Hyung Gon Lee

A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain.

OBJECTIVES Controversy exists regarding the efficacy of ligament prolotherapy in alleviating sacroiliac joint pain. The inconsistent success rates reported in previous studies may be attributed to variability in patient selection and techniques between studies. It was hypothesized that intra-articular prolotherapy for patients with a positive response to diagnostic block may mitigate the drawbacks of ligament prolotherapy. The purpose of this study was to evaluate the efficacy and long-term effectiveness of intra-articular prolotherapy in relieving sacroiliac joint pain, compared with intra-articular steroid injection. DESIGN This was a prospective, randomized, controlled trial. SETTINGS/LOCATION The study was conducted at an outpatient pain medicine clinic at Chonnam National University Hospital in Gwang-ju, Korea. SUBJECTS The study included patients with sacroiliac joint pain, confirmed by ≥50% improvement in response to local anesthetic block, lasting 3 months or longer, and who failed medical treatment. INTERVENTIONS The treatment involved intra-articular dextrose water prolotherapy or triamcinolone acetonide injection using fluoroscopic guidance, with a biweekly schedule and maximum of three injections. OUTCOME MEASURES Pain and disability scores were assessed at baseline, 2 weeks, and monthly after completion of treatment. RESULTS The numbers of recruited patients were 23 and 25 for the prolotherapy and steroid groups, respectively. The pain and disability scores were significantly improved from baseline in both groups at the 2-week follow-up, with no significant difference between them. The cumulative incidence of ≥50% pain relief at 15 months was 58.7% (95% confidence interval [CI] 37.9%-79.5%) in the prolotherapy group and 10.2% (95% CI 6.7%-27.1%) in the steroid group, as determined by Kaplan-Meier analysis; there was a statistically significant difference between the groups (log-rank p < 0.005). CONCLUSIONS Intra-articular prolotherapy provided significant relief of sacroiliac joint pain, and its effects lasted longer than those of steroid injections. Further studies are needed to confirm the safety of the procedure and to validate an appropriate injection protocol.

Role of neuronal nitric oxide synthase in the antiallodynic effects of intrathecal EGCG in a neuropathic pain rat model

Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is known to have antioxidant activity against nitric oxide (NO) by scavenging free radicals, chelating metal ions, and inducing endogenous antioxidant enzymes. NO and NO synthase (NOS) play an important role in nociceptive processing. In this study, we examined the effects of intrathecal EGCG in neuropathic pain induced by spinal nerve ligation and the possible involvement of NO. Intrathecal EGCG attenuated mechanical allodynia in spinal nerve ligated-rats, compared to sham-operated rats, with a maximal possible effect of 69.2%. This antinociceptive effect was reversed by intrathecal pretreatment with l-arginine, a precursor of NO. Intrathecal EGCG also blocked the increase in nNOS expression in the spinal cord of spinal nerve-ligated rats, but iNOS expression was not significantly suppressed. These findings suggest that intrathecal EGCG could produce an antiallodynic effect against spinal nerve ligation-induced neuropathic pain, mediated by blockade of nNOS protein expression and inhibition of the pronociceptive effects of NO.

Antinociceptive effect of intrathecal cannabinoid receptor agonist WIN 55,212-2 in a rat bone tumor pain model

Bone tumor pain is a poorly controlled pain comprising background and severe pain on moving or weight-bearing postures that decreases the quality of life for cancer patients; thus, more effective analgesics are clearly needed. This study evaluated the efficacy of a cannabinoid (CB) receptor agonist (WIN 55,212-2) on bone tumor pain in the spinal cords of rats, and clarified the roles of the CB1 and CB2 receptors in WIN 55,212-2-induced antinociception at the spinal level. Bone tumor pain was induced by injecting MRMT-1 tumor cells (1×10(5)) into the right tibias of female Sprague-Dawley rats under sevoflurane anesthesia. Bone tumor development was monitored radiologically. Under sevoflurane anesthesia, a polyethylene catheter was inserted into the intrathecal space for drug administration. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cell inoculation site. The effect of intrathecal WIN 55,212-2 was investigated. Next, the WIN 55,212-2-mediated antinociception was reversed using CB1 (AM 251) and CB2 (AM 630) receptor antagonists. The intratibial injection of MRMT-1 tumor cells produced radiologically confirmed bone tumors. The paw withdrawal threshold decreased significantly (mechanical allodynia) with tumor development; however, intrathecal WIN 55,212-2 dose-dependently increased the withdrawal threshold. The antinociceptive effect of WIN 55,212-2 was reversed by both CB1 and CB2 receptor antagonists. Intrathecal WIN 55,212-2 reduced bone tumor-related pain behavior mediated via spinal CB1 and CB2 receptors. Therefore, spinal CB receptor agonists may be novel analgesics in the treatment of bone tumor pain.

