Analgesic activity of fixed dose combinations of paracetamol with diclofenac sodium and paracetamol with tramadol on different pain models in healthy volunteers - A randomized double blind crossover study.

AIM: To evaluate and compare the analgesic activity of fixed dose combinations (FDC) of Paracetamol with Diclofenac sodium and Paracetamol with Tramadol on different human pain models in healthy human volunteers.
MATERIALS AND METHODS: A randomized double blind crossover study was carried out in 30 healthy human volunteers using three pain models; cold-water stress test, radiant heat method, and BP cuff inflation method. The subjects were randomized into two groups of 15 each, group A received FDC of Paracetamol 500 mg with Diclofenac sodium 50 mg and group B was given a FDC of Paracetamol 375 mg and Tramadol 50 mg. All the volunteers were tested on three pain models. Observations for pain tolerance were recorded at baseline and at the interval of 30, 60, 120, and 180 minutes after drug administration. Crossover was done after a washout period of 7 days. The results of both the study periods were analyzed using an independent t-test.
RESULTS: Mean age of the participants was 23±1 years and the male:female ratio was 2:1. In the radiant heat method, paracetamol with tramadol combination treatment showed a significant increase in pain tolerance at 2 hours and 3 hours (P 0.028 and 0.055 respectively) compared to paracetamol with diclofenac combination. Other two pain models did not show any significant difference in the study groups.
CONCLUSION: Paracetamol with tramadol combination was more effective than paracetamol with diclofenac sodium combination on the radiant heat model. In human pain models, there is an incomplete understanding of mechanisms and activated pathways are not precisely determined that needs further evaluation.

RCT Entities:   Population Interventions Outcomes

Introduction

Pain is the most common clinical complaint and causes considerable human suffering.[1] In the United States alone, approximately 100 million people suffer from moderate to severe pain during any given year.[1] Analgesic pharmacotherapy with drugs, such as acetic acid derivatives, nonsteroidal anti-inflammatory drugs (NSAIDS), and opioids, has made significant advances to date. NSAIDS are most commonly prescribed drugs for acute and chronic pain or for long-term anti-inflammatory therapy. They inhibit the cyclo-oxygenase enzyme, reduce prostaglandin synthesis (particularly PGE1 and PGE2 that promote inflammation), and other inflammatory agents.[2] Opioid analgesics block mu receptors in CNS and relieve pain.[2] However, these medications are not devoid of side effects. In fact, some drugs have been associated with serious adverse drug reactions and dependence liability. Of the total number of patients seeking treatment for pain, 50% are not satisfied with the available pharmacological options.[3-6]

Developing an ideal pain model to evaluate analgesics in healthy human volunteers is difficult. Various established pain models are used for evaluating analgesic action. The parameters recorded in these models are “pain threshold” (time between the stimulus applied and the feeling of pain sensation) and “pain tolerance” (time interval from feeling of pain to unbearable pain causing withdrawal of hand away from painful stimulus).[6]

World Health Organization (WHO) has suggested a pain management protocol which states that simple analgesics should be selected first and in case the patient does not respond to that, one can choose any other nonsteroidal anti-inflammatory drug (NSAID) and thereafter give a combination of NSAID with opioid analgesic. There is no place for fixed dose combination (FDC) of two NSAIDs in it. Currently FDC of diclofenac with paracetamol are available in Indian market and are widely used for pain relief.[78] Two drugs having the same mechanism of action are ideally not combined in a FDC, as they serve no added advantage and their adverse drugs reactions are additive, which may increase the potential of developing serious consequences.[9] However, limited data show that addition of NSAID to paracetamol may confer additional analgesic and anti-inflammatory activity compared to paracetamol alone.[10] The FDC of tramadol hydrochloride 50 mg with paracetamol 375 mg are also in use as the drugs act by different mechanism and synergism is proven.[9] This FDC is effective in acute postoperative pain of dental,[11] orthopedic and abdominal surgery,[12] fibromyalgia,[13] low back pain,[14-16] migraine,[17] and as add-on therapy for osteoarthritis[18] and rheumatoid arthritis.[19] The efficacy of fixed-dose combination of tramadol with paracetamol in the management of moderate to severe pain has been reported.[20] Therefore, the objective of this study was to compare the analgesic activity of fixed dose combination of paracetamol + diclofenac sodium and paracetamol + tramadol on different human pain models in healthy volunteers.

