despite the enormous advances in drug development over the past two decades , development of novel analgesics has lagged behind . analgesics that are used widely are opioids and nonsteroidal anti - inflammatory agents ( nsaids ) , all of which have potentially threatening toxicities even when used in therapeutic doses . their adverse effects and insufficient effectiveness in many types of pain are the main driving forces in the development of new analgesics . the main factors contributing to the apparent draught of novel analgesics are insufficient mechanism - based approach to clinical pain syndromes and inadequate predictive validity of animal models of pain in humans . in addition , the neurobiology of nociceptive systems differs between species , and this limits the extrapolation of findings from animal studies to man even further . experimental pain models in healthy volunteers for evaluation of analgesic action minimize the gap between knowledge gained in animal and human clinical studies . among several experimental approaches in humans for early screening of new analgesics , the method originally described by randall and selitto has been used by many investigators and has been proven to detect the efficacy of analgesics . ugo basile analgesy meter ( randall  selitto test ) was used to measure the analgesic property in the present study as terminalia chebula was found to have analgesic and anti - inflammatory properties probably mediated by the peripheral and central mechanisms . have indicated anti - inflammatory activity for the aqueous extracts of fruits of t. chebula and could inhibit cyclooxygenase-1 ( cox-1 ) , cox-2 , 5-lipoxygenase ( 5-lox ) , tumor necrosis factor - alpha ( tnf- ) , and down - regulation of nuclear factor - kappa b. in the present study , we have evaluated the effect of 1000 mg of aqueous extract of t. chebula on pain in healthy human volunteers using a mechanical pain model . the present study was approved by the institutional ethics committee and was performed as per the good clinical practice and declaration of helsinki guidelines . this was a randomized , double - blind , placebo - controlled , cross - over study . twelve healthy male volunteers aged 18 - 40 years , with a body mass index in the range of 19.5 - 25.9 kg / m participated in the study . the study medication consisted of two capsules ( 500 mg each ) of t. chebula and two placebo capsules , both given as single dose in a randomized manner . each capsule of t. chebula contained a patented standardized aqueous extract of t. chebula with  15% of chebulinic acid ,  10% of chebulagic acid and  15% of other low molecular weight hydrolysable tannins and is highly standardized by high performance liquid chromatography . placebo capsules were identical to t. chebula capsules in size , shape , and color and were supplied by the study sponsor , natreon inc . , new jersey , usa . the volunteers were screened for eligibility into the study . the successfully screened healthy volunteers were trained on two separate occasions for the randall  selitto test procedure prior to participation into study . in the present study , we evaluated the analgesic activity of t. chebula using mechanical pain model by randall selitto test using analgesy meter ( ugo - basile , biological research apparatus , milan , italy ) . participant 's nail bed of index finger of nondominant hand was placed on a small plinth of basile analgesy meter , under a cone shaped pusher with a rounded tip as shown in figure 1 . a pedal switch was pressed by the investigator to apply force to the nail bed . the instrument is geometrically designed to increase the force on the finger at a constant rate of 80 g / s . the participant was asked to lift his index finger of the other hand when he first experiences pain ( noted as pain threshold ) and when he was unable to tolerate the pain ( noted as pain tolerance ) . then , pressure on the pedal switch was removed , and the weight - bearing arm of the instrument was lifted to release the pressure on the nail bed . the average of the three readings was taken and the force ( in grams ) exerted on the nail bed and the threshold time and tolerance time were calculated . components of ugo basile analgesy meter the volunteers were given either two capsules of 500 mg t. chebula or identical looking placebo capsules with 240 ml of water at 8:00 am as per prior randomization schedule ( run 1 ) , in a double - blind manner . after taking the drug , the subject was asked to sit upright on the chair for 2 h. randall  selitto test was repeated 3 h after the drug administration and the readings were noted . after 2 weeks of washout period , the second drug ( run 2 ) was administered according to the randomization sequence and the same procedure was repeated . unpaired student 's t - test were used to assess the analgesic efficacy of t. chebula with p < 0.05 considered to be statistically significant . all statistical analyses were performed using the graphpad prism software 4 ( graphpad software inc . 