Lofexidine + Buprenorphine for PTSD

Recruiting at 1 trial location

Overseen By Christopher D Verrico, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Pharmacotherapies for Alcohol and Substance Abuse Consortium

Must be taking: Buprenorphine

Must not be taking: Benzodiazepines, Methadone, Antipsychotics, others

Disqualifiers: Substance use disorders, Methadone use, others

Stay on Your Current Meds You can continue your current medications while participating

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

The overall objective of the proposed study is to determine if lofexidine (LFX) as an adjunct to buprenorphine (BUP) treatment improves symptoms of both opioid use disorder (OUD) and Post-Traumatic Stress Disorder (PTSD). Other study objectives are to compare the safety, tolerability, and efficacy of BUP treatment alone, to BUP treatment with adjunct LFX, on measures of OUD and PTSD symptoms in Veterans with both prognosis .

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as benzodiazepines, methadone, and some antidepressants, 30 days before joining. If you're on a stable dose of buprenorphine, you can continue with it. Check with the study team to see if your specific medications are allowed.

What evidence supports the effectiveness of the drug combination Lofexidine and Buprenorphine for treating PTSD?

Research suggests that Buprenorphine, which is part of the drug combination, may help reduce PTSD symptoms. It has been studied for its potential to treat PTSD and depression, and it works by affecting certain brain receptors involved in stress and mood. ^{1 2 3 4 5}

Is Lofexidine safe for use in humans?

Lofexidine, also known as Lucemyra, has been used for opioid withdrawal and is generally considered safe, though it can cause low blood pressure (hypotension) which can be managed by adjusting the dose. ^{6 7 8 9 10}

How does the drug Lofexidine + Buprenorphine for PTSD differ from other treatments?

Lofexidine combined with Buprenorphine is unique for PTSD treatment as it leverages Lofexidine's ability to manage withdrawal symptoms and Buprenorphine's role in opioid dependency, which is not a standard approach for PTSD. This combination may offer a novel mechanism by addressing both withdrawal symptoms and potential opioid-related issues, unlike traditional PTSD treatments that focus on psychotherapy or antidepressants. ^{8 10 11 12 13}

Research Team

Thomas R Kosten, MD

Principal Investigator

Baylor College of Medicine

Christopher D. Verrico, PhD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for Veterans aged 18-65 with both PTSD and OUD, on stable buprenorphine therapy, who can consent in English. They must have normal lab tests (liver function up to 5X normal) and no severe health issues. Excluded are those with certain infections, other substance use disorders, recent methadone use, significant withdrawal symptoms or heart problems.

Inclusion Criteria

I am not on a stable dose of BUP but will join the study once it's stable.

Has a previous diagnosis of PTSD documented in CPRS or meets criteria for current PTSD as assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).

Have hematology and chemistry laboratory tests within 3 months of study entry that are within normal (± 15%) limits, except liver function test results, which can be 5X the upper limit of normal.

Exclusion Criteria

Self-reported use of methadone in the last 14 days.

I am using reliable birth control and am not pregnant or planning to become pregnant or breastfeed during the study.

I haven't taken drugs that affect the enzyme CYP3A4 in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive Lofexidine (LFX) or placebo in combination with Buprenorphine (BUP) for 12 weeks to assess efficacy on OUD and PTSD symptoms

12 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Lofexidine

Trial Overview The study aims to see if lofexidine helps improve PTSD and OUD symptoms when added to buprenorphine treatment in Veterans. Participants will either receive lofexidine or a placebo alongside their regular buprenorphine regimen to compare the effects on managing their conditions.

Participant Groups

Group I: Lofexidine (LFX) Experimental Treatment 1 Intervention

LFX starting dosage is two 0.2 mg LFX tablet taken orally 2 times daily (i.e., 0.8 mg/day). At study visit 2 (Day 3), the dosage is increased to 1.2mg/day (3 tablets, BID). At visit 3 (Day 5), the dose is increased to the target dose of 1.6mg/day (4 tablets, BID). Participants enter the flexible dosing period at visit 4, at which point the LFX dose can be maintained at 1.6 mg/day or decreased to 1.2 mg/day based on symptoms and the clinical judgement of the investigator. The flexible dosing period extends through to visit 6, however, doses will be adjusted during the study as needed.

Group II: Placebo (PLB) Placebo Group 1 Intervention

A placebo drug will be employed as the comparison group to active study drug.

Who Is Running the Clinical Trial?

Pharmacotherapies for Alcohol and Substance Abuse Consortium

Lead Sponsor

Trials

4

Recruited

200+

Pharmacotherapies for Alcohol and Substance Use Disorders Alliance

Lead Sponsor

Trials

9

Recruited

350+

Foundation for Advancing Veterans' Health Research

Collaborator

Trials

3

Recruited

330+

RTI International

Collaborator

Trials

201

Recruited

942,000+

Michael E. DeBakey VA Medical Center

Collaborator

Trials

68

Recruited

17,200+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

USWM, LLC (dba US WorldMeds)

Industry Sponsor

Trials

24

Recruited

1,800+

Findings from Research

In a study of 382 veterans with PTSD, chronic pain, and substance use disorders, those treated with buprenorphine showed a significantly higher rate of improvement in PTSD symptoms (23.7%) compared to those on standard opioid therapy (11.7%).

Veterans receiving buprenorphine experienced continuous improvement in PTSD symptoms over 24 months, indicating its potential as an effective treatment option for managing PTSD alongside chronic pain and substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observational Evidence for Buprenorphine's Impact on Posttraumatic Stress Symptoms in Veterans With Chronic Pain and Opioid Use Disorder. Seal, KH., Maguen, S., Bertenthal, D., et al.[2023]

Recent studies suggest that buprenorphine may have potential as a treatment for major depressive disorder and PTSD, particularly due to its interaction with the kappa opioid receptor (KOR), although results have been mixed and further investigation is needed.

