Nalbuphie의 병용투여에 의한 morphine의 내성 및 의존성 헝성 저하효과

정면우(Myeon Won Chung),임화경(Hwa Kyung Lim),전용준(Yong Joon Jeon),김혜정(Hye Jung Kim),박인숙(In Sook Park),오우용(Woo Yong Oh),왕소영(So Young Wang),박윤주(Yoonju Park),강주희(Ju Hee Kang),김동섭(Dong Sup Kim),김주일(Joo Il Kim) 대한약학회 2002 약학회지 Vol.46 No.4

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to morphine by repeat application is a major problem in pain therapy: The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, k-agonist may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 days. The variable dose of nalbuphine (0.1,1.0 and 5.0 mg/kg) was administered (I.p.) in combination with morphine injection. The development of tolerance to morphine was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 20 min after injection of naloxone (10 mg/kg,I.p.). Nalbuphine did not attenuate antinociceptive effect of mofhine in rats. Interesting1y; combined administration of morphine with nalbuphine (100:1) sign- nifcantly attenuated the development of morphine tolerance and dependence. These results suggest that the co-admin-istration of nalbuphine with morphine in chronic morphine treatment can be one of therapies to reduce the development of dependence on morphine.

Attenuation of Morphine Tolerance and Withdrawal Syndrome by Coadministration of Nalbuphine

Jang, So-Yong,Kim, Hee-Jeong,Kim, Dong-Hyun,Jeong, Myeon-Woo,Ma, Tangen,Kim, Seong-Youl,Ho, Ing K.,Oh, Sei-Kwan The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.8

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, ${\kappa}-agonist$ may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10:1) significantly attenuated the development of dependence on morphine. The elevation of $[^3H]MK-801$ binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.

Plasma Concentrations of Morphine during Postoperative Pain Control

( Hahck Soo Park ),( Jong Hak Kim ),( Yi Jeong Kim ),( Dong Yeon Kim ) 대한통증학회 2011 The Korean Journal of Pain Vol.24 No.3

Background: Morphine has been commonly used for postoperative pain control. We measured plasma concentrations of morphine and compared the efficacy and safety of continuous epidural analgesia (CEA) using morphine- bupivacaine with intravenous patient controlled analgesia (IV-PCA) with morphine for 48 hrs after the end of the operation. Methods: Nineteen patients undergoing Mile`s operation were assigned to receive a morphine loading dose of 5 mg followed by IV-PCA with 0.1% morphine (IV-PCA group, n = 9) or a morphine loading dose of 2 mg and 0.125% bupivacaine 10 ml, followed by CEA with 0.004% morphine and 0.075% bupivacaine at a rate of 5 ml/hr (CEA group, n = 10). The plasma concentrations of morphine were measured and visual analog scales (VAS) for pain were recorded at 1, 6, 12, 24, and 48 hr postoperatively and the effects on respiration and any other side effects were noted. Results: The mean maximal and minimal levels of plasma morphine were 40.2 ± 21.2 ng/ml and 23.4 ± 9.7 ng/ml for the IV-PCA group and 11.8 ± 3.5 ng/ml and 8.2 ± 1.9 ng/ml for the CEA group, respectively. Resting and dynamic pain scores were significantly lower in the CEA group than in the IV-PCA group. There were no significant differences for the effects on respiration and for any side effects between the two groups. Conclusions: We evaluated plasma concentrations of morphine with CEA using morphine-bupivacaine and IV-PCA using morphine for the postoperative pain control. The CEA group had better postoperative analgesia than that of the IV-PCA group and the incidence of side effects were not significantly different between the two groups. (Korean J Pain 2011; 24: 146-153)

Plasma Concentrations of Morphine during Postoperative Pain Control

Park, Hahck-Soo,Kim, Jong-Hak,Kim, Yi-Jeong,Kim, Dong-Yeon The Korean Pain Society 2011 The Korean Journal of Pain Vol.24 No.3

