Please select the eligibility criteria that correspond to the clinical trial below.
Title: Intranasal Ketamine as an Adjunct to Fentanyl for the Prehospital Treatment of Acute Traumatic Pain
Brief Summary: STUDY SYNOPSIS Objectives The primary objective is to estimate the proportion of subjects who report clinically important reductions in pain score (defined as 2 points on a 0-10 verbal numerical rating scale) after receiving a single dose of fentanyl (per local standard) with or without intranasal (IN) ketamine (50mg) prior to hospital arrival for the treatment of acute traumatic pain.

Design and Outcomes This protocol describes two linked studies conducted as a prospective, randomized, placebo-controlled single-site clinical trial. The primary study has a primary outcome variable of reduction of reported pain of at least 2 points (on the 0-10 Verbal Numerical Rating Scale1,2) when comparing the pretreatment pain score to the pain score obtained upon reassessment 30 minutes after medication administration; secondary outcomes of the primary trial include reduction of reported pain at Emergency Department (ED) arrival; the incidence of adverse events; additional opiate requirements prior to ED arrival and in the first three hours of ED care. The secondary study explores secondary outcomes including: development of chronic pain (measured by the Brief Pain Inventory,3) or post-traumatic stress disorder (measured by the PTSD Checklist for DSM-54) and overall satisfaction with life (measured by the Satisfaction With Life Scale5) at 90-days after injury.

Interventions and Duration Adult men who qualify for prehospital pain treatment under paramedic standing orders will be screened for inclusion and will undergo informed consent for the primary trial. After ED arrival, subjects who consented for the primary trial will be approached for inclusion in the secondary trial. Prehospital consent for primary trial enrollment and study drug administration will occur concurrent with receiving a single dose of fentanyl (IV, IM or IN per current standard practice). Consenting subjects will be 1:1 randomized to receive either 50mg IN ketamine or IN saline placebo. Pain will be rated on a 0-10 scale by the subject prior to treatment and at 30 minutes following treatment and will receive further pain assessments at 30 minute intervals for the first three hours of their ED care. Additional pain medications given prior to hospital arrival and within the first three hours of ED care will also be recorded. The primary outcome of the primary trial will be reduction in baseline pain between the pretreatment measurement and 30 minutes after medication administration. Consent for the secondary trial will be obtained for the additional baseline assessments for secondary outcomes and at 90-day follow-up. Overall satisfaction with life and symptoms of PTSD and chronic pain will be assessed before hospital disposition (in-person) and via phone follow-up at 90-days (+/- 14 days) after injury.The subject will have the option to complete the 90-day follow-up assessments in-person if it coincides with a clinical appointment on the medical campus.

Sample size and Power We consider a 2-point reduction in pain to be clinically significant, and thus our primary outcome for the primary trial will compare the proportion of subjects achieving a 2-point reduction in pain at 30 minutes post-medication administration between the treatment group and the control group. Sample size considerations are based on this primary analysis. To test the hypothesis that the proportion of those treated with fentanyl alone that have at least a 2-point reduction in their pain will be lower than the proportion of those treated with the combination of fentanyl and single-dose ketamine who have a 2-point reduction in their pain, we will use a chi-square test (or the Fisher's Exact Test if appropriate). An intent to treat approach will be used. We expect the response rate in the two groups to be 40% and 60%, respectively. These estimates are based on the response rates in a study comparing pain management efficacy between subjects treated with morphine alone and morphine plus ketamine.6 With this magnitude of effect, a sample size of 97 per group will have 80% power to detect the difference between the two groups when the critical level of significance is set to 5%. To allow for subject drop-out, protocol deviations, and missing outcome data, we plan to enroll an additional 15% in each arm, for a total of 224 subjects.


Options:
A: Adult males with acute traumatic pain that are eligible to receive pain medication prior to hospital arrival under current practice will be screened for enrollment in the primary trial. The inclusion and exclusion criteria mirror this existing protocol (Appendix 1: Prehospital Protocols).

Inclusion Criteria of Primary Trial

* Subjects must be experiencing pain due to acute trauma (i.e. extremity deformity, tourniquet placement, or severe burns).
* A Verbal Numerical Rating Scale pain score ≥7 prior to any pain medication administration.
* Age: ≥18 through 65 years (i.e. subjects must have had their 18th birthday, but not had their 66th birthday).
* Systolic blood pressure ≥100mmHg and \<180mmHg.
* Transported directly from the scene of injury to the Emergency Department at University of Cincinnati Medical Center by a participating EMS agency.
* English-speaking.
* Male sex.
* Receiving fentanyl IV/IM/IN as part of standard care. Exclusion Criteria of Primary Trial
* Subject reported allergy to morphine, fentanyl, or ketamine.
* EMS treatment with ketamine (any), morphine (any), or more than one dose of fentanyl prior to enrollment.
* Inter-facility transfers.
* Prisoners or those in police custody.
* Female sex.
* Paramedic clinical concern of acute agitation or psychosis.
* Pain medication not needed in judgment of prehospital provider.
* Altered level of consciousness, mental status change, or suspected head injury.
* Paramedic clinical concern of circulatory shock.
* Inability to provide Verbal Numerical Rating Scale.
* Facial injury or suspicion of nasal bone fracture.
* Paramedic judgment that subject cannot consent due to underlying cognitive impairment.
* Systolic blood pressure ≥180mmHg

Justification for Exclusions Medications are generally withheld if there is a reported drug allergy. This is a study of acute pain management, and pretreatment with additional medications may bias results. EMS does not routinely provide inter-facility (between hospital) transfers, and these subjects will likely be transferred several hours after injury and should have received pain medications from the original hospital. Prisoners or those in police custody represent a protected population. Ketamine is pregnancy class N (unknown); while frequently used in developing countries for analgesia/sedation for Cesarean sections, 73-75 obtaining a serum or urine pregnancy test is not possible in the prehospital setting. Breast feeding women and women of childbearing age will be excluded. To avoid introducing bias from a partially included population, all women will be excluded. Ketamine may cause psychomotor agitation in some subjects (even though ketamine is frequently used as treatment of excited delirium76). Pre-existing agitation or mental status changes and inability to provide VNRS prevent outcomes assessments. Current prehospital protocols do not allow pain medications for patients with circulatory shock. Nasal trauma may interfere with medication delivery or absorption. Previous trials have excluded patients with a systolic blood pressure ≥180mmHg.6,38,49

Inclusion Criteria for Secondary Trial Subjects enrolled in the primary trial will be approached for participation in the secondary trial. Enrollment in the secondary trial will involve a second and separate consent process (further described below). Participation in the secondary trial is not required to participate in the primary trial.
B: Inclusion Criteria:

* Male or female outpatients at least 18 years of age with a primary (the condition that is most central to the patient's current distress) symptoms of Acute Stress Disorder as defined by DSM-IV criteria: A1, A2 and at least one additional category of Acute Stress Disorder symptoms (i.e., B, C and or D criteria).
* Patients must have had a medical trauma (even if fully resolved or minor) within the prior 3 weeks resulting in admission to the emergency room and/or inpatient hospital as part of their acute trauma resulting in ASD symptoms.

Exclusion Criteria:

* Patients will be excluded from entry into the study for current serious medical instability such as hemodynamic compromise, or serious head injury resulting in impaired mental status. Patients with a history of medical instability associated with their traumatic injury will be allowed study entry once the problem has resolved (as long as resolves within 3 weeks of trauma as per inclusion criteria).
* Patients with a trauma resulting in head injury related seizures, or with epilepsy (except a prior history of febrile seizures of infancy which are not exclusionary).
* Pregnant or lactating women or those of childbearing potential not using medically accepted forms of contraception will be excluded.
* Concurrent use of other antidepressants, with the exception of trazodone \< 100mg/day for sleep, or amitriptyline in doses ≤ 50 mg daily for pain. Patients may remain on concomitant benzodiazepines (\<2 mg/d clonazepam or its equivalent), or sleep aids (i.e., trazodone, zolpidem (Ambien), zaleplon (Sonata)) as long as the drug therapy was initiated at 1 week prior to randomization; the dose will be held constant through the study, and will be controlled for in the analysis.
* Lifetime diagnosis of schizophrenia or any other psychosis, mental retardation, organic mental disorders, bipolar disorder; obsessive-compulsive disorder, eating disorders, cutting or other significant self-injurious behavior, or alcohol/substance abuse disorders within the last 3 months are study exclusions. Patients with a current primary diagnosis of major depression, dysthymia, social anxiety disorder, panic disorder, and generalized anxiety disorder are excluded; thus, the presence of these disorders is permissible as long as the ASD symptoms constitute the predominant symptomatology.
* Patients with a history of hypersensitivity or prior poor response to escitalopram are excluded.
* Concurrent dynamic or supportive psychotherapy is permitted as long as it has been ongoing for at least 1 month prior to onset of study entry.
* Patients with a positive toxicology screen at baseline consistent with evidence of current substance abuse or dependence as determined by clinical interview.
C: Inclusion Criteria:

* Level 2 trauma patients admitted to the trauma floors or trauma ICU at Westchester Medical Center
* Experienced fear at the time of the trauma

Exclusion Criteria:

* Vulnerable populations, such as pregnant women, prisoners, persons with decisional incapacity.
* History of coronary artery disease, heart failure, prior stroke, heart surgery
* Bood pressure \>160/90
* Acutely psychotic
* Current diagnosis of anorexia nervosa, bulimia
* Current diagnosis of cancer
* Drug abuse or dependence in the preceding 3 months,
* Any unstable medical condition
* Active suicidal/homicidal ideation
* Cannot speak, read, write and understand English at least at 8th grade level.
D: Inclusion Criteria:

1. Persons over the age of 21, who have been exposed to an event meeting the DSM-IV "A.1" criterion for trauma exposure, expressing marked anxiety, and/ or emotional distress and/or dissociation, as assessed by the Visual Analog Scales
2. Who provide written, informed consent to participate in the study.

Exclusion Criteria:

1. Physical injury that would contraindicate participation or interfere with a subject's ability to give informed consent or cooperate with the screening or collection of initial measures. Examples include severe burn injury, life-threatening medical or surgical condition, condition requiring surgical intervention under general anesthesia, as indicated by Abbreviated Injury Scale (AIS), or by clinical judgment;
2. Head injury involving confusion, loss of consciousness, or amnesia;
3. Medical conditions such as extreme obesity, psoriasis, herpes, Cushing's syndrome, current infectious disease, current viral disease, tuberculosis, unstable diabetes or hypertension, myasthenia gravis, and heart failure. Persons taking medications that can interfere with the HPA axis (e.g.,steroids, betablockers,indomethacin) will be excluded;
4. Weight below 45 or above 120 kg.
5. Pregnancy (in suggestive cases, a pregnancy test will be performed);
6. Traumatic exposure that reflects ongoing victimization (e.g., domestic violence) to which the subject is likely to be re-exposed during the study period.
7. Overt psychopathology, intoxication, or under the influence of substances.
8. Evidence or history of schizophrenia, bipolar, other psychotic condition;
9. Prior history of PTSD;
10. Current or past history of dementia, amnesia, or other cognitive disorder predating trauma exposure;
11. Assessed serious suicide risk.

Answer: A