1 

### U.S. Department of Justice

Drug Enforcement Administration

Schedules of Controlled Substances: Pl acement of Ezogabine into Schedule V

Background, Data, and Analysis:

Eight Factors Determinative of Control

and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section Washington, D.C. 20537 September 20112 

### I. Background

Ezogabine (N-[2-amino-4-(4-fluorobenzylamino )-phenyl]-carbamic acid ethyl ester) is a

new chemical substance with central nervous system depressant properties. A New Drug Application (NDA) for ezogabine was recently approved by the Food and Drug Administration (FDA) as an adjunct treatment of partial onset seizure. Ezogabine primarily acts as a ligand at ion-gated channels in the brain to enhan ce potassium currents mediated by neuronal KCNQ (Kv7) channels. Additionally, ezogabine indi rectly enhances the gamma-aminobutyric acid (GABA) mediated neurotransmission.

On January 25, 2011, the Department of Huma n Health Service ( HHS) provided to the Drug Enforcement Administration (DEA) a scientif ic and medical evaluation entitled “Basis for the Recommendation to Control of Ezogabine in Schedule V of the Controlled Substances Act” and a scheduling recommendation. Following cons ideration of the eight factors and findings related to the substance’s abuse potential, legiti mate medical use, and dependence liability, HHS recommended that ezogabine be controlled in Schedule V of the Contro lled Substances Act (CSA) under 21 U.S.C. 812(b).

The CSA requires DEA, as delegated by the Attorney General, 1 to determine whether HHS’s

scientific and medical evaluation and all other relevant data constitute substantial evidence of potential for abuse such that the substance should be scheduled. 21 U.S.C. 811(b).

1 28 CFR 0.100(b)3 

### II. Eight Factors Determinative of Control

Pursuant to 21 U.S.C. 811(c), DEA must consider eight factors in making any finding of substantial evidence of potential for abuse, in cluding the data and law enforcement information

relevant thereto.

Factor 1: Ezogabine's Actual or Relative Potential for Abuse

In addition to the information HHS provided in its scientific a nd medical evaluation document for ezogabine, DEA considers all other re levant data regarding ezogabine’s actual or relative potential for abuse. Sin ce ezogabine is a new chemical entity and has not been marketed

in the United States or in a ny other country, information on act ual abuse of ezogabine is not available. However, the legislative history of the CSA suggests using the following criterion in determining whether a particular drug or substance has a potential for abuse:

The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a poten tial for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be si gnificant diversions from legiti mate channels, significant use contrary to or without medica l advice, or that it has a subs tantial capability of creating hazards to the health of the user or to the safety of the community. 2

According to HHS, ezogabine, similar to pr egabalin (Schedule V) and lacosamide (Schedule V), acts like a ligand at ion-gated chan nels in the brain and produces behavioral

effects in animals and humans. Also similar to pregabalin and lacosamide, ezogabine will be used for the treatment of epileptic conditions in humans. Thus, it is very likely that ezogabine will have an abuse potential that is similar to that of Schedule V substances such as pregabalin

and lacosamide.

In animal studies referenced by the HHS review, ezogabine produced a sedative behavioral profile, including incr eased ataxia and decr eased muscle tone and locomotion, similar to that generated by pregabalin and lacosamide. Studies from Phase 1 clinical trials indicated that the rate of euphoria-related adverse events (AE) resultin g from ezogabine administration was 6 – 9%, which is similar to the correspond ing rates resulting from pregabalin (10%) and lacosamide (>7%). The rate of euphoria-related AEs in Phas e 2/3 studies was also similar between ezogabine (<1%) and l acosamide (<2%). Like other Schedule V sedative-hypnotics such as pregabalin and lacosamide, ezogabine produces euphoria-like effects as well as somnolence and abnormal feeling and thinking. In abuse potential stud ies with sedativehypnotic abusers, ezogabine, pregab alin and lacosamide are simila r in their ability to produce statistically significant increases in subjective responses includ ing “Drug Liking,” “Overall Drug Liking,” “Good Drug Effects,” and “High.”

Due to its commercial unavailability in any c ountry, there is a lack of evidence to date regarding ezogabine’s diversion, il licit manufacturing, or deliberate misuse or abuse. However,

2 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601.4 since ezogabine is not readily synthesized fr om available substan ces, its diversion will potentially be from legitimate channels.