Background: Morphine has been commonly used for postoperative pain control. We measured plasma concentrations of morphine and compared the efficacy and safety of continuous epidural analgesia (CEA) using morphinebupivacaine with intravenous patient controlled analgesia (IV-PCA) with morphine for 48 hrs after the end of the operation. Methods: Nineteen patients undergoing Mile's operation were assigned to receive a morphine loading dose of 5 mg followed by IV-PCA with 0.1% morphine (IV-PCA group, n = 9) or a morphine loading dose of 2 mg and 0.125% bupivacaine 10 ml, followed by CEA with 0.004% morphine and 0.075% bupivacaine at a rate of 5 ml/hr (CEA group, n = 10). The plasma concentrations of morphine were measured and visual analog scales (VAS) for pain were recorded at 1, 6, 12, 24, and 48 hr postoperatively and the effects on respiration and any other side effects were noted. Results: The mean maximal and minimal levels of plasma morphine were $40.2{\pm}21.2\;ng/ml$ and $23.4{\pm}9.7\;ng/ml$ for the IV-PCA group and $11.8{\pm}3.5\;ng/ml$ and $8.2{\pm}1.9\;ng/ml$ for the CEA group, respectively. Resting and dynamic pain scores were significantly lower in the CEA group than in the IV-PCA group. There were no significant differences for the effects on respiration and for any side effects between the two groups. Conclusions: We evaluated plasma concentrations of morphine with CEA using morphine-bupivacaine and IV-PCA using morphine for the postoperative pain control. The CEA group had better postoperative analgesia than that of the IV-PCA group and the incidence of side effects were not significantly different between the two groups.

Attenuation of Morphine Tolerance and Withdrawal Syndrome by Coadministration of Nalbuphine

장소용,Heejeong Kim,Donghyun Kim,Myeon Woo Jeong,Tangen Ma,Seongyoul Kim,Ing K. Ho,오세관 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.8

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, κ-agonist may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10:1) significantly attenuated the development of dependence on morphine. The elevation of [3H]MK-801 binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.

TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens

Hong, S.I.,Nguyen, T.L.,Ma, S.X.,Kim, H.C.,Lee, S.Y.,Jang, C.G. Elsevier/North-Holland Biomedical Press 2017 Behavioural brain research Vol.334 No.-

Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular mechanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho-p38 MAPK, phosphor-NF-κB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction.

Formalin에 의해 통각과민이 유발된 흰쥐의 척수강내로 혼합투여한 Morphine, Ketorolac 및 L-NAME의 상호작용

심재항,전종헌,김경헌,염종훈,서정국 대한마취과학회 2002 Korean Journal of Anesthesiology Vol.43 No.6

Background: Morphine has a direct action on morphine receptors in the brain and spinal coed. Intrathecally administered L-NAME, a nitric oxide synthase inhibitor, is known to have an antinociceptive effect on formalin-induced pain in animal studies. Efficacy of intrathecally administered ketorolac, a cyclooxygenase inhibitor, is somewhat controversial. The interactions of intrathecally administered morphine, ketorolac and L-NAME on formalin-induced nociception was studied. Methods: Male Sprague-Dawley rats were implanted with chronic lumber intrathecal catheters and were tested for paw flinch by a formalin injection. Drugs were intrathecally administered 15 min before the formalin injection, and biphasic painful behaviors were observed. We obtained the ED_50 for each agent (ketorolac, L-NAME and morphine). ED_50 fraction (1, 1/2 and 1/4) of drug combinations of L-NAME-ketorolac, morphine-L-NAME and ketorolac-morphine were administered. The ED_50 of each combined drug was established and isobolographic analysis of the drug interactions was carried out. Results: Intrathecal administration of ketorolac, L-NAME and morphine produced a dose-dependent suppression of pain behaviors in phases 2. ED_50 values were 297.04 ㎍ for ketorolac, 207.46 ㎍ for L-NAME and 0.17㎍ for morphine in phase 2. Isobolographic analysis showed that the combination of intrathecal morphine and L-NAME synergistically reduced pain behaviors in phase 2. Cinclusions: Intrathecally administered morphine, L-NAME and ketorolac produced a dose-dependent decrease in the number of paw flinches in both phase 1 and phase 2 on the formalin test. Morphine with L-NAME showed synergistic analgestic effects on formalin-induced pain in phase 2. (Korean J Anesthesiol 2002; 43: 780~789)

