Why it is so difficult to develop new types of painkillers

Why it is so difficult to develop new types of painkillers

The statistics on Americans’ opioid addiction are staggering. Since 2010, opioid overdose deaths have nearly quadrupled. More than 80,000 people died from an opioid overdose last year. That’s one death every six and a half minutes. Opioid use disorder is a particularly difficult disease to treat. We do have safe and effective medicines to curb withdrawal symptoms, reduce illicit opioid use, and help people stay on treatment. They also reduce the risk of a fatal overdose. However, a study published in mid-August shows that only one in five people with opioid use disorder are on these drugs.

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It is clear that we must do more. That means improving treatment, but also finding alternative methods of pain control—a task that has proven extremely difficult. But the results of a recently published study suggest that Boston-based biotech Vertex may be on the right track with its VX-548, a post-surgery pain relief pill. The highest dose of the drug produced greater pain relief than a placebo after bunion surgery or a tummy tuck. Unlike opioids, it is not intended to be addictive. This is good news in an area that has seen many setbacks.

Pain management: It’s complicated

Treating pain is complicated because pain itself is complicated. Doctors categorize how long it lasts—acute or chronic—and also how it begins. Some pain begins with an injury to the body, such as a cut, burn, broken arm, tumor. Sensory nerves (neurons) in our body detect damage and send pain signals to the brain. Some pain, such as the stinging and burning sensation that occurs with diabetic nerve damage, begins with injury to the neurons themselves.

Opioids like heroin, morphine, fentanyl and all the others work by masking the pain. They bind to receptors in the brain and spinal cord and block pain signals. Prescription opioids are extremely effective at relieving pain in certain situations. However, they don’t just block the pain. Activating the opioid receptors also triggers a dopamine surge: we suddenly feel good, even euphoric. However, this feeling does not last long. However, the more opioids you take, the more you need to experience the same high. This is why these drugs are so easily addictive.

Of course, there are also non-opioid pain relievers, such as ibuprofen, aspirin, acetaminophen, and naproxen sodium. Many of them are probably well known because they are available over the counter. They do not trigger dopamine release and are not addictive like opioids. Nevertheless, these drugs also have some serious disadvantages: They can lead to stomach ulcers, bleeding, heart problems, among other things.

Most (with the exception of the active ingredient acetaminophen in acetaminophen) belong to a class called nonsteroidal anti-inflammatory drugs, or NSAIDS for short. As the name suggests, they target inflammation in the body and block the production of chemicals that trigger our perception of pain. However, they do not work for many other types of pain.

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Obstacles in the development of painkillers

Efforts to develop new classes of pain relievers have encountered many obstacles. Just last year, Regeneron stopped developing a compound to treat osteoarthritis and chronic back pain. An experimental pain therapy from the Illinois biotech company Aptinyx failed in a study to treat people with fibromyalgia. And California-based Acadia reported that its drug didn’t work any better than a placebo in people who had bunion surgery. In 2021, Eli Lilly and Pfizer halted development of the monoclonal antibody tanezumab to treat osteoarthritis pain. The reasons for these failures are not entirely clear, making it difficult to develop better painkillers.

Vertex’s new compound now belongs to a class of drugs that target the sodium channels on the nerves that transmit the sensation of pain. Stephen Waxman, a Yale University neurologist and pain specialist, describes them as “tiny molecular batteries” that control the production of nerve impulses.

Sodium channel blockers already exist, including the anesthetic lidocaine. However, since they block all sodium channels, even blocking the important channels in heart cells and the brain, they are often only given as local anesthetics. VX-548, on the other hand, targets a specific channel called Nav1.8, which is found only in neurons that are sensitive to pain. This means it can target these neurons throughout the body without blocking the heart or brain from working. Because it doesn’t activate any opioid receptors, it doesn’t trigger the release of dopamine that causes the intoxication of previous drugs.

“New Generation of Painkillers”

The drug was tested in phase 2 studies in patients with moderate to severe pain after tummy tuck or bunion surgery. They were randomly divided into different groups. Some participants received VX-548 in one of three dose levels, others received a placebo pill, while other patients received a hydrocodone tablet, an opioid. Those subjects who received the highest dose of VX-548 experienced a greater reduction in pain than participants in the other groups.

In an editorial accompanying the study, the effect is described as “minor”. The results are nonetheless exciting, partly because the search for non-opioid painkillers has met with so few successes of any magnitude. “Here we have a human clinical trial that shows that by targeting one of these peripheral sodium channels, you can manage pain in humans without any unwanted side effects,” Waxman told the New England Journal of Medicine. “I see us in the first stage of a new generation of painkillers.” So we can hope.

(jl)

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