In the nineteenth century, the invention of anesthesia was considered a gift from God. But post-operative pain relief has continued to rely on opioids, derivatives of opium, the addictive substance employed since ancient times. Although no other drug has managed to match the rapid, potent, and broadly effective relief delivered by opioids, their side effects have led to decades of addiction and overdose, leaving researchers keen to find a better solution.
This all changed in January 2025, when the FDA approved Vertex Pharmaceuticals’s Journavx (suzetrigine): the first non-opioid pain reliever suitable for treating post-surgery pain. Clinical trials found no signs of the problematic side effects associated with opioids: no drug abuse, tolerance, or withdrawal. But this was not an easy win: Vertex and other pharma companies spent decades searching for drugs like this to no avail.
Opioids are used primarily to treat nociceptive pain, pain caused by tissue damage from injury or disease. This damage activates nearby nociceptors: sensory neurons that signal physical or chemical harm. These nociceptors send signals up to the central nervous system – the brain and spinal cord – and the brain then creates a localized sensation of pain, drawing your attention to the threat.
Traditional opioids mimic opium, a compound found in the poppy plant that contains morphine. Opioids alleviate pain by acting on one of the three main opioid receptors, mu (μ) opioid receptors, which are distributed throughout the central nervous system, particularly in the brain. When opioids bind to the brain’s mu receptors, this suppresses incoming pain signals from the damaged site’s nociceptors, preventing the brain from creating the sensation of pain even when tissue damage is present.
Our bodies naturally produce their own opioids – such as endorphins, endogenous morphine – to briefly blunt pain during moments of stress or injury. However, these are far weaker and shorter-acting than prescription opioids since they degrade quickly, remain localized, and are released in short, controlled bursts. Prescription opioids, on the other hand, flood the brain with higher doses that linger for hours.
Crucially, opioids don’t just kill pain: they also incite pleasure. When the mu opioid receptors present in the reward center of the brain are activated, this reduces the secretion of a neurotransmitter called GABA, which works to inhibit dopamine-producing neurons. As GABA release declines, dopamine spikes, lighting up the reward center and inducing pleasure.
With the body’s natural opioids, this is fleeting and unproblematic. When properly prescribed, even synthetic opioids are no issue for most patients: under severe post-surgical pain, opioids mostly function to normalize disrupted brain function, dampening any pleasurable effect. But for some, whether due to genetics or inappropriate administration (e.g. a prescription that goes on after the pain’s source has been relieved), the intensity of prescription opioids produces a prolonged dopamine spike, along with a marked sensation of euphoria: a recipe for addiction.
With chronic use, the body’s natural opioid system becomes dysfunctional. Fewer natural opioids are produced and opioid receptors become desensitized. As a result, the patient develops a tolerance, requiring higher and higher doses to even feel normal.
The nineteenth century witnessed the creation of morphine, codeine, and heroin (which was sold over-the-counter), as well as the invention of the hypodermic syringe. By the turn of the century, 15 percent of all prescriptions dispensed in Boston were for opioids, which were used for everything from menstrual cramps to children’s coughs, and as many as 300,000 Americans, or 0.5 percent of the population, were opiate addicts. Anti-narcotics laws proliferated throughout the states, and the medical community expressed concerns about the liberal provision of addictive drugs. These mounting pressures led to the passage of the Harrison Narcotic Act in 1914, which made opium and opiates the first regulated substances in the United States.
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