Non-inflammatory Pain Model Research Articles

Synthesis of 2-Organylchalcogenopheno[2,3-b]pyridines from Elemental Chalcogen and NaBH4 /PEG-400 as a Reducing System: Antioxidant and Antinociceptive Properties.

An alternative method to prepare 2-organylchalcogenopheno[2,3-b]pyridines was developed by the insertion of chalcogen species (selenium, sulfur or tellurium), generated in situ, into 2-chloro-3-(organylethynyl)pyridines by using the NaBH4 /PEG-400 reducing system, followed by an intramolecular cyclization. It was possible to obtain a series of compounds with up to 93 % yield in short reaction times. Among the synthesized products, 2-organyltelluropheno[2,3-b]pyridines have not been described in the literature so far. Moreover, the compounds 2-phenylthieno[2,3-b]pyridine (3 b) and 2-phenyltelluropheno[2,3-b]pyridine (3 c) exhibited significant antioxidant potential in different in vitro assays. Further studies demonstrated that compound 3 b exerted an antinociceptive effect in acute inflammatory and non-inflammatory pain models, thus indicating the involvement of the central and peripheral nervous systems on its pharmacological action. More specifically, our results suggest that the intrinsic antioxidant property of compound 3 b might contribute to attenuating the nociception and inflammatory process on local injury induced by complete Freund's adjuvant (CFA).

Comparison of TENS, spinal cord stimulation and acupuncture in inflammatory, neuropathic and non-inflammatory pain models in rats

Comparison of TENS, spinal cord stimulation and acupuncture in inflammatory, neuropathic and non-inflammatory pain models in rats

Electrical stimulation reduces secondary mechanical hyperalgesia in a non-inflammatory pain model in rats

Fibromyalgia is a musculoskeletal disease characterized by widespread pain. Its physiological mechanisms are not clear yet, which directly interferes on the quality of pain management. Electrical therapeutic approaches such as interferential current (IFC) and transcutaneous electrical nerve stimulation (TENS) have been used in several pain conditions. To our knowledge this is the first study investigating the effects of both IFC and TENS on reduction of secondary mechanical hyperalgesia in a non-inflammatory muscle pain models in rats. Double intramuscular injection of acid saline (Ph 4.0) was performed five days apart on the left gastrocnemius muscle. Twenty male Wistar rats were divided in four groups: high frequency TENS (100Hz), low frequency TENS (5Hz), interferential current-IFC (modulated frequency of 100Hz) and sham stimulation. Control animals received the same treatment but with no delivery of electrical stimulation. A pair of round electrodes were placed at the lateral and medial aspects of the left gastrocnemius muscle. Animals were lightly anesthetized (5%-2%) with isoflurane and received a single stimulation for 20 minutes. Sensorial intensity was set for starting stimulation. Mechanical hyperalgesia was assessed through von Frey filaments with increasing bending forces before both first and second acid saline injections, 24 h after second injection and following the treatment. All animals showed significant reduction of the mechanical hyperalgesia 24 h after the second injection (p< 0.05). There was a significant reduction of the mechanical hyperalgesia in IFC-treated (p< 0.01) and both high and low frequency TENS-treated animals (p<0,03) compared to sham animals. Thus we suggest that both IFC and TENS at both high and low frequencies promote antinociceptive effect on muscle pain model. Fibromyalgia is a musculoskeletal disease characterized by widespread pain. Its physiological mechanisms are not clear yet, which directly interferes on the quality of pain management. Electrical therapeutic approaches such as interferential current (IFC) and transcutaneous electrical nerve stimulation (TENS) have been used in several pain conditions. To our knowledge this is the first study investigating the effects of both IFC and TENS on reduction of secondary mechanical hyperalgesia in a non-inflammatory muscle pain models in rats. Double intramuscular injection of acid saline (Ph 4.0) was performed five days apart on the left gastrocnemius muscle. Twenty male Wistar rats were divided in four groups: high frequency TENS (100Hz), low frequency TENS (5Hz), interferential current-IFC (modulated frequency of 100Hz) and sham stimulation. Control animals received the same treatment but with no delivery of electrical stimulation. A pair of round electrodes were placed at the lateral and medial aspects of the left gastrocnemius muscle. Animals were lightly anesthetized (5%-2%) with isoflurane and received a single stimulation for 20 minutes. Sensorial intensity was set for starting stimulation. Mechanical hyperalgesia was assessed through von Frey filaments with increasing bending forces before both first and second acid saline injections, 24 h after second injection and following the treatment. All animals showed significant reduction of the mechanical hyperalgesia 24 h after the second injection (p< 0.05). There was a significant reduction of the mechanical hyperalgesia in IFC-treated (p< 0.01) and both high and low frequency TENS-treated animals (p<0,03) compared to sham animals. Thus we suggest that both IFC and TENS at both high and low frequencies promote antinociceptive effect on muscle pain model.

