Denver—For clinicians on the front line of the opioid crisis, there may be a new weapon against the significant symptom burden associated with abrupt opioid withdrawal: the novel alpha-2-adrenergic agonist lofexidine. A pooled database of two trials found that the severity of opioid withdrawal symptoms over seven days was significantly reduced among patients treated with lofexidine (Lucemyra, US WorldMeds), relative to placebo.
“The recent CDC guidelines regarding opioid discontinuation were created with the best of intentions to help act as recommendations for primary care physicians,” said Joseph V. Pergolizzi, MD, the chief operating officer at NEMA Research in Naples, Fla. “Now, however, it looks like many state licensing boards and prescribers have almost weaponized the guidelines, and are using them in a direction such that certain chronic pain patients who are opioid tolerant are being abruptly discontinued from opioids.
“If that’s going to be the clinical decision, then we need to start somewhere with these patients,” said Dr. Pergolizzi, who is also a member of the Pain Medicine News editorial advisory board. “And right now, there’s very poor evidence on how to actually do that. We’ve used a lot of off-label drugs in the past, but lofexidine is the first FDA-approved nonopioid medication to address the mitigation of opioid withdrawal syndrome.”
The pooled analysis used data from two randomized, double-blind, placebo-controlled clinical trials. Each study evaluated lofexidine for the treatment of opioid withdrawal symptoms in opioid-dependent men and women (≥18 years of age) who had undergone abrupt discontinuation from short-acting opioids, including heroin, oxycodone and hydrocodone.
The trial participants were determined to be opioid dependent based on either the Structured Clinical Interview Axis I or the Mini International Neuropsychiatric Interview.
In the first study, participants were randomly assigned to receive placebo or 2.88 mg per day (0.72 mg, four times a day) of lofexidine for five days. (All patients received placebo on days 6 and 7.) In addition to placebo, the second trial also randomly assigned patients to one of two lofexidine doses: 2.88 mg daily (0.72 mg, four times a day) or 2.16 mg daily (0.54 mg, four times a day) for seven days.
The studies’ primary efficacy measure was the Short Opiate Withdrawal Scale of Gossop (SOWS-G). The scale is a validated, subject-rated, 10-item assessment, in which each symptom is rated from 0 (none) to 3 (severe); the maximum total score is 30.
As Dr. Pergolizzi discussed, the pooled database consisted of 865 patients, all of whom took at least one dose of the study medication. Prescription opioid analgesics were the primary misused opioid, affecting 27% of placebo patients and 21% of lofexidine patients.
“We observed a couple of important things,” Dr. Pergolizzi told Pain Medicine News. “One, people are afraid of withdrawing from their opioids; it’s the No. 1 reason why they avoid it. What’s more, there’s little guidance regarding rapid discontinuation for them and the practitioners who are taking care of them. But what this drug [lofexidine] allows you to do in a very standardized manner—through the data that’s been collected—is address that very critical period between two and four days, depending on the half-life of the opioid they’re on.”
Reporting at the 2019 annual meeting of the American Academy of Pain Medicine (abstract 147), Dr. Pergolizzi noted that the mean total SOWS-G scores over seven days were significantly reduced in both lofexidine dose groups compared with placebo (2.16 mg, P<0.05; 2.88 mg, P<0.0001).
In addition, a significantly greater proportion of lofexidine-treated patients completed the seven-day trial period: 28% for placebo; 42% for 2.16 mg lofexidine (P=0.002); and 41% for 2.88 mg lofexidine (P=0.001).
“This drug allows patients to get over that acute opioid withdrawal symptom ‘hump,’ reduce their symptomology, and transition them to post-treatment therapy,” Dr. Pergolizzi explained. “Clinically for me, it’s great because it starts the conversation.
“Let’s say you want to take your patient off opioids, but they’re scared,” he said. “Now I can tell them I can address their withdrawal symptoms with a drug that’s been tested and FDA approved for this specific indication; I can use my skills and expertise to guide them through the process; and we can rapidly discontinue their opioids, transition them to something else.”
