Ibuprofen Versus Acetaminophen for Treatment of Mild Traumatic Brain Injury
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Post-concussion symptoms
研究概览
简要总结
Traumatic brain injury (TBI) is an important public health problem with an estimated 1.7 million new cases in the United States each year. Although the vast majority of these victims sustain mild TBI, many still develop headache, difficulty concentrating, and decreased memory with potential for serious long-term consequences. In particular, mild TBI is an important consequence of combat-related injuries sustained by military personnel and sports-related injuries in young adults. Unfortunately, treatment of mild TBI is usually limited to oral analgesics for headache pain such as acetaminophen (Tylenol) or ibuprofen (Motrin or Advil). Since there are no previous randomized trials of these medications for mild TBI, their comparative effectiveness is not known. Increasing animal based evidence suggests that mild TBI is related to brain cell injury caused by overexpression of a cellular enzyme (COX-2) that causes neuroinflammation. Fortunately, inhibition of COX-2 is easily achieved using ibuprofen. We hypothesize that head injured patients treated with ibuprofen will have a lower incidence of mild TBI symptoms than patients treated with acetaminophen. We will conduct a randomized clinical trial to measure the comparative effects of ibuprofen versus acetaminophen on the incidence of specific symptoms of mild TBI in emergency department patients with head injury.
详细描述
OBJECTIVES
The long-term goal of the proposed project is to develop an effective pharmacological therapy for patients with mild TBI to improve functional outcomes. The main objective is to compare the effects of ibuprofen versus acetaminophen for reducing the short-term development post-concussion symptoms in patients with mild TBI. We will conduct a double-blinded randomized clinical trial (RCT) with the specific aim of measuring the comparative effects of equipotent doses of ibuprofen versus acetaminophen on the incidence of concussion symptoms to be measured 7 to 10 days after mild TBI in emergency department patients with isolated closed head injury. The main study hypothesis of our research project is that patients with mild TBI who are treated with ibuprofen will have a lower incidence of post-concussion symptoms compared to patients treated with acetaminophen. The proposed investigation is novel because it will be the very first RCT to compare analgesic medications for the specific treatment of mild TBI.
BACKGROUND
Pathophysiology of Mild TBI. TBI results from external mechanical force applied to the cranium leading to parenchymal brain damage. This resultant brain injury can range from mild temporary impairment to severe disability. TBI transpires in two phases: (1) primary brain injury occurs at the moment of the application of mechanical force on the cranium and results in lacerations, contusions, hematomas and shearing injuries of the brain; and (2) secondary brain injury begins immediately after the primary brain injury and results from the cellular mediation of neuroinflammation.15,16 The principal injury of mild TBI is diffuse axonal injury from shearing forces that is not usually identified by CT brain scan.17-20 Secondary brain injury activates multiple cellular pathways that are initially adaptive, but become pathological with overexpression and persistence.21-23 The biochemical consequences of these responses develop over a period of hours with the accumulation of arachidonic acid from cellular membrane stores and the induction of cyclooxygenase-2 (COX-2) gene expression and enzyme activity.15,16 Arachidonic acid is then converted to detrimental vasoactive prostanglandins and free radicals by COX-2 enzyme leading to neuronal cell death (Figure 1 see appendix). Neural COX-2 enzyme activity remains elevated for 1 to 3 days.24 Severity of neuronal injury is correlated to COX-2 overexpression which results in a "vicious cycle" of neuroinflammation when secondary injury propagates further COX-2 activity.15,16
Potential Effect of COX-2 Inhibition. If COX-2 overexpression causes neuronal cell damage after brain injury, then COX-2 inhibition may provide neuroprotective effects through two important mechanisms: (1) by reducing detrimental vasoactive prostanglandins and free radical synthesis; and (2) shunting of arachidonic acid down alternate pathways that produce beneficial eicosanoids.15 These cellular mechanisms are based on findings from several animal studies over the past 30 years that strongly suggest potential beneficial effects of NSAID inhibition of the COX-2 enzyme as a treatment for TBI-activated neuroinflammation.25-35 Although these studies examined different NSAID COX-2 kinhibitors and utilized different animal models of TBI, they found an overall consensus of beneficial effects (i.e., reduced prostaglandin synthesis, reduced brain edema, improvement in cognitive and motor function, improvements in memory, and reduced mortality) suggesting COX-2 inhibition may have effects beyond analgesia in patients with mild TBI. In fact, COX-2 inhibition has been shown to be beneficial for animal models for other types of brain insults including ischemic brain injury.36-40
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Closed head injury within the past 24 hours with history (loss of consciousness, amnesia, mechanism of injury such as motor vehicle collision or fall from height) or specific symptoms and signs (headache, vomiting, dizziness, head injury, short-term memory deficit, confusion, blurred vision, balance problems) that prompts computerized tomography (CT) brain evaluation as determined by an emergency physician.
