Lidocaine Infusion as a Treatment for Cocaine Relapse and Craving
Phase: PHASE2
Conditions: Cocaine Addiction
Sponsor: Bryon Adinoff

Official title: Lidocaine Infusion as a Treatment for Cocaine Relapse and Craving 
 
 NCT number: NCT01929343 
 
Document date: May 21, 2015 

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The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Protocol Template (for Investigator Initiated Studies) 
 
 
1. Title 
Lidocaine Infusion as a Treatment for Cocaine Relapse and Craving 
 
2. Principal Investigator and Co-Investigator 
PI: Bryon Adinoff, M.D. 
Co-Investigators: Edson Brown M.D., Ph.D.; Francesca Filbey, Ph.D.; Enas Kandil, M.D.; Alina Suris, 
Ph.D. 
 
3. Sponsor of the Study 
NIH-NIDA 
 
4. Investigational New Drug (IND)/Investigational Device Exemption (IDE) 
IND 119175 for Lidocaine Hydrochloride Injection 
 
5. Purpose of the Study, Including the Hypothesis to be Tested  
Pharmacologic approaches have been generally unsuccessful in decreasing cocaine use in addicted 
patients and behavioral approaches have limited utility. While some medications and novel 
approaches show promise, there are presently no FDA approved drugs for the treatment of cocaine 
addiction. Furthermore, pharmacologic approaches directly targeting monoamine, GABAergic, and 
NMDA receptors have not been fruitful. Thus, the need for novel targets and approaches for cocaine 
addiction is imperative.  
Primary Aim 1: Assess the effects of lidocaine in reducing cue-induced cocaine craving. 
Hypothesis P1: Cue-induced craving assessed one week after infusion will be less in patients 
administered lidocaine+cue-induced relative to those given saline+cue-induced craving or 
lidocaine alone. 
Hypothesis P1b: Physiologic responses to cue-induced craving assessed one week after 
infusion will be significantly less in patients administered lidocaine relative to those 
administered saline. 
Primary Aim 2: Assess the effects of lidocaine on cocaine use [as measured by urine drug screen 
(UDS)] and craving for four weeks following lidocaine or saline administration. 
Hypothesis P2a: Cocaine use will be significantly less in the patients administered lidocaine 
[+cue-induced craving] compared to those administered saline+cue-induced craving or 
lidocaine alone. 
 
Hypothesis P2b: Craving will be significantly less in the patients administered lidocaine+cue-
induced craving compared to those administered saline+cue-induced craving or lidocaine 
alone. 
 
If our hypotheses are proven correct, these findings will (1) demonstrate the feasibility of 
interfering with reconsolidation memories in substance-dependent patients, (2) support a role 
for lidocaine in the treatment of cocaine addiction, and (3) guide the development of a larger 
study to assess treatment outcome with lidocaine. 
 
 
6. Background and Results of Previous Related Research  

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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 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 approved medication that inhibits 
activation of NMDA receptors and suppresses production of NO and ERK. 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 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.  
 
7. Concise Summary of Project: 
In this proof-of-concept approach for the treatment of cocaine addition (modeled on a paradigm 
developed by our group to assess pharmacologic disruptors of PTSD-related trauma memories), the 
effect of lidocaine infusion following cue-induced craving will be assessed in treatment-seeking, 
cocaine-addicted outpatients. Immediately following the induction of cue-induced craving, lidocaine or 
saline will be administered in a double-blind, randomized design. A third arm will also assess lidocaine 
in the absence of cue-induced craving. One week following the infusion, cue-induced craving will be 
assessed. Cocaine use and craving (non cue-induced) will be monitored for four weeks. 
 
8. Study Procedures: 
66 participants with active cocaine use disorder will be studied. After consent and screening, on Study 
Day 1, participants will describe scenarios in which they experience cocaine cravings. Participants will 
also be asked to describe scenarios that they find relaxing. This study session lasts approximately 
one hour. On Study Day 2, participants will be checked in overnight at Zale Hospital. If the participant 
is not currently on a residential treatment unit, they may be asked to stay overnight for 3 days prior to 
Study Day 2. Upon arrival the participants will have a physical exam and drug and pregnancy tests. 
The following day, scripts will be read to participants and lidocaine (n=22) or saline (n=22) will be 
administered immediately following craving reactivation. Since lidocaine may be effective in the 
absence of craving induction, a third group of subjects (n=22) will be given lidocaine but not a craving 
script. One week later (Study Day 3), craving intensity and physiologic activation following cue-
induced craving will be assessed. Costs incurred from these visits will be covered by the research 
team’s funding for this study. Follow-up sessions post-infusion will include 3 times weekly UDS for 4 
weeks. Weekly therapy visits conducted for all outpatient participants will be audio recorded for 
research purposes only. Recordings will not be used for commercial purposes.  
If participant is attending a residential treatment program, Study Day 2 will take place one week prior 
to discharge from their program. Study Day 3 will take place immediately following discharge from 
their treatment program. 
Due to sex differences in craving (106), randomization will be stratified by sex. 
 
