Non-opioid painkillers: Another tool to fight the opioid epidemic

The opioid epidemic is still an ongoing problem and there is no single solution to bring it under control. Ben Hargreaves finds that a new line of attack could be the development of more effective non-opioid painkillers, with one potential therapy moving closer to approval.

The opioid epidemic in the US has not gone away. According to the US Centers for Disease Control and Prevention (CDC), the current wave of opioid overdoses began in 2013 and deaths from opioids continue to spike upwards. Drug overdose deaths in the US exceeded 100,000 in 2023 for the first time.

The difficulty in tackling the issue stems from the various contributing factors that have created the current situation. The root of the problem began through the excessive prescription of opioid medications and the aggressive marketing of such products, alongside economic and social factors. Certain lawsuits are still being settled in recent months, after many such cases have been brought to court due to actions taken by various pharmaceutical companies in the initial phase of the opioid epidemic.

In 2018, the FDA sought to use its influence to tackle the opioid epidemic, with one example being to expedite the approval of emergency treatments for overdoses. Another action it has taken is to encourage the development of non-opioid painkillers. The pharma industry has a considerable responsibility in aiding the rise of the crisis, however, there are companies that have taken up the challenge of developing a new generation of alternative options to opioids.

The problem with opioids

Opioids have been used as painkillers for centuries, but the tendency for addiction and dependency led to restrictions being placed on their use in the early 1900s in the US. The class of drugs function by attaching to opioid receptors on nerve cells in the brain, spinal cord, gut, and other parts of the body. When this happens, the opioids block pain messages sent from the body through to the brain and also release dopamine, hence their addictive nature.

The FDA approved the first non-opioid treatment for the management of opioid withdrawal symptoms in 2018. The treatment, Lucemyra (lofexidine hydrochloride), was found to be able to help nearly two-thirds of individuals to be opioid-free post-withdrawal during a study. In the results, the treatment was found to be superior to clonidine, which is commonly used off-label for opioid withdrawal, but is also by itself potentially addictive.

One of the advantages of lofexidine is that it is considered non-addictive, which would be the primary aim of developing a non-opioid painkiller. There already exist non-opioid painkillers, such as ibuprofen, paracetamol, and aspirin; however, they may not be appropriate for more severe forms of acute pain. This is why there is a need for non-opioid painkillers that are able to more effectively reduce pain.

Arriving at alternatives

One of the new generation of treatments that is edging closer to becoming a new non-opioid painkilling option is Vertex Pharmaceuticals’ VX-548 (suzetrigine). The company released Phase 3 results that showed the potential treatment was able to demonstrate a statistically significant improvement on the primary endpoint of the time-weighted sum of the pain intensity difference from zero to 48 hours compared to placebo. The treatment was also found to have a clinically meaningful reduction in pain from baseline at 48 on the Numeric Pain Rating Scale.

The drug is an oral, selective NaV1.8 pain signal inhibitor that is targeted at NaV1.8 relative to other channels. NaV1.8 itself is a voltage-gated sodium channel that plays a role in pain signalling in the peripheral nervous system. The adverse events associated with the drug in trials were nausea, constipation, and headaches, with no serious adverse events recorded.

Vertex announced in April that the FDA had granted a rolling New Drug Application (NDA) submission for suzetrigine in moderate-to-severe acute pain. The company added that it expects to complete the process in the second quarter of 2024. After this, the drug could become the first new class of medicine for acute and neuropathic pain in more than two decades.

However, despite the positive results, the drug was not able to measure up against comparably opioid-based treatments in the clinical trial results. This could dampen its potential use, but the company does plan to pursue further indications, as it continues its clinical development programme. According to GlobalData, the treatment could generate $1.4 billion in global sales in 2030.

Investment arrives

Another company working on developing a non-opioid pain medicine is Latigo Biotherapeutics. The biotech emerged in February 2024 with the backing of $135 million and its lead oral NaV1.8 inhibitor asset that is currently in a Phase 1 trial to treat acute and chronic pain. LTG-001, the potential drug, shares the same target as Vertex’s clinical asset, but the biotech suggests its compound has the potential to be ‘best-in-class’.

In addition to its lead asset, the biotech also stated that it has ‘a suite of NaV1.8 inhibitors,’ allowing Latigo to bring additional assets through the clinic targeting the channel. Outside of NaV1.8, the biotech also has other small molecule programmes at the discovery phase.

With its lead asset some way behind Vertex’s treatment, the biotech is banking on not needing first mover advantage if its chosen asset can show some advantages over its rival’s treatment. Arriving at the table with $135 million in backing suggests that investors think it is a gamble worth taking.

In a statement on Latigo’s launch, Nancy Stagliano, the company’s chair, noted that until recently there was little activity in the pain therapeutic space against a backdrop of the risks posed by opioids. With treatments moving through trials and more investment being funnelled into the space, it might not be long before more options are on the table for those in need of pain relief. As part of the broader fight against opioid abuse, it could be another useful tool to reduce the number of deaths and prevent more individuals from becoming addicted in the first place.