Cocaine Addiction
Conditions
Keywords
cocaine, addiction, lidocaine, memory, drug abuse
Brief summary
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.
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.
Interventions
DRUGlidocaine following cue-induced craving
as described in Arm Description
DRUGlidocaine following neutral stimulus
as described in Arm Description
DRUGsaline
as described in Arm Description
Sponsors
National Institute on Drug Abuse (NIDA)
Bryon Adinoff
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Physiological Responses as Measured by Heart Rate After Lidocaine/Saline Administration. | 120 seconds, during reading of the script. | 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. |
| Physiological Responses as Measured by Galvanic Skin Response (GSR) After Lidocaine/Saline Administration. | 2 minutes during script reading. | 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. |
| Physiological Responses as Measured by EMG (Electromyography) After Lidocaine/Saline Administration. | 2 minutes during administration of script. | 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. |
| Cue-induced Craving After Lidocaine/Saline Administration. | craving measured immediately following reading of the script. | 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. |
| Physiological Responses as Measured by Blood Pressure After Lidocaine/Saline Administration. | BP will measured during the two minutes of script reading. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cocaine Craving | cocaine craving will be measure during the 4 weeks following infusion | 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 Use | cocaine use will be measure during the 4 weeks following infusion | 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. |
Countries
United States
Participant flow
Pre-assignment details
84 participants were consented to participate in the study. 48 were withdrawn as they did not meet inclusion/exclusion criteria (insufficient use of cocaine, medical concerns, positive drug screens or psychiatric disorders) upon further screening and evaluation. Thus, we are reporting on 36 participants.
Participants by arm
| Arm | Count |
|---|---|
| Lidocaine Following Cue-induced Craving Lidocaine will be administered immediately following craving induction. 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.
lidocaine following cue-induced craving: as described in Arm Description | 12 |
| 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.
lidocaine following neutral stimulus: as described in Arm Description | 9 |
| Saline Saline will be administered at same volume of lidocaine in active arms.
saline: as described in Arm Description | 12 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Lidocaine Following Cue-induced Craving | Lidocaine Following Neutral Stimulus | Saline | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 9 Participants | 12 Participants | 33 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 9 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 9 | 0 / 12 |
| other Total, other adverse events | 0 / 12 | 0 / 9 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 9 | 0 / 12 |
Outcome results
Primary
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.
Time frame: craving measured immediately following reading of the script.
Population: 3 participants were lost to follow-up and hence we could analyze only the available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lidocaine Following Cue-induced Craving | Cue-induced Craving After Lidocaine/Saline Administration. | 31.7 units on a scale | Standard Deviation 12.6 |
| Lidocaine Following Neutral Stimulus | Cue-induced Craving After Lidocaine/Saline Administration. | 17.3 units on a scale | Standard Deviation 9.5 |
| Saline | Cue-induced Craving After Lidocaine/Saline Administration. | 22.7 units on a scale | Standard Deviation 11.9 |
Primary
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.
Time frame: BP will measured during the two minutes of script reading.
Population: The data was not collected and hence was not analyzed.
Primary
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.
Time frame: 2 minutes during administration of script.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lidocaine Following Cue-induced Craving | Physiological Responses as Measured by EMG (Electromyography) After Lidocaine/Saline Administration. | 21.6 uV | Standard Deviation 44.5 |
| Lidocaine Following Neutral Stimulus | Physiological Responses as Measured by EMG (Electromyography) After Lidocaine/Saline Administration. | 28.1 uV | Standard Deviation 57.8 |
| Saline | Physiological Responses as Measured by EMG (Electromyography) After Lidocaine/Saline Administration. | 5.9 uV | Standard Deviation 2.1 |
Primary
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.
Time frame: 2 minutes during script reading.
Population: 3 participants were lost to follow-up and hence we could analyze only the available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lidocaine Following Cue-induced Craving | Physiological Responses as Measured by Galvanic Skin Response (GSR) After Lidocaine/Saline Administration. | 19.1 EDA Amplitute (uS) | Standard Deviation 4.5 |
| Lidocaine Following Neutral Stimulus | Physiological Responses as Measured by Galvanic Skin Response (GSR) After Lidocaine/Saline Administration. | 20.1 EDA Amplitute (uS) | Standard Deviation 0.2 |
| Saline | Physiological Responses as Measured by Galvanic Skin Response (GSR) After Lidocaine/Saline Administration. | 20.4 EDA Amplitute (uS) | Standard Deviation 0.7 |
Primary
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.
Time frame: 120 seconds, during reading of the script.
Population: 3 participants were lost to follow-up and hence we could analyze only the available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lidocaine Following Cue-induced Craving | Physiological Responses as Measured by Heart Rate After Lidocaine/Saline Administration. | 67.4 beats per minute | Standard Deviation 27.4 |
| Lidocaine Following Neutral Stimulus | Physiological Responses as Measured by Heart Rate After Lidocaine/Saline Administration. | 73.0 beats per minute | Standard Deviation 19.4 |
| Saline | Physiological Responses as Measured by Heart Rate After Lidocaine/Saline Administration. | 77.5 beats per minute | Standard Deviation 16.6 |
Secondary
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.
Time frame: cocaine craving will be measure during the 4 weeks following infusion
Population: Only available data were analyzed. Some participants were lost to follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lidocaine Following Cue-induced Craving | Cocaine Craving | 32.3 units on a scale | Standard Deviation 18.5 |
| Lidocaine Following Neutral Stimulus | Cocaine Craving | 15.8 units on a scale | Standard Deviation 4.8 |
| Saline | Cocaine Craving | 20.9 units on a scale | Standard Deviation 15.6 |
Secondary
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.
Time frame: cocaine use will be measure during the 4 weeks following infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lidocaine Following Cue-induced Craving | Cocaine Use | 3.8 days of cocaine used/week | Standard Deviation 1.8 |
| Lidocaine Following Neutral Stimulus | Cocaine Use | 2.7 days of cocaine used/week | Standard Deviation 0.8 |
| Saline | Cocaine Use | 3.0 days of cocaine used/week | Standard Deviation 0 |