9. Sub-Study Procedures: 
NA 

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10. Criteria for Inclusion of Subjects: 
Inclusion criteria:  All participants must be 25-60 years old, of either sex, and of any race. The 
relatively small sample size necessitates that variability be limited. Participants will be either 
outpatient and treatment seeking or attending a residential treatment program at the VA Medical 
Center or Homeward Bound, Inc (a local public-sector treatment facility). If attending a residential 
treatment facility, participants will be studied just prior to discharge. Patients must meet DSM-IV 
criteria for cocaine dependence (by Structured Clinical Interview DSM-IV Lifetime) and must identify 
cocaine as their primary present and lifetime drug of abuse. Participants must live close enough to 
the sites and have reliable transportation such that they can attend all assessments, study sessions, 
and follow-up and treatment sessions.  
 
11. Criteria for Exclusion of Subjects: 
Patients with active DSM-IV other Substance Dependence (except nicotine) within the previous three 
months, Affective Disorder, Schizophrenic Disorders, or significant cognitive impairment (WTAR<70). 
Due to the complicating presentation of substance-induced mood or psychotic disorders, these 
disorders will only be cause for exclusion if symptoms persist upon cocaine abstinence. Patients 
concomitantly using tricyclic anti-depressants, benzodiazepines, cimetidine, mood stabilizers, opioids, 
lithium, sympathomimetics, anticonvulsants that act on sodium and L-type channels similar to 
lidocaine, sedative/hypnotics, -blockers, or dopamine agonists will be excluded from the study. 
Participants on stable doses of SSRIs and SNRIs for at least two weeks will not be excluded. 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. 
 
12. Sources of Research Material: 
Initial screening will consist of questionnaires, routine blood chemistry and cell blood count, EKG, 
pregnancy test and urine tests for illicit drug use. Questionnaires will include lifetime use of 
substances (drugs and alcohol), personal psychiatric history, psychiatric history of family members, 
demographic and medical information, and development of craving script. Subjective measures of 
craving, mood, and anxiety and physiological measures will be obtained during infusion and 
reactivation sessions. Measures of craving, mood and urine tests for illicit drug use will be obtained 
upon follow-up. All measures will be used for research purposes only. 
 
13. Recruitment Methods and Consenting Process: 
Subjects will be recruited from the VA substance dependence program, flyers, Internet and 
newspaper ads, and links to our Website. Participants will be evaluated after they contact us 
expressing an interest in study participation. General information about the study and brief screening 
will be provided over the phone. Interested participants will be scheduled for further evaluation and 
obtaining informed consent. Assessment will then include a history and medical evaluation, routine 
laboratory tests, EKG, urine drug screen (UDS), Wechsler Test of Adult Reading (WTAR) (107) and 
urine pregnancy test. Structured Clinical Interview for DSM-IV (SCID) (108) will be used for diagnosis. 
Subjects meeting inclusion/exclusion criteria will be further assessed with demographic/clinical 
variables (including menstrual phase), Time Line Follow Back (109) to determine lifetime and previous 
90 days cocaine use (number of days used, amount used in $), the Inventory of Drug Use 
Consequences (InDUC) (110) and the SF-36 Health Survey assessing quality of life (111). 
 
