There has been a growing interest in opioid-induced hyperalgesia (OIH), which is an increased sensitivity to pain caused by opioid exposure. Multiple underlying pathways may contribute to the development of OIH, and the mechanism may vary with the duration of opioid exposure, dose, type and route of administration. In addition, the distinction between OIH, tolerance and withdrawal should be made in both the basic and clinical science literature so as to help translate findings to the clinical phenomenon and to help determine the best strategies to prevent or treat OIH.
Analgesics, Opioid ; adverse effects ; Drug Tolerance ; Humans ; Hyperalgesia ; chemically induced ; prevention & control ; Pain Measurement

AIMTo explore the effects of intrathecal injection of selective cyclooxygenase-1 (COX-1) inhibitor, SC-560, on mechanical allo dynia and spinal ERK protein expression in rats with postoperative pain.

METHODSRats were divided into 4 groups: control group, postoperative pain group, SC-560 group and DMSO group. Mechanical withdrawal threshold (MWT), immunohistochemical and Western blotting technique were used to evaluate mechanical hypersensitivity and the expression of phospho-ERK in the spinal cord, respectively.

RESULTS(1) Behavior test rats developed allodynia 1 h after operation and SC-560 100 microg administrated intrathecally demonstrated a significant reduction in postoperative hypersensitivity. (2) Immunohistochemical staining Phospho-ERK positive neurons in the rat superficial spinal dorsal horn increased significantly 1 h after incision compared with that of non-incision group. Intrathecal administration of SC-560 preoperatively could significantly reduce the number of phospho-ERK positive neurons. (3) Western blot expression of phospho-ERK1/2 protein in the lumbar spinal cord increased significantly 1 h after incision and decreased by intrathecal injection of SC-560.

CONCLUSIONSC-560 administrated intrathecally can inhibit mechanical hypersensitivity induced by postoperative pain in rats and this anti-allodynic process may mediated by spinal ERK.

Animals ; Cyclooxygenase Inhibitors ; pharmacology ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Male ; Pain Measurement ; drug effects ; Pain, Postoperative ; metabolism ; Pyrazoles ; pharmacology ; Rats ; Rats, Wistar ; Spinal Cord ; drug effects ; metabolism

OBJECTIVETo investigate the effect of L-838,417 on the results of behavioral test in rats with experimentally induced trigeminal neuralgia.

METHODSMale SD rats were randomized into model group (n=34), sham-operated group (n=30) and control group (n=6). Thirty rats with trigeminal neuralgia induced by chronic constriction injury of the infraorbital nerve below the zygomatic bone were randomly divided into 5 equal groups for treatment with 1.0 mg/kg L-838,417 (L1 group), 10.0 mg/kg L-838,417 (L10 group), 5 mg/kg morphine (M group), 3 mg/kg diazepam (D group), or normal saline (NS group). The pain threshold of the tentacles pad to von-Frey filament stimulation was measured in the rats before and at 1, 2, 3, 4, 5 h after the treatments. The sedative effect of L-838,417 was evaluated by recording the position scores and righting reflex scores, and the drug tolerance was also evaluated.

RESULTSNine days after the operation, the pain threshold of the rats in the model group was significantly decreased compared with that before operation and that of the sham group (P<0.01). The threshold of L1 and L10 groups were both significantly increased 1 h after L-838,417 administration (P<0.01). The rats in the NS, L1, and L10 groups did not show unusual posture or righting reflex. In L1 and L10 groups, L838,417 did not show attenuated efficacy after prolonged use (10 days).

CONCLUSIONL-838,417 can effectively improve hyperalgesia in rats with trigeminal neuralgia without causing sedation, motor impairment, or drug tolerance.

Animals ; Fluorobenzenes ; pharmacology ; Hyperalgesia ; drug therapy ; Male ; Pain Measurement ; Pain Threshold ; drug effects ; Rats ; Rats, Sprague-Dawley ; Triazoles ; pharmacology ; Trigeminal Neuralgia ; drug therapy ; physiopathology

