• The Korean Journal of Pain
• /
• v.18 no.1
• /
• pp.19-22
• /
• 2005

Background: Most terminal cancer patients suffered from intractable pain. For the treatment of these patients, opioids, via various routes, are usually administered. Continuous epidural opioid, especially morphine, administration is a good method for the management of intractable cancer pain. Methods: We retrospectively analyzed 347 terminal cancer patients, who had been treated with continuous epidural morphine infusion, between 1999 and 2004. For the epidural infusion, an epidural catheter was inserted, tunneled subcutaneously and exited from the anterior chest or abdomen. Multiday $Infursor^{(R)}$ (Baxter, 0.5 ml/h) was used for the continuous infusion. Results: Of the 347 patients studied, there were 211 males and 136 females. The mean treatment time was 54.7 days, ranging from 5 to 481 days. The mean starting and termination doses of morphine were 32.4 (for 5 days) and 100.0 mg, respectively. The doubling time of the morphine dose was 26.3 days, corresponded to a 3.8 percent increase per day. Incidental catheter removal was the most common side effect, which occurred 130 times in 61 cases. Conclusions: The procedure of epidural catheterization, with subcutaneous tunneling, was simple and inexpensive. Despite the disadvantages, such as incidental catheter removal, it is a useful method for the control of terminal cancer pain.

• Biomolecules & Therapeutics
• /
• v.5 no.1
• /
• pp.53-58
• /
• 1997

$[Lys^7$]dermorphin, abbreviated K7DA, which has structural features similar to a metabolically stable $\mu$-opioid peptide agonist $[D-Arg^2, Lys^4$]dermorphin analogue (DALDA), but is intrinsically more potent with respect to binding to the $\mu$-opioid peptide receptor. The present studies report on attempts to enhance brain uptake of systemically administered K7DA by conjugation to a complex of streptavidin (SA) and the OX26 murine monoclonal antibody to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the blood-brain barrier (BBB). SA-OX26 conjugate mediates BBB transport of biotinylated therapeutics. The K7DA is monobiotinylated at the $\varepsilon$-amino group of the $[Lys^7$] residue with cleavable linker using NHS-SS-biotin. The brain uptake of $^{125}I$ labeled biotinylated K7DA ($^{125}I$-bio-SSa-K7DA) was very small and rapidly metabolized after intravenous injection. The brain uptake, expressed as percent of injected dose delivered per gram of brain, of the $^{125}I$-bio-55-K7DA bound to the SA-OX26 conjugate $^{125}I$-bio-SS-K7DA/SA-OX26) was 0.14$\pm$0.01, a level that is 2-fold greater than the brain uptake of morphine. The cleavability of the disulfide linker in vivo in rat plasma and brain was assessed with gel filtration HPLC and intravenous injection of labeled opioid chimeric peptides. The disulfide linker is stable in plasma in vivo but is cleaved in rat brain in vivo. In conclusion, these studies show that delivery of these potential opioid peptides to the brain may be improved by coupling them to vector-mediated BBB drug delivery system.

• Journal of Hospice and Palliative Care
• /
• v.5 no.1
• /
• pp.24-30
• /
• 2002

Background : Pain is one of the most feared consequences of cancer. $65{\sim}85%$ of cancer patients experienced severe pain, and sometimes high dose morphine is used to these patients. But many doctors still have 'opioid-phobia' and hesitate to use high dose morphine. We investigated the morphine therapy in terminal cancer patients during the last 1 week to death, and found any differences according to the morphine dosage. Methods : 93 patients admitted to National Health Insurance Corporation Ilsan Hospital, department of family medicine for hospice care between September 2000 and the end of October 2001 and lived more than 1 week entered in the study. We investigated the demographic data, laboratory tests and sufficient dosage of morphine for pain control. According to the calculated dosage by OME(oral morphine equivalent), patients were divided into low dosage group (${\leq}150mg/day$) and high dosage group (>150 mg/day). The chi-squared test were used to evaluate the influence of age, gender, tumor sites, metastasis and adverse effects of morphine. Results : Mean age was $65.0{\pm}13.1year$ in low dosage group and $59.9{\pm}11.6year$ in high dosage group. 32 men (50.0%) and 32 women (50.0%) were included in low dosage group and 15 men (51.7%) and 14 women (48.3%) in high dosage group. Stomach was the most frequent tumor site and lung was the next. Metastasis were found 58 (90.6%) in low dosage group and 28 (96.6%) in high dosage group. In other palliative radiotherapy and adverse effects, there were no differences in both group. Conclusion : During the last 1 week to death in cancer patients, there were no difference according to the morphine dosage. So we don't have to have 'opioid-phobia' in treating the terminal cancer patients.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1994.04a
• /
• pp.284-284
• /
• 1994

