• The Korean Journal of Physiology and Pharmacology
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• 제4권4호
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• pp.291-299
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• 2000

Morphine or butorphanol was continuously infused into cerebroventricle (i.c.v.) with the rate of $26\;nmol/{\mu}l/h$ for 3 days, and the withdrawal from opioid was rendered 7 hrs after the stopping of infusion. The expression of physical dependence produced by these opioids was evaluated by measuring the naloxone-precipitated withdrawal signs. The withdrawal signs produced in animals dependent on butorphanol (kappa opioid receptor agonist) were similar to those of morphine (mu opioid receptor agonist). Besides the behavioral modifications, opioid withdrawal affected G protein expression in the central nervous system. The G-protein ${\alpha}-subunit$ has been implicated in opioid tolerance and withdrawal. The effects of continuous infusion of morphine or butorphanol on the modulation of G protein ${\alpha}-subunit$ mRNA were investigated by using in situ hybridization study. In situ hybridization showed that the levels of $G\;{\alpha}s$ and $G\;{\alpha}i$ were changed during opioid withdrawal. Specifically, the level of $G\;{\alpha}s$ mRNA was decreased in the cortex and cerebellar granule layer during the morphine and butorphanol withdrawal. The level of $G\;{\alpha}i$ mRNA was decreased in the dentate gyrus and cerebellar granule layer during the morphine withdrawal. However, the level of $G\;{\alpha}i$ mRNA was significantly elevated during the butorphanol withdrawal. These results suggest that region-specific changes of G protein ${\alpha}-subunit$ mRNA were involved in the withdrawal from morphine and butorphanol.

• Toxicological Research
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• 제11권1호
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• pp.63-68
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• 1995

N-methyl-D-aspartate(NMDA) receptor has been well known as an important mediator of several forms of neural and behavioral plasticity. But different results were reported about the effect of MK-801 or dextromethorphan on opioid dependence. The present studies examined whether NMDA receptor antagonists can alter the opioid dependence and tolerance in rodents. Naloxone precipitated withdrawal symptoms and changes of locomotor activities were observed in MK-801 or dextromethorphan pretreated morphine-dependent rats. Tail-flick assay was used for morphine analgesia and tolerance was found after 4 day's consecutive injections (10 mg/kg, s.c., twice/day) of morphine in mice. Locomotor activity was increased and the withdrawal symptoms were decreased by the pretreatment of MK-801 in morphine-dependent rats. But 0.3 mg/kg i.p. of MK-801 intensified the body weight loss and produced severe ataxia and rotation although some withdrawal signs were attenuated. Morphine induced analgesic tolerance was inhibited by the pretreatment of MK-801 and dextromethorphan. Dextromethorphan was more potent than MK-801 in inhibiting the development of the analgesic tolerance in mice. These results suggest that NMDA system may be involved in opioid withdrawal and analgesic tolerance but appropriate caution should be requested when MK-801 is used in combination with opioid because of untoward neurologic signs.

• Journal of Hospice and Palliative Care
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• 제20권2호
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• pp.131-135
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• 2017

목적: 경구 oxycodone/naloxone 복합제는 아편유사제에 의해 유발되는 변비를 완화시키거나 예방하는 목적으로 사용되고 있다. Naloxone에 의해 oxycodone의 진통 효과가 상쇄되거나 금단증상이 나타난다는 보고는 거의 없었으나 저자는 실제 임상에서 몇몇 금단증상 예를 경험하였기에 이 환자들에 대한 조사 연구를 수행하였다. 방법: 2012년 1월 1일부터 2016년 12월 31일까지 경남 지역 암센터에 방문했던 진행성 암환자들로 oxycodone/naloxone extended-release tablets를 투약 받고 마약 금단증상이 나타났던 환자들의 의무기록을 후향적으로 조사하였다. 결과: 연구 기간 중 경구 oxycodone/naloxone을 처방 받은 1,641명의 암 환자 중, 총 10예(0.6%) 에서 마약 금단 증상을 겪었다. 금단증상 관련 통증 강도의 변화는 oxycodone/naloxone 투여 전 NRS 3에서 평균 NRS 6점으로 증가하였다. 금단증상 중 오한이 10예 중 7예에서 나타나 가장 많이 나타난 증상이었으며 그 외에 식은땀, 전신 쇠약감, 근육경련, 복부경련(각 5예), 불안(4예), 열, 어지럼증, 의식혼란, 하품(각 2예)의 순으로 빈번하게 관찰되었다. 결론: Oxycodone/naloxone extended-release 복합제에 의한 마약 금단증상은 흔하지는 않아도 적은 수의 환자에서라도 나타날 수 있다. 향후 이에 대한 다기관, 전향적 연구가 필요하다.

