Lidocaine Infusion as a Treatment for Cocaine Relapse and Craving (LIDO)

We propose that the systemic administration of lidocaine following the induction of cue-induced craving, relative to saline plus cue-induced craving or lidocaine without cue-induced craving, will block the reconsolidation of cue memories. This will lead to a reduction in cue-induced craving upon repeated testing as well as subsequent cocaine use and basal craving.

Study Overview

• Status: Completed
• Conditions: Cocaine Addiction
• Intervention / Treatment: Drug: lidocaine following cue-induced craving; Drug: lidocaine following neutral stimulus; Drug: saline

Detailed Description

Cocaine dependence is among the most tenacious of the substance use disorders yet remains one of the few lacking an effective pharmacological intervention. As other pharmacologic approaches have not been fruitful, new targets are required. A novel treatment approach is to disrupt the neural processes involved in cue-related memories (memory links between the external stimuli associated with drug use and the subjective drug effect). These engrained memories, when reactivated by cues, elicit craving and a return to drug use. Each cue re-exposure, however, requires the re-remembering (or reconsolidation) of the drug cue. Key molecular processes required for memory reconsolidation are NMDA (N-methyl-D-aspartate) receptor activation, the induction of nitric oxide (NO) synthesis and increased extracellular signal-regulated kinase (ERK) activity. In rodent models, blocking these processes changes the cue-related memory; the cue loses its potency to induce a return to drug self-administration. Lidocaine is an FDA (Food and Drug Administration) approved medication that inhibits activation of NMDA (N-methyl-D-aspartate) receptors and suppresses production of NO (nitric oxide) and ERK (extracellular signal-regulated kinase). Lidocaine, like cocaine, is a local anesthetic with potent effects as a sodium-channel blocker. Unlike cocaine, lidocaine is essentially devoid of activity at monoamine re-uptake transporters and has no rewarding or addictive properties. As lidocaine suppresses the molecular processes required for drug cue reconsolidation and has relatively specific effects upon the striatal regions necessary for drug cue reconsolidation, lidocaine may offer a novel approach for interfering with memory reconsolidation. Two other (Sodium) Na+ channel blockers have also decrease craving and/or substance use in substance-dependent subjects. We propose that the systemic administration of lidocaine following the induction of cue-induced craving, relative to saline plus cue-induced craving or lidocaine without cue-induced craving, will block the reconsolidation of cue memories. This will lead to a reduction in cue-induced craving upon repeated testing as well as subsequent cocaine use and basal craving. If our hypotheses are proven correct, these findings will 1) support a role for lidocaine in cocaine addiction treatment, 2) demonstrate the feasibility and efficacy of attenuating cue-induced memories, and 3) guide the development of a larger study with lidocaine.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390-8564
      • UT Southwestern Medical Center at Dallas, Division on Addictions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 56 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 25-60 years old
• men or women
• any race or ethnicity
• cocaine addition is primary present and lifetime drug of abuse
• live locally

Exclusion Criteria:

