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出境医 / 临床实验 / Sub-Dissociative Ketamine and Fentanyl to Treat Moderate to Severe Pain

Sub-Dissociative Ketamine and Fentanyl to Treat Moderate to Severe Pain

Study Description
Brief Summary:
The objective of this study is to evaluate the potential opioid-sparing effect associated with the novel combination of fentanyl and sub-dissociative ketamine in adult patients with moderate to severe pain in the emergency department.

Condition or disease Intervention/treatment Phase
Pain, Acute Drug: Fentanyl Combination Product: Fentanyl and Ketamine Drug: Ketamine Phase 4

Detailed Description:
Pain is a very common complaint in the emergency department (ED). The use of opioids to treat moderate to severe pain has increased over the last decade as well as the number of opioid related deaths. In 1999 to 2016, more than 630,000 people died from a drug overdose. Treatment for acute pain has been assessed in the ED, with review of several different pain medications. Sub-dissociative ketamine (SDK) has become a valuable treatment option for acute pain and in recent years, has been of increased interest due to the growing concerns regarding opioid abuse and opioid shortage in the United States. Sub-dissociative ketamine, an NMDA receptor antagonist, has been studied in dose ranges of 1-4.5 mg/kg for dissociative sedation, as well as dose ranges of 0.1-0.3 mg/kg to treat pain. The onset of action for an IV dose of 2 mg/kg has been studied, with onset usually within 30 seconds after injection and anesthetic effect lasting 5-10 minutes. Common side effects include elevated blood pressure, diplopia or nystagmus, nausea and vomiting. More rare and more severe side effects in dissociative doses include respiratory depression, emergency phenomenon, tonic and clonic movements, and anaphylaxis. However, these were rarely, if ever seen, findings in sub-dissociative doses. Several studies indicate that SDK is a safe and effective alternative to opioids for patients with complaints of moderate to severe pain that provides adequate analgesic effect by itself. In particular, several studies have compared SDK versus morphine, particularly looking at pain in individuals with abdominal pain, flank pain, low back pain or musculoskeletal pain, and acute fractures. SDK has also shown to decrease opioid consumption and the need for rescue analgesia. The studies showed that that there was no difference in average pain scores, but the amount of morphine required was significantly decreased. SDK has proven to be a safe alternative, but the side effects, although short, make it less desirable to use. To the investigator's knowledge, there has never been a study focusing on the use of combination fentanyl and SDK. Fentanyl, an opioid agonist, has been studied in low dose forms of 2 mcg/kg for pain, moderate dose forms of 2-20 mcg/kg for major surgical procedures, and high dose forms of 20-50 mcg/kg for orthopedic and open heart surgeries. Onset of action is almost immediate when given IV, and maximal effect of the drug may take several minutes. The usual duration of action is 30-60 minutes. Common side effects include hypertension, hypotension, dizziness, blurred vision, nausea, vomiting and laryngospasm. Serious side effects included respiratory depression, apnea, rigidity, bradycardia, serotonin syndrome, adrenal insufficiency, and if left untreated could cause cardiac arrest and circulatory depression. There have been several combination studies with SDK, but none regarding fentanyl and ketamine. In one study, combination SDK and reduced dose hydromorphone produced rapid pain relief without significant side effects. Another study indicated that morphine and SDK both provided adequate pain relief alone, but combined morphine and SDK required less morphine administration, had faster onset of relief, and provided sustained reduction in pain intensity for up to 2 hours.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: A Combination Study With Sub-Dissociative Ketamine and Fentanyl to Treat Moderate to Severe Pain in the Emergency Department
Actual Study Start Date : November 18, 2019
Actual Primary Completion Date : June 5, 2020
Actual Study Completion Date : June 5, 2020
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Sub-Dissociative Ketamine alone
0.3 mg/kg of Sub-Dissociative Ketamine IV administered over at least 1 minute
 Drug: Ketamine
0.3 mg/kg of Sub-Dissociative Ketamine IV administered over at least 1 minute
Other Name: Ketamine Hydrochloride
Active Comparator: Fentanyl alone
1 mg/kg of Fentanyl IV administered over at least 1 minute
 Drug: Fentanyl
1 mg/kg of Fentanyl IV administered over at least 1 minute
Other Name: Fentanyl Citrate
Experimental: Sub-dissociative Ketamine and Fentanyl
Combined dose of 0.15 mg/kg of Sub-dissociative Ketamine and 0.5 mg/kg of Fentanyl IV administered over at least 1 minute
 Combination Product: Fentanyl and Ketamine
Combined dose of 0.15 mg/kg of Sub-dissociative Ketamine and 0.5 mg/kg of Fentanyl IV administered over at least 1 minute.
Outcome Measures
Primary Outcome Measures :
  1. Analgesia of combination fentanyl and SDK as assessed using the pain scale 1-10 [ Time Frame: ED encounter (less than 24 hours) ]
    Analgesia of combination fentanyl and SDK as assessed using the pain scale 1-10