The effectiveness of buprenorphine in treating these conditions may also involve other opioid receptors, highlighting the complexity of its action and the importance of understanding the endogenous opioid system in relation to mental health disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine: prospective novel therapy for depression and PTSD. Madison, CA., Eitan, S.[2021]

In a retrospective study of PTSD patients, those treated with buprenorphine showed a significant reduction in PTSD symptoms, achieving the lowest average PTSD score and the largest improvement from baseline compared to those treated with SSRIs or opioids.

The findings suggest that targeting the kappa opioid receptor system with buprenorphine may be a more effective treatment option for PTSD, highlighting the need for further prospective studies to confirm these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine for the treatment of posttraumatic stress disorder. Lake, EP., Mitchell, BG., Shorter, DI., et al.[2022]

A Phase II trial involving 75 participants tested the combination of buprenorphine and naltrexone for treating comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD), but the results showed no significant improvement over placebo.

The study found that the placebo group had a higher rate of reduction in alcohol risk levels compared to the buprenorphine plus naltrexone group, indicating that this combination may not be effective for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comorbid alcohol use disorder and posttraumatic stress disorder: A proof-of-concept randomized placebo-controlled trial of buprenorphine and naltrexone combination treatment. Davis, LL., Petrakis, IL., Pilkinton, PD., et al.[2023]

Selective serotonin reuptake inhibitors (SSRIs) like sertraline and paroxetine are the most effective first-line treatments for PTSD, showing significant efficacy in short-term trials (6-12 weeks) and reducing relapse rates with continued treatment for 6-12 months.

If SSRIs are not effective, alternative treatments such as serotonin-potentiating non-SSRIs and atypical antipsychotics can be considered, with the latter showing promise in managing symptoms like paranoia and flashbacks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations. Asnis, GM., Kohn, SR., Henderson, M., et al.[2022]

Lofexidine, an alpha(2)-agonist, has been shown to effectively reduce opioid withdrawal symptoms in a review of nine clinical studies involving 354 patients, demonstrating efficacy comparable to opioid receptor agonists used for detoxification.

While lofexidine can alleviate many withdrawal symptoms, it may not address all issues, such as insomnia and aches, and it has a lower incidence of adverse effects compared to clonidine, making it a promising non-opioid option for opioid detoxification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Gish, EC., Miller, JL., Honey, BL., et al.[2013]

Lofexidine has been shown to effectively manage opiate withdrawal symptoms, demonstrating similar efficacy to clonidine but with fewer issues related to hypotension, making it a safer option for patients.

Compared to methadone, lofexidine provides a quicker resolution of withdrawal symptoms, particularly with an accelerated 5-day treatment protocol, and is generally more acceptable to patients than clonidine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Strang, J., Bearn, J., Gossop, M.[2019]

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 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 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]

In a study involving 23 opioid-dependent patients, transferring from methadone doses of 30-70 mg/d to buprenorphine (12-16 mg/d) was largely successful, with only two patients not completing the transfer.

The use of lofexidine during the transfer helped manage withdrawal symptoms, although patients on higher methadone doses experienced slightly more withdrawal symptoms initially, indicating that the transfer process is generally safe and effective in an inpatient setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of patients with moderately severe methadone dependence onto buprenorphine. Glasper, A., Reed, LJ., de Wet, CJ., et al.[2015]

In a randomized controlled trial involving 80 opiate-dependent individuals, both buprenorphine/naloxone and methadone/lofexidine showed similar overall outcomes in managing opiate withdrawal symptoms and treatment retention.

However, during the induction phase, withdrawal symptoms decreased more slowly and cravings were higher in the buprenorphine/naloxone group, while methadone/lofexidine led to earlier peak withdrawal symptoms during detoxification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine/naloxone versus methadone and lofexidine in community stabilisation and detoxification: A randomised controlled trial of low dose short-term opiate-dependent individuals. Law, FD., Diaper, AM., Melichar, JK., et al.[2018]

A systematic review of 23 randomized controlled trials involving 2112 participants found that buprenorphine and methadone are the most effective treatments for opioid detoxification.

While buprenorphine was suggested to be the most effective, the study indicates that more research is needed to definitively determine if it is superior to methadone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of methadone, buprenorphine and alpha(2) adrenergic agonists for opioid detoxification: a mixed treatment comparison meta-analysis. Meader, N.[2018]

References

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

Observational Evidence for Buprenorphine's Impact on Posttraumatic Stress Symptoms in Veterans With Chronic Pain and Opioid Use Disorder. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Buprenorphine: prospective novel therapy for depression and PTSD. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Buprenorphine for the treatment of posttraumatic stress disorder. [2022]

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

Comorbid alcohol use disorder and posttraumatic stress disorder: A proof-of-concept randomized placebo-controlled trial of buprenorphine and naltrexone combination treatment. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations. [2022]

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

Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. [2013]

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

Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. [2019]

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

Pharmaceutical Approval Update. [2020]

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

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

10. England pubmed.ncbi.nlm.nih.gov

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

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

Induction of patients with moderately severe methadone dependence onto buprenorphine. [2015]

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

Buprenorphine/naloxone versus methadone and lofexidine in community stabilisation and detoxification: A randomised controlled trial of low dose short-term opiate-dependent individuals. [2018]

13. Ireland pubmed.ncbi.nlm.nih.gov

A comparison of methadone, buprenorphine and alpha(2) adrenergic agonists for opioid detoxification: a mixed treatment comparison meta-analysis. [2018]