14 subjects were screened for participation with two excluded due to hypertension . the mean age of the volunteers was 32.3  3.1 years , and average body mass index was 22.4  1.0 kg / m . a statistically significant increase in mean pain threshold force , mean pain threshold time , mean pain tolerance force and mean pain tolerance time was observed with t. chebula with a p < 0.001 . the increase in mean pain threshold force , mean pain threshold time , mean pain tolerance force and mean pain tolerance time observed with placebo was statistically nonsignificant [ table 1 ] . pain threshold force and time ; pain tolerance force and time with t. chebula and placebo at baseline and postdrug when compared to baseline , there was 20.8% increase in pain threshold force postdrug with t. chebula , and 1.0% with placebo . whereas 20.1% increase in pain threshold time was observed with t. chebula , and 0.86% with placebo . pain tolerance force postdrug increased by 13.4% with t. chebula , and 0.2% with placebo . whereas 13.4% increase in pain tolerance time was observed with t. chebula , and 0.2% with placebo . both the drugs were well tolerated , and none of the subjects reported any adverse events . all safety lab investigations were done before and after administration of each drug and were found to be normal . in the present study , aqueous extract of t. chebula has demonstrated analgesic activity in healthy human volunteers using experimentally - induced mechanical pain by showing a significant increase in the pain threshold force and time ; pain tolerance force and time compared to placebo . t. chebula is widely used in ayurvedic medicine and found to have anti - inflammatory and analgesic effect by inhibition of cox-1 , cox-2 , 5-lox , tnf- and down - regulation of nf-b . terminalia chebula showed analgesic , anti - pyretic and anti - inflammatory properties without producing gastric ulceration in rats . kaur and jaggi evaluated the extracts of t. chebula fruit for their analgesic activity using the tail immersion model in mice exhibiting analgesic response at 200 , 400 and 800 mg / kg body weight in acute pain and in chronic pain with maximum analgesic response on 14 day . the results suggested that t. chebula could be a potential candidate for bioactivity - guided isolation of natural analgesic agents in the management of chronic pain . in another study by nair et al . , hydroalcoholic extract of t. chebula produced a significant inhibition of joint swelling compared to control in both formaldehyde - induced and complete freund 's adjuvant - induced arthritis in mice . t. chebula treatment also reduced serum tnf- level and synovial expression of tnf - r1 , interleukin-6 ( il-6 ) and il-1 thereby exhibiting its therapeutic potential as a disease - modifying agent in the treatment of rheumatoid arthritis . in a study by ramani and pradhan acetone extract of fruits of t. chebula in doses of 160 and 320 mg / kg showed anti - inflammatory and antiarthritic effects as it decreased the paw edema significantly ( p < 0.05 ) which was comparable to dexamethasone treated group . also , in contrast to the traditional nsaids , which are reported to produce gastric ulceration and gastrointestinal bleeding , t. chebula extract is reported to have gastro protective effect . to the best of our knowledge , there is limited published data on evaluation of the analgesic activity of t. chebula alone in human subjects . in the present study , we used ugo basile analgesy meter for conducting randal  selitto test as it is associated with good precision and smaller inter - individual and intra - individual variation of baseline effect . in the present study , aqueous extract of t. chebula 1000 mg given as single dose was well tolerated without producing any adverse effects . t. chebula significantly increased pain threshold and pain tolerance force and time compared to placebo in healthy volunteers . both the study medications were well tolerated , and no adverse events were observed during the study . further multiple dose studies may be needed to establish the analgesic efficacy of the drug in patients suffering from osteoarthritis , rheumatoid arthritis and other painful conditions which require analgesics .
background and aims : to evaluate analgesic activity and safety of single oral dose ( 1000 mg ) of terminalia chebula using a mechanical pain model in healthy human volunteers.material and methods : twelve healthy volunteers were randomized to receive either single oral dose of 2 capsules of t. chebula 500 mg each or identical placebo capsules in a double - blinded manner . 
 mechanical pain was assessed using ugo basile analgesy meter ( randall  selitto test ) before and 3 h after administration of test drug . 
 the parameters evaluated were pain threshold force and time ; pain tolerance force and time . a washout period of 1-week 
 was given for crossover between active drug and placebo.results:terminalia chebula significantly increased the mean percentage change for pain threshold force and time , and pain tolerance force and time compared to placebo ( p < 0.001 ) . 
 the mean percentage change for pain threshold force and time ( 20.8% and 21.0% ) was increased more than that of pain tolerance force and time ( 13.4% and 13.4% ) . 
 no adverse drug reaction was reported with either of the study medications during the study period.conclusion:t . 
 chebula significantly increased pain threshold and pain tolerance compared to placebo . 
 both the study medications were well tolerated . 
 further multiple dose studies may be needed to establish the analgesic efficacy of the drug in patients suffering from osteoarthritis , rheumatoid arthritis and other painful conditions .