개심술마취를 위한 척수강내 Fentanyl과 Morphine 병용 주입

김진모,전재규,이정호 啓明大學校 醫科大學 1998 계명의대학술지 Vol.17 No.1

개심술이 계획된 18명의 환자를 질병과 수술의 종류 및 심장기능에 까라 3군으로 분류하여 척수강내 fevtanly과 morphine의 용량을 서로 다르게 병용 주입하여 다음과 같은 결과를 얻었다. 1) 수축기 동맥압과 심박수는 모든 군에서 마취유도 후부터 심폐회로술 직전까지 안정적으로 유지되었으며 호기말 isoflurane농도는 Ⅰ군는 0.6∼0.8 vol%, Ⅱ군과 Ⅲ군에서는 0.4∼0.6 vol%에서 심박수와 동맥압의 변화가 최소화되면서 술중 흡입마취제 요구량이 감소되었다. 2) 술중 및 술후 진통제 요구량은 술후 12시간 이내에는 모든 군에서 추가로 진통제를 투여할 필요가 없었으며 술후 24시간 이후에도 진통제의 요구량은 감소되었다. 3) 척수강내 fentanly과 morphine 주입에 따른 합병증인 오심, 구토, 뇨정체 및 소양감 등은 흔히 볼 수 있었으나 개심수 환자관리에 있어서는 별 문제가 되지 않았다. 4) 기관내 삽관튜브의 발관시기는 Ⅰ군은 술후 8.5±3.2시간, Ⅱ군과 Ⅲ군은 각각 12.7±4.5, 22.3±7.8시간이었다. 이상의 결과로 개심술 마취시 척수강내 fentanly과 morphine의 병용 주입으로 술중 흡입마취제 요구량의 감소는 척수강내 fentanly주입으로 술후 진통제 요구량의 감소는 척수강내 morphine주입에 의한 작용으로 사료되었으며, 기관내 삽관튜브의 발관시기는 흡입마취만 사용할 경우 술후 수술실에서 발관할 수 있을 정도인 심 페기능이 정상인 Ⅰ군에서도 술후 자발호흡 능력이 현저히 감소된 것으로 미루어 척수강내 마약제 주입으로 인한 호흡억제로 발관시기가 지연되었고 Ⅱ, Ⅲ군에서 조기 발관이 불가능한 원인은 척수 강내 주입한 마약제의 영향보다는 심장기능의 저하가 주요 원인으로 생각되었다. Intrathecal (IT) opioids have been used widely, both intraoperatively as adjuvant anesthesia and postoperatively for analgesia. The intense intraoperative analgesia provided by IT fentanyl along with the postoperative analgesia provided by IT morphine, makes the combination suitable for cardiac surgery. The investigation was designed to evaluate 1) the timing of extubation following the cardiac surgery, 2) intraoperative hemodynamic changes on the end tidal isoflurane concentration, 3) morphine requirement during the postoperative periods, and 4) incidence of complications with IT opioids. Eighteen patients undergoing cardiac surgery were divided into three groups receiving intrathecal fentanyl 200㎍ and morphine 1 mg (Grouop I), fentanyl 300 ㎍ and morphine 1 mg (Grouop II) and fentanyl 300㎍ and morphine 2mg (Group III) according to surgical procedures and heart functions. All of them were injected into L3-4 prior to induction IT opioids with normal saline to enhance spread cephaladly. Inhalation anesthesia was maintained with air, oxygen and isoflurane. The end tidal isoflurane concentration was measured by mass spectrometry. After initiation of CPB, the patient was cooled to 28℃. Perfusion pressure was maintained at 50-70mmHg. After extubation, patients were evalusted the occurrence of IT opioids complications. The systolic BP and HR remained stable between induction and initiation of CPB at the Group I, II and III. The end tidal isoflurane concentration was maintained oat 0.6~0.8 vol. % (Group I) and 0.4~0.6 vol. % (Group II and Group III). Postoperative extubation time was required 8.5±3.2 (Group I), 12.7±4.5 (Group II) and 22.3±7.8 hours (Group III). Complications of IT opioids were pruritus (5/18), nausea/vomiting (3/18), headache (2/18) and urinary retention (7/18). The combination of IT fentanyl and morphine provided stable intraoperative hemodynamics group I, but postoperative demediate tracheal extubation did not allowed of normal ventricular and espiratory function due to due to respiratory depression related to IT opioids. Prolonged intubation was needed in Group III (AVR, MVR with Atrial fibrillation) due to undeslying cardiac disease. We could not determine the optimal dos-age of IT opioid in each group due to the different IT opioid dosages in the three groups. However, dosage of IT opioid in Group II (CABG, MVR with normal sinus rhythm) was found to be relatively suitable compared to the other groups. All patients required significantly less dosage of postoperative intravenous morphine. We observed no clinical evidence of a subarachnoid or epidural hematoma.