14. Potential Risks: 

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The insertion of an intravenous catheter may cause a slight pain when inserted.  A bruise may form 
temporarily at the spot where the catheter is inserted.  There is a slight chance of inflammation of the 
vein and/or clot formation, but this is rare. 
Lidocaine is FDA approved as a local anesthetic (applied intradermally) and for cardiac arrhythmias 
and status epilepticus (11).  Lidocaine may commonly (1-10%) cause central nervous system 
symptoms such as numbness and tingling, dizziness, drowsiness, anxiety and nervousness. Rare 
side effects (0.01 to 0.09%) include dizziness, a metalic taste, lightheadedness, nervousness, 
apprehension, euphoria, confusion, ringing in the ear, blurred vision, nausea and vomiting, sensations 
of heat, cold or numbness, twitching, tremors, and convulsions.  Rarely, irregular heart beats and/or 
slowed heart rate may progress to respiratory depression and heart attack. At the injection site, you 
may experience a burning sensation, pain, skin irritation, or swelling. Rarely (0.01 to 0.09%), an 
allergic reaction can be experienced, including hives, difficulty breathing, swelling of face, lips, tongue, 
or throat. 
A report from Stanford University Pain Management Center reports on the use of lidocaine infusion 
for chronic pain. No serious adverse events were reported in over 3000 lidocaine infusions (121). 
Other reviews also note the safety of lidocaine infusion at doses similar to that being used in the 
present study (12). A recent Cochrane review of 395 patients receiving lidocaine during surgery notes 
that lidocaine did not result in toxicity or clinically significant adverse events (49). 
In a previous study assessing the rCBF effects of procaine infusion in cocaine-addicted subjects, 
participants were followed (including urine drug screen) for three months after the study, at one week, 
one month, and three months post-infusion (37).  This follow-up was conducted to assure that there 
were no long-term, untoward and unexpected adverse effects to procaine infusion. Seven of 12 
patients (58%) had not relapsed at three months. One patient was abstinent at two weeks and then 
moved out of town. Four patients relapsed by two weeks following treatment. These relapse rates are 
comparable to those observed in clinical drug trials.  
Subjects will be assessed for pregnancy and cocaine use prior to lidocaine infusion. If participants 
report cocaine use within previous 72 hours or their UDS is positive for cocaine, lidocaine will not be 
administered and the session will be rescheduled.  If a participant is positive upon rescheduling, they 
will be terminated from the study and referred for care. If a female is positive for pregnancy, study 
participation will end and she will be referred for care. 
CBT is an efficacious behavioral treatment for cocaine dependence. Since there are no FDA 
approved medications for cocaine dependence, even subjects receiving placebo infusion will receive 
an acceptable, albeit limited, treatment.   
Some of the questions that are asked may make participants feel uncomfortable.  
 
 
15. Subject Safety and Data Monitoring: 
All subjects will be carefully assessed prior to participation in the studies, including psychiatric 
and medical history (as appropriate), laboratory tests, and examination by a board-certified physician 
(Dr. Kandil).  Subjects with medical or psychiatric problems that would increase risk for participation 
will be excluded from the study.   
 Craving will likely be increased during script development, lidocaine/saline infusion session, and 
craving reactivation. During craving induction, participants will be monitored at all times. A neutral 
imagery session will follow all craving imagery followed by a 20-min muscle relaxation session. 
Persistent craving that occurs following the craving reactivation session will be referred to the treating 
therapist (the first CBT session follows craving reactivation). Any participant who demonstrates need 
for additional intervention due to serious psychiatric/medical symptoms will be referred to emergency 
psychiatric services located in the VA Medical Center (if eligible for care) or other public sector 
(Homeward Bound, Inc.) or private (Presbyterian Medical Center) treatment programs. Participants 
demonstrating severe psychiatric/medical symptomology will be walked or transported by shuttle bus 
or taxi to one of those centers, as determined by the PI. 
Participants will be provided a car service to and from Study Session 2. If the participant is 
outpatient they will be picked up and dropped off at home. If the participant is attending a residential 
facility they will be transported back to the treatment program.  

