TENS of millions of people live with chronic and in some cases disabling daily pain in the US alone, in addition to those experiencing acute pain. Yet treatments for pain relief remain only partially effective and only work for some people.
For instance, paracetamol (acetaminophen) may have little or no effect on extreme pain and exceeding the recommended dose can be toxic to the liver. Similarly, ibuprofen and other non-steroidal anti-inflammatory drugs – which tackle the inflammation that presses on nerve endings and causes pain – have a range of side effects, including headaches and indigestion, as well as interacting with drugs used for several other conditions. This leaves opioids, which mimic the body’s natural painkillers and are among the most effective form of pain relief.
Yet while opioids may work for many types of acute and chronic pain, they can be ineffective against others, and are associated with addiction and the risk of overdose. The opioid epidemic has cost hundreds of thousands of lives in the US and has underlined the need for alternative treatments. But as , a pain researcher at University College London, puts it: “There has been a tremendous succession of failures trying to make new analgesics.”
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For years, pharmaceutical companies had been looking for a way in through a single gene that might be vital for pain, he says. So, in 2006, when a team led by at the University of Cambridge discovered such a gene, called SCN9A(see “What is pain, how does it work and what happens when it goes wrong?“), “this seemed to be like manna from heaven”, says Wood.
Sodium channels are a vital part of the process that allows neurons to fire. There are nine known types of sodium channel, each found in different parts of the nervous system and the heart. Blocking them all would be fatal, but SCN9A suggested a way to block pain signalling while leaving other sodium channel activity intact, because , a type of sodium channel found almost exclusively in sensory neurons.
Gene therapy benefits
However, while experiments had demonstrated that animals and people without SCN9A feel no pain, . Then, in 2015, Wood and his colleagues showed that also differ in people and animals without Nav1.7 channels. This may explain why drugs that selectively block the channels fail to generate the full pain-blocking effect found in people who lack SCN9A. approach is looking promising in rodent trials.
A surprising source of pain relief might be bacterial toxins. Researchers had previously attributed the pain of bacterial infection to the activation of immune cells causing inflammation, with the resulting swelling leading to pain. However, in 2013, immunologist and neurobiologist , both at Harvard University, and their colleagues found that that signal pain – as well as silence them.
The reasons for these effects aren’t well understood. However, in 2021, Chiu led a study on mice with either acute or chronic pain and showed that , the bacterium that causes anthrax, could silence sensory neurons. Crucially, the pain returned, indicating that the toxin hadn’t damaged or destroyed the neurons, only temporarily blocked their activity. “This does show that microbes can be a source for therapeutics,” says Chiu.
Yet chronic pain includes much more than a physical sensation – it is a complex emotional experience, too, and it should be treated as such, says Beth Darnall at Stanford University in California. She advocates embracing other methods, such as psychological treatments. “It’s common practice to recommend such psychosocial strategies for pain only after all medications have failed, but our research is suggesting that we should apply this approach in all people, because a substantial subset benefit from it.
In a study of people undergoing surgery for breast cancer, for instance, those who participated in a programme of mindfulness, pain education and techniques to self-regulate pain called needed opioid medication after surgery for five days less than a control group, without reporting higher pain.
In another study of a psychological treatment called , which involves learning to reframe pain as non-threatening, 50 people were given four weeks of PRT and compared with groups given either a placebo therapy or routine care. At the end of the trial, or nearly pain-free, compared with 20 per cent in the placebo group and 10 per cent of those who received usual care. Brain scans taken before and after the trial showed significantly reduced responses in pain pathways among people in the PRT group.
Darnall has developed her own programme called , which consists of a single 2-hour session that is similar to My Surgical Success. According to , it can be as effective as eight 2-hour sessions of cognitive behavioural therapy, a well-established psychological treatment for pain, and it offers greater pain relief than a health education session that included information about nutrition and managing medications.
“We don’t yet have very clear data on the mechanism,” says Darnall, but she believes that these pain education programmes can help where opioids sometimes don’t, because they equip people with a skill set to calm the nervous system, including pain and other stressors. “Medications alone don’t do that,” she says.
Placebo power
A placebo describes a treatment that has no true medical effect, yet provides a benefit. According to Beth Darnall at Stanford University in California, pain’s universality and malleability make it a useful paradigm to study placebo and nocebo, the opposite effect in which negative beliefs can worsen the pain experience. Researchers are trying to leverage the placebo effect to improve pain treatments.
“Placebo is really well studied in the context of pain,” says Darnall. The effectiveness of placebos historically rests on deception: people experience a benefit because they have been told they were receiving an active treatment. But more recently, many studies have shown that “” – when people are explicitly told that a treatment is inert – can relieve pain as well.
Surprisingly, a study published in Scientific Reports in January suggests that . Participants who had possession of a placebo oil were able to withstand the pain of ice-cold water longer than those who didn’t have the oil.