Pentazocine은 opioid 수용체에 대한 흥분작용과 길항작용을 겸유한 opioid계 약물로 알려져 있다. 본 연구에서 흰쥐 적출 관류부신 으로 부터 pentazocine의 catecholamine (CA) 분비작용을 관찰하여 그 기전을 규명하고 또한 다른 opioid의 작용과 비교하여 얻어진 결과는 다음과 같다. Pentazocine (30-300$\mu\textrm{g}$)을 부신정맥내에 주사하였을때 현저한 용량 의존성의 CA 분비 작용을 나타내었다. Pentazocine의 이러한 CA 분비작용은 chlorisondamine ($10^{-6}$M), naloxone (1.22 $\times$ $10^{-7}$M), morphine (1.73 $\times$ $10^{-5}$M). enkephalin (9.68 $\times$$10^{-6}$M), nicardipine ($10^{-6}$M) 및 TMB-8 ($10^{-5}$M)등의 전처치로 뚜렷이 억제되었으나 pirenzepine (2 $\times$ $10^{-6}$M)의 전처치에 의해서는 영향을 받지 않았다. $Ca^{++}$-free Krebs 용액으로 30분간 관류한 후에 pentazocine의 CA 분비작용은 현저한 감소를 나타내었다. Pentazocine (1.75 $\times$ $10^{-4}$M)을 20분간 관류시킨 후에 ACh (5.32 $\times$ $10^{-3}$M)과 DMPP ($10^{-4}$M)에 의한 CA 분비작용이 의의있게 감약되었다.

• 한국유가공학회:학술대회논문집
• /
• 2005.10a
• /
• pp.1-9
• /
• 2005

The ubiquitous presence of lactoferrin (LF) receptor in human as reported by the research group of Prof, Bo Lonnerdal, Univ. California, encouraged us to search for the unknown physiological roles of LF. Under the collaboration with Prof. Etsumori Harada, Tottori Univ., and his research group, we have found two novel biological activities of LF as the control of the lipid metabolism and the effect on the central nervous system. Relating to the lipid metabolism, LF could, in animal experiments, reduce triglyceride and total cholesterol both in blood and liver. LF increased plasma HDL-C and lowered LDL-C. In the central nervous system, LF showed anti-nociceptive activity mediated by ${\mu}$-opioid receptor in the rat spinal cord. LF enhanced analgesic action of morphine synergistically via nitric oxide synthesis. LF showed opioid-mediated suppressive effect on distress induced by maternal separation in rat pups.

• The Korean Journal of Physiology and Pharmacology
• /
• v.2 no.2
• /
• pp.155-163
• /
• 1998

The purpose of present study was to compare the effects of somatostatin (SOM) and morphine (Mor) on the responses of wide dynamic range (WDR) cells to peripheral noxious stimulation. Single neuronal activity was recorded with a carbon-filament electrode at the lumbosacral enlargement of cat spinal cord. After identifying WDR cells, their responses to peripheral noxious mechanical or thermal stimuli were characterized and the effects of SOM and Mor, applied either iontophoretically or intrathecally, were studied. In most cells SOM and Mor suppressed noxious stimulus-evoked WDR neuronal activity, though a few WDR neurons showed no change or were excited by SOM and Mor. Systemically applied naloxone, a non-specific opioid antagonist, always reversed the Mor induced suppression of neuronal activity evoked by noxious mechanical stimuli, but did not always reverse the suppression of neuronal activity elicited by SOM. The suppressive effect of Mor on thermal stimulus-evoked neuronal activity was partially reversed by naloxone, while that of SOM were not reversed at all. The above results suggest that both Mor and SOM exert an inhibitory effect on thermal and mechanical stimulus-evoked WDR neuronal activity in cat spinal dorsal horn, but the mechanisms are dependent upon the functional populations of dorsal horn nociceptive neurons.