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All lidocaine/saline infusions will be supervised by Dr. Enas Kandil, an anesthesiologist and co-
investigator. Either Dr. Kandil or an ACLS certified nurse will be in attendance during throughout the 
infusion. Heart rate, including EKG rhythm strip, will be monitored continuously throughout the 
infusion and blood pressure will be obtained every 15 minutes, and more frequently if indicated. If the 
participants’ hemodynamics (heart rate and blood pressure) change by more than 20% (typically a 
consequence of cardiac arrhythmias) the infusion will be stopped. The more serious toxic effects of 
lidocaine (e.g. unconsciousness, confusion, convulsions, respiratory arrest) are preceded by 
numbness of the tongue, lightheadedness, visual disturbances and muscle twitching; infusions will be 
terminated if the subject reports of any of these latter signs or symptoms and they persist for more 
than two minutes. The infusion may also be stopped at any time per physician discretion. A checklist 
of signs and symptoms will be obtained every 15 minutes. Subjects will be observed for at least two 
hours (approximately one half-life of lidocaine) following the cessation of lidocaine (or saline) infusion. 
Dr. Kandil must approve discharge for all participants on the infusion study day. There is a crash cart 
in the CRU and a 24-hour code team in the hospital. 
Lidocaine labels carry warnings and precautions for use in patients with various cardiac 
conditions, notably conduction abnormalities (e.g., heart block, QT prolongation). Cardiac conditions 
will be identified by ECG, medical history and physical exam. Participants with any medical history of 
cardiac disease (e.g. myocardial infarction, congestive heart failure, cardiac arrhythmia) or an 
abnormal ECG (including any arrhythmia, heart block, QT prolongation) will be excluded. Lidocaine 
labels carry warnings and precautions regarding the dangers its use in patients with significant renal 
disease, due to the risk of accumulating active metabolites. Renal impairment will be identified 
through medical history and physical exam as well as laboratory measures of creatinine and BUN, 
electrolyte panel, and urinalysis. Participants with abnormal levels of creatinine or BUN will be 
excluded. Participants with any evidence of renal insufficiency identified by laboratory measures or 
medical history or physical exam will be excluded from the study. 
Since lidocaine can increase cocaine lethality (122), participants with a positive UDS for cocaine 
(or amphetamine) or who report stimulant use within the previous 72 hours will not receive an 
infusion.  Women with a positive pregnancy test or who report unprotected heterosexual sex since 
their previous menses not receive an infusion and will be referred for appropriate care. If an infusion is 
not administered due to cocaine use, the subject may be rescheduled for another session (at the PIs 
discretion). If the rescheduled infusion cannot be performed (due to stimulant use or pregnancy), the 
subject will be terminated from the study and referred for care. In addition, subjects will be observed 
for at least two hours (approximately one half-life of lidocaine) following the cessation of lidocaine (or 
saline) infusion. Participants will be advised of the potential for increased cocaine toxicity for 24 hours 
after lidocaine administration and will be discharged to the care of a family member or friend. All 
participants will receive a 24-hour call-in number to contact research staff in the advent of problems. 
An IND for the use of lidocaine (administered over one hour in outpatient cocaine-addicted patients 
during a neuroimaging paradigm) has recently been approved by the FDA using a similar paradigm, 
including the two-hour wait prior to discharge (IND 115555). 
Investigators, other research staff, therapists, and other clinical care staff will be blind to the status 
of the subjects in the study. If necessary, the blind can be broken by the VHANTX research 
pharmacist. Breaking the blind would be unlikely, however, as any adverse event experienced during 
the infusion will be treated acutely with the assumption that the participant is receiving active drug. 
As lidocaine is not FDA approved for the treatment of cocaine addiction or to attenuate memory 
reconsolidation, an IND will be obtained from the FDA for its use in this proposal. In addition, the 
DSMB will obtain interim unblinded primary outcome measures following the assessment of 15 
participants (n=5/group) and 30 participants (n=10/group) (see Section IV.E.4). 
At the final follow-up session, all outpatient participants will receive a referral list of local 
substance use intervention centers, both public sector and private. If a participant’s substance use 
worsens during the study and more intensive treatment is required, the participant will be referred for 
more intensive treatment and terminated from the study.  
 
All adverse events that occur at any time point will be reported (SAEs within 48 hours) to the 
UTSW and VA IRB (the HRRC) and to the Project Officer. 
 

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The proposed study is placebo-controlled and conducted in a group of patients with cocaine 
dependence. Given the potentially vulnerable nature of the participants, in addition to monitoring and 
review by the UT Southwestern and VA North Texas Health Care System (VANTHCS) IRB, we have 
implemented an additional data and safety monitoring plan that includes the formation of a Data and 
Safety Monitoring Board (DSMB). 
 
Informed Consent Process  
1) All investigators and research assistants and other staff (including administrative staff) will receive 
training in the protection of human research subjects in the form of a UT Southwestern and/or 
VANTHCS required on-line tutorial.  
2) All persons obtaining informed consent will, in addition to the training above, attend a UT 
Southwestern-sponsored day-long symposium on the informed consent process, ethical conduct 
of research, and patient safety.  
3) A psychiatrist (PI or a co-I) will, in all cases, be involved in the informed consent process providing 
additional information about the study, including risks, benefits and alternatives, and to answer 
questions.  
4) All investigators and staff involved with patient care will remain updated on issues related to 
patient rights and safety through educational programs and updates provided by UT Southwestern 
and the VANTHCS IRB. 
 