When looking at SOWS-G scores by study day, the researchers found that scores peaked on day 2, and were significantly lower in both lofexidine dose groups on days 1 to 2 versus placebo. Furthermore, patients who received the higher dose of the study drug reported significantly lower SOWS-G scores on days 3 to 5 as well.
A descriptive analysis of individual SOWS-G symptoms (on the day of peak SOWS-G total score) showed the mean item scores were lower in the lofexidine groups for all items.
Despite lofexidine’s effectiveness, the drug was associated with its own set of hemodynamic side effects. “As you would expect with the drug class, hypotension, bradycardia, dizziness, sedation and somnolence were expected to be more prominent with lofexidine, and that’s exactly what we saw,” said Mark Pirner, MD, PhD, the senior medical director at US WorldMeds, the manufacturer of lofexidine (Table).
| Table. Common Adverse Events With Lofexidine | ||
| Condition | Placebo, % (n=280) | Lofexidine, % (n=585)a |
|---|---|---|
| Orthostatic hypertension | 2.5 | 28.4 |
| Hypotension | 1.1 | 27.2 |
| Bradycardia | 3.9 | 23.1 |
| Dizziness | 3.6 | 19.7 |
| Sedation | 3.6 | 11.3 |
| Somnolence | 3.2 | 10.1 |
| Any | 32.9 | 70.3 |
| a For all doses (2.16 and 2.88 mg). | ||
Serious adverse events were infrequent, reported in 2.1% of patients receiving lofexidine and 3.6% of those taking placebo. Most serious adverse events were related to hypotension or bradycardia with lofexidine, and briefly prolonged hospitalization to stabilize withdrawal symptoms among placebo patients.
Yet as Dr. Pirner was quick to note, lofexidine is not a treatment for opioid use disorder. “If a patient has opioid use disorder, this is just a bridge to get them over to whatever agent is next. So they have to be covered by buprenorphine, extended-release naltrexone or methadone to reduce the risk of overdose and death.”
For Dr. Pergolizzi, the novel agent offers patients and clinicians a starting point that was previously lacking. “This drug allows us to start having the conversation about withdrawal symptoms the right way.”
According to Bennett Doughty, PharmD, BCPS, BCPP, lofexidine joins a group of several medications commonly used for treating acute opioid withdrawal, including methadone, buprenorphine and clonidine. “Personally, I am glad that there is now an alpha-2 agonist that is approved for acute opioid withdrawal,” said Dr. Doughty, a clinical assistant professor of pharmacy practice at Binghamton University School of Pharmacy and Pharmaceutical Sciences in Binghamton, N.Y.
“However, just as buprenorphine is used for this indication and not FDA approved, clonidine seems to be the most clinically appropriate and affordable agent if buprenorphine or methadone cannot be used/are inaccessible,” he continued. “If a patient is first treated with clonidine and cannot tolerate the hypotension associated with the medication, then lofexidine may be the best option, but this seems to be a small subset of patients.”
Dr. Doughty echoed Dr. Pergolizzi’s sentiments that alleviating opioid withdrawal is not a solution to the current opioid epidemic. “Increasing engagement in medication-assisted treatment, including buprenorphine, Vivitrol [Alkermes; naltrexone for extended-release injectable suspension] and methadone maintenance therapy, is where our focus should be for decreasing harm secondary to opioid use disorder,” he said. “Further research is required to more clearly define lofexidine’s place in practice, especially when compared to clonidine.”
—Michael Vlessides
Dr. Doughty reported no relevant financial disclosures. Dr. Pergolizzi reported consultant/speaker and researcher relationships with Adapt Pharma, BioDelivery Sciences International, Daiichi Sankyo, Enalare Therapeutics, Neumentum, Salix and US WorldMeds. Dr. Pirner reported he is an employee of US WorldMeds.