Mario I. Ortiz

Pharmacological evidence for the activation of K+ channels by diclofenac

The involvement of K(+) channels in the antinociceptive action of diclofenac was assessed in the formalin test. Local administration of diclofenac produced a dose-dependent antinociceptive effect due to a local action because drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with glibenclamide and tolbutamide (ATP-sensitive K(+) channel inhibitors), charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) prevented diclofenac-induced antinociception. Given alone, K(+) channel inhibitors did not modify formalin-induced nociceptive behavior. Pinacidil (an ATP-sensitive K(+) channel opener) also produced antinociception which was blocked by glibenclamide. The peripheral antinociceptive effect of morphine (positive control) was blocked by glibenclamide and 4-aminopyridine but not by charybdotoxin or apamin. The results suggest that the peripheral antinociceptive effect of diclofenac may result from the activation of several types of K(+) channels, which may cause hyperpolarization of peripheral terminals of primary afferents.

Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test

The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.

The peripheral antinociceptive effect of resveratrol is associated with activation of potassium channels

The possible participation of K(+) channels in the antinociceptive action induced by resveratrol was assessed in the 1% formalin test. Local administration of resveratrol produced a dose-dependent antinociception in the second phase of the test. The antinociception produced by resveratrol was due to a local action as its administration in the contralateral paw was not active. Local pretreatment of the injured paw with glibenclamide, tolbutamide or glipizide (ATP-sensitive K(+) channel inhibitors) did not modify resveratrol-induced antinociception. In contrast, charybdotoxin and apamin (large and small conductance Ca(2+) activated-K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) dose-dependently prevented resveratrol-induced antinociception. Local peripheral administration of glibenclamide, but not charybdotoxin or apamin, significantly reduced the antinociceptive effect produced by peripheral morphine (positive control). At the highest effective doses, none of the drugs used induced behavioral side effects as revealed by the evaluation of stepping, righting, corneal and pinna reflexes. In addition, when given alone, none of the inhibitors modified the nociceptive behavior induced by 1% formalin. The results suggest that resveratrol opens large and small conductance Ca(2+)-activated K(+) channels, but not ATP-sensitive K(+) channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K(+) channels was also suggested, but since non-selective inhibitors were used the data awaits further confirmation.

Primary dysmenorrhea among Mexican university students: prevalence, impact and treatment

OBJECTIVE To evaluate the prevalence, impact and treatment of primary dysmenorrhea among Mexican university students. STUDY DESIGN A multiple-choice questionnaire was administered to 1539 students in six university programs: medicine, nursing, nutrition, dentistry, pharmacy and psychology. Data on the presence, severity, symptoms, treatment and limitations caused by dysmenorrhea were obtained and analyzed. RESULTS The mean+/-SD age of the women was 20.4+/-2.0 years; the mean age of menarche was 12.3+/-1.5 years. A total of 64% of the women experienced dysmenorrhea. Dysmenorrhea was more prevalent among nutrition and psychology students than among medicine, pharmacy and dentistry students (p<0.05). Dysmenorrhea was mild in 36.1% of women, moderate in 43.8% and severe in 20.1%. Nursing students showed an intensity of pain that was significantly higher than that of medicine and dentistry students (p<0.05). Sixty-five percent of the women with dysmenorrhea reported that it limited their daily activities, and 42.1% reported school absenteeism (SA) as a result. Of those who experienced dysmenorrhea, 25.9% consulted a physician, and 61.7% practiced self-medication (SM). The most common medications used were an over-the-counter (OTC) medication with paracetamol (an analgesic), pamabrom (a diuretic), and pyrilamine (a histamine antagonist), another OTC with metamizol (a non-steroidal anti-inflammatory drug [NSAID]) plus butylhioscine (an antispasmodic drug) and naproxen (a NSAID). Of those women using prescribed medications, 18.4% reported complete remission of their symptoms, while 78.1% reported little to moderate alleviation, and 3.6% reported no effect on their menstrual distress. Similarly, of the women who practiced SM, 23.4% reported complete relief, 75.5% reported little to moderate effectiveness, and 1.0% reported no efficacy. CONCLUSION The prevalence of dysmenorrhea among Mexican university students is high, and the pain that these women suffer can be severe, disabling and result in short-term SA. The pain is often not completely relieved despite the use of medication. It is necessary to improve the therapeutic options for relief of pain caused by dysmenorrhea and to minimize the impact of dysmenorrhea on social, economic and school activities.

Prevalence and impact of primary dysmenorrhea among Mexican high school students

To evaluate factors affecting the prevalence of dysmenorrhea in a group of Mexican students.

Synergistic effects between codeine and diclofenac after local, spinal and systemic administration

This study was designed to evaluate the extent of the antinociceptive interaction between codeine and diclofenac at the local, spinal and systemic level. The effects of individual and fixed-ratio combinations of locally, spinally or orally given codeine and diclofenac were assayed using the formalin test in rats. Isobolographic analysis was employed to characterize the synergism produced by the combinations. Codeine, diclofenac and fixed-ratio codeine-diclofenac combinations produced a dose-dependent antinociceptive effect when administered locally, spinally or systemically. ED(30) values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED(30) values for the combination estimated from the isobolograms were 422.2+/-50.5 microg/paw, 138.5+/-9.2 microg/rat, and 9.3+/-1.1 mg/kg for the local, spinal and oral routes, respectively. These values were significantly higher than the actually observed ED(30) values which were 211.1+/-13.6 microg/paw, 45.9+/-3.9 microg/rat, and 2.5+/-0.2 mg/kg, indicating a synergistic interaction. Systemic administration resulted in the highest increase in potency, being about fourfold, while spinal and local administration increased potency in two- and threefold, respectively. The fact that the highest synergism was observed after systemic administration suggests that the interaction is occurring at several anatomical sites. The results support the clinical use of this combination in pain management.

