Treatment of Withdrawal Symptoms and Prevention of Relapse in Patients With Tramadol Abuse
Condition: Opiate Withdrawal Syndrome
MeSH terms: Substance Withdrawal Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      Tramadol abuse is a public health problem in Egypt. There are no approved medications for
      treatment of withdrawal symptoms or prevention of relapse in patients with tramadol abuse.
      The objective of this study was to compare the efficacy of venlafaxine and lofixidine in
      treating the withdrawal symptoms and to compare between venlafaxine and naltrexone in relapse
      prevention of tramadol abuse. Patients with tramadol abuse will be divided randomly to use
      venlafaxine or lofixidine after discontinuation of tramadol. The efficacy will be measured by
      the Clinical Opiate Withdrawal Scale. The medications will be used for 10 days after
      discontinuation of tramadol. After the detoxification stage, patients who used venlafaxine
      will continue to use it while patients who used lofixidine will use naltrexone during the
      relapse prevention phase (2 months).
    

Detailed description: 
      Introduction Venlafaxine is a nontricyclic antidepressant that selectively inhibits serotonin
      reuptake at low doses, but at higher doses, it blocks neuronal reuptake of serotonin,
      norepinephrine, and, to a lesser degree, dopamine (Debonnel et al., 2007).

      Venlafaxine was also proved to have analgesic and antinociceptive effects through opioid
      mechanisms (Markowitz & Patrick, 1998; Schreiber et al., 1999; Schreiber et al., 2002).

      In the study of McDowell et al. (2000), venlafaxine was successfully used to treat patients
      with cocaine dependence comorbid with major depression. In animal studies, venlafaxine
      demonstrated effectiveness to attenuate morphine withdrawal symptoms (Lu et al., 2001) and
      attenuate acquisition of intravenous self-administration of heroin in rats (Magalas et al.,
      2005). Lin et al. (2008) found that venlafaxine is effective in alleviating withdrawal
      symptoms of heroin with good tolerability and safety.

      Lofixidine works by blocking the release of norepinephrine, a hormone similar to adrenaline
      that contributes to opioid withdrawal symptoms. Lofexidine is a non-opioid prescription
      medicine used in adults to help with the symptoms of opioid withdrawal that may happen when
      you stop taking an opioid suddenly.

      Naltrexone, is an opioid antagonist, without abuse liability and the oral formulation was
      found to be a safe option for motivated individuals who prefer not to be treated with opioid
      agonist medication or where opioid agonist medications are not legally available (Krupitsky
      et al., 2010, Ling et al., 2012, Mooney, 2016). Although oral naltrexone had a limited side
      effect profile, the clinical evidence demonstrating its efficacy for the treatment of opioid
      use disorder has revealed limitations in its use, particularly as it requires detoxification
      and a several days period of opioid abstinence prior to initiation (Ling et al., 2012, Nunes
      et al., 2015, Mooney, 2016).

      Rational Tramadol abuse is a public health problem in Egypt affecting both adults and
      adolescents. Dissatisfaction with current available regimens for treatment of tramadol abuse
      has led to the search for alternatives. This study will investigate the efficacy and
      tolerability of venlafaxine versus lofexidine for management of withdrawal symptoms of
      tramadol abuse and venlafaxine versus naltrexone in preventing relapse.

      Research question:

        -  Is venlafaxine as effective as lofexidine for treatment of tramadol withdrawal symptoms?

        -  Is venlafaxine as effective as naltrexone in relapse prevention of tramadol abuse?

      HYPOTHESIS:

      We assume that venlafaxine is as effective as lofexidine for treatment of tramadol withdrawal
      symptoms and as effective as naltrexone in prevention of tramadol relapse.

      AIM:

      - This study aims at finding an effective and safe treatment for patients with tramadol
      abuse.

      OBJECTIVES:

        1. To compare the efficacy of venlafaxine versus lofexidine for treatment of tramadol
           withdrawal symptoms.

        2. To compare the efficacy of venlafaxine versus naltrexone in prevention of tramadol
           relapse.

      SUBJECTS AND METHODS:

      I -Technical design This study was be carried out at the outpatient clinics and inpatient
      wards of addiction unit at Zagazig university hospitals, Egypt.

      Sample size Assuming that the mean number of opioid negative tests in a previous study
      comparing buprenorphine and naltrexone in relapse prevention was 19.7+_6.1 for buprenorphine
      VS 15.4+_4.9 for naltrexone. The sample was estimated to be 52 cases of tramadol abuse (26
      cases in each treatment group) with 95% confidence interval and 80% test power (open epi
      program).

      II-Operational design:

      This was a a randomized comparative clinical trial, which included 52 patients with tramadol
      abuse who were divided randomly into 2 groups:

      Detoxification stage (10 days) Group 1: patients received venlafaxine xr 75mg once daily +
      symptomatic treatment.

      Group 2: received lofexidine .2mg ( 0.8 - 1.6 mg per day) + symptomatic treatment.

      Relapse prevention stage (2 month) Group 1: patients continued to use venlafaxine xr, which
      increased gradually on weekly intervals to 225 mg/d Group 2: patients used naltrexone 50mg/d
      The diagnosis of tramadol abuse and any comorbid psychiatric disorder was based on the
      Structured Clinical Interview for DSM-IV axis I disorders (SCID-I) done on Day 1 of the study
      (First et al., 2012). The severity of withdrawal symptoms was assessed using the Clinical
      Opiate Withdrawal Scale (COWS) done on day 3 and 10 of the study (Wesson & Ling, 2003).
      Hamilton anxiety rating scale (HAM-A) (Hamilton, 1959), Hamilton depression rating scale
      (HAM-D) (Hamilton, 1960) and Beck Depression Inventory (Beck et al., 1996) were used to
      assess anxiety and depressive symptoms on day 1 and at the end of the study after 2 months.
      Urine screen for drugs of abuse was done twice weekly to verify abstinence. Craving was
      assessed monthly. Outcome measures were treating tramadol withdrawal symptoms, the retention
      rate in every group and the result of urine screen test at the end of the study.

      III-Administrative design:

        1. Approval was obtained from the Institutional Review Board (IRB) and the Department of
           Psychiatry, Zagazig University, Egypt.

        2. A written consent was signed by the study participants.
    

Intervention name(s): Venlafaxine; Lofexidine
Intervention type(s): Drug; Drug
Intervention description(s): patients with tramadol abuse will use venlafaxine for 10 days.; patients with tramadol abuse will use lofixidine for 10 days.
Intervention MeSH terms: Lofexidine; Venlafaxine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: tramadol abuse; withdrawal; lofixidine; venlaaxine