PURPOSE: The purpose of this study was to examine the effect of DHEA (Dehydroepiandrosterone) on muscle weight and Type I and II fiber cross-sectional area of affected and unaffected hindlimb muscles in rats with neuropathic pain induced by unilateral peripheral nerve injury. METHODS: Neuropathic pain was induced by ligation and cutting of the left L5 spinal nerve. Adult male Sprague-Dawley rats were randomly assigned to one of two groups: The DHEA group (n=10) had DHEA injections daily for 14 days, and the Vehicle group (n=10) had vehicle injections daily for 14 days. Withdrawal threshold, body weight, food intake and activity were measured every day. At 15 days all rats were anesthetized and soleus, plantaris and gastrocnemius muscles were dissected from the both hindlimbs. Body weight, food intake, activity, muscle weight and Type I, II fiber cross-sectional area of the dissected muscles were measured. RESULTS: The DHEA group showed significant increases (p<.05), as compared to the vehicle group for muscle weight of the unaffected plantaris, and in Type II fiber cross-sectional area of the gastrocnemius muscle. The DHEA group demonstrated a higher pain threshold than the vehicle group whereas total diet intake and activity score were not significantly different between the two groups. CONCLUSION: DHEA administration for 14 days attenuates unaffected plantaris and gastrocnemius muscle atrophy.
Animals ; Body Weight ; Dehydroepiandrosterone/*administration & dosage ; Disease Models, Animal ; Eating/drug effects ; *Hindlimb ; Male ; Muscle Fibers, Skeletal/*drug effects/pathology ; Muscle, Skeletal/drug effects ; Muscular Atrophy/*drug therapy ; Pain/etiology ; Pain Measurement ; Peripheral Nerves/*injuries ; Rats ; Rats, Sprague-Dawley

Nefopam has a pharmacologic profile distinct from that of opioids or other anti-inflammatory drugs. Several recent studies demonstrate that nefopam has a mechanism of action similar to those of anti-depressants and anticonvulsants for treating neuropathic pain. The present study investigates the mechanical antiallodynic effect of nefopam using immunohistochemical study and western blot analysis in a rat neuropathic pain model. Twenty-eight male Sprague-Dawley rats were subjected to left fifth lumbar (L5) spinal nerve ligation and intrathecal catheter implantation, procedures which were not performed on the 7 male Sprague-Dawley rats in the sham surgery group (group S). Nefopam, either 10 or 100 microg/kg (group N10 or N100, respectively), and normal saline (group C) were intrathecally administered into the catheter every day for 14 days. The mechanical allodynic threshold of intrathecal nefopam was measured using a dynamic plantar aesthesiometer. Immunohistochemistry targeting cluster of differentiation molecule 11b (CD11b) and glial fibrillary acidic protein (GFAP) was performed on the harvested spinal cord at the level of L5. Extracellular signal-regulated kinase 1/2 (ERK 1/2) and cyclic adenosine monophosphate response element binding protein (CREB) were measured using western blot analysis. The N10 and N100 groups showed improved mechanical allodynic threshold, reduced CD11b and GFAP expression, and attenuated ERK 1/2 and CREB in the affected L5 spinal cord. In conclusion, intrathecal nefopam reduced mechanical allodynia in a rat neuropathic pain model. Its mechanical antiallodynic effect is associated with inhibition of glial activation and suppression of the transcription factors' mitogen-activated protein kinases in the spinal cord.
Analgesics, Non-Narcotic/administration & dosage ; Animals ; Dose-Response Relationship, Drug ; Hyperalgesia/*drug therapy/etiology/*physiopathology ; Injections, Spinal ; Male ; Nefopam/*administration & dosage ; Neuralgia/complications/*drug therapy/*physiopathology ; Pain Measurement/drug effects ; Pain Perception/*drug effects ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome

INTRODUCTIONCancer pain is one of the most frequently encountered pain syndromes. With the application of the World Health Organization analgesic ladder, adequate analgesia is achieved in 75% to 90% of patients. The remaining patients suffer from intractable pain requiring intrathecal analgesia. The aim of this study was to retrospectively analyse the pain intensity before and after intrathecal analgesia and review the complications associated with the implantation and the care of the intrathecal device.

MATERIALS AND METHODSWe reviewed medical records of all cancer patients whose pain were managed by intrathecal catheter implants in our centre from February 2005 to August 2008. The pain intensity, medication and complications related to intrathecal catheter insertion or drug delivery were reviewed at the time before starting the intrathecal analgesia (T0) and time of discharge from the hospital/time prior to death during their stay in the hospital (Tdsc).

RESULTSTwenty-nine patients were included. Out of these 29 patients, 86.2% had metastatic cancer. The most common indication was poor pain control. Pain intensity was reduced significantly at the time of discharge from hospital (P < 0.001). The number of patients with side effects from opioids decreased after intrathecal treatment. We found 4 patients with short-term catheter complications e.g. kinked or displaced catheter and catheter-related infection.