Data Handling/Confidentiality 
1) Training outlined above addresses issues of confidentiality in research. 
2) All subjects are immediately assigned a 3-letter unique ID upon entry into the study.  All Personal 
Health Information (PHI) that is linked to the unique ID is entered into a spreadsheet in the 
VANTHCS server.  This spreadsheet can only be accessed by the PI’s administrative assistant. 
No PHI is linked with the unique ID in electronic form or hard copies other than on the spreadsheet 
noted. 
3) Hard copies with PHI are kept in a locked file cabinet separate from research files using the 
unique ID. 
4) All patient records for the research study will be maintained on the UT Southwestern or VANTHCS 
Health Care campus in locked file cabinets or computers with password-protected access.  
5) To ensure accuracy, data will be checked and reviewed by both research assistants and 
investigators involved in the study.  
 
Adverse Events 
1) Exclusion criteria include active suicidal ideation, pregnant or nursing women, or prisoners to 
minimize the risk to vulnerable populations or adverse events.  
2) All adverse events will be discussed with and evaluated by a physician or psychologist investigator 
as soon as the event is reported by the participant. 
3) All adverse events will be reported to the IRB and DSMB. Serious adverse events (e.g., death of a 
participant) will be reported within 48 hours to the IRB, DSMB and NIDA program official. As part 
of this reporting process the PI evaluates the severity of the adverse event, its relationship to the 
study, and whether changes in the protocol are warranted.  
5) The PI, co-investigators involved with clinical care, and the research assistant will be available 24 
hours each day to patients and other investigators should an emergency arise.  
6) At the completion of the study participants will be given referrals for further treatment of cocaine 
dependence.  
8) The PI will submit an annual safety and adverse event report to the NIDA program official. 
 
Data and Safety Monitoring Board 
In addition to the safeguards listed above, we will form a Data and Safety Monitoring Board that 
will periodically review the project. This board will consist of Dr. Matt Byerly M.D.(chair), Dr. Joan 
Reisch, and one additional board member to be determined.  

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None of the proposed members is a co-investigator or consultant on the proposed grant. Thus, the 
board will provide an independent review and oversight of the study. The board will meet immediately 
prior to the initiation of enrollment in the study and again after 10 and 30 participants have been 
enrolled and at the end of the study. The study's research assistant will present safety data to the 
board for review, including changes in cocaine use/craving and dropouts prior to cue-memory 
reactivation and during follow-up. The PI (Dr. Adinoff) will also attend the meeting. In addition, 
materials provided to the IRB, including serious adverse events leading to death, hospitalization, or 
ER visits will be forwarded to board members. The board will review preliminary data on adverse 
events and outcomes. As lidocaine has not previously been assessed for use in the treatment of 
cocaine addiction or to attenuate memory reconsolidation, the study statistician (Dr. Leonard) will 
conduct a blinded analyses of the primary outcome measures after 15 and 30 subjects have been 
assessed. If notable differences are observed between treatment groups, the research pharmacist will 
unblind the groups for the DSMB (see Letter from DSMB Chair, Dr. Byerly). If a pattern begins to 
emerge and the Board feels that protocol modifications are needed, based on a preponderance of 
adverse events occurring in a particular treatment group or lidocaine is increasing cocaine craving 
and/or cocaine use (the opposite of what is hypothesized), it will have the authority to recommend 
modifications of safety procedures and recommend temporarily or permanently discontinuation of 
enrollment. However, the final decision on these matters will rest with the local IRBs and NIDA.  
 
16. Procedures to Maintain Confidentiality: 
Subject confidentiality will be maintained at all times. Results of the urine drug screens and all 
other research tests will be strictly confidential. The investigative team will retain all of the information 
obtained in this research.  None of the data will be presented in any publications in such a way to 
identify a particular subject.  All data and copies of executed consent forms will be maintained in the 
offices of the study     personnel at the UT Southwestern Medical Center or VA Medical Center. A 
Certificate of Confidentiality will be obtained for the study.  
 
17. Potential Benefits: 
Direct Benefit to Participants: The assessment, including a history and physical, routine labs, and 
diagnostic interview may be some direct benefit to participants. All subjects will receive CBT, which is 
a beneficial treatment for cocaine dependence.  Frequent follow-up visits with study staff have also 
been shown to have a positive effect on treatment outcome. If lidocaine is effective in disrupting 
cocaine-cue memories, the group given lidocaine will directly benefit from this intervention. 
Direct Benefit to Others: This study may provide the basis for both a new pharmacological treatment 
(lidocaine) and new approach (disruption of memory reconsolidation) cocaine dependence.  
 
18. Biostatistics: (omit this section for peer-reviewed research such as cooperative group, or NIH- 
sponsored studies, and for industry-sponsored research which has been submitted to FDA) 
Study is funded by NIDA.