Upward trajectory

In the United States, opioid prescription rates have been falling since 2011. But in the same period, the number of opioid-related deaths has increased dramatically.

Rising death toll: Fatalities involving opioids now account for more deaths in the United States than motor-vehicle accidents or firearms incidents.

Source: CDC

Falling prescriptions: For many years, the trend in opioid-related deaths in the United States correlated roughly with that in opioid prescriptions. But as opioid sales began to fall in 2011, the death toll continued to rise.

Source: SHADAC/DEA

Moving underground

Addictions to prescription opioids have helped to create a market for heroin, an illegal opioid often adulterated with the potent opioid fentanyl.

Three-act tragedy: Deaths from prescription opioids have plateaued. After a sharp rise in deaths caused by heroin overdose, those linked to fentanyl are skyrocketing.

Source: CDC

Shifting gateways: In the past, opioid-use disorders typically began with the use of prescription opioids, although many people progressed to illicit opioids. Since 2011, the proportion of addictions initiated by heroin has been rising.

Source: Adapted from T. J. Cicero, Z. A. Kasper & M. S. Ellis Addict. Behav. 87, 267–271 (2018).

A safer prescription

Opioid prescription rates vary markedly between countries. Some nations use this class of drug widely for pain relief without high death rates.

Leading prescribers: Although the United States prescribes the most opioids of all high-income countries, other nations also use prescription opioids in large quantities.

Source: OECD/INCB

Variable relationship: Prescription opioid use varies between countries in terms of many factors. These include opioid strength, monitoring of patients and the level of social support available to users. Such differences could help to account for variations in mortality rate.

Source: OECD/INCB

The path to pain relief

Opioids can provide strong pain relief, or analgesia, but they are also extremely addictive. The benefits and risks of taking prescription and illicit opioids arise from the activation of a signalling system used by the brain to regulate numerous functions.

Opioid receptors: There are several types of opioid receptor in cells. Prescription and illicit opioids activate the μ-opioid receptor (μOR), which inhibits the activity of neurons by two main signalling pathways.

The presence of μORs on the surface of many types of neuron throughout the central nervous system, as well as in the gut, mediates the diverse effects of opioids.

Painless reversal

Halting the opioid crisis will require action on several fronts, including these three crucial areas.

Alternative painkillers: The search for effective non-opioid painkillers continues, and new ways of targeting μORs could deliver safer opioids.

Opioids that are pH-sensitive might activate μORs only in inflammed tissue.

Opioids that mainly activate the G-protein signalling pathway might be less addictive.

Decreasing dependence: Opioid dependency is a long-term, relapsing medical condition. The feelings of euphoria and reward that help to trigger it are caused by a spike in dopamine levels. Opioids induce this effect by halting the release of GABA, a neurotransmitter that inhibits dopamine neurons.

Several approaches might help to tackle opioid dependency.

• Widened treatment programmes: Providing a weaker opioid in combination with counselling and social support can be an effective treatment for dependency, but access to such programmes is often limited.

• Improved monitoring: Better oversight of people taking prescription opioids could enable earlier intervention.

• Fresh treatments: Neuroscientists are studying opioid-induced changes in neurons to develop new treatments.

Harm reduction: Abruptly withdrawing prescription opioids can lead people to use illicit drugs.

Needle-exchange services, fentanyl-contamination testing kits and naloxone (a medication that blocks the effects of opioids) can reduce disease transmission and overdose among opioid users.

In 2011, Scotland launched a programme to issue naloxone to opioid-dependent people on their release from prison. The scheme has contributed to a decrease in overdose deaths that occur in the month following release.