Lofexidine + Pregabalin for Opioid Withdrawal

(UH3 Trial)

Recruiting at 1 trial location

Overseen By Matthew R Taylor

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must be taking: Opioid antagonists

Must not be taking: Sympathomimetics, Thiazolidinediones, CYP2D6 inhibitors, others

Disqualifiers: Psychotic disorders, Sedative use, Seizure disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 10 days

150 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including opioids for pain management, sympathomimetic drugs, thiazolidinedione antidiabetics, and medications that strongly or moderately inhibit CYP2D6, like fluoxetine or paroxetine.

What data supports the effectiveness of the drug Lofexidine/Pregabalin for opioid withdrawal?

Lofexidine has been shown to be effective in treating opioid withdrawal symptoms, as it is FDA-approved for this purpose. Pregabalin has been reported in a case study to help reduce withdrawal symptoms in a patient, although more research is needed to confirm its effectiveness for opioid withdrawal. ^{1 2 3 4 5}

How is the drug Lofexidine/Pregabalin unique for treating opioid withdrawal?

Lofexidine is unique because it is a non-opioid drug that helps manage opioid withdrawal by reducing the overactivity of the nervous system that occurs when stopping opioids. Pregabalin, often used for nerve pain, may complement this by further easing withdrawal symptoms, making the combination potentially more effective than using Lofexidine alone. ^{1 3 5 6 7}

What is the purpose of this trial?

A placebo-controlled trial in which male and female outpatients with an opioid use disorder who express interest in extended-release injectable naltrexone (XR-NTX) are randomized 1:1 to lofexidine/pregabalin or lofexidine/pregabalin placebo for withdrawal management and offered XR-NTX if after completing withdrawal.

Eligibility Criteria

This trial is for adults over 18 with opioid use disorder who've used opioids on most days in the past month and are interested in naltrexone treatment. They must have a stable address, no severe medical or psychiatric conditions, not be pregnant or breastfeeding, and meet specific heart health criteria.

Inclusion Criteria

Interested in opioid antagonist treatment

Used opioids in 20 or more of the last 30 days

Have documents for ID check

Exclusion Criteria

High risk for suicide as determined by answering 'yes' to questions 4 and/or 5 on C-SSRS

ALT and/or AST >4X upper limit of normal

Homicidal or otherwise behaviorally disturbed requiring immediate attention

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants are randomized to receive either lofexidine/pregabalin or lofexidine/placebo for withdrawal management over 10 days

10 days

Daily visits for medication administration and monitoring

Transition to XR-NTX

Participants who complete withdrawal management are offered extended-release injectable naltrexone (XR-NTX)

Up to 2 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Lofexidine/Pregabalin

Trial Overview The study tests if combining lofexidine with pregabalin (LFX/PGB) or its placebo (LFX/PLA-PGB) helps manage withdrawal symptoms in outpatients seeking to start extended-release injectable naltrexone therapy. Participants are randomly assigned to one of these two groups.

Participant Groups

Group I: LFX/PGB Experimental Treatment 2 Interventions

PGB/day 1=400mg, day 2-7=600mg each day, day 8=400mg, day 9=200mg, day 10=100mg LFX/day 1=1.62mg, day 2-7=2.16mg each day, day 8=1.44mg, day 9=0.72mg, day 10=0.72mg

Group II: LFX/PLA-PGB Active Control 2 Interventions

PLA-PGB/day 1-7= 0mg each day, day 8, 9, and 10 =0mg each day LFX/ day 1=1.62mg, day 2-7=2.16mg each day, day 8=1.44mg, day 9=0.72mg, day 10=0.72mg

Lofexidine/Pregabalin is already approved in United States, United Kingdom, European Union for the following indications:

Approved in United States as Lucemyra for:

• Mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults

Approved in United Kingdom as Lofexidine for:

• Management of opioid withdrawal symptoms

Approved in United States as Lyrica for:

• Neuropathic pain
• Seizures

Approved in European Union as Pregabalin for:

• Neuropathic pain
• Epilepsy
• Generalized anxiety disorder

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

Lofexidine, at doses of 2.16 mg and 2.88 mg per day, significantly reduced opioid withdrawal symptoms compared to placebo in a study involving 603 participants over 7 days, demonstrating its efficacy as a nonopioid treatment for opioid withdrawal syndrome.

The study also found that lofexidine improved completion rates of the withdrawal program by 14% and 12% compared to placebo, indicating it not only helps manage symptoms but also encourages patients to complete the treatment process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial. Fishman, M., Tirado, C., Alam, D., et al.[2020]

Lofexidine has been recently FDA approved for treating opioid withdrawal symptoms in adults and has shown effectiveness in randomized controlled trials compared to placebo.

The safety profile of lofexidine is favorable, and its efficacy is comparable to other first- and second-line treatments for opioid withdrawal, although its higher cost may limit its accessibility in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal. Doughty, B., Morgenson, D., Brooks, T.[2020]

Lofexidine, an alpha-2 agonist, has been shown to effectively manage acute withdrawal symptoms from opiate addiction, helping to alleviate issues like anxiety and gastrointestinal upset caused by increased noradrenaline during withdrawal.

The use of Lofexidine is considered safe and could serve as a valuable tool in withdrawal programs, potentially aiding individuals before they transition to maintenance treatments like methadone or buprenorphine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comprehensive Update of Lofexidine for the Management of Opioid Withdrawal Symptoms. Urits, I., Patel, A., Zusman, R., et al.[2021]

Pregabalin, which targets calcium channels in neurons, was successfully used by a 43-year-old patient to manage withdrawal symptoms during opiate detoxification, suggesting its potential efficacy in this context.

This case highlights that Pregabalin may help control withdrawal symptoms and prevent relapse in opiate-dependent patients, marking the first report of its use for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pregabalin for the reduction of opiate withdrawal symptoms]. Kämmerer, N., Lemenager, T., Grosshans, M., et al.[2015]

Lofexidine hydrochloride (Lucemyra) is effective in managing opioid withdrawal symptoms, providing a non-opioid treatment option for individuals undergoing detoxification.

Erenumab-aooe (Aimovig) has been shown to significantly reduce the frequency of migraine attacks, offering a targeted approach to migraine prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

Lofexidine, a non-opioid treatment for opioid withdrawal, was studied in 681 participants, showing small, temporary increases in QTcF (a measure of heart rhythm) during the first 24 hours, which resolved by Day 4.

By Day 7, QTcF levels decreased from baseline in all groups, suggesting that while lofexidine can cause transient changes in heart rhythm, it may ultimately have a stabilizing effect, likely due to its sympatholytic actions that alter autonomic tone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal. Darpö, B., Pirner, M., Longstreth, J., et al.[2020]

Lofexidine is an effective option for managing symptoms of opiate withdrawal by reducing sympathetic outflow, but it remains largely experimental in the US and Canada despite its approval in other regions since the 1980s.

The development of lofexidine has faced challenges due to market factors and regulatory considerations, but recent clinical trials are starting to rectify past oversights by exploring improved formulations and specific enantiomers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The preclinical discovery of lofexidine for the treatment of opiate addiction. Vartak, AP.[2014]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

A Comprehensive Update of Lofexidine for the Management of Opioid Withdrawal Symptoms. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

[Pregabalin for the reduction of opiate withdrawal symptoms]. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. [2020]

6. Ireland pubmed.ncbi.nlm.nih.gov

Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal. [2020]

7. England pubmed.ncbi.nlm.nih.gov

The preclinical discovery of lofexidine for the treatment of opiate addiction. [2014]