Randomized double-blind placebo controlled crossover study of acetaminophen, ibuprofen, acetaminophen/hydrocodone, and placebo for the relief of pain from a standard painful stimulus

Objectives: The objective was to compare subjects’ change in perceived acute pain from an identical painful stimulus after receiving three separate, commonly used pain medications and placebo. Methods: This was an institutional review board–approved, randomized, double-blind crossover study of healthy human volunteers. Subjects received 1000 mg of acetaminophen, 800 mg of ibuprofen, the combination of 650 mg of acetaminophen with 10 mg of hydrocodone, or placebo (800 mg of lactose) in a randomized order over four separate occasions each 1 week apart. Prior to receiving the drug on each study day, subjects placed their nondominant hand in a bath of 0°C water for 45 seconds. The bath was divided into two sections; the larger was the reservoir of cooled water monitored at 0°C, and the other half was filled from constant overflow. Water drained from the overflow section into the cooling unit and was then pumped up into the base of the reservoir through a diffusion grid. Subjects completed a 100-mm visual analog scale (VAS) representing perceived pain during the exposure. The cold water exposure and VAS were repeated 1 hour after receiving the study drug, and then subjects were observed for side effects for 4 hours. Data were compared using descriptive statistics, 95% confidence intervals (CIs), and repeated-measures analysis of variance (ANOVA). Results: Twenty-five subjects were enrolled. The mean VAS preexposure was 56.9 mm (±15.1 mm; range = 5 to 92 mm). The mean decrease in VAS after receiving the study drug for acetaminophen was 10.2% (95% CI = −1.4 to 20.4), for ibuprofen was −6.6% (95% CI = −16.5 to 3.20), for acetaminophen/hydrocodone was 9.5% (95% CI = 1.4 to 20.4), and for placebo was −6.9% (95% CI = −15.2 to 1.4). The range in change in pain scores for all agents was −91.3% to 57.6%. Mild side effects (nausea, dizziness, or somnolence) were reported in 11 subjects (44%) after receiving acetaminophen/hydrocodone; no other side effects were reported. Conclusions: There was a wide range of changes in pain scores from this identical painful stimulus after receiving the study medications. Acetaminophen and acetaminophen/hydrocodone resulted in a similar decrease in pain (10.2 and 9.5%), while ibuprofen and placebo had a similar lack of effect (−6.6 and −6.9%). Forty-four percent of subjects receiving acetaminophen/hydrocodone reported mild side effects; no other side effects were seen. In this noninflammatory pain model, the VAS is not able to distinguish differences in pain relief between acetaminophen and acetaminophen/hydrocodone or ibuprofen and placebo.

Randomized Double‐blind Placebo Controlled Crossover Study of Acetaminophen, Ibuprofen, Acetaminophen/Hydrocodone, and Placebo for the Relief of Pain From a Standard Painful Stimulus

The objective was to compare subjects' change in perceived acute pain from an identical painful stimulus after receiving three separate, commonly used pain medications and placebo. This was an institutional review board-approved, randomized, double-blind crossover study of healthy human volunteers. Subjects received 1000 mg of acetaminophen, 800 mg of ibuprofen, the combination of 650 mg of acetaminophen with 10 mg of hydrocodone, or placebo (800 mg of lactose) in a randomized order over four separate occasions each 1 week apart. Prior to receiving the drug on each study day, subjects placed their nondominant hand in a bath of 0 degrees C water for 45 seconds. The bath was divided into two sections; the larger was the reservoir of cooled water monitored at 0 degrees C, and the other half was filled from constant overflow. Water drained from the overflow section into the cooling unit and was then pumped up into the base of the reservoir through a diffusion grid. Subjects completed a 100-mm visual analog scale (VAS) representing perceived pain during the exposure. The cold water exposure and VAS were repeated 1 hour after receiving the study drug, and then subjects were observed for side effects for 4 hours. Data were compared using descriptive statistics, 95% confidence intervals (CIs), and repeated-measures analysis of variance (ANOVA). Twenty-five subjects were enrolled. The mean VAS preexposure was 56.9 mm (+/-15.1 mm; range = 5 to 92 mm). The mean decrease in VAS after receiving the study drug for acetaminophen was 10.2% (95% CI = -1.4 to 20.4), for ibuprofen was -6.6% (95% CI = -16.5 to 3.20), for acetaminophen/hydrocodone was 9.5% (95% CI = 1.4 to 20.4), and for placebo was -6.9% (95% CI = -15.2 to 1.4). The range in change in pain scores for all agents was -91.3% to 57.6%. Mild side effects (nausea, dizziness, or somnolence) were reported in 11 subjects (44%) after receiving acetaminophen/hydrocodone; no other side effects were reported. There was a wide range of changes in pain scores from this identical painful stimulus after receiving the study medications. Acetaminophen and acetaminophen/hydrocodone resulted in a similar decrease in pain (10.2 and 9.5%), while ibuprofen and placebo had a similar lack of effect (-6.6 and -6.9%). Forty-four percent of subjects receiving acetaminophen/hydrocodone reported mild side effects; no other side effects were seen. In this noninflammatory pain model, the VAS is not able to distinguish differences in pain relief between acetaminophen and acetaminophen/hydrocodone or ibuprofen and placebo.

The synergistic analgesic interactions between hydrocodone and ibuprofen.

The practice of combining opioids with nonsteroidal antiinflammatory drugs is widespread in the clinical management of acute and chronic pain. Using the mouse radiant heat tail-flick nociception model, we observed potent analgesia with hydrocodone. In contrast, ibuprofen as a single drug was inactive in this model of moderate to severe pain, perhaps reflecting its limited analgesic potential. Despite the inactivity of ibuprofen alone in this model, the inclusion of ibuprofen with hydrocodone markedly enhanced the analgesic response. Dose-response studies revealed an 50% effective dose for hydrocodone alone in mice of 11 mg/kg, SC. Inclusion of a fixed ibuprofen dose with the various hydrocodone doses shifted the 50% effective dose value almost seven-fold to the left to 1.6 mg/kg, SC, despite the lack of effect of ibuprofen alone in this model. Using a fixed hydrocodone:ibuprofen ratio (1:40) also revealed a marked four-fold shift to 2.6 mg/kg, SC. These findings suggest a synergistic interaction between ibuprofen and hydrocodone in a noninflammatory pain model. Opioids are frequently used in combination with nonsteroidal antiinflammatory drugs clinically. These studies demonstrate strong interactions between ibuprofen and hydrocodone, implying synergy between the two drugs, which may help explain their utility when given together.