Evaluation for the interaction between intrathecal melatonin and clonidine or neostigmine on formalin-induced nociception.

AIMS We examined the nature of pharmacological interaction after coadministration of melatonin with clonidine or neostigmine on formalin-induced nociception at the spinal level. Further, the role of melatonin receptor subtypes in melatonin-induced antinociception was clarified. MAIN METHODS Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. Pain was assessed using the formalin test (induced by a subcutaneous injection of 50 microl of a 5% formalin solution to the hindpaw). Isobolographic analysis was used for the evaluation of drug interaction between melatonin and clonidine or neostigmine. Non-selective MT1/MT2 receptors antagonist (luzindole), MT2 receptor antagonist (4-P-PDOT), and MT3 receptor/alpha-1 adrenoceptor antagonist (prazosin) were intrathecally given to verify the involvement of the melatonin receptor subtypes in the antinociception of melatonin. Furthermore, the effect of intrathecal MT3 receptor ligand (GR 135531) was observed. KEY FINDINGS Intrathecal melatonin, clonidine, and neostigmine dose-dependently suppressed the flinching response during phase 1 and phase 2 in the formalin test. Isobolographic analysis showed additivity between melatonin and clonidine or neostigmine in both phases. The antinociceptive effect of melatonin was antagonized by luzindole, 4-P-PDOT, and prazosin in the spinal cord. Intrathecal GR 135531 was ineffective against the formalin-induced flinching response. SIGNIFICANCE These results suggest that melatonin interacts additively with clonidine and neostigmine in the formalin-induced nociception at the spinal level. Furthermore, the antinociception of melatonin is mediated through the MT2 receptor, but not the MT3 receptor. However, it seems that alpha-1 adrenoceptor plays in the effect of melatonin.

Antiallodynic Effect of Thalidomide and Morphine on Rat Spinal Nerve Ligation-induced Neuropathic Pain

Background Tumor necrosis factor-alpha and other proinflammatory cytokines are becoming well recognized as key mediators in the pathogenesis of many types of neuropathic pain. Thalidomide has profound immunomodulatory actions in addition to their originally intended pharmacological actions. There has been debate on the analgesic efficacy of opioids in neuropathic pain. The aim of this study was to investigate the effect of thalidomide and morphine on a spinal nerve ligation model in rats. Methods Male Sprague-Dawley rats weighing 100-120 g were used. Lumbar (L) 5 and 6 spinal nerve ligations were performed to induce neuropathic pain. For assessment of mechanical allodynia, mechanical stimulus using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of intraperitoneal thalidomide (6.25, 12.5, 25 and 50 mg/kg, respectively) and morphine (3 and 10 mg/kg, respectively) were examined on a withdrawal threshold evoked by spinal nerve ligation. Results After L5 and 6 spinal nerve ligation, paw withdrawal thresholds on the ipsilateral side were significantly decreased compared with pre-operative baseline and with those in the sham-operated group. Intraperitoneal thalidomide and morphine significantly increased the paw withdrawal threshold compared to controls and produced dose-responsiveness. Conclusions Systemic thalidomide and morphine have antiallodynic effect on neuropathic pain induced by spinal nerve ligation in rat. These results suggest that morphine and thalidomide may be alternative therapeutic approaches for neuropathic pain.

Roles of opioid receptor subtypes on the antinociceptive effect of intrathecal sildenafil in the formalin test of rats

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.