In summary, the significant euphoric effects produced by ezo gabine in humans predict that there would be significant abuse potential when ezogabine is commercially available, and the overall abuse potential of ezogabine is most similar to the Schedule V drugs pregabalin and

lacosamide.

Factor 2: Scientific Evidence of Ezogabine's Pharmacological Effects

Neurophysiology studies showed that ezogabi ne acts to enhance potassium currents mediated by neuronal KCNQ (Kv7) channels with a secondary action through the augmentation

of GABA-mediated neurotransmission without direct GABA receptor stimulation. The receptor binding studies on ezogabine did no t show a significant profile of central nervous system binding sites associated with abuse potential including acetylcholine, dopamine, GABA, glutamate, glycine, histamine, opioid, serotonin, and nor epinephrine receptors. Other ion channels including calcium, chloride, potassium, and sodium channels are not bind ing sites for ezogabine.

Pre-clinical Behavioral Studies

According to the HHS review, in preclinical studies in rats and monkeys, ezogabine, similar to a central nervous system depressant , reduced locomotor behavior and muscle tone, while increased doses of ezogabine produced seiz ure and death. This behavioral profile in animals is similar to that reported for Schedule V drugs pregabalin and lacosamide. In rats trained to self-administer the stimulant cocaine (Schedule II), the substitution of ezogabine did

not maintain self-administrati on. Instead, the rate of self-a dministration by ezogabine was equivalent to that produced by saline.

Human Behavioral Studies

According to the HHS review, the abuse potential studies in individual s with histories of recreational sedative-hypnotic drug abuse indi cate that ezogabine ( 300 and 600 mg orally) produced an increased rating on positive primar y subjective scales ( VAS-Drug Liking, VASOverall Drug Liking, ARCI-MBG [Euphoria], VAS-T ake Drug Again) for peak responses that were significantly different from the placebo. This effect is simila r to that produced by alprazolam (1.5 and 3.0 mg orally; Schedule IV). On secondary positive subjective scales (VASHigh, VAS-Good Effects, ARCI-Amphetamine [Activ ation]) for peak responses, both ezogabine and alprazolam produced significant increases co mpared to the placebo, while there were no differences between ezogabine and alprazolam on those measures. The HHS review document further concluded that the ratings on each of the positive subjective responses in human abuse potential studies conducted with ezogabine, pregab alin and lacosamide, were very similar to those produced by the Schedule IV benzodiazepine (alprazolam or diazepam) positive control. Although this appears to suggest that ezogabine, pregabalin, a nd lacosamide have an abuse potential similar to that of Schedule IV substanc es, the adverse effect profile data from safety, efficacy, and preclinical animal behavioral stud ies collected from ezogabine, pregabalin, and5 lacosamide demonstrate that these three drugs ha ve less abuse potential than Schedule IV drugs.

These are described below.

As referenced in the HHS review, the nega tive and sedating subj ective measures (VASBad Effects, ARCI-LSD [ dysphoria] and ARCI-PCAG [sedation]) produced by oral administration of ezogabine (300 and 600 mg) incr eased significantly compared to the placebo, but lower than those produced by alprazolam. Da ta from negative subjec tive scales in human abuse potential studies conducted with lacosa mide also produced responses that were significantly different from alprazolam. These data from negative subjective scales suggests that ezogabine is more like a Schedul e V drug and less like a Schedule IV drug. A higher dose of ezogabine (900 mg) produced ratings on VAS-Dr ug-liking and VAS-Good Effects that were higher than those reported for the two lower dos es of ezogabine (300 and 600 mg) and either dose of alprazolam (1.5 and 3.0 mg). The va lues for VAS-Bad Effects and ARCI-LSD (dysphoria) from the 900 mg dose were less than or similar to those reported for the lower doses of ezogabine (300 and 600 mg) and either dose of alprazolam (1.5 and 3.0 mg). Besides several cardiac events, the high dose of ezogabine (900 mg) caused multiple abnormal neuro-cognitive effects including euphoria, somnolence, hall ucination, visual dist urbance, amnesia, hypoaesthesia, paranoia, fear, and confusion, similar to those eff ects observed with the Schedule V drug lacosamide.

