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The objective of this study was to evaluate the efficacy of a non-selective COX inhibitor (tolfenamic acid) and a selective COX-2 inhibitor (robenacoxib) for post-operative pain control in cats. Thirty cats undergoing ovariohysterectomy were randomly divided into three groups: the control (placebo) group, the tolfenamic acid (4 mg/kg/day) group, and the robenacoxib (1 mg/kg/day) group. Non-steroidal anti-inflammatory drugs (NSAIDs) were administered orally 2 hr before anesthesia induction and 24 and 48 hr post-operation. Buccal mucosal bleeding times (BMBTs) were assessed prior to anesthesia induction. Colorado pain scores and composite pain scores were evaluated in a blinded fashion before induction and 2, 8, 24, 30 and 48 hr post-operation. The Colorado pain scores of cats receiving robenacoxib were significantly lower than those of cats in the control group at 30 (P=0.0126) and 48 (P=0.0439) hr post-operation. The composite pain scores of cats from the robenacoxib group were lower than those of cats in the control group at 30 (P=0.0299) and 48 (P=0.0103) hr post-operation. The Colorado pain scores of cats receiving tolfenamic acid were significantly lower than those of cats in the control group at 30 hr (P=0.0186) post-operation. The composite pain scores in cats in the tolfenamic acid group were lower than the scores of cats in the control group at 24 (P=0.0403) and 48 (P=0.0413) hr post-operation. BMBTs remained within normal limits in all groups. Both tolfenamic acid and robenacoxib are useful for post-operative pain control in cats.

Background: This is an updated version of the original Cochrane review published in Issue 3, 2012. Caffeine has been added to common analgesics such as paracetamol, ibuprofen, and aspirin, in the belief that it enhances analgesic efficacy. Evidence to support this belief is limited and often based on invalid comparisons., Objectives: To assess the relative efficacy of a single dose of an analgesic plus caffeine against the same dose of the analgesic alone, without restriction on the analgesic used or the pain condition studied. We also assessed serious adverse events., Search Methods: We searched CENTRAL, MEDLINE, and EMBASE from inception to 28 August 2014, the Oxford Pain Relief Database, and also carried out Internet searches and contacted pharmaceutical companies known to have carried out trials that have not been published., Selection Criteria: We included randomised, double-blind studies that compared a single dose of analgesic plus caffeine with the same dose of the analgesic alone in the treatment of acute pain., Data Collection and Analysis: Two review authors independently assessed the eligibility and quality of studies, and extracted data. Any disagreements or uncertainties were settled by discussion with a third review author. We sought any validated measure of analgesic efficacy, but particularly the number of participants experiencing at least 50% of the maximum possible pain relief over four to six hours, participants reporting a global evaluation of treatment of very good or excellent, or headache relief after two hours. We pooled comparable data to look for a statistically significant difference, and calculated numbers needed to treat to benefit (NNT) with caffeine. We also looked for any numerical superiority associated with the addition of caffeine, and information about any serious adverse events., Main Results: We identified no new studies with available results for this update. The earlier review included 20 studies (7238 participants) in valid comparisons, but because we used different outcomes for some headache studies, the number of participants in the analyses of the effects of caffeine is now 4262 when previously it was 5243. The studies were generally of good methodological quality, using standard designs and mostly standard scales of pain measurement, although many of those treating postoperative pain were small.Most studies used paracetamol or ibuprofen, with 100 mg to 130 mg caffeine, and the most common pain conditions studied were postoperative dental pain, postpartum pain, and headache. There was a small but statistically significant benefit with caffeine used at doses of 100 mg or more, which was not dependent on the pain condition or type of analgesic. About 5% to 10% more participants achieve a good level of pain relief (at least 50% of the maximum over four to six hours) with the addition of caffeine, giving a NNT of about 14 (high quality evidence).Most comparisons individually demonstrated numerical superiority with caffeine, but not statistical superiority. One serious adverse event was reported with caffeine, but was considered unrelated to any study medication.We know of the existence of around 25 additional studies with almost 12,500 participants for which data for analysis were not obtainable. The additional analgesic effect of caffeine remained statistically significant but clinically less important even if all the known missing data had no effect; the bulk of the unobtainable data are reported to have similar results as this review., Authors' Conclusions: The addition of caffeine (≥ 100 mg) to a standard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief.