  2. Analgesia of fentanyl as assessed using the pain scale 1-10 [ Time Frame: ED encounter (less than 24 hours) ]
    Analgesia of fentanyl as assessed using the pain scale 1-10

  3. Analgesia of ketamine as assessed using the pain scale 1-10 [ Time Frame: ED encounter (less than 24 hours) ]
    Analgesia of katamine as assessed using the pain scale 1-10


Secondary Outcome Measures :
  1. OARRS report [ Time Frame: ED encounter (less than 24 hours) ]
    A retrospective review of OARRS report will be performed with each patient.

  2. Opioid sparing response as assessed by number of times additional rescue doses of fentanyl were required [ Time Frame: ED encounter (less than 24 hours) ]
    Opioid sparing response as assessed by number of times additional rescue doses of fentanyl were required


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 18 - 65 years old
  • Moderate pain defined as 4-6 out of 10, severe pain defined as ≥ 7 out of 10 as defined by the numeric rating pain scale (NRS)
  • Proficient in reading and understanding English
  • Are deemed by the attending physician to require opioid therapy.

Exclusion Criteria:

  • Inability to give consent,
  • Inability to use the numeric rating scale (NRS) score
  • Long-term use of opioids, history of chronic pain
  • Known substance abuse known as excessive use of a drug such as (e.g. alcohol, narcotics or cocaine)
  • Known hypersensitivity to ketamine or fentanyl
  • Pregnancy
  • Alcohol intoxication
  • Depression
  • Anxiety
  • Chronic obstructive pulmonary disease
  • Asthma
  • Cirrhosis
  • On dialysis
  • Acute ischemic stroke
  • Heart rate (HR) less < 60 bpm or > 120 bpm
  • Systolic blood pressure (SBP) < 90 mmHg or > 180 mmHg
  • Ischemic heart disease
  • Ketamine prior to arrival
  • Trauma patients
  • Sepsis or septic shock
  • Weight > 100 kg.
Contacts and Locations