• The Korean Journal of Pain
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• 제35권4호
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• pp.361-382
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• 2022

The third opium war may have already started, not only due to illicit opioid trafficking from the Golden Crescent and Golden Triangle on the international front but also through indiscriminate opioid prescription and opioid diversion at home. Opioid use disorder (OUD), among unintentional injuries, has become one of the top 4 causes of death in the United States (U.S.). An OUD is defined as a problematic pattern of opioid use resulting in clinically significant impairment or distress, consisting of 2 or more of 11 problems within 1 year, as described by the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Observation of aberrant behaviors of OUD is also helpful for overworked clinicians. For the prevention of OUD, the Opioid Risk Tool and the Current Opioid Misuse Measure are appropriate screening tests before and during opioid administration, respectively. Treatment of OUD consists of 3 opioid-based U.S. Food and Drug Administration-approved medications, including methadone, buprenorphine, and naltrexone, and non-opioid-based symptomatic medications for reducing opioid withdrawal syndromes, such as α₂ agonists, β-blockers, antidiarrheals, antiemetics, non-steroidal anti-inflammatory drugs, and benzodiazepines. There are at least 6 recommendable guidelines and essential terms related to OUD. Opioid stewardship programs are now critical to promoting appropriate use of opioid medications, improving patient outcomes, and reducing misuse of opioids, influenced by the successful implementation of antimicrobial stewardship programs. Despite the lack of previous motivation, now is the critical time for trying to reduce the risk of OUD.

• Journal of Hospice and Palliative Care
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• 제26권1호
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• pp.18-21
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• 2023

The combination of oxycodone and naloxone is useful for cancer pain management. Naloxone, as a pure opioid antagonist, cannot be used simultaneously with opioids. However, owing to its low bioavailability, it can be used in an oral composite formulation. We present the case of a 55-year-old man with gastric cancer who experienced severe opioid withdrawal syndrome (OWS) triggered by oxycodone/naloxone that was successfully managed with dexmedetomidine. He had been in a stable condition on intravenous morphine to alleviate cancer pain. Intravenous morphine was switched to oral oxycodone/naloxone for discharge from the hospital. The patient suddenly developed restlessness, heartburn, and violent behavior 30 minutes after taking oxycodone/naloxone. We attempted sedation with midazolam and propofol, but paradoxical agitation and desaturation occurred. Next, we tried dexmedetomidine and the patient showed a decreased heart rate and reduced agitation. The patient was eventually stabilized by increasing the dose of dexmedetomidine. This report informs clinicians of the possibility of OWS when switching from opioids to oxycodone/naloxone, which can be overcome with the appropriate use of sedatives and dexmedetomidine depending on the patient's condition.

• The Korean Journal of Pain
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• 제35권4호
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• pp.413-422
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• 2022

Background: The neocortex, including the medial prefrontal cortex (mPFC), contains many neurons expressing nitric oxide synthase (NOS). In addition, increasing evidence shows that the nitric oxide (NO) and opioid systems interact in the brain. However, there have been no studies on the interaction of the opioid and NO systems in the mPFC. The objective of this study was to investigate the effects of administrating L-arginine (L-Arg, a precursor of NO) and N(gamma)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NOS) into the mPFC for neuropathic pain in rats. Also, we used selective opioid receptor antagonists to clarify the possible participation of the opioid mechanism. Methods: Complete transection of the peroneal and tibial branches of the sciatic nerve was applied to induce neuropathic pain, and seven days later, the mPFC was cannulated bilaterally. The paw withdrawal threshold fifty percent (50% PWT) was recorded on the 14th day. Results: Microinjection of L-Arg (2.87, 11.5 and 45.92 nmol per 0.25 µL) increased 50% PWT. L-NAME (17.15 nmol per 0.25 µL) and naloxonazine (an antagonist of mu opioid receptors, 1.54 nmol per 0.25 µL) inhibited anti-allodynia induced by L-Arg (45.92 nmol per 0.25 µL). Naltrindole (a delta opioid receptor antagonist, 2.45 nmol per 0.25 µL) and nor-binaltorphimine (a kappa opioid receptor antagonist, 1.36 nmol per 0.25 µL) were unable to prevent L-Arg (45.92 nmol per 0.25 µL)-induced antiallodynia. Conclusions: Our results indicate that the NO system in the mPFC regulates neuropathic pain. Mu opioid receptors of this area might participate in pain relief caused by L-Arg.