According to the HHS review, studies on Phase 1 from the Integrated Clinical Pharmacology (ICP) Analysis Set (n = 468 healthy s ubjects) showed that or al doses of ezogabine

resulted in adverse events re lated to abuse potenti al ranging from 200 mg to 1650 mg, while in Phase 2/3 studies (n = 1365 patients) thos e doses ranged from 300 mg to 1200 mg. The incidence of abuse-related AEs was much highe r in Phase 1 studies with healthy subjects compared to Phase 2/3 trials with patients. Spec ifically, the healthy subj ects taking ezogabine in the Phase 1 studies had a highe r rate (5.5 – 8.5%) of “euphoria,” “feeling drunk,” and “confusion state,” accompanied by a lower rate (1.5 -1.7%) for “disorientation,” “hallucination,” and “feeling abnormal.” The high rate for “somnolen ce” (13.4%) in the Phase 1 studies is similar to the rate of this AE produced by placebo (11.9%) in the Phase 2/3 Pivotal Clinical Trial (PCT) studies. The Phase 2/3 trial data suggests that patients who were taking ezogabine in combination with other anti-epileptic and CNS-ac tive drugs showed a relatively low rate of “euphoria” (0.4-0.5%), but a higher rate for “feeling drunk” (0.9 – 1.5%) compared to the placebo (none for both AEs). In this group, the rate of “disorientation” (1.7 – 2.1% compared to 0.7% from placebo) was similar to that seen in the Phase 1 studies, although the rate of “hallucination” (1.0 – 1.1% compared to 0% fr om placebo) and “feeling abnormal” (0. 1 – 0.3% compared to 0% from placebo) were lower than those observed in the Phase 1 trials. However, there was a much higher rate of “somnolence” in Phase 2/3 studies (22 - 28.5% compared to 11.9% from placebo) compared to the rate in Phase 1 studies. This fact is similar to the clinical study data in the NDAs for Schedule V drugs pr egabalin and lacosamide. Pregabalin and lacosamide produced additional abused-related AEs similar to those from ezogabine, including somnolence, abnormal feeling and thinking, and dizziness.

In another Phase 1 trial, th e incidence of AEs related to abuse potential was observed following administration of a placebo, ezogabine, and alprazolam. Both doses of alprazolam (1.5 and 3.0 mg) and the highest dose of ezogabi ne (900 mg) produced the highest levels of6 somnolence (57%, 97% and 67%, respectively), co mpared to the placebo (15%). The 3.0 mg dose of alprazolam and all thr ee doses of ezogabine (300, 600 and 900 mg) also produce higher levels of euphoria (17%, 18%, 21% and 33%, resp ectively), compared to the placebo (8%). In general, doses of ezogabine above 400 mg pr oduced the greatest number of abuse-related AEs and the 900 mg dose of ezogabine was terminated from the protocol following serious cardiac effects. This trend is very similar to the clinical data in the NDA for the Schedule V drug

lacosamide.

In summary, the abuse-related AEs produced by ezogabine are similar to those indicated in the NDA for the human abuse potential study conducted with lacosamide.

Factor 3: The State of Current Scie ntific Knowledge Regarding Ezogabine

As stated in the HHS review document, the chemical name of ezoga bine is N-[2-amino4-(4-fluorobenzylamino)-phenyl]-carbamic acid ethyl ester. It is an achiral molecule with a

molecular formula of C 16 H 18 FN 3 O 2 and a molecular weight of 303.3 g/mol. Ezogabine is a nonhygroscopic white to slightly colore d powder with a melting point of 140-143 0 C. It is soluble in 0.9% saline, methanol, and chloroform, but only sparingly soluble in ethanol and 0.1N HCL.