Background: Acute and chronic pain commonly accompany various clinical conditions such as contusion, fracture, osteoarthritis, peripheral neuropathy, and postherpetic neuralgia. Recent studies have found that antioxidative drugs can have analgesic effects. The present study tested the hypothesis that a new anthranilic acid derivative, EAntS-GS, exerts antinociceptive effects on inflammatory pain in a rat model., Methods: We induced subacute pain with a plantar injection of Freund's complete adjuvant (FCA) in Sprague-Dawley rats. EAntS-GS (1 mg/kg subcutaneous injection or 1% application) was administered every 12 h beginning 24 h after FCA administration, and the plantar test was used to determine its effect on pain. Levels of myeloperoxidase, inducible nitric oxide synthase (iNOS), and protease activated receptor 2 (PAR2) were measured to elucidate the mechanism of action of EAntS-GS., Results: EAntS-GS significantly reduced FCA-induced pain and myeloperoxidase, iNOS, and PAR2 levels. Our findings suggest that the new anthranilic acid derivative, EAntS-GS, exerts antinociceptive effects, and that the mechanism involves iNOS and PAR2., Conclusion: We conclude that EAntS-GS should be considered a new therapeutic tool to treat acute and chronic pain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Mexican people employed infusion of leaves of Choisya ternata Kunth for their antispasmodic and "simulative properties"., Aim of the Study: In the present study the detailed GC and GC-MS analyses of the essential oil of Choisya ternata Kunth (Rutaceae) were performed. The presence of a minor constituent isopropyl N-methylanthranilate (1) was revealed among other identified volatiles. A synthesis of 1 was undertaken in order to corroborate this find and obtain gram quantities that would allow the testing of its biological activity (peripheral and central antinociceptive activity)., Materials and Methods: The oils were investigated by GC and GC-MS. Synthesized compounds were spectrally characterized (UV-Vis, IR, 1D and 2D NMR, MS). The obtained synthetic samples of compounds were assayed for peripheral and central antinociceptive activity in two models (effects on acetic acid induced writhing in mice and the hot plate test for nociception)., Results: Detailed GC and GC-MS analyses of the essential oil of Choisya ternata Kunth (Rutaceae) among 157 other identified volatiles revealed the presence of a minor constituent isopropyl N-methylanthranilate (1). Compound 1, named ternanthranin, is therefore detected as a natural product for the first time with a very restricted occurrence (samples of several citrus oils were screened for the presence of 1). The antinociceptive activities were assayed for ternanthranin, the two other synthetic analogs, methyl and propyl N-methylanthranilate, as well as the essential oil and the crude ethanol extract of the leaves. The results clearly demonstrate a very high (even significant at 0.3 mg/kg) dose dependent activity for the anthranilates (and the extracts). Isopropyl N-methylanthranilate showed the highest, while methyl N-methylanthranilate showed the lowest activity (with the methyl ester at 3 mg/kg still better than acetylsalicylic acid, at 200 mg/kg, in the first, or comparable with morphine, at 5mg/kg, in the second test)., Conclusion: This study once again revealed that detailed investigations of plant species with ethnopharmacologically documented activity may yield new natural compounds-a new alkaloid (ternanthranin), a volatile simple anthranilate that can be considered responsible for the antinociceptive activity of the crude plant extracts., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To investigate the efficacy of meloxicam or tolfenamic acid administered preoperatively and postoperatively (five days in total) to cats undergoing surgical fracture repair., Methods: Eighty-eight otherwise healthy cats were matched according to fracture site and then randomly allocated to one of two groups, receiving 0·2 mg/kg meloxicam by subcutaneous injection (group M) or 1·5 to 3 mg/kg tolfenamic acid orally (group T) before anaesthesia. Analgesia was continued with 0.05 mg/kg oral meloxicam once daily or 1·5 to 3 mg/kg oral tolfenamic acid twice daily for four days postoperatively. Pain was assessed by a blinded observer using visual analogue scales and a functional limb score. The drug administrator assessed feed intake and palatability of the treatment., Results: Data from 66 cats were analysed. Visual analogue scale pain scores and functional limb scores decreased over time in both groups but were not significantly different between treatments. Feed intake was similar in both groups. Meloxicam was significantly more palatable than tolfenamic acid on all treatment days., Clinical Significance: Meloxicam and tolfenamic acid demonstrated comparable analgesia, without clinically observable side effects. Meloxicam may be associated with superior compliance in clinical practice due to the higher palatability and once daily treatment resulting in better ease of administration., (© 2010 British Small Animal Veterinary Association.)

