Effect of Ultra-low Dose Naloxone on Remifentanil-Induced Hyperalgesia
关键词
抽象
描述
Purpose:
Opioid antagonists at ultra-low doses have been used with opioid agonists to prevent or limit opioid tolerance. Remifentanil, a rapid onset/offset opioid that is often used as an anesthesia adjunct intraoperatively, has been associated with the development of hyperalgesia and opioid tolerance postoperatively. Opioid-induced hyperalgesia (OIH) induced by remifentanil intraoperatively may be a factor contributing to an increase in postoperative pain as well as difficulty in controlling such pain. The purpose of this study will be to evaluate whether an ultra-low dose of naloxone, an opioid antagonist, could block remifentanil-induced hyperalgesia and tolerance following surgery.
This research will help elucidate the degree of OIH after surgeries involving remifentanil and determine if a new technique can be employed to decrease remifentanil-induced OIH. By mitigating OIH, patients should have a decrease in postoperative pain and an increase in patient satisfaction at UCI and other hospitals where such a technique is employed.
There are 3 study groups: (1) low dose remifentanil (LO, 0.1 micrograms/kg/mL), (2) high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL), or (3) high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone).
Background:
Opioid-induced hyperalgesia is a paradoxical increase in pain sensitivity following opioid exposure. The mechanism for this is likely due to an alteration in opioid receptor signaling with disruption of G-protein coupling and opioid-induced activation and hypertrophy of spinal glial cells (gliosis). Opioid-induced hyperalgesia has been noted with many different opioids, and the most well documented hyperalgesic effect is with remifentanil.
Various agents have been used in an attempt to reduce the development hyperalgesia following remifentanil. While there are few reports on the effect of ultra-low dose naloxone on opioid-induced hyperalgesia, recent evidence is emerging regarding its use in pain management. Ultra-low dose naloxone has been shown to prevent remifentanil-induced pain hypersensitivities (allodynia and hyperalgesia) in rats. However, there are little to no studies on reducing the adverse effects of remifentanil with naloxone in human subjects.
Existing knowledge and previous research:
Attempts have been made with various agents to reduce the development of tolerance and hyperalgesia following remifentanil. Postoperative hyperalgesia and its prevention has been studied with ketamine , Magnesium , Gabapentin, Clonidine, Lornoxicam , Dextromethorphan , Paracetamol , Morphine , Dexmedetomidine , Adenosine, COX inhibitors , Amantadine , Nitrous oxide, Fentanyl, Pregabalin , Buprenorphine, Midazolam, Dexamethasone. Relevant to our current hypothesis is the report that concomitant administration of ultra-low dose naloxone and naltrexone with remifentanil prevented OIH. However, there are no studies on reducing the adverse effects of remifentanil with ultra-low dose naloxone in human subjects.
While the traditional role of opiate antagonists have been in cases of opioid overmedication, recent evidence is emerging regarding their use in pain management. Gan et al. 1997 used an ultra-low dose naloxone infusion (0.00025 mg/kg/h or 0.001 mg/kg/h) in postoperative patients receiving IV morphine via a patient-controlled analgesia (PCA) device. Good pain relief was experienced in all groups, however consumption of PCA morphine was significantly reduced in patients that received the lowest infusion of naloxone and opioid-induced side effects (nausea, vomiting, pruritus) were reduced by naloxone at both dose.
Naloxone and/or naltrexone at ultra-low doses may enhance the analgesic effects of opioids, enhance the antinociceptive effects of methadone, and decrease or block the development of opioid tolerance in rodents. The combination of oxycodone with an ultra-low dose of the antagonist naltrexone as a singular oral medication, Oxytrex, has been developed to prevent the development of tolerance in the treatment of moderate to severe chronic pain.
Aguado et. al. 2013 recently evaluated the effects of the opioid antagonist, naloxone, on remifentanil-induced tolerance or hyperalgesia in rats. Hyperalgesia was considered to be a decrease in mechanical nociceptive thresholds (von Frey), while opioid tolerance was considered to be a decrease in sevoflurane MAC reduction by remifentanil. An ultra-low dose of naloxone was able to block remifentanil-induced hyperalgesia and the MAC increase associated with hyperalgesia, but did not change opioid tolerance under inhaled anesthesia.
日期
最后验证: | 01/31/2017 |
首次提交: | 02/20/2017 |
提交的预估入学人数: | 02/22/2017 |
首次发布: | 02/27/2017 |
上次提交的更新: | 02/27/2017 |
最近更新发布: | 03/02/2017 |
实际学习开始日期: | 02/28/2017 |
预计主要完成日期: | 11/30/2019 |
预计完成日期: | 05/31/2020 |
状况或疾病
干预/治疗
Drug: LO-low dose remifentanil
Drug: HI-high dose remifentanil with placebo
Drug: HN-high dose remifentanil with ultra-low dose naloxone
相
手臂组
臂 | 干预/治疗 |
---|---|
Active Comparator: LO-low dose remifentanil low dose remifentanil (LO, 0.1 micrograms/kg/mL), | Drug: LO-low dose remifentanil 0.1 micrograms/kg/mL |
Active Comparator: HI-high dose remifentanil with placebo high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL) | Drug: HI-high dose remifentanil with placebo high dose remifentanil (0.4 mg) combined with placebo (HI, 0.4 micrograms/kg/mL) |
Active Comparator: HN-high dose remifentanil with ultra-low dose naloxone high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone). | Drug: HN-high dose remifentanil with ultra-low dose naloxone high dose remifentanil (0.4 mg) combined with ultra-low dose naloxone (HN, 0.004 micrograms/kg/mL naloxone |
资格标准
有资格学习的年龄 | 18 Years 至 18 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | Inclusion Criteria: - Subjects who provide written informed consent. - Age 18 years old or older (no upper age limit for inclusion) - Gender: male or female. - Surgery: Posterior spinal fusions Exclusion Criteria: - Allergy to opiates - Chronic pain other than the primary indication for surgery - Psychiatric illness - History of substance abuse problem including alcohol &/or cannabis - BMI > 35 - Subjects under 18 years of age. - Subject without the capacity to give written informed consent. 8. Female subjects who are pregnant |
结果
主要结果指标
1. Occurrence of Opioid-induced hyperalgesia (OIH) [24 hr Post-surgery]
2. Occurrence of Opioid-induced hyperalgesia (OIH) [48 hr Post-surgery]
次要成果指标
1. Opioid consumption [24 hr post surgery]
2. Opioid consumption [48 hrs post surgery]
3. Cold Pressure Test [24 hr post surgery]
4. Cold Pressure Test [48 hrs post surgery]
5. Visual Analog Scale (VAS) Pain scores [Baseline]
6. McGill short form questionnaire [Baseline]
7. Brief Pain Inventory [Baseline]