Pharma & drug development War on drugs

Relief without the opioids

The  opiate epidemic has been much discussed, with the addictive characteristics of opioid painkillers taking a serious toll on public health. Abi Millar investigates the latest innovations in analgesics that don’t rely on opioids. 

Pain relief sits at the cornerstone of any modern healthcare system. Though the precise incidence is unclear, it is estimated that between 10% and 55% of the population live with some form of chronic pain, with around 100 million sufferers in the United States alone.

This pain is highly variable in nature and severity. It can range from mild and intermittent to constant and incapacitating. It may originate in a particular part of the body, or it may be neuropathic (deriving from the nervous system). And while the causes are sometimes clear-cut – e.g., a persistent twinge after injury – in other cases the provenance is more mysterious. The rheumatic condition fibromyalgia, for instance, can be exacerbated by psychological stress.

Finding ways to alleviate, or even just to manage, chronic pain is therefore critical. For those at the milder end of the spectrum, over-the-counter remedies may prove sufficient: paracetamol for headaches, ibuprofen for period pain. However, the more severely afflicted are often prescribed powerful opioid drugs. In 2014, US doctors wrote nearly 200 million prescriptions for opioid painkillers such as Percocet, Vicodin and OxyContin.

Opioid epidemic

Opioids are so prevalent because, simply put, they work. They act on opioid receptors in the central and peripheral nervous system, reducing the number of pain messages sent to the brain. However, this efficacy may come at a cost: when used routinely, the patient stands at risk of physical dependence, abuse, and addiction. As a result, opioids are not recommended for long-term pain management unless other, less risky, treatments have failed.


As Dr David M Dickerson, assistant professor of anesthesiology and pain medicine at the University of Chicago, explains: “Opioids frequently cause significant sedation, nausea, constipation, and respiratory depression. Over time, they lose efficacy and cause tolerance and dependence. Leftover, unused pills can be diverted for misuse or abuse by patients, their friends or family members fueling the already rampant opioid epidemic.”

Unfortunately, the problem is on the rise. Deaths from opioid drug overdoses have been climbing for decades, reaching 28,000 Americans in 2014. In more than half these cases, prescription drugs were implicated.

That same year, 1.9 million Americans had a substance use disorder involving prescription opioids, and a further 586,000 were addicted to its infamous sister drug, heroin. It would be a mistake to consider the two in isolation. Four out of five new heroin users started out misusing prescription painkillers, graduating to heroin because it was cheaper or easier to obtain.

Even if users don’t reach the point of addiction, abuse is rampant: in May 2016, the Los Angeles Times reported that over 7 million Americans had abused oxycodone. The problem is now making waves at the highest levels, with President Obama proposing $1.1bn in new funding for opioid addiction treatment, and Congress passing a bill intended to curb abuse.

Of course, while treatments are sorely needed, it would be better still if opioid misuse never arose in the first place. The need for non-opioid analgesics is therefore not in doubt. Ideally speaking, such a treatment would be as effective as opiates, but would lack their less desirable characteristics.

Luckily, the last few years have seen significant advances in this field, with a range of new treatment options hitting the market. We might divide these solutions into three categories: non-opioid pain medicines, abuse-resistant narcotics, and various pioneering treatment avenues that don’t use drugs at all.

Non-opioid pain medicines

A patient might be prescribed anticonvulsants for neuropathic pain; serotonin and norepinephrine reuptake inhibitors for fibromyalgia; or non-steroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis. In many cases, several different drugs are administered together.

“Non-opioid pain medicine aims to temporarily put nerves to sleep, reduce inflammation, or suppress hyperactivity in nerves transmitting pain with a far superior side effect profile when compared to opioid medications,” says Dickerson. “A combination of different non-opioids, each separately addressing these pain targets, provides improved quality of recovery after procedures as well as a more sustained benefit over time in the treatment of chronic pain conditions.”

One promising contender is Hospira’s drug Dyloject, an injectable NSAID that was approved in late 2014 following a five-year delay. Indicated for both mild to moderate, and moderate to severe pain, the drug is notable for its convenience – uniquely for an injectable non-opioid analgesic, it can be administered within a speedy 15 seconds. Although it does not constitute a true substitute for opioids, it ties well into the new, multi-modal approach now being recommended.

Abuse-resistant narcotics

A number of pharma companies have taken a different tack, asking not how opioids might be replaced, but how their safety profile might be improved. So far, the FDA has approved a number of abuse-resistant opioids, with others on the pathway to the clinic.

Take ALO-02 by Pfizer, which is on course to hit the US market. It contains both naltrexone and oxycodone, with the former released to counteract the latter. Teva has a long-acting analgesic on the way, Vantrela ER, which has minor abuse-deterrent properties, and Purdue Pharma has already received approval for Hysingla ER. This drug is difficult to crush, break, dissolve or inject, reducing its potential for misuse.

“While the science of abuse deterrence is still evolving, the development of opioids that are harder to abuse is helpful in addressing the public health crisis of prescription drug abuse in the US,” said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, announcing Hysingla’s approval.

Rather more innovatively, scientists at Tulane University have developed a drug similar to the neurochemical endomorphin, which targets the same opioid receptor as morphine. In animal studies, it performed as well as morphine but without the side effects. Human trials are expected to begin within the next two years.

There is also a new opioid drug candidate in development, which has been created not by tweaking the structure of existing opiates but by effectively starting from scratch; developing a new, hyper-efficacious molecule using sophisticated computational techniques. The international research team responsible, who published their findings in Nature in August, claimed molecule PZM21 has an “unprecedented, weird and cool” biology.

Non-drug alternatives

We are also seeing the emergence of various novel techniques, designed to aid pain management without the need for drugs. One slightly far-flung option is stem cell therapy, which is speculative at present but may hold promise in the future. Another, even more remote, possibility is nanotechnology, in which sub-molecular surgical instruments are ingested and targeted at areas of need.

More imminently, we can expect to see more devices used for pain relief, such as transcutaneous electric nerve stimulation (TENS) devices that deliver a low-voltage electric current down the nerve fibres. A certain subset of patients also benefit from neurostimulation, in which an electric impulse is delivered to the spine and scrambles the painful nerve signals. At a more basic level, physical rehabilitation is also advancing fast, as pain management doctors team up with physiotherapists to restore function.

Clearly. chronic pain is not a simple problem with a single solution, but rather a heterogeneous condition that should be tackled on an individual basis. And until truly non-addictive versions do hit the market, opiates should always be used with caution.

Dr Tim McCormick, Consultant Anaesthetics at the Oxford University Hospitals NHS Foundation Trust, said: “There is a popular misconception that all pain can be treated with our current painkillers. Pain is a far more complex sensory and emotional experience. Opioids can be useful drugs for short-term pain but their role in tackling long-term pain is far less certain. Only with further research will we be able to help the 28 million adults in the UK with chronic pain.”

This article appears in the October 2016 edition of Pharma Technology Focus

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