According to the HHS review, ezogabine in humans has a T

max (Time required for ezogabine to reach maximum plasma concentrati on) ranging from 1-4 hours following both acute and multiple dosing. Without the involvement of cytochrome P450, ezogabine undergoes extensively and exclusively a pha se 2 metabolic biotransformati on. Ezogabine is predominantly metabolized by N-glucuronidation re sulting in the formation of two distinct N-glucuronides of the unchanged parent drug and to a lesser extent by N-acetylation to form N-acetyl-retigabine, the major bioactive metabolite of ezogabine. The half-life of both ezogabine and N-acetylretigabine is around eight hours and the C

max (maximum plasma concentration) of both components is dose proportional after both acute and multiple dosing, suggesting a lack of accumulation with repeated administration. The or al administration of ezogabine produces an absolute bioavailability of approximately 60%. Ezogabine is excreted ma jorly by the renal route and using radio-labeled ezogabi ne it was found that a total of 84% of the administrated dose of ezogabine was recovered in the urine either as unchanged parent drug, N-glucuronides of the parent drug and the acetyl metabo lite, or the mono-acetyl metabolite.

Factor 4: Ezogabine's History and Current Pattern of Abuse

According to the HHS review, the informati on on ezogabine's history and current pattern

of abuse is unavailable since it has not been ma rketed in any country. Thus, the evaluation of abuse potential of ezogabine derives from positive indictors in pre-market clinical trials which are believed to be predictive of drug abuse. As stated in pr evious sections, in human abuse potential study, ezogabine (300 and 600 mg) produced increased rating on positive subjective scales higher than that of placebo, but similar to that produced by alpr azolam (1.5 and 3.0 mg, Schedule IV). The negative and sedating subj ective measures produced by ezogabine (300 and 600 mg) increased significantly compared to the placebo, but lower than those produced by alprazolam (Schedule IV). These data are sim ilar to that reported in previously conducted human abuse potential studies with Schedule V drugs such as pregab alin and lacosamide. In that7 study, abuse-related AE events in cluded euphoric mood, dizziness, memory impairment, anxiety,

and disturbed attention. These AEs are similar to those described in the NDA for the human abuse potential study conducted with lacosamide . The 900 mg dose of ezogabine caused serious adverse cardiac events that suggest that if ezogabine was misuse d or abused at this dose or above, it could pose seri ous safety risks.

As stated in the HHS review, in clinical safety and efficacy studies, ezogabine produced a high incidence of abuse-related AEs such as euphoria, hallucinations, cognitive changes, and somnolence. The incidence of these AEs was highe r in Phase 1 studies with healthy individuals than in Phase 2/3 studies in patients with seiz ure disorders who were al so on antiepileptic and psychoactive medications. This differential incidence of AEs following ezogabine in Phase 1

versus Phase 2/3 studies is si milar to the clinical study da ta mentioned in the NDAs for pregabalin and lacosamide in which the somnol ence, abnormal thinking and dizziness were the most frequently observed.

Factor 5: The Scope, Duration, and Significance of Abuse of Ezogabine

An assessment of the scope, duration, and significance of ezogabine abuse is not available since it has not been marketed in any co untry. However, as stated in the HHS review, the epidemiological data on pregabalin, a Schedule V drug with an abuse poten tial similar to that of ezogabine, are available from Drug Abuse Warning Network (D AWN) database. DAWN is a public health surveillance system that monito rs drug-related visits to hospital emergency departments (EDs). This data is reported to DAWN by a sample of participating general, nonFederal hospitals with operating 24-hour EDs. DAWN provides information on all drug-related ED visits, regardless of the motive for using th e drug. DAWN captures data on all drugs such as illicit drugs, prescription and over-the-count er pharmaceuticals, dietary supplements, nonpharmaceutical inhalants, alcohol when it is comb ined with other drugs, and, for patients under age 21, ED visits where alc ohol is the only substance.

HHS used the non-medical use of a drug, one of the measures reported by DAWN, and the prescription data collected from the SDI Vector One TM database to estimate the “abuse frequency ratio” as a relative measure for abuse potential of a drug. HHS found that the “abuse frequency ratio” for pregbalin, calculated as the ratio of nonmedical use re lated annual ED visits (as reported in DAWN) to the total number of annual prescrip tions, is less than that for alprazolam. The “abuse frequency ratio” for pr egabalin ranges from 29 to 47, while those for alprazolam are about 3-6 times higher, ranging from 160 to 235. Thus, the epidemiological data show that placement of pregaba lin into Schedule V based on abuse-related human and animal data submitted in its NDA justifies its placement re lative to drugs in Schedule IV. Given that ezogabine has similar abuse-related human and an imal data in its NDA to the data generated by pregabalin, it is likely that ezogabine will ha ve an abuse potential similar to this Schedule V drug.