CONCLUSIONIntractable cancer pain could be managed effectively by intrathecal analgesia with a significant decrease in pain intensity and reduced opioid-related side effects. The side effects due to intrathecal opioids and complications from intrathecal catheter were minimal.

Adult ; Aged ; Analgesics ; administration & dosage ; adverse effects ; pharmacology ; Catheterization ; Female ; Humans ; Injections, Spinal ; Male ; Medical Audit ; Middle Aged ; Neoplasms ; physiopathology ; Pain Measurement ; Pain, Intractable ; drug therapy ; Retrospective Studies

Using the latency of paw withdrawal (PWL) from a noxious thermal stimulus as a measure of hyperalgesia, the effects of i.p. injection of meptazinol and its isomers, 112824 and 112825, on carrageenan-induced thermal hyperalgesia were studied in awaked carrageenan-inflamed rats. Peripheral inflammation was induced by intraplantar (i.pl.) injection of carrageenan (2 mg/100 microl) into one hindpaw in rats. Carrageenan produced marked inflammation (edema and erythema) and thermal hyperalgesia in the injected paws, which peaked at 3 h after injection and showed little change in magnitude for another 3 h. Injection of 0.1 mg/kg meptazinol (i.p.) at 3 h after carrageenan had no effect on the PWLs of either inflamed or non-inflamed hindpaw during the next 100 min (P>0.05, n=8). At the dosage of 1 and 10 mg/kg, meptazinol produced marked anti-nociception and anti-hyperalgesia in non-inflamed and inflamed hindpaw, respectively (P<0.05, n=8-11). The prolonging effect of meptazinol on PWL in inflamed hindpaw was more potent than that in non-inflamed hindpaw. Pre-administration of 1.5 mg/kg naloxone significantly antagonized meptazinol-induced anti-nociception and anti-hyperalgesia. Intraperitoneal injection of an isomer of meptazinol, 112825 (1.5 mg/kg), but not 112824 (1 mg/kg), markedly increased the PWL of the non-inflamed hindpaw. Nevertheless, both the isomers produced similar anti-hyperalgesic effect to that of meptazinol (P<0.05, n=8), which was completely reversed by naloxone (1.5 mg/mg). The results suggest that meptazinol and its isomers have anti-nociceptive and anti-hyperalgesic properties with the former more potent. The effects are mainly mediated by mu opioid receptors. This study provides an important clue for extending clinical utilization of meptazinol and its isomers.
Analgesics, Opioid ; pharmacology ; Animals ; Carrageenan ; Hyperalgesia ; chemically induced ; physiopathology ; Inflammation ; chemically induced ; Isomerism ; Male ; Meptazinol ; pharmacology ; Nociceptors ; drug effects ; Pain ; physiopathology ; Pain Measurement ; methods ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo evaluate the therapeutic effects of galvanism penetration of traditional Chinese medicine combined with ultrasonic wave and manipulation in the treatment of strain of the infrapatellar fat pad, to study an effective approach in the treatment of this diseas.

METHODSEighty patients were divided randomly into treatment group and control group, there were 40 cases in each group. In treatment group 40 cases were treated by galvanism penetration of traditional Chinese medicine, ultrasonic wave and manipulation, included 22 males and 18 females with an average age of (63.15 +/- 8.10) years old and a mean disease course of (6.84 +/- 3.50) years. In control group, 40 cases were treated with ultrasonic wave and manipulation, included 23 males and 17 females with an average age of (62.63 +/- 8.20) years old and the course was (6.59 +/-3.70) years. visual analogue scale (VAS) and the scales for pain with finger press were evaluated before and after treatment in two groups. The clinical effects were researched and analysed statistically.

RESULTSIn treatment group,12 patients were in remarkable effects, 17 in good effective, 9 in effective and 2 in ineffective. As well in control group, above data were 8,15, 8 and 9 respectively. There was a significant difference in the rate of general effective between treatment group and control group (P < 0.05). In treatment group, the scales for VAS before and after treatment were (7.92 +/- 2.21) and (2.16 +/- 1.87) and the scales for pain with finger press before and after treatment were (3.01 +/- 0.63) and (0.86 <-- 0.46). As well in control group, above data were (7.71 +/2.65), (3.83 +/- 2.45), (2.98 +/- 0.61) and (1.32 +/- 0.52) respectively. The comparison of the scales for VAS and pain with finger press before and after treatment in two groups had significant difference (P < O.01).