Materials and Methods

A randomized double blind crossover study carried out in the clinical pharmacology unit of Department of Pharmacology after prior approval from Institutional Ethics Committee. The participants were explained the nature, purpose, and risks and benefits involved in the study and a written informed consent obtained. Before entering the study, a full medical history taken and a qualified physician performed clinical examination to declare the participant healthy. Thirty healthy volunteers aged between 19 and 35 years of either sex were included in the study. Exclusion criteria for the study were regular use of any medication; participation in any clinical trial in the preceding 2 weeks or during the study; history of hypersensitivity to the trial drug or to chemically similar drugs; history or presence of gastrointestinal, pulmonary, liver or kidney diseases; any conditions known to interfere with pharmacokinetics of study drugs; and pregnancy and/or breast-feeding. Subjects were asked to abstain from alcohol, nicotine, and caffeinated drinks during the study period.

All the volunteers were exposed to three pain models for evaluation of analgesic activity.[26] Details of these pain models were as under:

Cold stress test[26]

Volunteers were asked to immerse their nondominant hand up to a specific mark just above the wrist joint into container of warm water (34.5--35.5°c) for 2 minutes. The hand was then immediately transferred and immersed in to another container of cold ice water (0.5--1.5°c) until the pain was tolerated (pain tolerance). The time of onset of pain and the pain became intolerable were recorded in seconds before and after drug administration.

Radiant heat method[26]

The instrument for delivering the radiant heat (drier, Bajaj Electronics) was kept at a fixed distance of 25 cm from the nonhairy marked skin surface of the middle of the forearm. Hypersensitivity was checked initially. The subjects indicated the time of pain threshold and maximum pain tolerance. The volunteers withdrew the forearm away from the apparatus as soon as the pain became intolerable. Observations were recorded before and after drug administration.

Blood pressure (BP) cuff inflation method[26]

In this method, an adult BP cuff was tied to the middle of the arm keeping a cap of a cold drink bottle under the cuff with its edges facing to skin. The cuff was inflated till the pain was felt. The cuff pressure was maintained till the pain became unbearable. The cuff deflated. The time was noted at the onset of pain, and when it became intolerable.

The eyes of the subjects remained covered with eye shield during experiment to avoid time clues and visual distraction. Volunteers were advised to take adequate overnight sleep and light morning breakfast preferably 2 hours before on the days of experiments.

The study was a randomized, double-blind balanced two-way crossover trial. The sequence of study sessions balanced for the overall study population. The dextrality effect of the dominant and nondominant side was avoided in the trial. Each of the two study sessions consisted of two study days as shown in Figure 1.

Figure 1

Study protocol

The subjects were randomized into two groups, A and B, of 15 each by using a computer-generated random number table. Treatment assigned was not revealed to the subject or to the person administering the drug until the study period was complete. Group A received a FDC of paracetamol 500 mg with diclofenac sodium 50 mg (Unison Pharmaceuticals, Ahmedabad) and group B received a FDC of paracetamol 375mg with tramadol 50 mg (Biochem Pharmaceuticals, Mumbai) orally as a single dose with 200 ml of water. All the volunteers were tested for all the three pain models. Baseline observations were recorded for pain threshold and pain tolerance before the administration of the drugs. After drug administration, test readings were taken at the interval of 30, 60, 120, and 180 minutes. Both groups were given a washout period of 7 days. Crossover was done and the above-mentioned procedure repeated.

The results were analyzed as under:

Efficacy analysis

Primary end point -- an increase in the pain tolerance as denoted by the increase in time interval for which the subject can withstand the pain.

Safety analysis

Identification, analysis and reporting of adverse drug reactions occurred during the study were done. All the reported adverse drug events were analyzed for causality by using the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale.[21] A physician gave appropriate treatment for the adverse drug reactions.

Statistical analysis of the data was done using SPSS software version 14. The independent t-test was applied for analysis of analgesic efficacy for the two groups before and after drug administration. The chi-square test was used to analyze adverse drug reactions in two groups. A P value < 0.05 was considered significant.

Results

Out of 30 participants, 29 completed the trial. One volunteer could not come for the crossover because of malarial infection. Mean age of participants was 23±1 years. Twenty participants were male and 10 were female having a male:female ratio of 2:1 [Table 1]. The results of the cold-water stress test were analyzed by an independent t-test [Table 2]. There was no significant difference between the two groups in both sessions (P value >0.05). The results of the radiant heat test suggested that paracetamol with tramadol treatment significantly increased pain tolerance at 2 hours and 3 hours (P 0.02 and 0.05 respectively) compared to the paracetamol with diclofenac combination group [Table 3]. The results of the BP cuff inflation method revealed no significant difference between the two groups in both the sessions (P>0.05) as shown in Table 4, though this model is considered specific for evaluation of anti-inflammatory action.