Aim: To assess the welfare impact of lameness on dairy cattle in New Zealand by measuring the duration of allodynia (decreased nociceptive threshold) and increased locomotion score, and to evaluate the influence of treatment on that duration., Methods: After lame cows were treated using corrective paring by a veterinarian, they were allocated to one of six treatment groups. If the veterinarian determined that additional elevation of the lesion was not required the cow was randomly allocated to receive one of four treatments, viz 2 mg/kg tolfenamic acid, a plastic shoe to elevate the lesion, both treatments, or no further treatment. Cows that required additional elevation were treated using a plastic shoe and then randomly allocated to two separate treatment groups, either 2 mg/kg tolfenamic acid or no further treatment. Assessments of locomotion score (based on posture and gait) and mechanical nociceptive threshold (using a pneumatically actuated blunt pin) were made prior to treatment, and 3, 8, 28 and 100 days later., Results: Data were collected from 149 lame cows from nine dairy farms. There were significant improvements in mean locomotion score and nociceptive threshold in all treatment groups. At all time-points after treatment, locomotion score and nociceptive threshold were significantly improved when compared with the previous time-point. Thus, in these cows, the deleterious effects of lameness persisted for longer than 28 days, despite treatment, as the mean locomotion scores and nociceptive threshold on Day 100 were better than those on Day 28. No significant long-term benefit of using tolfenamic acid at the time of treatment was observed on either locomotion score or nociceptive threshold, nor was there any benefit in using a plastic shoe in cases where it had been determined that such treatment was not necessary., Conclusions: This study demonstrated that the welfare impact of lameness on dairy cattle in New Zealand is of long duration even when treated effectively. In contrast to previous studies, no significant long-term benefit of using non-steroidal anti-inflammatory drugs (NSAID) at the time of treatment was observed, probably because unlike those previous studies the nociceptive threshold improved in the cattle which did not receive an NSAID, perhaps because treated cattle were kept on pasture rather than housed., Clinical Relevance: The long duration of increased allodynia after treatment demonstrates that prevention of lameness rather than therapeutic treatment is the key to reducing its impact on the welfare of dairy cows.

The migraine prophylactic effect of tolfenamic acid 300 mg versus pizotifen 1.5 was evaluated in a prospective, randomized, double-blind, parallel group study. 192 patients were included with a frequency of 4-8 moderate to severe migraine attacks monthly, with or without aura, fulfilling the diagnostic criteria for migraine as defined by the International Headache Society. A four-week baseline period without medication was followed by 12 weeks of treatment with tolfenamic acid 300 mg or pizotifen 1.5 mg. In both periods patients were allowed to take escape medication (paracetamol and codeine) if the treatment was inefficient. All the patients had a headache diary before and during treatment. The primary criterion of efficacy was reduction in attack frequency per 4 weeks. Also reduction in intensity or duration of migraine attacks in hours at the end of 12 weeks treatment compared to the baseline period was measured. Both groups exhibited significant reduction in attack frequency (p < 0.001). Tolfenamic acid significantly reduced severity compared to the run-in period (p = 0.009). Patients treated with pizotifen needed more escape medication when compared to the run-in period (p < 0.01). Tolerance, especially weight gain, was a major drawback with pizotifen. Because of its high efficacy, excellent tolerability and low cost, tolfenamic acid is an interesting option for migraine prophylaxis.

