period with regard to duration of surgery. Observations recorded suggest [Table 2] that total surgical duration was identical in both groups and statistically insignificant when compared between the groups. The sustained release ability of Diclofenac sodium was demonstrated in an in-vivo study, showing the presence of the drug in plasma for about 14 h.[12]

Mean VAS Scale (subjective) between the groups at corresponding times i.e. First (VAS 1), second (VAS 2) and third (VAS 3) reading at every 8 hrs of third post operative day were observed. The results seem to suggest VAS 1 to be statistically insignificant and VAS 2, VAS 3 to be significant between the group A (Control) and Group B (study). Pain has decreased from VAS 1 up to VAS 3 in both groups. But the reduction in the control group is more than that in the study group. Difference in VAS 1 and VAS 3 between both groups statistically insignificant and equal. Difference of VAS 1 of first post operative day with VAS 1 of third post operative day and VAS 3 of first post operative day with VAS3 of third post operative day between groups is equal and statistically insignificant. All the above proves the analgesic property of Karamardādi Yoga compared to Diclofenac sodium. As VAS scale decreased on all three days between control group and study group equally, a statistically insignificant result is obtained. Except last day where VAS Scale decrease in control group is earlier than in the study group. This goes to prove the analgesic property of Karamardādi Yoga and it being lesser than that of Diclofenac sodium.

Statistical comparison of difference in mean VAS Scale (Objective) between the groups at corresponding time i.e., first (VAS 1), second (VAS 2) and third (VAS 3) reading at every 8 hr interval of first post-operative day was observed. VAS 1, VAS 2 is equal and insignificant in both groups but VAS3 is significant statistically. VAS 3 is more in Study group and that means that the patients experience discomfort. In control group, VAS 3 is zero and hence the patients experience no discomfort are completely at ease. This shows that Control drug is associated with lesser pain than the study drug. No major difference is observed between the groups was observed on second and third day respectively and it is zero for all results in both groups. Both group patients was having no discomfort and patient completely at ease on second and third day. The above proves the analgesic property of both drugs. Difference of VAS1 of first post operative day with VAS1 of third post-operative day which is statistically insignificant and difference of VAS 3 of first post operative day with VAS 3 of third post operative day between groups, both of which are statistically significant results, are obtained.

Rescue analgesic required was 27% in Study group which almost 3 times than in control group. This also shows that the study group patients felt more pain than control group in spite of the drug. This proves that Karamardādi Yoga has less analgesic property than study group and it alone is not sufficient to control post operative pain [Figure 1].

CONCLUSIONS

Karamardādi Yoga has analgesic property but it's analgesic property and pain threshold capacity is lesser than control drug. Karamardādi Yoga does not show any toxic effect in animals and neither does it show undesirable effects in humans. It is used solitarily, hence is not sufficient to control post-operative pain. Characterization of compounds responsible for analgesic property in Karamardādi Yoga needs to be studied further to enhance the potency of Karamardādi Yoga to make it a novel analgesic.

Financial support and sponsorship

KLE Ayurved Institute, Belagavi, Karnataka.

Conflicts of interest

There are no conflicts of interest.

Table 3

Result of total surgical time