CONCLUSIONUltrasonic wave and manipulation have a good effect in the treatment of stain of the infrapatellar fat pad, when the galvanism penetration of traditional Chinese medicine is applied at the same time, the therapeutic efficiency can be improved significantly. Three therapies are used in treatment at the same, it can improve the therapeutic effect, and it is an easy, economic, practical and effective comprehensive approach.

Adipose Tissue ; drug effects ; injuries ; Female ; Humans ; Male ; Medicine, Chinese Traditional ; Middle Aged ; Musculoskeletal Manipulations ; Pain Measurement ; Patella ; Sprains and Strains ; drug therapy ; physiopathology ; therapy ; Treatment Outcome ; Ultrasonic Therapy

To evaluate the effects and safety of varying doses of Guizhi Fuling capsule on treating primary dysmenorrhea. From August 2010 to March 2011, 240 subjects (aged 18-30) with primary dysmenorrheal, were enrolled in 8 sites. They were randomized into Guizhi Fuling capsule high dose group, low dose group and placebo control group, 80 cases in each group. These patients were treated for three consecutive menstrual cycles, then were followed up in another three consecutive menstrual cycles. Visual analogue scales (VAS) was used to determine the pain intensity. During the treatment, the high-, low-dose and placebo groups efficiency on pain relief are 68.42%, 67.57% and 47.89% respectively. Guzhi Fuling (included high- and low- dose group) significantly relieves the pain compared to placebo. In follow-up, Guzhi Fuling groups are still superior to the placebo group (73.68%, 72.97% and 53.52%). During the treatment, pain duration reduces 57.88% in high dose group, while 46.17% in low dose group, and 30.40% in placebo group. In follow-up, pain lasting time decrease 67.93%, 53.56%, 47.46%, respectively. Guizhi Fuling significantly reduces the pain duration compared to placebo and high-dose is better than low-dose. The efficacy of Guzhi Fuling (high- and low-dose) displays certain dosage-effect relationship. Among these group, no serious adverse event was reported. Guizhi Fuling capsule at high or low dose significantly relieves the pain, improves symptoms, reduces the duration of pain, and has a better overall treatment effect and long-term treatment effect in patients with primary dysmenorrhea.
Adult ; Capsules ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Dysmenorrhea ; drug therapy ; Female ; Humans ; Pain Measurement

OBJECTIVETo evaluate the effects of tramadol on the proinflammatory responses in a rat model of incisional pain by investigating its effects on nociceptive thresholds and serum interleukin-6 (IL-6) and IL-2 levels.

METHODSForty-two male Sprague-Dawley (SD) rats scheduled for plantar incision were randomly divided into 7 groups (n=6 in each group). Rats in Group 1 receiving general anesthesia with no incision were served as control; At 30 min before skin incision, Groups 2 to approximately 5 were given 5 ml normal saline or 1, 10, and 20 mg/kg tramadol, respectively, intraperitoneally (i.p.); Group 6 received 10 mg/kg tramadol after operation; Group 7 received 10 mg/kg tramadol before incision, followed by 200 microg/kg naloxone after operation. Mechanical allodynia was measured by electronic von Frey filament to evaluate the nociceptive thresholds 1 h before incision, and 1 h and 2 h after operation. Serum IL-6 and IL-2 levels were measured by enzyme-linked immunosorbent assay (ELISA) 2 h after operation.

RESULTSMechanical thresholds decreased significantly and serum IL-6 level increased significantly after operation in Group 2 compared with control (P<0.01), and these changes were reversed respectively by tramadol in a dose-dependent manner (P<0.05 and P<0.01, respectively). IL-2 level remained unchanged after operation in Group 2, but decreased in Group 3 (P<0.05), then gradually returned to the normal level in Groups 4 and 5. The intraperitoneally injected tramadol (10 and 20 mg/kg) produced a potent and dose-dependent antinocicptive effect on the lesioned paw. The antinocicptive effects of tramadol were partially antagonized by naloxone (200 microg/kg), suggesting an additional non-opioid mechanism.

CONCLUSIONThe results suggest that tramadol could be a good choice for the treatment of pain under the conditions that immunosuppression may be particularly contraindicated.

Analgesics, Opioid ; pharmacology ; Animals ; Dose-Response Relationship, Drug ; Interleukin-2 ; biosynthesis ; blood ; Interleukin-6 ; biosynthesis ; blood ; Male ; Pain Measurement ; methods ; Pain Threshold ; drug effects ; Pain, Postoperative ; blood ; drug therapy ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Tramadol ; pharmacology