The adequacy of postoperative analgesia was assessed in 40 cats following ovariohysterectomy. At extubation, cats were given one dose of carprofen, ketoprofen, meloxicam or tolfenamic acid. Postoperative analgesia was assessed using visual analogue scale (VAS) scoring for pain and sedation; measurement of mechanical nociceptive thresholds at the wound; recognition of the requirement for rescue intervention analgesia; and an overall clinical assessment score at 18 hours. VAS pain scores were low throughout the trial, with no significant differences found between the groups. Postoperative mechanical nociceptive thresholds decreased significantly from baseline in all four groups, with no significant differences between the groups. One cat in each of the tolfenamic acid, ketoprofen and meloxicam groups required rescue intervention analgesia. Nine out of 10 cats in all four groups were classified as having desirable overall clinical assessment scores. In summary, all four drugs provided good postoperative analgesia, although none was able to prevent postoperative wound tenderness.

Although sumatriptan is an effective drug for the treatment of acute migraine attacks, recurrence has been cited as an important limitation for its use. Tolfenamic acid is also effective in the acute treatment of migraine attacks. We studied the recurrence rate of migraine attacks with the use of sumatriptan plus tolfenamic acid among patients who presented frequent recurrence with sumatriptan. Fifty migraineurs were retrospectively studied, all having treated at least 10 attacks with 100 mg P.O.; sumatriptan was effective in at least eight of them. The patients also presented recurrence in less than 24 h in at least five of the treated attacks. We then used sumatriptan 100 mg plus tolfenamic acid 200 mg P.O. during the first 60 min of the attack; 240 attacks were treated and there was recurrence in 57 (23.8%). With sumatriptan alone, 5 out of 8 attacks (62.5%) presented recurrence. We therefore conclude that the combination sumatritpan plus tolfenamic acid is effective in reducing the recurrence rate from 5 of 8 (62.5%) to 1.19 of 5 (23.8%). Further prospective studies with a double-blind design and a higher number of treated attacks are necessary to confirm these initial observations.

The current practice of postoperative pain management among Finnish oral surgeons was evaluated in a two-phase study. In the first phase, a questionnaire was sent to specialist members of the Finnish Society of Oral and Maxillofacial Surgeons that concerned the routine use of analgesic drugs after surgical removal of third molar teeth. In the second phase, the clinical adequacy of pain medication was assessed in 84 patients who had the same procedure. Patients estimated the intensity of pain with a 100 mm visual analogue scale at five time points during the day of surgery and on three postoperative days. Anti-inflammatory analgesics were widely used either alone or in combination with centrally acting analgesic drugs. Tolfenamic acid, diclofenac, and ketoprofen were the most commonly used analgesic drugs. The analgesic effect of the currently used drug combinations proved to be sufficient except in a few patients during the first night after surgery.

In a double-blind cross-over study we compared tolfenamic acid with paracetamol in out-patients with common migraine (migraine without aura). Each patient was treated during (at least) 4 attacks with one of the following alternatives: tolfenamic acid 200 mg, tolfenamic acid 400 mg, paracetamol 500 mg or paracetamol 1000 mg in a randomized sequence. The same sequence of treatments was applied to (preferably) 4 more attacks. Dosage was repeated after 2 h if the attack had not abated. Escape medication was allowed after 4 h if the treatment was inefficient. A total of 83 patients were admitted to the study, but 3 dropped out, while 10 completed less than 4 attacks. Seventy completed 4 attacks, and 58 completed all 8. The total number of attacks treated was 545. We found a significant superiority of tolfenamic acid over paracetamol with regard to effect on pain after 2 h (p less than 0.01), patients' global evaluation (p less than 0.001), and use of escape medication (p less than 0.02). The trend was the same for duration of attacks, confinement to bed during attack and nausea, but the results were not statistically significant. There was no significant difference between the smaller and the larger dose of either drug nor between the need for escape medication, although the trend favoured tolfenamic acid. Side effects were few. Tolfenamic acid is evidently valuable in treatment of migraine.

