MMA: Memory Modulation by Pain During Anesthesia

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Completed
• CT.gov ID: NCT02515890
• Collaborator: Foundation for Anesthesia Education and Research (Other)
• Enrollment: 32
• Location: 1
• Arms: 5
• Actual Duration (Months): 36.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effects of pain on facilitating long-term auditory memory in the presence and absence of distinct intravenous anesthetics. The ability to identify previously presented words from a list assessed the degree of memory formation. In a subset of subjects, functional magnetic resonance imaging was used to identify the neural correlates of memory inhibition or facilitation by the combination of pain and anesthetic used.

Condition or Disease	Intervention/Treatment	Phase
Amnesia; Pain; Anesthesia	Drug: Dexmedetomidine; Drug: Midazolam; Device: Peripheral nerve stimulation; Drug: Ketamine	Phase 1

Detailed Description

This study adds specific details to the current incomplete body of knowledge examining the effect of pain on memory formation under the influence of anesthetic agents.

Pain and anesthetic agents were administered as experimental variables in this study. Healthy adult subjects were played repeated lists of words and performed several decision-making tasks that encourage memory encoding. Some words were consistently paired with painful electric shock, and was anticipated to improve subsequent memory performance specifically for those items. The same experiment was repeated in all subjects during the administration of 1-2 possible agents that reduce memory formation: dexmedetomidine, a predominantly sedative agent, and midazolam, a well-known amnestic agent, and ketamine, a well-known dissociative analgo-sedative. The extent to which pain modulates memory performance under the effects of the anesthetic agents was the primary outcome of interest.

Further, a subset of the subjects performed the same experimental procedures while undergoing functional magnetic resonance imaging, which continuously reflects neuronal activity throughout the brain. Classic memory areas were predicted to be activated by the auditory processing task, but how these neural circuits change under the two anesthetic agents with the concomitant experience of pain were of interest. It was anticipated that pain recruits a parallel memory pathway using limbic structures, known for their involvement in fear conditioning. Additionally, stronger and more diffuse cortical processing likely occurs with concomitant pain, as level of sedation was reduced by this strong stimulus. Discovering the anatomic correlates specific to each experimental variable (pain and anesthetic), and their interplay, may help refine our model of brain function during the dynamics of pain and sedation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: There are 3 single drug arms completed by a few participants. The majority of participants participated in a crossover design with two drugs, midazolam & ketamine.There are 3 single drug arms completed by a few participants. The majority of participants participated in a crossover design with two drugs, midazolam & ketamine.
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Modulation of Long-term Memory by the Experience of Pain During Sedation With Anesthetics
• Actual Study Start Date: Nov 19, 2015
• Actual Primary Completion Date: Dec 12, 2018
• Actual Study Completion Date: Dec 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dexmedetomidine Only All subjects receive saline (control), followed by a dexmedetomidine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation.	Drug: Dexmedetomidine; Selected subjects received this drug during a portion of the study; Other Names: Precedex ; Device: Peripheral nerve stimulation; Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.; Other Names: electric nerve stimulation
Experimental: Midazolam Only Subjects receive saline (control), followed by midazolam infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation.	Drug: Midazolam; Selected subjects received this drug during a portion of the study; Other Names: Versed ; Device: Peripheral nerve stimulation; Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.; Other Names: electric nerve stimulation
Experimental: Ketamine Only All subjects receive saline (control), followed by ketamine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation.	Device: Peripheral nerve stimulation; Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.; Other Names: electric nerve stimulation ; Drug: Ketamine; Selected subjects received this drug during a portion of the study; Other Names: Ketalar
Experimental: Saline/Midazolam/Saline/Ketamine All subjects receive saline (control), followed by midazolam infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. Subjects then returned at least 1 week later for another set of experimental sessions with the same design, however the saline was followed by ketamine infusion.	Drug: Midazolam; Selected subjects received this drug during a portion of the study; Other Names: Versed ; Device: Peripheral nerve stimulation; Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.; Other Names: electric nerve stimulation ; Drug: Ketamine; Selected subjects received this drug during a portion of the study; Other Names: Ketalar
Experimental: Saline/Ketamine/Saline/Midazolam All subjects receive saline (control), followed by ketamine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. Subjects then returned at least 1 week later for another set of experimental sessions with the same design, however the saline was followed by midazolam infusion.	Drug: Midazolam; Selected subjects received this drug during a portion of the study; Other Names: Versed ; Device: Peripheral nerve stimulation; Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.; Other Names: electric nerve stimulation ; Drug: Ketamine; Selected subjects received this drug during a portion of the study; Other Names: Ketalar

