Buprenorphine as a Post-operative Analgesic in Opioid-Naive Patients After Ankle Fracture Surgery

Официальное название

A Single-institution, Parallel, Double-blinded, Randomized Study Assessing the Safety and Efficacy of Transdermal Buprenorphine as a Post-operative Analgesic in Opioid-Naive Patients After Ankle Fracture Surgery

Обзор

Addictive full-agonist opioids, like oxycodone and hydrocodone, are often used to treat pain after surgery. However, these full-agonist opioids can be very addictive. After ankle fracture surgery, about 1 in 5 patients that did not take opioids before surgery become addicted to opioids after surgery. Buprenorphine is an opioid with unique properties that may offer a way to reduce the number of patients that become addicted to opioids after surgery. Buprenorphine has good analgesic (painkilling) effects. It is also thought to be less addictive and cause less of a high than full-agonist opioids, like oxycodone and hydrocodone. This project's goal is to determine if transdermal buprenorphine can safely and effectively control pain after ankle fracture surgery. This study will be a pilot study, which sets the stage for future studies that investigate whether buprenorphine can reduce the rate that patients become addicted to opioids after surgery. This study's multidisciplinary team will divide patients into two groups. Participants in one group will be treated with a 7-day transdermal buprenorphine patch (where the buprenorphine is slowly absorbed through the skin over 7 days). Participants in the other group will be treated with a placebo patch. A placebo has no drug in it, it just looks like the buprenorphine patch. Aside from the buprenorphine patch or placebo patch, both groups' pain management plans will be the same as if they were not in the study. Over the first week after surgery, the investigators will measure the amount of full-agonist opioids (for example, oxycodone or hydrocodone) that participants consume, participants' pain scores, the frequency of side effects related to opioids, and the number of calls and patient portal messages to the clinic for uncontrolled pain. The investigators will also assess whether participants are continuing to use opioids 3 months after surgery for pain related to their ankle fracture.

Подробное описание

Addictive full-agonist opioids, like oxycodone, remain a staple of post-operative analgesia after many types of surgery. However, perioperative exposure to opioid analgesics risks addiction in up to 7% of cases. Moreover, opioid overdoses kill over 80,000 in the United States (US) annually. Buprenorphine, a partial-agonist of the μ-opioid receptor and an antagonist of the κ-opioid receptor, may be able to safely function as a post-operative analgesic, reducing our reliance on full-agonist opioids post-operatively. Compared to full-agonist opioids, buprenorphine has a favorable safety profile. It has been hypothesized that buprenorphine's unique pharmacodynamics give it a lower addictive potential compared to full-agonist opioids. Moreover, it endows a ceiling on respiratory depression, has reduced dysphoric and psychotomimetic effects, and does not result in immunosuppression at therapeutic analgesic doses. International studies have suggested that transdermal buprenorphine is noninferior to tramadol, transdermal fentanyl, and oral celecoxib in the management of acute post-operative pain in opioid-naïve patients following orthopaedic surgery. However, the efficacy of buprenorphine for postoperative analgesia has never been studied in the United States, whose population has different beliefs and expectations surrounding pain control when compared to international populations. The major goal of this project is to determine the safety and efficacy of transdermal buprenorphine for postoperative analgesia, as a first step toward exploring the ability of buprenorphine to mitigate the incidence of opioid dependence in the postoperative setting.

This study will assess whether buprenorphine can reduce the use of full-agonist opioids following ankle fracture surgery. Approximately one in five opioid-naïve patients undergoing ankle fracture surgery continue to use opioids 3 to 6 months out from surgery, suggesting that this population is relatively susceptible to developing post-operative opioid dependence. The investigators will divide patients into two groups. One group will be treated with a 7-day transdermal buprenorphine patch. The other will be treated with a placebo patch. Both groups will otherwise receive a post-operative pain management regimen that is in accordance with the standard of care. The investigators hypothesize that participants treated with the buprenorphine patch will experience improved analgesia with the use fewer full-agonist opioids following ankle fracture surgery than those treated with the placebo patch. This hypothesis will be tested with the following aims.

Specific Aim 1: To measure the analgesic effect of buprenorphine on post-operative analgesia. In this Aim, the investigators will test the hypothesis that use of buprenorphine patches will reduce the average pain scores and consumption of full-agonist opioids after ankle fracture surgery. In sub-Aim 1.1, the investigators will quantify postoperative pain by monitoring participants' visual analog scale pain scores and full-agonist opioid consumption over the first post-operative week. In sub-Aim 1.2, the investigators will track the number of episodes of breakthrough pain in the hospital, the number of calls to the clinic with a chief complaint of uncontrolled pain, and the number of presentations to an emergency department for uncontrolled surgery-related pain.

Specific Aim 2: To examine the safety of buprenorphine as a post-operative analgesic following ankle fracture surgery. In this Aim, the investigators will test the hypothesis that participants treated with buprenorphine patches will experience fewer adverse events related to opioid exposure compared to those treated with placebo patches. The investigators will monitor for adverse effects of buprenorphine and full-agonist opioids, including respiratory depression, constipation, nausea, and vomiting. The investigators will track the number of presentations to an emergency department with a diagnosis of opioid toxicity. For pilot data, the investigators will also monitor use of opioids for analgesia at the 3-month postoperative time point as a secondary outcome.

This study assesses whether buprenorphine safely reduces full-agonist opioid use after orthopaedic surgery. Completion of the Aims of this study will permit future studies assessing whether buprenorphine comprises a less-addictive alternative for postoperative analgesia compared to full-agonist opioids. Annually, there are 40-50 million major surgeries performed in the US. As 6-7% of opioid-naïve patients develop long-term opioid use after major surgery, exploring avenues to decrease the impact of post-operative analgesia on the opioid epidemic is critical.