Locations
Layout table for location information
United States, Ohio
St. Elizabeth Boardman Hospital
Boardman, Ohio, United States, 44512
Sponsors and Collaborators
Mercy Health Ohio
Investigators
Layout table for investigator information
Study Director: David Gemmel Director of Research
Tracking Information
First Submitted Date  ICMJE March 12, 2019
First Posted Date  ICMJE May 22, 2019
Last Update Posted Date September 11, 2020
Actual Study Start Date  ICMJE November 18, 2019
Actual Primary Completion Date June 5, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
  • Analgesia of combination fentanyl and SDK as assessed using the pain scale 1-10 [ Time Frame: ED encounter (less than 24 hours) ]
    Analgesia of combination fentanyl and SDK as assessed using the pain scale 1-10
  • Analgesia of fentanyl as assessed using the pain scale 1-10 [ Time Frame: ED encounter (less than 24 hours) ]
    Analgesia of fentanyl as assessed using the pain scale 1-10
  • Analgesia of ketamine as assessed using the pain scale 1-10 [ Time Frame: ED encounter (less than 24 hours) ]
    Analgesia of katamine as assessed using the pain scale 1-10
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
  • OARRS report [ Time Frame: ED encounter (less than 24 hours) ]
    A retrospective review of OARRS report will be performed with each patient.
  • Opioid sparing response as assessed by number of times additional rescue doses of fentanyl were required [ Time Frame: ED encounter (less than 24 hours) ]
    Opioid sparing response as assessed by number of times additional rescue doses of fentanyl were required
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sub-Dissociative Ketamine and Fentanyl to Treat Moderate to Severe Pain
Official Title  ICMJE A Combination Study With Sub-Dissociative Ketamine and Fentanyl to Treat Moderate to Severe Pain in the Emergency Department
Brief Summary The objective of this study is to evaluate the potential opioid-sparing effect associated with the novel combination of fentanyl and sub-dissociative ketamine in adult patients with moderate to severe pain in the emergency department.
Detailed Description Pain is a very common complaint in the emergency department (ED). The use of opioids to treat moderate to severe pain has increased over the last decade as well as the number of opioid related deaths. In 1999 to 2016, more than 630,000 people died from a drug overdose. Treatment for acute pain has been assessed in the ED, with review of several different pain medications. Sub-dissociative ketamine (SDK) has become a valuable treatment option for acute pain and in recent years, has been of increased interest due to the growing concerns regarding opioid abuse and opioid shortage in the United States. Sub-dissociative ketamine, an NMDA receptor antagonist, has been studied in dose ranges of 1-4.5 mg/kg for dissociative sedation, as well as dose ranges of 0.1-0.3 mg/kg to treat pain. The onset of action for an IV dose of 2 mg/kg has been studied, with onset usually within 30 seconds after injection and anesthetic effect lasting 5-10 minutes. Common side effects include elevated blood pressure, diplopia or nystagmus, nausea and vomiting. More rare and more severe side effects in dissociative doses include respiratory depression, emergency phenomenon, tonic and clonic movements, and anaphylaxis. However, these were rarely, if ever seen, findings in sub-dissociative doses. Several studies indicate that SDK is a safe and effective alternative to opioids for patients with complaints of moderate to severe pain that provides adequate analgesic effect by itself. In particular, several studies have compared SDK versus morphine, particularly looking at pain in individuals with abdominal pain, flank pain, low back pain or musculoskeletal pain, and acute fractures. SDK has also shown to decrease opioid consumption and the need for rescue analgesia. The studies showed that that there was no difference in average pain scores, but the amount of morphine required was significantly decreased. SDK has proven to be a safe alternative, but the side effects, although short, make it less desirable to use. To the investigator's knowledge, there has never been a study focusing on the use of combination fentanyl and SDK. Fentanyl, an opioid agonist, has been studied in low dose forms of 2 mcg/kg for pain, moderate dose forms of 