Outcome Measures

Primary Outcome Measures

1. Memory Testing [At memory testing 1 day later]

   Subjects completed the Remember, Know, New (RKN) task during next day testing. Their d' memory score was calculated based on their ability to discriminate between previously heard words and new words. A higher d' score indicates stronger recollection. D' scores were compared across the control condition (saline) and the drug conditions dexmedetomidine, midazolam, and ketamine. Performance was also calculated according to words associated with Pain and No Pain conditions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 39 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy adult volunteers, with normal memory and hearing, whose native language is English

Exclusion Criteria:

• pregnancy

• significant memory or hearing loss

• sleep apnea

• chronic pain

• metal or electronic implants

• claustrophobia

• Currently taking: antidepressants, anti-psychotics, antihistamines, anti-anxiety medication, stimulants, sleep-aids, or pain medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• University of Pittsburgh
• Foundation for Anesthesia Education and Research

Investigators

• Principal Investigator: Keith M Vogt, MD, PhD, University of Pittsburgh

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 24, 2020
• Informed Consent Form - Feb 23, 2018
• Study Protocol - Jan 30, 2019

More Information

Publications

None provided.

• Responsible Party: Keith M. Vogt, MD, PhD, Assistant Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02515890
• Other Study ID Numbers: PRO14050609
• First Posted: Aug 5, 2015
• Last Update Posted: Jul 1, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by Keith M. Vogt, MD, PhD, Assistant Professor, University of Pittsburgh: midazolam; dexmedetomidine; memory; ketamine
• Additional relevant MeSH terms: Amnesia; Midazolam; Dexmedetomidine; Ketamine

Study Results

Participant Flow

Arm/Group Title	Dexmedetomidine	Midazolam	Ketamine	Drug Order A	Drug Order B
Arm/Group Description	subjects received dexmedetomidine and saline (control)	subjects received midazolam and saline (control)	subjects received ketamine and saline (control)	Subjects received saline (control) and midazolam during their first set of experimental sessions, and then received saline (control) and ketamine during a second set of sessions	Subjects received saline (control) and ketamine during their first set of experimental sessions, and then received saline (control) and midazolam during a second set of sessions
Period Title: Overall Study
STARTED	7	4	5	8	8
COMPLETED	7	4	5	8	8
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Dexmedetomidine Only	Midazolam Only	Ketamine Only	Drug Order A	Drug Order B	Total
Arm/Group Description	All subjects received saline (control) followed by dexmedetomidine infusion while performing memory task and receiving intermittent painful electric nerve stimulation.	All subjects received saline (control) followed by midazolam infusion while performing memory task and receiving intermittent painful electric nerve stimulation.	All subjects received saline (control) followed by ketamine infusion while performing memory task and receiving intermittent painful electric nerve stimulation.	All subjects received saline (control) followed by midazolam infusion while performing memory task and receiving intermittent painful electric nerve stimulation on their first experimental visit. For another experimental session, all subjects received saline (control) followed by ketamine infusion while performing memory task and receiving intermittent painful electric nerve stimulation.	All subjects received saline (control) followed by ketamine infusion while performing memory task and receiving intermittent painful electric nerve stimulation on their first experimental visit. For another experimental session, all subjects received saline (control) followed by midazolam infusion while performing memory task and receiving intermittent painful electric nerve stimulation.	Total of all reporting groups
Overall Participants	7	4	5	8	8	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	4 100%	5 100%	8 100%	8 100%	32 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	3 42.9%	2 50%	1 20%	3 37.5%	5 62.5%	14 43.8%
Male	4 57.1%	2 50%	4 80%	5 62.5%	3 37.5%	18 56.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	4 100%	5 100%	8 100%	8 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Memory Testing
Description	Subjects completed the Remember, Know, New (RKN) task during next day testing. Their d' memory score was calculated based on their ability to discriminate between previously heard words and new words. A higher d' score indicates stronger recollection. D' scores were compared across the control condition (saline) and the drug conditions dexmedetomidine, midazolam, and ketamine. Performance was also calculated according to words associated with Pain and No Pain conditions.
Time Frame	At memory testing 1 day later

