Journavx is a newly approved non-opioid painkiller

A painkiller (analgesic) is a type of medication used to relieve pain. Painkillers work by blocking pain signals in the nervous system or by reducing inflammation. There are two main types of analgesics: non-opioid and opioid. The former includes acetaminophen (e.g. Tylenol), which works in the brain to reduce pain and fever, and non-steroidal anti inflammatory drugs (NSAIDs) which reduce pain, inflammation, and fever (e.g. ibuprofen, aspirin) closer to the site of injury/inflammation (peripherally). Opioid analgesics are powerful pain relievers that act on the opioid receptors in the central nervous system (e.g. morphine, codeine, oxycodone, fentanyl) and have a high potential for addiction.

NSAIDs reduce inflammation by blocking enzymes (COX-1 and COX-2) that produce prostaglandins (chemicals involved in pain and inflammation). Prostaglandins can sensitize nerve endings to magnify pain perception, as well as increase inflammation. Acetaminophen affects pain perception in the brain but does not reduce inflammation through mechanisms not fully characterized but may involve the endocannabinoid and serotonin systems. Opioids bind to opioid receptors in the brain and spinal cord, blocking pain signals.

Pain can be acute or chronic; the main difference lies in duration, cause, and function (purpose). Acute pain is a short-term discomfort that typically arises suddenly in response to a specific injury or illness, such as a broken bone, surgery, or infection. It serves as a warning signal to the body, indicating that something is wrong and needs attention. This type of pain usually resolves once the underlying cause is treated or heals. In contrast, chronic pain persists for longer periods—often beyond three to six months—and may continue even after the original injury has healed. It can result from conditions like arthritis, nerve damage, or other long-term health issues, and often requires ongoing management. While acute pain has a protective function, chronic pain can become a condition in itself, significantly affecting a person’s quality of life.

NSAIDs and opioids are used to treat both acute and chronic pain. However, the role of opioids is more limited and controversial due to addiction potential, and tolerance (needing higher doses over time). As a result, they are more commonly used in specific circumstances such as cancer-related chronic pain, palliative and end-of-life care, and severe, refractory non-cancer pain, but typically only after other treatments have failed.

Given this backdrop, there was excitement over the recent FDA approval of suzetrigine (marketed as Journavx by the biotech company Vertex) for moderate-to-severe acute pain. Most notably, suzetrigine is the first non-opioid pain drug approved in over 20 years, and is not an NSAID, but instead uses a completely different mechanism—selectively blocking sodium channels to reduce pain. 

It has been highly praised by clinicians due to its lower risk of addiction and reduced side effects compared to opioids. The standard dosage is two oral tablets per day.

Voltage-gated sodium channels (NaV, Na is the abbreviation for sodium and V stands for voltage) generate action potentials (nerve signals) transmitting pain signals from peripheral nerves to the brain. However, traditional sodium channel blockers (like the dentistry anesthetic Novocain) block all sodium channel subtypes indiscriminately and must be used locally to prevent broad side effects. There are several different subtypes of voltage-gated sodium channels in the human body (e.g. NaV1.1 through NaV1.9, plus an atypical NaV2.1), which have have slightly different properties and are expressed in different tissues (neurons, heart muscle, skeletal muscle). In particular, if Novocaine got into the blood and spread globally to the heart, it could have a dampening effect on heart activity.

Thus, researchers focused on more selective inhibitors. In the 1990s, researchers discovered three sodium channel subtypes (NaV1.7, NaV1.8, NaV1.9) concentrated mostly in pain-sensing, peripheral sensory neurons (nociceptors), so that inhibition of these channels would not greatly affect other organs like the heart. Initially, NaV1.7 was heavily targeted due to compelling genetic evidence linking it to pain insensitivity or hypersensitivity. However, clinical trials repeatedly failed because of difficulties achieving selectivity arising from the high structural similarity between the subtypes. Pharmaceutical companies, most notably Vertex Pharmaceuticals, then shifted focus to NaV1.8 after setbacks with NaV1.7. Vertex overcame these issues by achieving extremely high selectivity (30,000–40,000-fold) of suzetrigine for NaV1.8 versus other NaV channels. In summary, by selectively blocking NaV1.8 sodium channels on pain-sensing nerve cells, suzetrigine significantly reduces pain signals without addiction, sedation, or overdose risks associated with opioids.

Vertex evaluated the drug against acute pain in two pivotal phase III clinical trials involving over 2,000 post-operative patients from surgical procedures such as abdominal surgery (e.g. tummy tucks) and bunion removal (bunionectomy). Suzetrigine provided similar pain relief at 48 hours post-dose to standard opioid treatment (hydrocodone plus acetaminophen) and was significantly better than placebo. This comparable effectiveness with standard of care came with fewer side effects and no addiction risk. The common side effects (headache, dizziness, nausea, constipation) were mild, making it well-tolerated. 

The NaV1.8 channel is expressed at low levels in heart tissue, which helps explain the good safety profile of suzetrigine for acute pain patients, but raises concerns about potential cardiovascular safety for chronic pain patients who must take the drug for longer periods of time.

The FDA approval was for moderate-to-severe acute pain in adults. However, Vertex has begun trials examining suzetrigine for chronic pain conditions. So far, it has demonstrated uncertain efficacy in a phase 2 chronic sciatica trial, performing similarly to placebo due to strong placebo effects common in chronic pain studies. Sciatica refers to pain that radiates along the path of the sciatic nerve, typically from the lower back through the hips, buttocks, and down one leg; the most common cause is a herniated disc.

In addition, Vertex initiated a phase 3 trial in diabetic peripheral neuropathy (DPN), another chronic pain disorder caused by prolonged high blood sugar levels, primarily damaging the peripheral nerves, especially in the legs and feet. It is the most common complication associated with diabetes.

For the future, Vertex is working on a next-generation candidate (VX-993) that inhibits NaV1.8 to a greater extent than suzetrigine, and hence could be more potent. There are other companies such as Latigo Biotherapeutics and SiteOne Therapeutics that are also developing new NaV1.8 inhibitors with superior pharmacodynamic properties such as faster onset, higher selectivity, and fewer interactions with other drugs.

Finally, another possibility Vertex is considering is combining NaV1.8 inhibitors with NaV1.7 inhibitors for superior efficacy, potentially surpassing opioids. Of course with greater efficacy comes challenges from potential cardiovascular side effects due to systemic inhibition of sodium channels.

In summary, an exciting road lies ahead with suzetrigine (Journavx) representing the first step in a new class of analgesics which lack the addictive potential of opioids (Figure 1).

Figure 1. Journavx (suzetrigine) is the first representative of a new class of painkilling drugs that may replace opioids for certain cases of acute pain, and perhaps even chronic pain in the future.