Beyond epidemiological data, ezogabine and Sc hedule V drugs such as pregabalin and lacosamide produced positive subjective effects in a human abuse potential study that are similar to those produced by Schedule IV benzodiazepin es (diazepam or alprazolam). In a HHS-cited study, recreational sedative-hypnotic abusers receiving single dos es of ezogabine (300, 600, 9008 mg) reported incidences of euphor ia-type AEs at a rate which wa s significantly higher than that reported for the placebo, but indi stinguishable from that produced by 1.5 or 3.0 mg alprazolam. In this population, euphoric mood following si ngle doses of 300, 600 and 900 mg ezogabine occurred in 18%, 21%, and 33% of subjects re spectively, as compared to 8% following a placebo. The high dose (900 mg) of ezogabine, but not the placebo, produced hallucinations. In another human abuse potential study, lacosamide produced euphoria as an adverse event (15%) following a single oral dose of 800 mg, as comp ared to none following placebo administration. Similarly, in individuals with a history of recreational abuse of sedative-hypnotic drugs, 450 mg pregabalin received high ratings of “Good Drug E ffect,” “High,” and “Liking” that was similar to a single dose of 30 mg diazepam.

In Phase 2/3 clinical studies in patients w ith partial seizures, 300 to 1200 mg doses of ezogabine produced euphoric mood in 0.5% and feeling drunk in 1.5% of the subjects as compared to none in placebo-treated condition. Similarly, the rate of euphoria as an AE following ezogabine was comparable to th e corresponding rates of euphoria following therapeutic doses of lacosamide (less than 1%). Pregabalin, in cont rolled clinical studies involving 5500 patients, produced euphoria in 4% of the subjects compared to 1% in placebo condition. Thus, despite some similarities betwee n ezogabine and alprazolam, the overall abuse potential of ezogabine is more similar to th e Schedule V drugs pregab alin and lacosamide.

Factor 6: What, If Any, Ri sk to the Public Health

Based on the review of clinical data, HHS conc luded that the abuse of ezogabine is likely to pose a similar risk to public health as th at of Schedule V substances, pregabalin and lacosamide. In Phase 1 clinical safety studi es, the rate of euphoria-related AEs following ezogabine administration was about 6-9%, which is similar to th at from pregabalin (10%) and lacosamide (>7%). The overall AE profiles following ezogabine, pregab alin, and lacosamide include not only euphoria, but also somnolen ce and feeling or th inking abnormally.

The human abuse potential study with hist ories of recreationa l abuse of sedativehypnotics showed that the majority of subj ects receiving the 900 mg dose of ezogabine experienced multiple AEs such as euphoria, somnolence, visual disturbance, amnesia, hypoaesthesia, paranoia, fear, confusion, and hallu cinations. Although the 900 mg dose is three times greater than the recommended therapeu tic dose, drug abusers typically use supratherapeutic doses. Thus, this data indicates that ezogabine ma y present a serious health risk to the public, with a predicted level of risk similar to that observed w ith pregabalin and lacosamide. Following ingestion of supra-th erapeutic doses, pregabalin caused euphoria, somnolence, hallucination, asthenia, headache, and dizziness , while lacosamide ingestion produced euphoric mood, somnolence, sensory motor impairment, and deficit in information processing.

In summary, the available study’s data indica te that ezogabine may present risks to the public health at a level similar to those pr oduced by the Schedule V drugs pregabalin and lacosamide, but are less than those pr oduced by Schedule IV benzodiazepines.9 Factor 7: Ezogabine's Psychic or Physiological Dependence Liability

The HHS review document states that studie s of abrupt disconti nuation of ezogabine

were not conducted and there are minimal data ava ilable to evaluate the ability of ezogabine to induce withdrawal syndromes that are indicative of physical de pendence. However, many AEs reported from the discontinuation of ezogabine we re also reported prior to the discontinuation including dizziness, somnolence, and a confusion st ate. Abrupt discontinua tion of pregabalin in human studies resulted in patient-reported sympto ms of nausea, headache ,or diarrhea, which are suggestive of physical dependence. Abrupt discontinuation of lacosa mide in clinical trials with diabetic neuropathic pain patients produced no signs or symptoms.

