Lamotrigine for Ketamine Dependence Trial
Condition: Addiction
MeSH terms: Behavior, Addictive
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The purpose of this study is to investigate the efficacy of lamotrigine in the treatment of
      ketamine dependence in a double-blind, placebo controlled design.
    

Detailed description: 
      Introduction

      Ketamine is an anesthetic derivative of phencyclidine (PCP; 'Angel dust') with dissociative,
      analgesic and psychedelic properties. Recreational use of ketamine was first documented on
      the west coast of the United States in the early 1970s. Ketamine is frequently described as a
      "unique drug" because it shows hypnotic (sleep producing), analgesic (pain relieving) and
      amnesic (short-term memory loss) effects; no other drug used in clinical practice combines
      these three important features at the same time. Ketamine produces an anaesthetic state,
      which has been termed "dissociative anaesthesia", characterized by analgesia and changes in
      vigilance and perception, but it is not a sedative or hypnotic. It appears that ketamine
      selectively interrupts the thalamocortical system. Ketamine has some anxiolytic- and
      antidepressant-like properties in sub-anesthetic doses.

      Mechanism of ketamine addiction

      The existence of binding sites for PCP and ketamine were first identified in 1979. Earlier
      reports indicate that ketamine essentially blocks the N-methyl-D-aspartate (NMDA) subtype of
      glutamate receptors. The antagonism of NMDA receptor is responsible for its specific
      properties including psychedelic, anesthetic, analgesic, anxiolytic, antidepressant, hypnotic
      effects and cognitive impairment. In fact, ketamine also binds to non-NMDA glutamate
      receptors and involves glutamate-independent mechanisms associated with nicotinic and
      muscarinic cholinergic, monoaminergic and opioid receptors.

      Currently there is no specific pharmacological treatment model for ketamine dependence.
      Continuous urine screen plus medications for psychiatric symptoms treatment revealed fair
      results.

      Study drug: Lamotrigine

      Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder.
      Besides it's sodium channels blocking effect as an antiepileptic drugs, lamotrigine also
      inhibits the release of glutamate through modulation of high voltage-activated calcium
      currents and sodium channels.

      Method

      Patient Patients with ketamine use disorder seeking treatment at Taipei City Hospital and
      Psychiatric Center will be invited to participate this clinical trial. Treatment and
      assessment Schedule After informed consent signature with explanations about the procedure of
      this study, the initiation includes collecting drug use history and medical history,
      conducting a physical examination, and performing clinical laboratory tests.

      The study duration will last for 12 weeks and patients will be monitored at week 0, week 1,
      week 2, week 4, week 8, and week 12 for 6 times. Urinary toxicology and visual analogue
      scales will be checked at each visit and laboratory chemistry at each visit.

      Randomization

      The study subjects will be randomly assigned by computer-generated numbers either to the
      lamotrigine or placebo group in a 1:1 ratio.

      Dosage of trial medication

      Trial medication and placebo will be sponsored by Lotus pharmaceutical, Taiwan. It is an
      extended release tablet form of lamotrigine or identical placebo. The preparation of double
      procedure will be handled by the Department of Pharmacy of Taipei City Hospital.

      Once a subject enters the treatment phase (after randomization) the dosage of study
      medication will be 25 mg/before bed (or one half placebo tablet at night) for 7 days. On day
      8 (visit 2 or the beginning of week 2), the dosage will be increased, as tolerated, to 50
      mg/day for another week. After then, the dosage will be increased to 100 mg/day (QD and HS)
      for 2 weeks. After 4 weeks, the dosage may be kept or increased, as judged by investigator,
      at the range of 100mg to 200mg /day to the end of 12 weeks. The dosage may be decreased at
      any time because of side effects, but not less than 100 mg. If the patient prefers, he or she
      may take all of his or her daily dose of medication in the morning or evening.

      The enroll period will be 2 years and total study duration will be 3 years.

      Concomitant and prohibited medications

      During study period, patients can take their original medications for systemic disorder. Due
      to patients with drug abuse usually have depressed mood, emotional disturbance or sleep
      problems during withdrawal period, benzodiazepines, or short acting novel hypnotics such as
      zolpidem or zaleplon can be used for ethical consideration. For those patient treated with
      antipsychotics due to drug-induced psychosis, the patients can be enrolled only when the
      psychotic symptoms remitted and lowest dose of antipsychotic can be used during the trial
      period. The prohibited medications include medications which have drug-drug interaction such
      as carbamazepine, phenytoin barbiturates, rifampicin, chlordiazepoxide and oral
      hypoglycaemics.

      Primary endpoint

      The primary endpoint will be the results from urinary drug screen of ketamine, and other
      substances including amphetamine, methylenedioxymethamphetamine, morphine and cannabis, which
      will be carried out at the baseline and during each visit of the study period.

      Secondary endpoint

      Subjective visual analogue scales of craving by patient and subjective clinical global
      impression of severity will be the second endpoint. The Brief Addiction Severity Index of
      ketamine use will also be analyzed.
    

Intervention name(s): Lamotrigine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Starting from 25 mg/day in the first week, then titrated up to 200 mg/day for 12 weeks; Same dosing schedule as study drug
Other intervention name(s): Lamofree ER; Identical to Lamofree ER
Intervention MeSH terms: Lamotrigine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: ketamine use disorder; lamotrigine; craving