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

Pain, Acute Clinical Trial

Official title:

A Combination Study With Sub-Dissociative Ketamine and Fentanyl to Treat Moderate to Severe Pain in the Emergency Department

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03959852
• Other study ID #: 18-040
• Status: Terminated
• Phase: Phase 4
• Start date: November 18, 2019
• Est. completion date: June 5, 2020

Study information

• Verified date: September 2020
• Source: Mercy Health Ohio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: June 5, 2020
• Est. primary completion date: June 5, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Pain
• Pain, Acute

Intervention

Drug:
• Fentanyl
1 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.

Drug:
• Ketamine
0.3 mg/kg of Sub-Dissociative Ketamine IV administered over at least 1 minute

Locations

Country	Name	City	State
United States	St. Elizabeth Boardman Hospital	Boardman	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Mercy Health Ohio

Country where clinical trial is conducted

United States, 

References & Publications (24)

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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. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

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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. — View Citation

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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. — View Citation

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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. — View Citation

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. — View Citation

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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. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Analgesia of combination fentanyl and SDK as assessed using the pain scale 1-10	Analgesia of combination fentanyl and SDK as assessed using the pain scale 1-10	ED encounter (less than 24 hours)
Primary	Analgesia of fentanyl as assessed using the pain scale 1-10	Analgesia of fentanyl as assessed using the pain scale 1-10	ED encounter (less than 24 hours)
Primary	Analgesia of ketamine as assessed using the pain scale 1-10	Analgesia of katamine as assessed using the pain scale 1-10	ED encounter (less than 24 hours)
Secondary	OARRS report	A retrospective review of OARRS report will be performed with each patient.	ED encounter (less than 24 hours)
Secondary	Opioid sparing response as assessed by number of times additional rescue doses of fentanyl were required	Opioid sparing response as assessed by number of times additional rescue doses of fentanyl were required	ED encounter (less than 24 hours)

External Links

•   (WONDER), W.-r. o. (2017, August 30). Centers for Disease Control and Prevention. Retrieved August 18, 2018, from CDC.gov: https://www.cdc.gov/drugoverdose/epidemic/index.html
•   U.S. Department of Health and Human Services. (2018, October 15). U.S. Food and Drug Administration. Retrieved October 15, 2018, from https://www.accessdata.fda.gov/scripts/drugshortages/