As cited by the HHS review, the ability of ezogabine to produce psychic dependence is suggested by AE reports of euphoric mood in sedative-hypnotic abusers in the human abuse potential study (18-33%) and in healthy individuals (8.5%) in c linical Phase 1 studies. Unlike ezogabine and pregabalin, the withdrawal syndr ome following discontinuation of other Schedule IV substances such as alprazolam can range from mild dysphoria and insomnia to a major syndrome including abdominal pain, muscle cramps, vomiting, sweating, tremors, and

convulsions. These are similar in character to th ose associated with other sedative-hypnotics. The withdrawal symptoms following abrupt termin ation of diazepam (Schedule IV) have been reported to include tremor, abdominal and musc le cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, c onfusion, and irritabilit y. In severe cases, especially in those patients w ho had received excessive doses over an extended period of time, the symptoms may include derealization, depe rsonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, nois e, and physical contact, and hallucinations or epileptic seizures.

The HHS review document concludes that the AEs relevant to ezogabine’s psychic and physiological dependence liability appear to be le ss severe and occur less frequently than those of Schedule IV benzodiazepines (diazepam and al prazolam) and are more similar to those of Schedule V substances like pregabalin and l acosamide. Thus, ezogabine produces limited psychic or physiological dependence liability foll owing extended administ ration and it is likely to be similar to those of pregabalin and lacosamide.

Factor 8: Whether Ezogabine Is an Imme diate Precursor of a Substance Already

Controlled

Ezogabine is not an immediate precurso r of a substance already controlled.

References

1. Department of Health and Human Servi ces (HHS) Review (2011): Basis for the Recommendation for Control of Ezogabine in Schedule V of the Cont rolled Substances

Act.10 

### III. Findings for Schedule Pla cement Pursuant to 21 U.S.C. 812(b)

21 U.S.C. 812(b) requires the evaluation of a substance’s abus e potential, accepted medical use, and safety for use under medical supervision for scheduling under the CSA as a

controlled substance. After consid eration of the above eight factor s determinative of control of a substance (21 U.S.C. 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by HHS, DEA finds that ezogabine meets the following criteria for placement in Schedule V of the CSA pursuant to 21 U.S.C. 812 (b)(5).

1) Ezogabine has a low potential for abuse relative to the drugs or other substances

in Schedule IV.

The collected information suggests that the abus e potential of ezogabine is less than that of Schedule IV drugs and is similar to that of Schedule V drugs such as pregabalin and lacosamide. Ezogabine, pregaba lin, and lacosamide, all produce positive subjective effects in human abuse potential studies a nd those effects are similar to those produced by Schedule IV benzodiazepines (diazepam or alprazolam). Ez ogabine, pregabalin, and lacosamide also produce high rates of euphoria and other abuse-related adverse effects in Phase 1 studies with healthy individuals. However, the effects produced by ez ogabine, pregabalin and lacosamide differ from diazepam or alprazolam in the negative subjec tive response profile, pharmacokinetics, cognitive impairment, and withdrawal syndromes followi ng drug discontinuation. Thus, despite some similarities between ezogabine and alprazolam (Schedule IV), the overall abuse potential of ezogabine is most similar to that of the Sc hedule V drugs pregabalin and lacosamide.

2) Ezogabine has a currently accepted medical use in the United States.

Ezogabine (Potiga®) was recently approved by FDA as an adjunct treatment of partial

onset seizures and has a currently accepted medical use in the United States.

3) Abuse of Ezogabine may lead to limited physical de pendence or psychological dependence relative to the drugs or other substances in Schedule IV.

Ezogabine may produce limited physical and psychological dependence relative to drugs in Schedule IV. Physical dependence was not fu lly assessed because abrupt discontinuation of ezogabine was not studied in subjects followi ng extended administration. Psychological dependence is suggested by the ability of ezoga bine to produce positiv e subjective response (euphoria) in participants of clinic al studies. This is similar to Schedule V substances such as pregabalin and lacosamide.

REFERENCES

1. Department of Health and Human Se rvices Review (2011): Basis for the Recommendation for Control of Ezogabine in Schedule V of the Cont rolled Substances

Act.