Table 1

Genderwise distribution of participants (n=30)

Table 2

Analysis of the cold-water stress test (n=30)

Table 3

Analysis of the radiant heat method: (n=30)

Table 4

Analysis of the BP cuff inflation method (n=30)

In the paracetamol with tramadol FDC group, four volunteers complained of sedation and one developed rash over the forearm. None of the volunteer receiving a FDC of paracetamol with diclofenac combination developed any adverse drug reactions during the study period. The difference between the two groups was statistically significant (P <0.05). All the reactions were in the category of “probable” according to WHO-UMC criteria of causality assessment.

Discussion

This study is conducted with the main objective of evaluating and comparing the analgesic activity of a FDC of paracetamol with diclofenac sodium and a FDC of paracetamol with tramadol on different human pain models in healthy volunteers. Human experimental pain models for the evaluation of analgesic efficacy use different algesic stimuli like heat, cold, pressure, ischemia, electricity, etc. for pain production. Mechanical, chemical, thermal, freezing, and ultraviolet A or B radiation are used to study the analgesic effect of NSAID.[22] Electrically induced pain models are able to discriminate the effect of diclofenac from placebo. It also differentiates the gender effect in response to ibuprofen.[22] In a laser-induced pain model paracetamol shows significant analgesic activity compared to placebo. However, paracetamol is less effective compared to the combined effect of paracetamol plus codeine.[22]

In the present study, three different pain models are used. The parameter taken to evaluate the analgesic efficacy of study drugs is pain tolerance. The wide difference in the pain tolerance at the baseline, though not statistically significant, can be because of individual variations in pain perception. Results of the cold-water stress test show no statistically significant difference between the efficacies of two groups in both the sessions possibly because of lack of inflammation or hyperalgesia in this model leading to inconsistent and unreliable results.[2] A cold-pressure test is known to activate the “diffuse noxious inhibitory control system,” which is a system of descending neuronal pathways arising in the brain stem that exerts negative feed-back control on the incoming activity to the spinal cord.[23] Other have also shown inconsistent analgesic effects of several NSAID in the cold-water stress pain model.[23]

In the radiant heat method, paracetamol with tramadol treatment significantly increased pain tolerance at 2 hours and 3 hours (P 0.028 and 0.055 respectively) compared to that of the paracetamol with diclofenac group. In this model there is rapid skin heating (more than 1°C/s) which activates A-δ fibers that evoke pain sensation within 0.4 seconds and is called “first pain.”[19] Slow heating less than 1°C/s preferentially activates C-fibers to cause “second pain.” It is thought to be due to activation of peripheral opioid receptors and is considered best for evaluation of the opioid analgesics. Radiant heat delivers fast heat so the evaluation of the “second pain” is not possible with this model. Lasers probably stimulate A-δ fibers giving a pricking pain followed by C-fiber mediated second pain. Compared to heat pain, the neuronal activation after cold pain is not completely described but it probably involves a mosaic of primary afferent input with a definite involvement of C-fibers.[23]

Results of the BP cuff inflammation method did not show statistically significant difference between the efficacies of two groups in both the sessions. This is an established method for evaluating inflammatory component of the pain. A FDC of paracetamol with diclofenac sodium has been justified stating that diclofenac sodium adds the anti-inflammatory component to the combination. Our results show that there is no superior efficacy of the FDC of paracetamol with diclofenac in the inflammatory pain model in this study.

Concerns over the marketing of increasing number of drug combinations by pharmaceutical companies, particularly in the developing countries, have been raised. A variety of NSAID combinations are available, often as over the counter products.[24] These FDC are an easy way to sell two drugs when one (or even none) may be needed. These FDC have become the largest selling antiinflammatory/analgesic/antipyretic products[24-26] and “single” drugs have almost become redundant and “old fashioned.” Combination of two drugs acting by same mechanism is not synergistic. Combining two NSAIDs or NSAID with analgesics like paracetamol does not improve the efficacy of treatment but imposes unnecessary financial burden, increases adverse effects leading to hospitalization, and deteriorate quality of life.[27]

In conclusion, the FDC of paracetamol with tramadol is more effective than the FDC of paracetamol with diclofenac sodium on the radiant heat model but the cold stress and blood pressure cuff inflation models did not show any difference between the two.