Experimental Research Article : Intrathecal Lamotrigine blocks and reverses antinociceptive morphine tolerance in rats

In Gu Jun,Jong Yeon Park,Yun Sik Choi,Tae Hee Kim 대한마취과학회 2009 Korean Journal of Anesthesiology Vol.56 No.6

Background: Chronic administration of morphine leads to the development of tolerance. We investigated the effects of intrathecal lamotrigine on the spinal morphine tolerance in rats that are undergoing tail flick tests. Methods: Sprague-Dawley rats were given intrathecal injections of saline 10 μl, lamotrigine 300 μg, morphine 15 μg or lamotrigine plus morphine combinations for 7 days (lamotrigine was given for days 1-7, days 1-3 or days 5-7). The acute and chronic nociceptive sensitivities were assessed using a tail flick test in which the distal 5 cm of the tail was dipped into warm water before and 30 minutes after the drug injection. With successive injections of morphine on day 8, a cumulative antinociceptive dose-response curve was constructed and the 50% effective dose (ED50) was calculated for each study group. Results: The coinjection group of lamotrigine with morphine blocked the development of tolerance, as was shown by the preservation of morphine antinociception over 7 days and the concomitant decrease in the ED50 values on day 8, as compared with the morphine-alone group. Coinjection of lamotrigine blocked the development of morphine tolerance, as shown by the preservation of morphine antinociception over 7 days and the concomitant decrease in the ED50 values on day 8, as compared with the morphine-alone group. Conclusions: This study suggests that lamotrigine augments the antinociceptive action of both acute and chronic morphine therapy, and it also attenuates the antinociceptive morphine tolerance in rats. (Korean J Anesthesiol 2009; 56: 687~92)

Intrathecal Lamotrigine Attenuates Antinociceptive Morphine Tolerance and Suppresses Spinal Glial Cell Activation in Morphine-Tolerant Rats

전인구,김성훈,윤영인,박종연 대한의학회 2013 Journal of Korean medical science Vol.28 No.2

Glial cells play a critical role in morphine tolerance, resulting from repeated administration of morphine. Both the development and the expression of tolerance are suppressed by the analgesic lamotrigine. This study investigated the relationship between the ability of lamotrigine to maintain the antinociceptive effect of morphine during tolerance development and glial cell activation in the spinal cord. In a rat model, morphine (15 μg)was intrathecally injected once daily for 7 days to induce morphine tolerance. Lamotrigine (200 μg) was co-administered with morphine either for 7 days or the first or last 3 days of this 7 day period. Thermal nociception was measured. OX-42 and GFAP immunoreactivity,indicating spinal microglial and astrocytic activation were evaluated on day 8. Tolerance developed after 7 days of intrathecal morphine administration; however, this was completely blocked and reversed by co-administration of lamotrigine. When lamotrigine was coinjected with morphine on days 5-7, the morphine effect was partially restored. Glial cell activation increased with the development of morphine tolerance but was clearly inhibited in the presence of lamotrigine. These results suggest that, in association with the suppression of spinal glial cell activity, intrathecally coadministered lamotrigine attenuates antinociceptive tolerance to morphine.