Treatment of Withdrawal Symptoms and Prevention of Relapse in Patients With Tramadol Abuse

A Comparative Study of the Efficacy of Venlafaxine and Naltrexone for Relapse Prevention in Patients With Opioid Use Disorder Attributed to Tramadol

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).

Study Overview

• Status: Completed
• Conditions: Opiate Withdrawal Syndrome
• Intervention / Treatment: Drug: Venlafaxine; Drug: Lofexidine

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Sharkia
    • Zagazig, Sharkia, Egypt, 44519
      • Faculty of medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 56 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Inclusion criteria:

1. All patients should meet DSM-IV criteria for opioid use disorder.
2. Both genders will be included.
3. Age will be above 18 years.
4. All socioeconomic classes and educational levels will be included.

Exclusion criteria:

1. Age: 18 years or below.
2. Presence of mental retardation, dementia or delirium. .
3. Pregnancy or lactation.
4. Known history of allergy, adverse effects or sensitivity to the study medication.
5. Unstable psychiatric or medical condition.
6. Immediate suicide risk.
7. Regular use of psychoactive drugs or dependence on substances other than opioids, nicotine, or caffeine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: venlafaxidine; venlafaxine 75-225 mg per day.	Drug: Venlafaxine; patients with tramadol abuse will use venlafaxine for 10 days.
Active Comparator: Lofixidine; Lofixidine 1.6 to 2.4 per day.	Drug: Lofexidine; patients with tramadol abuse will use lofixidine for 10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
detoxification stage	the efficacy was measured by decrease in the score of the "Clinical Opiate Withdrawal Scale (COWS). Increase in the score means worsening and score decrease means improvement. We compared the mean + SD for all groups. COWS Score: 5- 12 = mild; 1 3-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal.	10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse prevention	This outcome was measured by the number of patients who remains in treatment and have negative urine screen for tramadol.	2 months

Collaborators and Investigators

• Sponsor: Zagazig University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): December 15, 2021
• Study Completion (Actual): June 15, 2022

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 5, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Actual): October 6, 2022
• Last Update Submitted That Met QC Criteria: October 5, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: tramadol abuse; withdrawal; lofixidine; venlaaxine
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Substance Withdrawal Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Peripheral Nervous System Agents; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Narcotic Antagonists; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Venlafaxine Hydrochloride; Lofexidine
• Other Study ID Numbers: 4853

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No