In the light of a study involving a group of 50 patients hospitalised or seen on an ambulatory basis in a department of Stomatology and Maxillofacial surgery, Idarac (floctafenine) was felt to be an effective analgesic, at an average dose of 4 tablets. Tolerance was excellent from a clinical standpoint, rendering the drug easy to use, both on an out-patient basis as well as postoperatively.

Three hundred and twelve patients suffering from painful conditions were admitted to a multicentre, double-blind controlled trial, conducted in general practice in which five analgesics--floctafenine (Idarac), paracetamol, aspirin, dihydrocodeine and pentazocine--were compared. Overall ratings of analgesic effect placed floctafenine first in rank order. Floctafenine was statistically significantly superior in effect to pentazocine but not to the other three agents as far as doctor ratings were concerned; and superior to both pentazocine and dihydrocodeine in the opinion of patients. Fewer patients experienced side-effects on floctafenine than on the other four analgesics and this difference between floctafenine and pentazocine, and floctafenine and dihydrocodeine was statistically significant.

Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid (200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg + 100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences.

Floctafenine has been studied in comparison with acetyl-salicylic acid, indomethacin and d-propoxyphene in a series of tests for analgesic and anti-inflammatory activity. It is very active in the acetic acid-induced writhing test and on the inflamed paw in the Randall and Selitto test. Furthermore, like acetylsalicylic acid and indomethacin, but unlike d-propoxyphene, it has no effect on the non-inflamed paw, and similarly it is inactive in the tail flick and in the hot plate test. Floctafenine is also very effective in some acute inflammations such as naphtoylheparamine-induced oedema or in UV erythema, but it is distinctly less active in carrageenin-induced oedema or in adjuvant arthritis. In rat gastric and intestinal mucosa its tolerance is excellent. It has no action on the central and autonomous nervous systems. The pharmacological profile of this compound thus places it amongst the non-narcotic analgesics. It has an exceptionally high therapeutic index, much higher than that of acetylsalicylic acid and indomethacin.

The analgesic effect of 10 anti-inflammatory drugs was compared using a single-blind method in 90 patients with rheumatoid arthritis. Each patient received two different drugs, for three days each and each drug was evaluated in 18 patients. After the trial, the patients considered which of the drugs they preferred. The greatest relief from pain was achieved by diclofenac, indomethacin, naproxen and tolfenamic acid, each of these being preferred by the majority of patients and being significantly (p less than 0.01) better than the least effective drugs ketoprofen and proquazone. Acetylsalicylic acid, azapropazone, carprofen and ibuprofen were considered intermediate in efficacy.

Seventy-seven patients took part in a double-blind crossover trial to compare the effects of floctafenine, dextropropxyhene and aspirin in the relief of post-operative pain. Pain levels were recorded at hourly intervals and pain relief scores calculated. For Dose 1, the difference between the mean pain relief score for patients receiving floctafenin (12.8) and that for patients receiving dextropropoxyphen (6.2) was significant, (p smaller than 0.05) but the difference between the mean score for aspirin (9.2) and that for dextropropoxyphene was not significant. For Dose 2, there were no significant differences between the mean pain relief scores for floctafenine (12.5), for aspirin (10.9) and for dextropropoxyphene (13.2).

To compare the effect of tolfenamic acid and paracetamol in acute migraine, 149 patients participated in a double-blind controlled, multipractice study. 116 patients completed both treatments. The patients were asked to evaluate the two drugs in terms of the following parametres: 1) intensity of headache after three hours: as usual or less, 2) necessity of further medicine after three hours, 3) assessment of test medicine regarding the effect on strength, duration, and other inconveniences connected with the headache, 4) possible side effect connected with test medicine, and how these were experienced. After both forms of treatment, the patients were asked to give an overall judgement of the medicine, which had the best effect. No statistically significant difference was observed between the effect of 400 mg tolfenamic acid and 1 g paracetamol as to the five test parametres when using parametric or non-parametric statistics with a significance level of 5%. However, tolfenamic acid was numerically better than paracetamol with regard to headache after three hours, necessity of further medicine, judgement of attacks, and preference.