• Patients with active DSM (Diagnostic Statistical Manual)-IV other Substance Dependence (except nicotine) within the previous three months, Affective Disorder, Schizophrenic Disorders.
• significant cognitive impairment (WTAR<70) (Wechsler Test of Adult Reading <70)..
• use of tricyclic anti-depressants, benzodiazepines, cimetidine, mood stabilizers, opioids, lithium, sympathomimetics, anticonvulsants, sedative/hypnotics, β-blockers, or dopamine agonists will be excluded from the study.
• Medical conditions that might limit cooperation (e.g. dementia) or put the patient at medical risk (i.e. significant hematologic, hepatic, renal, or cardiovascular pathology - particularly arrhythmias) will be excluded.
• Patients with congenital or idiopathic methemoglobinemia or patients taking medications associated with increased risk of methemoglobinemia (including sulfonamides, acetaminophen, acetanilid, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, paraaminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, quinine) will be excluded.
• Patients with past or present neurologic disorders (i.e. severe head trauma, transient ischemic attacks, stroke, tumor, etc.) will be excluded. - Active suicidal ideation, pregnant or nursing women, and prisoners will be excluded from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: lidocaine following cue-induced craving; Lidocaine will be administered immediately following craving induction. Lidocaine will administered at a loading dose of 2mg/kg(milligrams per kilogram) initial bolus over 5 minutes lidocaine followed by continuous infusion at 2mg/kg /hour for 4 hours.	Drug: lidocaine following cue-induced craving; as described in Arm Description; Other Names: Xylocaine
Active Comparator: lidocaine following neutral stimulus; Lidocaine will be administered immediately following neutral stimulus. Lidocaine will administered at a loading dose of 2mg/kg initial bolus over 5 minutes lidocaine followed by continuous infusion at 2mg/kg /hour for 4 hours.	Drug: lidocaine following neutral stimulus; as described in Arm Description; Other Names: Xylocaine
Placebo Comparator: saline; Saline will be administered at same volume of lidocaine in active arms.	Drug: saline; as described in Arm Description; Other Names: 0.9% Sodium chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cue-induced Craving After Lidocaine/Saline Administration.	7 days after lidocaine/saline administration, cocaine craving will be measured during the administration of relaxation or craving script. Craving intensity will be measured by the subjective intensity of craving as reported by the participant. Measured via a visual analog scale based on 4 (out of 10) questions from the Cocaine Craving Questionnaire (1-strongly disagree to 7- strongly agree). Highest total score possible 28, lowest score possible is 4. If the score is low in the lidocaine group and high in the saline group, it would mean that lidocaine has successfully decreased the craving response relative to saline.	craving measured immediately following reading of the script.
Physiological Responses as Measured by Heart Rate After Lidocaine/Saline Administration.	7 days after lidocaine/saline administration, heart rate will be measured during the administration of a relaxation or craving script. Heart rate will be measured in beats per minute.	120 seconds, during reading of the script.
Physiological Responses as Measured by Blood Pressure After Lidocaine/Saline Administration.	7 days after lidocaine/saline administration, blood pressure (BP) response will be assessed during relaxation or craving script. Blood pressure will be measured by mmHg.	BP will measured during the two minutes of script reading.
Physiological Responses as Measured by Galvanic Skin Response (GSR) After Lidocaine/Saline Administration.	7 days after lidocaine/saline administration, GSR will be measured during the reading of the relaxation or saline script. It is predicted that higher GSR would be associated with higher cocaine craving and lower GSR will be associated with lower cocaine craving.	2 minutes during script reading.
Physiological Responses as Measured by EMG (Electromyography) After Lidocaine/Saline Administration.	Electromyography (frontal) will be measured during the administration of the relaxation or craving script seven days after infusion. EMG is assessed by uV (microvolts). Higher scores reflect greater amounts of EMG activity, lower scores reflect lower amounts of EMG activity. It was expected that EMG would be positively associated with cocaine craving.	2 minutes during administration of script.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cocaine Use	cocaine use will be measured by urine drug screen and participant self-report three times weekly after lidocaine/saline administration. Cocaine use will be assessed as positive (1) or negative (0) using urine drug screen for cocaine and/or by participant self-report of cocaine use.	cocaine use will be measure during the 4 weeks following infusion
Cocaine Craving	basal measures of cocaine craving will be measured by Cocaine Craving Questionnaire (CCQ) times weekly after lidocaine/saline administration. The higher the score the more craving and lower the score the less craving. The CCQ has 10 items, each item scored 1-7. Maximum score is 70, minimum score is 7.	cocaine craving will be measure during the 4 weeks following infusion

Collaborators and Investigators

• Sponsor: Bryon Adinoff
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Bryon Adinoff, MD, UT Southwestern Medical Center, VA North Texas Health Care System

Publications and helpful links

General Publications

• Becker JE, Price JL, Leonard D, Suris A, Kandil E, Shaw M, Kroener S, Brown ES, Adinoff B. The Efficacy of Lidocaine in Disrupting Cocaine Cue-Induced Memory Reconsolidation. Drug Alcohol Depend. 2020 Jul 1;212:108062. doi: 10.1016/j.drugalcdep.2020.108062. Epub 2020 May 12.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: August 22, 2013
• First Submitted That Met QC Criteria: August 22, 2013
• First Posted (Estimate): August 27, 2013

Study Record Updates

• Last Update Posted (Actual): December 31, 2020
• Last Update Submitted That Met QC Criteria: December 7, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: addiction; memory; lidocaine; cocaine; drug abuse
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Compulsive Behavior; Impulsive Behavior; Behavior, Addictive; Cocaine-Related Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Lidocaine
• Other Study ID Numbers: STU 032013-049

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No