• Biomolecules & Therapeutics
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• 제12권4호
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• pp.198-201
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• 2004

This review focuses on finding neurochemical changes in physical dependence on butorphanol, a relatively potent mixed agonist-antagonist opioid analgesic agent that is five times more potent than morphine in antinociceptive effects. The chronic administration of butorphanol induces physical dependence. Withdrawal from such dependence can be reliably precipitated by administration of a narcotic antagonist, e.g., naloxone. Evidence for critical involvement of excitatory aminoacid (glutamate), opioid receptors, and phosphorylation of proteins in these phenomena is summarized.

• 한국약용작물학회:학술대회논문집
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• 한국약용작물학회 2007년도 추계학술발표회
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• pp.281.1-281.1
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• 2007

• Journal of Ginseng Research
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• 제23권4호
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• pp.239-246
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• 1999

백서를 이용하여 진세노사이드 흑은 모르핀을 척수강내 투여한 다음 tail-flick test를 통하여 진통 작용을 연구하였다. 또한, 진세노사이드를 모르핀과 함께 척수강내 장기 처리할 경우 모르핀에 의한 내성 및 의존성 유발에 미치는 영향을 연구하였다. 연구 결과, 척수강내 진세노사이드의 투여는 200 ${\mu}g$/rat에서 약한 진통 작용이 있는 것으로 나타났다. 모르핀은 투여 농도에 의존적으로 좋은 진통 효능을 보여주었으며, $ED_50$은 1.2 ${\mu}g/rat$인 것으로 나타났다. 그러나 진세노사이드의 모르핀을 함께 척수강내 투여할 경우 모르핀의 진통 작용을 증가 시키지 않은 것으로 나타났다. 200 ug/rat 진세노사이드를 10 ${\mu}g$/rat모르핀을 7일 동안 같이 투여할 경우 모르핀에 의한 통증 작용에 대한 내성을 억제하였으며, 모르핀에 의한 의존성을 부분적으로 억제하는 것으로 나타났다. 이러한 연구 결과는 척수 수준에서 진세노사이드가 모르핀의 장기 투여에 의하여 유도되는 모르핀에 대한 내성 및 의존성을 억제하는 것으로 사료된다.

• The Korean Journal of Pain
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• 제32권2호
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• pp.87-96
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• 2019

Background: This study was performed in order to examine the effect of intrathecal sec-O-glucosylhamaudol (SOG), an extract from the root of the Peucedanum japonicum Thunb., on incisional pain in a rat model. Methods: The intrathecal catheter was inserted in male Sprague-Dawley rats (n = 55). The postoperative pain model was made and paw withdrawal thresholds (PWTs) were evaluated. Rats were randomly treated with a vehicle (70% dimethyl sulfoxide) and SOG ($10{\mu}g$, $30{\mu}g$, $100{\mu}g$, and $300{\mu}g$) intrathecally, and PWT was observed for four hours. Dose-responsiveness and ED50 values were calculated. Naloxone was administered 10 min prior to treatment of SOG $300{\mu}g$ in order to assess the involvement of SOG with an opioid receptor. The protein levels of the ${\delta}$-opioid receptor, ${\kappa}$-opioid receptor, and ${\mu}$-opioid receptor (MOR) were analyzed by Western blotting of the spinal cord. Results: Intrathecal SOG significantly increased PWT in a dose-dependent manner. Maximum effects were achieved at a dose of $300{\mu}g$ at 60 min after SOG administration, and the maximal possible effect was 85.35% at that time. The medial effective dose of intrathecal SOG was $191.3{\mu}g$ (95% confidence interval, 102.3-357.8). The antinociceptive effects of SOG ($300{\mu}g$) were significantly reverted until 60 min by naloxone. The protein levels of MOR were decreased by administration of SOG. Conclusions: Intrathecal SOG showed a significant antinociceptive effect on the postoperative pain model and reverted by naloxone. The expression of MOR were changed by SOG. The effects of SOG seem to involve the MOR.