2-20 mcg/kg for major surgical procedures, and high dose forms of 20-50 mcg/kg for orthopedic and open heart surgeries. Onset of action is almost immediate when given IV, and maximal effect of the drug may take several minutes. The usual duration of action is 30-60 minutes. Common side effects include hypertension, hypotension, dizziness, blurred vision, nausea, vomiting and laryngospasm. Serious side effects included respiratory depression, apnea, rigidity, bradycardia, serotonin syndrome, adrenal insufficiency, and if left untreated could cause cardiac arrest and circulatory depression. There have been several combination studies with SDK, but none regarding fentanyl and ketamine. In one study, combination SDK and reduced dose hydromorphone produced rapid pain relief without significant side effects. Another study indicated that morphine and SDK both provided adequate pain relief alone, but combined morphine and SDK required less morphine administration, had faster onset of relief, and provided sustained reduction in pain intensity for up to 2 hours.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE Pain, Acute
Intervention  ICMJE
  • Drug: Fentanyl
    1 mg/kg of Fentanyl IV administered over at least 1 minute
    Other Name: Fentanyl Citrate
  • Combination Product: Fentanyl and Ketamine
    Combined dose of 0.15 mg/kg of Sub-dissociative Ketamine and 0.5 mg/kg of Fentanyl IV administered over at least 1 minute.
  • Drug: Ketamine
    0.3 mg/kg of Sub-Dissociative Ketamine IV administered over at least 1 minute
    Other Name: Ketamine Hydrochloride
Study Arms  ICMJE
  • Active Comparator: Sub-Dissociative Ketamine alone
    0.3 mg/kg of Sub-Dissociative Ketamine IV administered over at least 1 minute
    Intervention: Drug: Ketamine
  • Active Comparator: Fentanyl alone
    1 mg/kg of Fentanyl IV administered over at least 1 minute
    Intervention: Drug: Fentanyl
  • Experimental: Sub-dissociative Ketamine and Fentanyl
    Combined dose of 0.15 mg/kg of Sub-dissociative Ketamine and 0.5 mg/kg of Fentanyl IV administered over at least 1 minute
    Intervention: Combination Product: Fentanyl and Ketamine
Publications *
  • Hebsgaard S, Mannering A, Zwisler ST. Assessment of acute pain in trauma-A retrospective prehospital evaluation. J Opioid Manag. 2016 Sep/Oct;12(5):347-353. doi: 10.5055/jom.2016.0351.
  • Motov SM, Nelson LS. Advanced Concepts and Controversies in Emergency Department Pain Management. Anesthesiol Clin. 2016 Jun;34(2):271-85. doi: 10.1016/j.anclin.2016.01.006. Review.
  • Todd KH. A Review of Current and Emerging Approaches to Pain Management in the Emergency Department. Pain Ther. 2017 Dec;6(2):193-202. doi: 10.1007/s40122-017-0090-5. Epub 2017 Nov 10. Review.
  • Bowers KJ, McAllister KB, Ray M, Heitz C. Ketamine as an Adjunct to Opioids for Acute Pain in the Emergency Department: A Randomized Controlled Trial. Acad Emerg Med. 2017 Jun;24(6):676-685. doi: 10.1111/acem.13172. Epub 2017 Mar 22.
  • Duncan C, Riley B. BET 2: Low-dose ketamine for acute pain in the ED. Emerg Med J. 2016 Dec;33(12):892-893. doi: 10.1136/emermed-2016-206440.2. Review.
  • Jennings PA, Cameron P, Bernard S, Walker T, Jolley D, Fitzgerald M, Masci K. Long-term pain prevalence and health-related quality of life outcomes for patients enrolled in a ketamine versus morphine for prehospital traumatic pain randomised controlled trial. Emerg Med J. 2014 Oct;31(10):840-3. doi: 10.1136/emermed-2013-202862. Epub 2013 Jul 13.
  • Lee EN, Lee JH. The Effects of Low-Dose Ketamine on Acute Pain in an Emergency Setting: A Systematic Review and Meta-Analysis. PLoS One. 2016 Oct 27;11(10):e0165461. doi: 10.1371/journal.pone.0165461. eCollection 2016. Review.
  • Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015 Mar;33(3):402-8. doi: 10.1016/j.ajem.2014.12.058. Epub 2015 Jan 7.
  • Motov S, Rockoff B, Cohen V, Pushkar I, Likourezos A, McKay C, Soleyman-Zomalan E, Homel P, Terentiev V, Fromm C. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2015 Sep;66(3):222-229.e1. doi: 10.1016/j.annemergmed.2015.03.004. Epub 2015 Mar 26.
  • Motov S, Rosenbaum S, Vilke GM, Nakajima Y. Is There a Role for Intravenous Subdissociative-Dose Ketamine Administered as an Adjunct to Opioids or as a Single Agent for Acute Pain Management in the Emergency Department? J Emerg Med. 2016 Dec;51(6):752-757. doi: 10.1016/j.jemermed.2016.07.087. Epub 2016 Sep 29. Review.