Outcome Measure Data

Analysis Population Description

The overall number analyzed for each drug condition represents the number of observations for that drug, which doesn't directly correspond to study arms. All participants received a saline control condition with their drug condition. Therefore, there were 48 saline observations (saline d' scores) which includes observations from all 5 study arms.

Arm/Group Title	Dexmedetomidine	Midazolam	Ketamine	Saline
Arm/Group Description	Subjects assigned to receive dexmedetomidine as part of the study	Subjects assigned to receive midazolam as part of the study. Includes subjects from groups Midazolam Only, Drug Order A, and Drug Order B	Subjects assigned to receive ketamine as part of the study. Includes subjects from groups Ketamine Only, Drug Order A, and Drug Order B	All subjects subjects received saline as a control condition during their study visits. Includes subjects from Dexmedetomidine Only, Midazolam Only, Ketamine Only, Drug Order A, and Drug Order B.
Measure Participants	7	4	5	16
Measure number of observations for each drug	7	20	21	48
All Conditions	1.20 (.27)	.56 (.05)	.82 (.07)	1.18 (.07)
No Pain Condition	1.12 (.35)	.55 (.06)	.85 (.11)	1.18 (.10)
Pain Condition	1.28 (.43)	.57 (.06)	.78 (.10)	1.10 (.10)

Adverse Events

Time Frame	up to 18 days after the final experimental session
Arm/Group Title	Dexmedetomidine Only		Midazolam Only		Ketamine Only		Drug Order A		Drug Order B
Arm/Group Description	Dexmedetomidine: Subjects received this drug during a portion of the study		Midazolam: Subjects received this drug during a portion of the study		Ketamine: Subjects received this drug during a portion of the study All adverse events for Ketamine Only subjects were experienced during ketamine administration.		Midazolam: Subjects received this drug during a portion of the study Ketamine: Subjects received this drug during a portion of the study These drugs were given on separate visits, occurring at least 14 days apart. All adverse events for Drug Order A subjects were experienced during ketamine administration.		Ketamine: Subjects received this drug during a portion of the study Midazolam: Subjects received this drug during a portion of the study These drugs were given on separate visits, occurring at least 14 days apart. All adverse events for Drug Order B subjects were experienced during ketamine administration.
All Cause Mortality
	Dexmedetomidine Only		Midazolam Only		Ketamine Only		Drug Order A		Drug Order B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/4 (0%)		0/5 (0%)		0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Dexmedetomidine Only		Midazolam Only		Ketamine Only		Drug Order A		Drug Order B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/4 (0%)		0/5 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Dexmedetomidine Only		Midazolam Only		Ketamine Only		Drug Order A		Drug Order B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/4 (0%)		1/5 (20%)		1/8 (12.5%)		1/8 (12.5%)
Gastrointestinal disorders
Nausea and vomiting	0/7 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	1/8 (12.5%)	1	0/8 (0%)	0
Psychiatric disorders
Dysphoria	0/7 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/8 (0%)	0	1/8 (12.5%)	1

Limitations/Caveats

Functional imaging results are being prepared for publication.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.