• The Korean Journal of Pain
• /
• v.25 no.1
• /
• pp.47-51
• /
• 2012

Intrathecal drug administration system (ITDAS) can reduce the side effects while increasing the effectiveness of opioids compared to systemic opioid administration. Therefore, the use of ITDAS has increased in the management of cancer pain and chronic intractable pain. Catheter obstruction is a serious complication of ITDAS. Here, we present a case of catheter obstruction by a mass formed at the side hole and in the lumen. A 37-year-old man suffering from failed back surgery syndrome received an ITDAS implantation, and the ITDAS was refilled with morphine every 3 months. When the patient visited the hospital 18 months after ITDAS implantation for a refill, the amount of delivered morphine sulfate was much less than expected. Movement of the pump rotor was examined with fluoroscopy; however, it was normal. CSF aspiration through the catheter access port was impossible. When the intrathecal catheter was removed, we observed that the side hole and lumen of the catheter was plugged.

• Journal of The Korean Dental Society of Anesthesiology
• /
• v.13 no.4
• /
• pp.167-178
• /
• 2013

Oxycodone is a semi-synthetic opioid synthesized from poppy-derived thebaine. It is a narcotic analgesic generally indicated for relief of moderate to severe pain. Although developed in an attempt to improve on the existing opioids, the adverse effects of oxycodone are those that are typically found in opioids. In recent years, the use of the opioid oxycodone has increased markedly and replacing morphine as the first line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. In 2013, intravenous oxycodone was approved for marketing by Ministry of Food and Drug Safety (MFDS), with the indication of postoperative intravenous patient-controlled analgesia (IV PAC). Simulation study of oxycodone demonstrated that minimum effective analgesic concentration (MEAC) of oxycodone was most quickly reached with higher loading dose and IV PCA with background infusion, which may reduce the necessity of rescue analgesics during immediate postoperative period. Previous studies for postoperative pain management with intravenous oxycodone are limited in sample size, mostly less than 100 patients, which may not be large enough to assess safety of intravenous oxycodone. The effectiveness and tolerability of IV PCA with oxycodone should, therefore, be evaluated in large scale clinical trials in Korean populations.

• The Korean Journal of Pain
• /
• v.18 no.2
• /
• pp.113-117
• /
• 2005

Background: Serotonin 3 receptor is involved in the modulation of nociceptive transmission in the spinal cord. The serotonin 3 receptor antagonist has been used for the management of opioid-induced nausea and vomiting. The aim of this study was to examine whether the analgesic effect of morphine is antagonized by serotonin 3 receptor antagonists at the spinal level. Methods: Rats were implanted with lumbar intrathecal catheters. For nociception, a formalin solution (5%, $50{\mu}l$) was injected into the hind paw of male Sprague-Dawley rats. To determine whether the effect of intrathecal morphine was mediated via serotonin 3 receptors, serotonin 3 receptor antagonists were intrathecally administered 10 min prior to the morphine delivery. Following the formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Results: Intrathecal morphine produced a dose-dependent suppression of the flinches in both phases during the formalin test. The analgesic action of morphine was not reversed by serotonin 3 receptor antagonists (LY-278,584, ondansetron), which had little per se effect on the formalin-induced nociception. Conclusions: Spinal serotonin 3 receptors may not be involved in the analgesia of morphine on a nociceptive state evoked by a formalin stimulus.

• Experimental and Molecular Medicine
• /
• v.50 no.11
• /
• pp.6.1-6.12
• /
• 2018

Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine-threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a ${\mu}$ opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance.