Intranasal Ketamine as an Adjunct to Fentanyl for the Prehospital Treatment of Acute Traumatic Pain
| Status: | Enrolling by invitation |
|---|---|
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 3/24/2019 |
| Start Date: | October 3, 2017 |
| End Date: | December 2020 |
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.
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.
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.
We found this trial at
1
site
234 Goodman Dr
Cincinnati, Ohio 45229
Cincinnati, Ohio 45229
(513) 584-1000
Principal Investigator: Jason McMullan, MD
Phone: 513-558-2953
University of Cincinnati Medical Center Opening in 1823 as the country
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