Вмешательства

• Препарат Buprenorphine Transdermal System
  The buprenorphine transdermal system is unique from other interventions in the study, as it is the experimental drug in the study. The buprenorphine transdermal system will be applied in the pre-operative holding area. Aside from the buprenorphine transdermal system, participants assigned to this intervention will otherwise receive the standard of care in their post-operative pain management following ankle fracture surgery.
• Препарат Placebo Patch
  The placebo patch is unique from other interventions in the study, as it is the placebo drug in the study. The placebo patch will be applied in the pre-operative holding area. Aside from the placebo patch, participants assigned to this intervention will otherwise receive the standard of care in their post-operative pain management following ankle fracture surgery.

Первичные конечные точки

• Morphine Milligram Equivalents of Full-agonist Opioid Consumed [Срок оценки: Post-operative days 0-7. First post-operative clinic visit (approximately 3 weeks after surgery).]

Вторичные конечные точки (12)

• Visual Analog Pain Scores [Срок оценки: Postoperative days 1-8, 21, 90.]
• Morphine Milligram Equivalents of Full-Agonist Opioids Administered in Perioperative Setting [Срок оценки: Perioperative/Periprocedural]
• Adverse Effects Related to Opioid Medication [Срок оценки: Post-operative days 1-8, 21.]
• Hospital Readmissions due to Uncontrolled Post-operative Pain [Срок оценки: From patch application through post-operative day 21.]
• Emergency Department Presentations due to Uncontrolled Pain [Срок оценки: From patch application through post-operative day 21.]
• Emergency Department Presentations due to Opioid Toxicity [Срок оценки: From patch application to post-operative day 21]
• Hospital Readmissions due to Opioid Toxicity [Срок оценки: From patch application to post-operative day 21]
• Time from Surgery Completion to Discharge [Срок оценки: Perioperative/periprocedural]
• Hospital Length of Stay [Срок оценки: From the completion of ankle fracture surgery to hospital discharge.]
• Number of Breakthrough Pain Episodes while Inpatient [Срок оценки: Post-operative day 0 through hospital discharge]
• Quality of Recovery after Anesthesia 15-Question Survey [Срок оценки: Post-operative day 7]
• Telephone Calls and MyChart Messages to Clinic or Call Center with a Chief Complaint of Uncontrolled Pain [Срок оценки: Post-operative days 0-21.]

Критерии участия

Критерии включения

• Patient is 18 years of age or older
• Patient is undergoing single stage ORIF of an ankle fracture
• Patient is English-speaking

Критерии исключения

• Patient is under 18 years of age
• Patient's ankle fracture is treated with external fixation
• Patient has a concomitant osseous or visceral injury
• Patient has a history of opioid use disorder or a current diagnosis of opioid use disorder
• Patient has a history of alcohol use disorder or a current diagnosis of alcohol use disorder
• Patient was taking opioid medication or narcotic drugs prior to their injury
• Patient has a current active malignancy
• Patient is taking a medication that carries a prohibitively high risk of drug-drug interaction with buprenorphine, hydrocodone, or oxycodone in the view of their treating physician or nurse anesthetist
• Patient has an anaphylactic allergy to buprenorphine, hydrocodone, or oxycodone
• Patient is not English-speaking
• Patient is pregnant
• Patient is unable to complete pain diary or communicate pain scores
• Patient is incarcerated
• Patient has a Gustilo-Anderson Type III open fracture

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Washington University in St. Louis/Barnes Jewish Hospital — St Louis

Публикации

• Lawal OD, Gold J, Murthy A, Ruchi R, Bavry E, Hume AL, Lewkowitz AK, Brothers T, Wen X. Rate and Risk Factors Associated With Prolonged Opioid Use After Surgery: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020 Jun 1;3(6):e207367. doi: 10.1001/jamanetworkopen.2020.7367. PMID 32584407
• Vadivelu N, Hines RL. Buprenorphine: a unique opioid with broad clinical applications. J Opioid Manag. 2007 Jan-Feb;3(1):49-58. doi: 10.5055/jom.2007.0038. PMID 17367094
• Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry. 1978 Apr;35(4):501-16. doi: 10.1001/archpsyc.1978.01770280111012. PMID 215096
• Walsh SL, Babalonis S. The Abuse Potential of Prescription Opioids in Humans-Closing in on the First Century of Research. Curr Top Behav Neurosci. 2017;34:33-58. doi: 10.1007/7854_2016_448. PMID 27356522
• Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994 May;55(5):569-80. doi: 10.1038/clpt.1994.71. PMID 8181201
• Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009 Mar;13(3):219-30. doi: 10.1016/j.ejpain.2008.04.011. Epub 2008 Jun 24. PMID 18567516
• Pergolizzi JV Jr, Magnusson P, LeQuang JA, Breve F, Mitchell K, Chopra M, Varrassi G. Transdermal Buprenorphine for Acute Pain in the Clinical Setting: A Narrative Review. J Pain Res. 2021 Mar 31;14:871-879. doi: 10.2147/JPR.S280572. eCollection 2021. PMID 33833565
• Desai SN, Badiger SV, Tokur SB, Naik PA. Safety and efficacy of transdermal buprenorphine versus oral tramadol for the treatment of post-operative pain following surgery for fracture neck of femur: A prospective, randomised clinical study. Indian J Anaesth. 2017 Mar;61(3):225-229. doi: 10.4103/ija.IJA_208_16. PMID 28405035

Идентификаторы

NCT: NCT06949826 · 202406162

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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