Lofexidine + Buprenorphine for PTSD
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byThomas R Kosten, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
Approved in 2 Jurisdictions
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.
12345Is 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.
678910How 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.
810111213Eligibility 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 between 18 and 65, can read and understand English, and can sign my own consent.
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).
+4 more
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.
+6 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Lofexidine (LFX)Experimental Treatment1 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 Group1 Intervention
A placebo drug will be employed as the comparison group to active study drug.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
South Texas Veterans Health Care SystemSan Antonio, TX
Michael E. DeBakey Veterans Affairs Medical CenterHouston, TX
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Who Is Running the Clinical Trial?
Pharmacotherapies for Alcohol and Substance Abuse ConsortiumLead Sponsor
Pharmacotherapies for Alcohol and Substance Use Disorders AllianceLead Sponsor
Foundation for Advancing Veterans' Health ResearchCollaborator
RTI InternationalCollaborator
Michael E. DeBakey VA Medical CenterCollaborator
United States Department of DefenseCollaborator
USWM, LLC (dba US WorldMeds)Industry Sponsor
References
Observational Evidence for Buprenorphine's Impact on Posttraumatic Stress Symptoms in Veterans With Chronic Pain and Opioid Use Disorder. [2023]Posttraumatic stress disorder (PTSD), chronic pain, and substance use disorders are prevalent co-occurring conditions that are challenging to treat individually, and there is no evidence-based treatment for all 3. Buprenorphine, used to treat opioid use disorder and chronic pain, is a partial nociceptin opioid receptor agonist. In preclinical studies, a nociceptin opioid receptor agonist was shown to mitigate PTSD symptoms in acute trauma. We compared buprenorphine to other opioid medications in its impact on PTSD symptoms in patients with chronic pain and opioid and/or other substance use disorders.
Buprenorphine: prospective novel therapy for depression and PTSD. [2021]Depression and post-traumatic stress disorder (PTSD) are leading causes of disability and loss of life by suicide. Currently, there are less than satisfactory medical solutions to treat these mental disorders. Here, we explore recent preclinical and clinical studies demonstrating the potential of using buprenorphine to treat major depressive disorder, treatment-resistant depression, and PTSD.
Buprenorphine for the treatment of posttraumatic stress disorder. [2022]The core pharmacological treatment of Post-Traumatic Stress Disorder (PTSD) is selective serotonin reuptake inhibitors (SSRIs), although remission is only around 30% with them. Many patients will self-treat with opioids and due to the opiate system involvement in dysphoric mood and anxiety/stress responses, it is likely that antagonism of the kappa opioid receptor (KOR) system represents a potential target for treatment of PTSD. The aim of this study is to compare response of PTSD symptoms when antagonizing KOR via buprenorphine/naloxone compared to SSRIs or opioid therapy.
Comorbid alcohol use disorder and posttraumatic stress disorder: A proof-of-concept randomized placebo-controlled trial of buprenorphine and naltrexone combination treatment. [2023]Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ-mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ-opioid receptor antagonist it available for clinical use, we tested this combination in a proof-of-concept study.
SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations. [2022]Post-traumatic stress disorder (PTSD) is a highly prevalent (7.8% lifetime rate) anxiety disorder with impairment in daily functioning, frequent suicidal behaviour and high rates of co-morbidity. Fortunately, PTSD is responsive to pharmacotherapy and psychotherapy. The selective serotonin reuptake inhibitors (SSRIs) are the most studied medications for PTSD, with the largest number of double-blind, placebo-controlled trials. Of the SSRIs, sertraline, paroxetine and fluoxetine have been the most extensively studied, with sertraline and paroxetine being US FDA-approved for PTSD. These studies have demonstrated that SSRIs are effective in short-term trials (6-12 weeks). Furthermore, continuation and maintenance treatment for 6-12 months decrease relapse rates. Besides being the most studied and effective drugs for PTSD, SSRIs have a favourable adverse effect profile, making them the first-line treatment for PTSD. If SSRIs are not tolerated or are ineffective, non-SSRIs should be considered. Serotonin-potentiating non-SSRIs, such as venlafaxine, nefazodone, trazodone and mirtazapine, have been evaluated in PTSD only in open-label and case studies. Because of their promising results and relatively good safety profile, they should be considered as second-line treatment. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) have both been evaluated in a small number of double-blind, placebo-controlled studies. The results have been inconsistent but promising. In the limited comparative studies, MAOIs appeared superior to TCAs but patients continued to have residual symptoms. These drugs have significant adverse effects, such as cardiovascular complications, and safety issues, such as ease of overdose. Therefore, TCAs and MAOIs should be considered as third-line treatment. Anticonvulsants have been evaluated in PTSD in open-label studies and results have been positive for carbamazepine, valproic acid, topiramate and gabapentin. A small double-blind, placebo-controlled study demonstrated efficacy of lamotrigine for PTSD. Anticonvulsants should be considered where co-morbidity of bipolar disorder exists, and where impulsivity and anger predominate. Bupropion (amfebutamone), a predominantly noradrenergic reuptake inhibitor, was ineffective in PTSD in an open-label study. Benzodiazepines were ineffective in a double-blind, placebo-controlled study despite encouraging case reports. They should be avoided or used only short term because of potential depressogenic effects, and the possibility that they may promote or worsen PTSD. Buspirone, a non-benzodiazepine anxiolytic, was found to be effective in PTSD only in open-label studies. Recently, atypical antipsychotics were as effective as monotherapy and as an augmenter to SSRIs in open-label/case studies and small double-blind, placebo-controlled trials; atypical antipsychotics should be considered in PTSD where paranoia or flashbacks are prominent and in potentiating SSRIs in refractory cases.
Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. [2013]To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines for lofexidine, an alpha(2)-agonist, for opioid detoxification.
Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. [2019]The objective of this article was to review the data from recently published trials of lofexidine in the treatment of opiate withdrawal, with particular attention to evidence on efficacy, side-effects (particularly hypotension), and the acceptability of this new treatment to the patient population. The authors reviewed data contained within peer-reviewed published reports of clinical trials of lofexidine compared with detoxification using reducing doses of the opiate agonist methadone or the alpha-adrenergic agonist clonidine. Five published reports of clinical trials of lofexidine have been identified from peer-reviewed journals in the eight years between 1990 and 1998--all published within the last three years. Three of the reports compare lofexidine with clonidine, while the remaining two compare it with methadone detoxification. The three comparisons with clonidine find lofexidine to be similar in its moderating effect on the withdrawal syndrome, but without the same extent of problems with hypotension. Comparisons with methadone show a more rapid resolution of withdrawal symptoms with lofexidine--particularly with the accelerated 5-day lofexidine protocol. Such problems of hypotension as were encountered with lofexidine were adequately managed with dose reduction. Acceptability of the treatment to the patient (as measured by retention in treatment) appears to be greater with lofexidine than clonidine, although possibly less than with methadone. Lofexidine is an alpha-2 adrenergic agonist that is increasingly used in the management of opiate withdrawal--notably in the UK. The available data indicate that it is a useful new addition to the armamentarium of the clinician. Future studies should explore its application with improved protocols and in new treatment settings. This article reviews the recent advances in the study of lofexidine as a new treatment for opiate detoxification. It examines the background of the development and introduction of lofexidine into the U.K., with data on the extent to which it is now used in the U.K. in the treatment of opiate addiction. A review is then provided of the published evidence on the use of lofexidine in the management of opiate detoxification, mainly concentrating on the data from recent double-blind randomised trials. Finally, the possible future role of lofexidine in this field is considered.
Pharmaceutical Approval Update. [2020]Lofexidine hydrocholoride (Lucemyra) for opioid withdrawal; erenumab-aooe (Aimovig) for migraine; and sodium zirconium cyclosilicate (Lokelma) for hyperkalemia.
Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal. [2020]To review the pharmacology, efficacy, and safety of lofexidine for the treatment of opioid withdrawal secondary to the recent Food and Drug Administration (FDA) approval.
The preclinical discovery of lofexidine for the treatment of opiate addiction. [2014]Lofexidine is one therapeutic option used for treating the onslaught of sympathetic outflow that typically commences upon induction of opiate withdrawal. It was approved for opiate detoxification in the UK, most of EU, and a select few countries worldwide during the 1980s and the 90s. Within the US and Canada, however, it remains an experimental drug.
Induction of patients with moderately severe methadone dependence onto buprenorphine. [2015]Current clinical practice allows patients with low levels of physiological dependence on opioids (equivalent to methadone doses of 30 mg/d or less) to be transferred to buprenorphine. This study investigated the response of opioid-dependent patients receiving doses of methadone between 30-70 mg/d when transferred to buprenorphine at doses between 12-16 mg/d. Twenty-three patients receiving inpatient opioid detoxification agreed to take part in a trial of facilitated transfer to buprenorphine. Following the last morning dose of methadone, buprenorphine was substituted in doses increasing from 4 mg to a maximum of 16 mg, with adjunctive lofexidine (maximum of 2.4 mg/d). All except two patients successfully completed transfer to buprenorphine. To investigate the effect of initial methadone dose, the group was split into intermediate dose (ID; 30 - 49 mg/d; n = 10) and high dose (HD; 50-70 mg/d; n = 11) groups. Average stabilisation dose of buprenorphine for the sample who completed transfer was 14.0 mg/d (SD 2.3) and average daily lofexidine dose during transfer was 0.57 mg (SD 0.39). The HD group used significantly more lofexidine to complete transfer compared to the ID group. Increased opioid withdrawal symptoms, of mild severity as measured by the Short Opiate Withdrawal Scale (SOWS), were found in the HD group compared with the ID group during the first and last day of buprenorphine stabilisation. However, average SOWS scores for the whole of the period of transfer were not significantly different from those during the period of stabilisation on buprenorphine in either the ID or HD groups. This study suggests that transfer to buprenorphine is relatively uncomplicated from daily methadone doses of 30-70 mg in an inpatient setting and may be facilitated by use of lofexidine. This procedure may allow a larger proportion of opioid-dependent patients access to buprenorphine treatment.
Buprenorphine/naloxone versus methadone and lofexidine in community stabilisation and detoxification: A randomised controlled trial of low dose short-term opiate-dependent individuals. [2018]Buprenorphine/naloxone, methadone and lofexidine are medications with utility in the treatment of opiate withdrawal. We report the first randomised controlled trial to compare the effects of these two medications on withdrawal symptoms and outcome during opiate induction/stabilisation and detoxification. A double-blind randomised controlled trial was conducted in an outpatient satellite clinic of a specialist drug service. Eighty opiate dependent individuals meeting DSM-IV criteria for opiate dependence, using ⩽ ½ g heroin smoked/chased or ¼ g heroin injected or ⩽ 30mg methadone, with ⩽ 3 years of opioid dependency, underwent a short-term opiate treatment programme involving induction/stabilisation on methadone 30mg or buprenorphine/naloxone 4mg/1mg, followed by detoxification (where the methadone group was assisted by lofexidine). The main outcome measures were urine drug screens for opiates and withdrawal and craving questionnaires. There were no overall differences in positive urine drug screens and drop-outs during any phase of the study. During induction/stabilisation, withdrawal symptoms subsided more slowly for buprenorphine/naloxone than for methadone, and craving was significantly higher in the buprenorphine/naloxone group ( p
A comparison of methadone, buprenorphine and alpha(2) adrenergic agonists for opioid detoxification: a mixed treatment comparison meta-analysis. [2018]The aim of this systematic review was to compare the efficacy of methadone, buprenorphine, clonidine and lofexidine for opioid detoxification. Mixed treatment comparison meta-analyses were used to synthesise the data as it is designed for data-sets where limitations in standard pairwise meta-analyses make comparisons difficult to interpret.