Bad News Continues for Non-Opioid Analgesics

By Pat Anson

The bad news keeps piling up for non-opioid analgesics, which are often touted as safer and more effective alternatives to opioid pain medication.

A large new study found that pregabalin (Lyrica) raises the risk of heart failure in older patients, while Vertex Pharmaceuticals said it was stopping development of an experimental drug for post-operative pain because it was less effective than a low dose of hydrocodone.   

The pregabalin study, recently published in JAMA Network Open, compared the drug to gabapentin (Neurontin) among Medicare patients with chronic non-cancer pain. Both pregabalin and gabapentin are gabapentinoids, a class of nerve medication that was originally developed to prevent seizures in epileptic patients.

Because they are not opioids and perceived as safer, both drugs are now widely being prescribed for a variety of pain conditions, usually off-label.  

In a subset of patients with cardiovascular disease, researchers found that hospitalizations and emergency department visits for heart failure were more common in pregabalin users compared to patients on gabapentin. The difference wasn’t significant (18.2 visits vs 12.5 per 1,000 person-years), but it was enough for researchers to recommend caution when prescribing pregabalin.

“Practicing clinicians should undertake a careful assessment of ongoing cardiovascular risk factors and perform adequate risk-benefit counseling for older patients before prescribing pregabalin for chronic pain,” wrote lead author Elizabeth Park, MD, Columbia University Irving Medical Center.

Pregabalin is believe to be riskier because it binds to calcium channels associated with heart failure and arrhythmias. Both the American Heart Association and European Medicines Agency already list pregabalin as a drug that increases the risk of heart failure.

"The study serves as an important reminder that not all gabapentinoids are created equal and that in the pursuit of safer pain control, vigilance for unintended harms remains paramount," said Robert Zhang, MD, and Edo Birati, MD, in an accompanying editorial.

"For older adults with chronic pain, particularly those with cardiovascular disease, clinicians should weigh the potential cardiovascular risks associated with pregabalin against its analgesic benefits. This is particularly relevant given the growing use of gabapentinoids in older populations and ongoing polypharmacy issues in this age group."

The research doesn’t give gabapentin a clean bill of health, since it also raises the risk of heart failure in older patients – just not as much as pregabalin. Last month another study found that gabapentin increases the risk of dementia and cognitive impairment.

Researchers have long been concerned about the effects of gabapentinoids on the brain, while many patients have complained the drugs cause brain fog, dizziness, weight gain and mood changes. Despite warnings that they are overprescribed for conditions they were never intended to treat, the use of gabapentinoids continues to grow in the United States. 

New Analgesic No Better Than Vicodin

The new analgesic being developed by Vertex Pharmaceuticals – called VX-993 -- will apparently never reach patients, after the company announced disappointing results from a Phase Two clinical trial.  VX-993 is a non-opioid that blocks pain signals in peripheral nerves before they reach the brain, which means it doesn’t have the same “liking” effects of opioids, which can lead to addiction.  

When given to patients recovering from bunionectomy surgery, VX-993 was slightly more effective than a placebo in reducing post-operative pain, but provided less pain relief than a low dose of a hydrocodone/acetaminophen combination (Vicodin).  

“Based on these results, as well as the totality of preclinical data and results from our previous bunionectomy clinical studies, VX-993 is not expected to be superior to our existing NaV1.8 inhibitors and therefore we will not be advancing it as monotherapy in acute pain,” Carmen Bozic, MD, Executive Vice President and Chief Medical Officer at Vertex, said in a statement.

VX-993 acts similarly to Journavx (suzetrigine), a non-opioid developed by Vertex that acts on peripheral nerves. Journavx was recently approved by the FDA to treat moderate to severe acute pain, despite lackluster results in clinical trials that also showed it was no more effective than Vicodin.

The FDA’s approval of Journavx coincides with implementation of the NOPAIN Act, which makes non-opioid analgesics in outpatient surgical settings eligible for higher Medicare reimbursement rates. Journavx costs about three times as much as Vicodin.

FDA Approves New Non-Opioid Pain Reliever

By Pat Anson

Despite lackluster results in clinical trials, the U.S. Food and Drug Administration has approved a new non-opioid pain reliever for moderate to severe acute pain in adults.

Journavx (suzetrigine) is the first new medication for acute, short-term pain in over two decades. Unlike opioids, Journavx blocks pain signals in the peripheral nervous system, not in the brain, so it doesn’t have the same “liking” effects of opioids, which can lead to dependence or addiction.

The FDA calls its approval “an important public health milestone.”

"A new non-opioid analgesic therapeutic class for acute pain offers an opportunity to mitigate certain risks associated with using an opioid for pain and provides patients with another treatment option. This action and the agency's designations to expedite the drug's development and review underscore FDA's commitment to approving safe and effective alternatives to opioids for pain management," said Jacqueline Corrigan-Curay, MD, acting director of the FDA's Center for Drug Evaluation and Research.

Journavx was developed by Vertex Pharmaceuticals, which anticipates the drug to be used primarily for relieving post-operative pain or trauma. It is also being studied as a treatment for diabetic peripheral neuropathy and other types of chronic pain.

“This is an incredible day for patients and physicians alike who now have an approved non-opioid treatment that delivers effective acute pain relief and a favorable safety profile without addictive potential,” said Jessica Oswald, MD, a Vertex consultant and Associate Physician in Emergency Medicine and Pain Medicine in San Diego.

“I believe Journavx could redefine the management of pain and become a foundational treatment option for people with all types of moderate-to-severe acute pain, where options aside from opioids have been so desperately needed.”

VERTEX IMAGE

The results from clinical trials suggest that Journavx is a mild pain reliever, at best.

In Phase 3 clinical studies of acute pain after minimally invasive surgeries, Journavx was no more effective than a low-dose combination of hydrocodone and acetaminophen, more commonly known as Vicodin.

In a recent Phase 2 study, Journavx was essentially no better than a placebo in relieving chronic back and hip pain caused by lumbosacral radiculopathy.

A recent report by ICER, an independent, non-profit research institute, said there were “uncertainties” about the efficacy and safety of Journavx.

“We have concerns about as-yet-unknown harms of suzetrigine as we would for any drug with a new mechanism of action; we are particularly concerned about whether there could be an increased risk for cardiac arrhythmias… and possible acute renal injury given a study in people with diabetes,” ICER said. “The above uncertainties inform our ratings that the evidence for suzetrigine for the treatment of acute pain in comparison with no systemic treatment, in comparison with opioid analgesics, and in comparison with NSAIDs are all promising but inconclusive.”

Journavx is being priced by Vertex at a wholesale cost for $15.50 per 50mg pill. When taken twice a day for acute pain, ICER estimates the cost at $420 for a one-week course. By comparison, a supply of 100 Vicodin tablets costs about $142.

The FDA’s approval of Journavx coincides with implementation of the NOPAIN Act, which makes non-opioid analgesics in outpatient surgical settings eligible for higher Medicare reimbursement rates.  

The risk of a surgery patient misusing opioids or becoming addicted is less than one percent. One study found that patients who received no opioids during surgery were more likely to have post-operative pain and require opioids during recovery.