  • Pourmand A, Mazer-Amirshahi M, Royall C, Alhawas R, Shesser R. Low dose ketamine use in the emergency department, a new direction in pain management. Am J Emerg Med. 2017 Jun;35(6):918-921. doi: 10.1016/j.ajem.2017.03.005. Epub 2017 Mar 2. Review.
  • Sin B, Ternas T, Motov SM. The use of subdissociative-dose ketamine for acute pain in the emergency department. Acad Emerg Med. 2015 Mar;22(3):251-7. doi: 10.1111/acem.12604. Epub 2015 Feb 25. Review.
  • Abbasi S, Bidi N, Mahshidfar B, Hafezimoghadam P, Rezai M, Mofidi M, Farsi D. Can low-dose of ketamine reduce the need for morphine in renal colic? A double-blind randomized clinical trial. Am J Emerg Med. 2018 Mar;36(3):376-379. doi: 10.1016/j.ajem.2017.08.026. Epub 2017 Aug 14.
  • Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015 Jul;16(7):1402-9. doi: 10.1111/pme.12705. Epub 2015 Feb 3.
  • Dickenson AH. NMDA receptor antagonists: interactions with opioids. Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 2):112-5.
  • Galinski M, Dolveck F, Combes X, Limoges V, Smaïl N, Pommier V, Templier F, Catineau J, Lapostolle F, Adnet F. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med. 2007 May;25(4):385-90.
  • Lilius TO, Jokinen V, Neuvonen MS, Niemi M, Kalso EA, Rauhala PV. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat. Br J Pharmacol. 2015 Jun;172(11):2799-813. doi: 10.1111/bph.12974.
  • Wiesenfeld-Hallin Z. Combined opioid-NMDA antagonist therapies. What advantages do they offer for the control of pain syndromes? Drugs. 1998 Jan;55(1):1-4. Review.
  • Ahern TL, Herring AA, Stone MB, Frazee BW. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. Am J Emerg Med. 2013 May;31(5):847-51. doi: 10.1016/j.ajem.2013.02.008. Epub 2013 Apr 18.
  • Ahmadi O, Isfahani MN, Feizi A. Comparing low-dose intravenous ketamine-midazolam with intravenous morphine with respect to pain control in patients with closed limb fracture. J Res Med Sci. 2014 Jun;19(6):502-8.
  • Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014 Nov;21(11):1193-202. doi: 10.1111/acem.12510.
  • Bossard AE, Guirimand F, Fletcher D, Gaude-Joindreau V, Chauvin M, Bouhassira D. Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain. 2002 Jul;98(1-2):47-57.
  • Jennings PA, Cameron P, Bernard S, Walker T, Jolley D, Fitzgerald M, Masci K. Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: a randomized controlled trial. Ann Emerg Med. 2012 Jun;59(6):497-503. doi: 10.1016/j.annemergmed.2011.11.012. Epub 2012 Jan 13.
  • Johansson P, Kongstad P, Johansson A. The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scand J Trauma Resusc Emerg Med. 2009 Nov 27;17:61. doi: 10.1186/1757-7241-17-61.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 9, 2020) 		6
Original Estimated Enrollment  ICMJE
 (submitted: May 21, 2019) 		334
Actual Study Completion Date  ICMJE June 5, 2020
Actual Primary Completion Date June 5, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 18 - 65 years old
  • Moderate pain defined as 4-6 out of 10, severe pain defined as ≥ 7 out of 10 as defined by the numeric rating pain scale (NRS)
  • Proficient in reading and understanding English
  • Are deemed by the attending physician to require opioid therapy.

Exclusion Criteria:

  • Inability to give consent,
  • Inability to use the numeric rating scale (NRS) score
  • Long-term use of opioids, history of chronic pain
  • Known substance abuse known as excessive use of a drug such as (e.g. alcohol, narcotics or cocaine)
  • Known hypersensitivity to ketamine or fentanyl
  • Pregnancy
  • Alcohol intoxication
  • Depression
  • Anxiety
  • Chronic obstructive pulmonary disease
  • Asthma
  • Cirrhosis
  • On dialysis
  • Acute ischemic stroke
  • Heart rate (HR) less < 60 bpm or > 120 bpm
  • Systolic blood pressure (SBP) < 90 mmHg or > 180 mmHg
  • Ischemic heart disease
  • Ketamine prior to arrival
  • Trauma patients
  • Sepsis or septic shock
  • Weight > 100 kg.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03959852
Other Study ID Numbers  ICMJE 18-040
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mercy Health Ohio
Study Sponsor  ICMJE Mercy Health Ohio
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: David Gemmel Director of Research
PRS Account Mercy Health Ohio
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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