Antinociceptive Effect of Memantine and Morphine on Vincristine-induced Peripheral Neuropathy in Rats

Background Vincristine-induced peripheral neuropathy is a major dose limiting side effect and thus effective therapeutic strategy is required. In this study, we investigated the antinociceptive effect of memantine and morphine on a vincristine-induced peripheral neuropathy model in rats. Methods Male Sprague-Dawley rats weighing 220-240 g were used in all experiments. Rats subsequently received daily intraperitoneal injections of either vincristine sulfate (0.1 ml/kg/day) or saline (0.1 ml/kg/day) over 12 days, immediately following behavioral testing. For assessment of mechanical allodynia, mechanical stimuli using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of N-methyl-D-aspartate receptors antagonist (memantine; 2.5, 5, 10 mg/kg intraperitoneal), opioid agonist (morphine; 2.5, 5, 10 mg/kg intraperitoneal) and vehicle (saline) on vicristine-induced neuropathy were evaluated. Results Mechanical allodynia developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same time. Morphine abolished the reduction in paw withdrawal threshold compared to vehicle and produced dose-responsiveness. Only the highest dose of memantine (10 mg/kg) was able to increase paw withdrawal threshold compared to vehicle. Conclusions Systemic morphine and memantine have an antinociceptive effect on the vincristine-induced peripheral neuropathy model in rats. These results suggest morphine and memantine may be an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

Antinociceptive Effect of Intrathecal Nefopam and Interaction with Morphine in Formalin-Induced Pain of Rats

Background Nefopam, a non-opiate analgesic, has been regarded as a substance that reduces the requirement for morphine, but conflicting results have also been reported. The inhibition of monoamine reuptake is a mechanism of action for the analgesia of nefopam. The spinal cord is an important site for the action of monoamines however, the antinociceptive effect of intrathecal nefopam was not clear. This study was performed to examine the antinociceptive effect of intrathecal (i.t.) nefopam and the pattern of pharmacologic interaction with i.t. morphine in the formalin test. Methods Male Sprague-Dawley rats were implanted with an i.t. catheter, and were randomly treated with a vehicle, nefopam, or morphine. Formalin was injected into the hind-paw 10 min. after an i.t. injection of the above experiment drugs. After obtaining antinociceptive ED50 of nefopam and morphine, the mixture of nefopam and morphine was tested for the antinociceptive effect in the formalin test at a dose of 1/8, 1/4, 1/2 of ED50, or ED50 of each drug followed by an isobolographic analysis. Results Intrathecal nefopam significantly reduced the flinching responses in both phases of the formalin test in a dose-dependent manner. Its effect, however, peaked at a dose of 30 µg in phase 1 (39.8% of control) and 10 µg during phase 2 (37.6% of control). The isobolograhic analysis indicated an additive interaction of nefopam and morphine during phase 2, and a synergy effect in antinociception during phase 1. Conclusions This study demonstrated that i.t. nefopam produces an antinociceptive effect in formalin induced pain behavior during both phases of the formalin test, while interacting differently with i.t. morphine, synergistically during phase 1, and additively during phase 2.

Additive Antinociception between Intrathecal Sildenafil and Morphine in the Rat Formalin Test

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 µL of 5% formalin solution was applied to the hind-paw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

Postoperative nausea and vomiting after mastoidectomy with tympanoplasty: a comparison between TIVA with propofol-remifentanil and balanced anesthesia with sevoflurane-remifentanil

Background There is growing interest in the anesthetic approach using total intravenous anesthesia (TIVA) with propofol and remifentanil for the prevention of postoperative nausea and vomiting (PONV). The aim of this study was to compare between the two anesthetic techniques for preventing PONV in the patients undergoing mastoidectomy with tympanoplasty. Methods After obtaining informed consent, 62 patients aged between 20 to 60 years undergoing elective mastoidectomy and tympanoplasty were randomized into two equal study groups: group P/R (n = 31) included patients undergoing TIVA with propofol and remifentanil, and group S/R (n = 31) included patients undergoing balanced anesthesia with sevoflurane and remifentanil. The incidences of PONV and complete response (no PONV, no rescue) were assessed at 1 and 24 h after surgery, using the Rhodes Index. Also, the usage of rescue antiemetics and pain intensity were recorded. Results The Rhodes Index including the occurrence score, distress score and experience score was significantly lower in the P/R group compared to that in the S/R group during the study period (P < 0.05), and the incidence of complete response was significantly higher in the P/R group compared to that in the S/R group, during the first 24 h after surgery. 4 patients in the S/R group requested antiemetics during the first 1 h after surgery. There were no significant differences in pain intensity among groups. Conclusions Compared to balanced anesthesia with sevoflurane and remifentanil, TIVA with propofol and remifentanil was followed by significantly lower incidence and severity of PONV.