- •Age 21 through 60 years of age.
- •Initial Glasgow Coma Score of 13 or greater at time of ED presentation with normal neurologic examination and Glasgow Coma Score of 15 within two hours of initial assessment.
- •Normal neurologic examination in the emergency department except for symptoms and signs described above (e.g., no focal neurologic deficit).
- •Normal brain and skull on CT scan in the ED.
- •Working cellular phone (for follow up assessment).
排除标准
- •Significant concomitant non-cranial injury requiring pain medication (e.g., facial fracture, severe extremity injury, major blunt trauma.)
- •Any type of skull or cervical spine fracture.
- •Post-traumatic seizure.
- •Currently taking NSAIDS, acetaminophen, or other pain medications on a regular basis.
- •Currently taking ANY coagulant medication (e.g., Plavix, aspirin, Xeralto, Coumadin).
- •Any bleeding disorder, predisposition to bleeding, or history of gastrointestinal bleeding.
- •Clinical intoxication with alcohol or illicit medication.
- •Chronic alcohol abuse.
- •Any liver or renal dysfunction or failure.
- •Justification of obtaining CT brain evaluation that included patient being intoxicated.
- •Intolerance, allergy or adverse reaction to either ibuprofen or acetaminophen.
- •Any current or previously diagnosed cardiovascular condition (e.g., hypertension, coronary arterial disease, myocardial infarct, angina, congestive heart failure, pulmonary embolism, deep venous thrombosis).
- •Any current or previously diagnosed neurovascular condition (e.g., stroke, TIA, multiple sclerosis, seizure disorder).
- •Any active cancer or malignancy.
研究组 & 干预措施
Ibuprofen
Ibuprofen is a nonselective NSAID that inhibits both COX-1 and COX-2 isoenzymes. COX-2 inhibition prevents arachidonic acid from converting to vasoactive prostaglandins and reactive oxygen species in brain cell. The analgesic, antipyretic, and antiinflammatory activity of ibuprofen operates mainly through inhibition of COX-2. The experimental treatment oral doses of either ibuprofen (800 mg three times per day). Subjects will receive the first medication dose in the emergency department and will be given the remaining 5 doses to take over 48 hours as outpatients.
干预措施: Ibuprofen (Drug)
Acetaminophen
Acetaminophen is a poor inhibitor of both COX isoenzymes in the CNS and has significantly weaker antiinflammatory effects than NSAIDs. Acetaminophen does not inhibit COX in peripheral tissues and is less effective in the presence of peroxides. The active comparator treatment is oral doses of acetaminophen (1000 mg three times per day). Subjects will receive the first medication dose in the emergency department and will be given the remaining 5 doses to take over 48 hours as outpatients.
干预措施: Acetaminophen (Drug)
结局指标
主要结局
Post-concussion symptoms
时间窗: 7 to 14 days after enrollment.
The main outcome variables will be the incidence of post-concussion symptoms that will be measured using NIH Common Data Elements and Neuro-QOL instruments. The Neuro-QOL instruments were developed for the NIH by the Northwestern University Department of Medical Social Sciences to provide clinically relevant and psychometrically robust health-related quality of life assessment tools for patients with common neurological disorders. In addition, the Neuro-QOL measurement system provides item banks and short forms that enable patient reported outcome measurement in neurological research which minimizes patient burden.41-44 This information will be collected at 7 to 14 days after initial ED evaluation. Emphasis will be placed on the Neuro-QOL instruments that measure headache pain and cognitive function as these are the most common and concerning symptoms of mild TBI.
次要结局
- Adverse drug reactions(7 to 14 days after enrollment)
研究者
Demetrios Kyriacou
Principal Investigator
Northwestern University