Possible activation of the NO-cyclic GMP-protein kinase G-K+ channels pathway by gabapentin on the formalin test.

The effect of modulators of the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway on the local peripheral antinociceptive action induced by gabapentin was assessed in the rat 1% formalin test. Local peripheral administration of gabapentin produced a dose-dependent antinociception in the second phase of the test. Gabapentin-induced antinociception was due to a local action as its administration in the contralateral paw was ineffective. Local peripheral pretreatment of the paws with NG-L-nitro-arginine methyl ester (L-NAME, a nitric oxide synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) and KT-5823 (a protein kinase G inhibitor) dose-dependently reduced gabapentin-induced antinociception. Likewise, glibenclamide or tolbutamide (ATP-sensitive K+ channel inhibitors), 4-aminopyridine or tetraethylammonium (non-selective inward rectifier K+ channel inhibitors) or charybdotoxin (large-conductance Ca2+-activated-K+ channel blocker), but not apamin (small-conductance Ca2+-activated-K+ channel blocker) or naloxone (opioid receptor antagonist), reduced the antinociception induced by gabapentin. Our data suggest that gabapentin could activate the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway in order to produce its peripheral antinociceptive effect in the rat 1% formalin test.

Possible involvement of potassium channels in peripheral antinociception induced by metamizol: lack of participation of ATP-sensitive K+ channels.

The present work assessed the possible participation of K+ channels in the peripheral antinociceptive action of metamizol in the 1% formalin test. Ipsilateral, but not contralateral, local peripheral administration of metamizol produced a dose-dependent antinociception only during the second phase of the formalin test. K+ channel blockers alone did not modify formalin-induced nociceptive behavior. However, local peripheral pretreatment of the paw with charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated K+ channel blockers, respectively), 4-aminopyridine and tetraethylammonium (voltage-dependent K+ channel inhibitors), but not glibenclamide or tolbutamide (ATP-sensitive K+ channel inhibitors), dose-dependently prevented metamizol-induced antinociception. The above results suggest that metamizol could open large- and small-conductance Ca(2+)-activated K+ channels, but not ATP-sensitive K+ channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K+ channels was also suggested, but since nonselective inhibitors were used, the data await further confirmation.

Comparison of Analgesic Effect between Gabapentin and Diclofenac on Post-Operative Pain in Patients Undergoing Tonsillectomy.

Background Tonsillectomy is a common procedure causing considerable postoperative pain. Postoperative pain intensity of 60 - 70 in the scale of visual analog scale (VAS) has been reported up to 3 - 4 days which could continue until 11 days after the surgery. Objectives The current study aimed to compare the analgesic effect of gabapentin and diclofenac on pain after tonsillectomy with the control group. Patients and Methods In this double-blind, placebo-controlled clinical trial, 90 patients aged 10-25 years, ASA classes I and II were randomly selected to receive 20 mg/kg oral gabapentin (n = 30), 1.0 mg / kg rectal diclofenac (n = 30) or placebo (n = 30) preoperatively. Pain was evaluated postoperatively on a visual analogue scale at 2, 6, 12 and 24 h. Opioid consumption in the first 24 h after surgery and the side effects were also recorded. Results There was no significant difference in terms of age, sex, and time of surgery in the three groups. Patients in the gabapentin and diclofenac groups had significantly lower pain scores at all-time intervals than those in the placebo group. The total meperidine consumed in the gabapentin (14.16 ± 6.97 P = 0.001) and diclofenac (16.66 ± 8.95, P = 0.004) groups was significantly less than that of the placebo (33.4 ± 13.97) group. The frequency of side effects such as vomiting, dizziness, and headache was not significantly different among the groups. Conclusions It can be concluded that gabapentin and diclofenac reduced postoperative pain and opioid consumption without obvious side effects.

Examination of the interaction between peripheral lumiracoxib and opioids on the 1% formalin test in rats

It has been shown that the association of non‐steroidal anti‐inflammatory drugs (NSAIDs) with opioid analgesic agents can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between lumiracoxib and codeine or nalbuphine at the local peripheral level in the rat using the 1% formalin test and isobolographic analysis. Lumiracoxib, codeine, nalbuphine or fixed‐dose ratios lumiracoxib—codeine or lumiracoxib—nalbuphine combinations were administrated locally in the formalin‐injured paw and the antinociceptive effect was evaluated using the 1% formalin test. All treatments produced a dose‐dependent antinociceptive effect. ED40 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED40s for the lumiracoxib—codeine and lumiracoxib—nalbuphine combinations were 423.4±31.3μg/paw and 310.9±24.2μg/paw, respectively, being significantly higher than the actually observed experimental ED40 values, 233.2±30.9μg/paw and 132.7±11.6μg/paw, respectively. These results correspond to a synergistic interaction between lumiracoxib and opioids at the local peripheral level, potency being about two times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the lumiracoxib—opioids combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.