Addressing the Empire of Pain

“Pain,” as Albert Schweitzer, a French theologian, once said, “is a more terrible lord of mankind than even death itself." It manifests in many forms, both mentally and physically, and holds enormous sway over an individual's life. The mere thought of pain influences us not only when it appears in full force, but also when it remains more or less invisible, dispersed across countless acts such as the care we take in handling a sharp knife. Pain provides stability to our lives; something we depend on, work around, and adjust to.

Opioids are one of the oldest medicines known to mankind, and have been used across history to treat acute and chronic cases of pain. First considered as a “wonder drug,” they activate an area of nerve cells in the brain and body that can block pain signals – but they are also highly addictive and activate the brain’s reward system. This, alongside the emergence of synthetic opioids, have been the primary reasons for their sharp reputational decline in recent years, with the medical community and society at large growing increasingly cautious about their use. A 2021 study even showed that a predominant number of patients believe addiction to be a risk when prescribed; many also suggested that it may lead to substance abuse, or, in extreme cases, overdose or death.

A common, historical explanation blames the crisis on the expanded prescribing and advertising of opioids, dating back to the 1990s; simply put, more prescribing equals more deaths. Most famously, Purdue Pharma – a company which still exists today – played a central role in misleading the public about the addiction risks of their flagship drug, OxyContin. The company’s marketing campaign convinced many that the product was safe for long-term use, while also downplaying its highly addictive nature. In 2007, Purdue settled for $600 million after pleading guilty to these claims, marking one of the largest settlements by a pharmaceutical firm. Purdue's president, top lawyer, and former chief medical officer were also fined $34.5 million collectively and sentenced to 400 hours of community service.

Federal and state governments have since implemented a range of policies to regain control of the crisis, and numerous pain management clinics have been targeted in raids for allegedly overprescribing medications. Nevertheless, critics argue that these measures, while well-intentioned, have driven many opioid users to seek out illegal alternatives. An example of this would be fentanyl: a powerful, synthetic opioid that was responsible for over 74,000 US drug-related deaths in 2023. Its potency means that even tiny amounts can be lethal, and its rapid onset of life-threatening respiratory depression – occurring within minutes – leaves a much narrower window for intervention compared to heroin. Some suggest that only a few tons of its purest form would be enough to satisfy America's annual consumption of illegally sourced opioids.

Today, more than 16 million people worldwide have opioid use disorder (OUD), with 2.1 million residing in the US. The condition is defined as the chronic use of opioids that causes clinically significant distress or impairment and symptoms include an overpowering desire to use opioids, increased opioid tolerance, and withdrawal syndrome when opioids are discontinued – ranging from dependence to addiction.

Challenges in OUD Treatment

As it stands, there are only three molecules approved for the treatment of OUD. The most recent of which, buprenorphine, came in 1981, along with a handful of related formulations. “The medications for OUD are highly effective, but they reach only a small percentage of patients and many drop out of treatment,” says Brian Fuehrlein, Associate Professor of Psychiatry at Yale School of Medicine. Indeed, retention rates for medications like buprenorphine hover at around 50 percent. Methadone has been generally better received, but there's still room for improvement. Fuehrlein suggests we also need to develop a fundamental understanding of how the disorder operates with more research on novel concepts, questioning: “Is there a role for GLP-1 agonists? What is the role of dopamine and can dopamine modulators be of benefit? Is there also a role for interventions such as TMS, DBS and others?”

There are several other reasons why treatment and research has struggled to maintain pace with the fast-changing landscape of the illicit drug community, including the difficulty of recruiting patients for clinical trials, which is especially true for substances that are illegal to use. “Research and development for any new medication is also very expensive, and retention rates for substance abuse disorders (SUD) treatment is low and chance of success variable,” says David Fipps, psychiatrist at the Mayo Clinic. “Therefore, it is difficult for pharma companies to designate a large sum of money to a product that may have an unclear trajectory.”

However, Fipps also adds that one way we can support further development would be to start identifying SUDs, like OUD, as chronic and relapsing diseases. Pharma companies regularly release new medications for similar recurring diseases – such as hypertension, diabetes, obesity, and asthma – that are not only efficacious, but also profitable. “If you look back in history,” says Fipps, “there was a time when treatment options for diabetes and obesity were both limited and stigmatized. However, these companies decided to fund investigations for new/better treatments despite the limitations and these diseases now have regular and quick advancements in pharmacologic treatment.”

In contrast, SUDs remain drastically neglected by the private sector. “While NIDA has been a massive supporter of drug development efforts, in addition to basic research on addiction, progressing novel treatments through the arduous regulatory process requires much more investment and attention from private investors,” says Barrett. “There are dozens of approved medications for major depression for example, and despite the availability of safe and effective treatment options, there continues to be massive investment in this space.”

Stigma arguably poses the biggest barrier to OUD and, more broadly, SUDs, as there is often little appreciation that it cannot be overcome through the lens of willpower alone. In fact, evidence tells us that SUDs have similar relapse rates as hypertension, diabetes, and asthma, except the manner in which these issues are dealt with vary greatly. “Addiction cuts across all socioeconomic and demographic stratifications,” argues Barrett. “This stigma has contributed, at least in part, to a lack of investment by healthcare-related venture capitalists.”

There are many ways to tackle stigma, and Fuehrlein suggests “we could start by modifying school curriculums to teach it appropriately, educating legal systems to reinforce OUD as a chronic medical condition best managed with treatment, and improving understanding in the public about its disease model.” To achieve this, partnerships with public health officials and government bodies will be essential and Fuehrlein advocates for “stricter penalties for manufacturing and distributing dangerous opioids, as well as preventative measures to keep the supply of these drugs low.”

Another way to curtail overdose deaths would be to make naloxone (narcan), which is a medicine that attaches to opioid receptors and blocks the effects of other opioids, more readily available. “If we as a society made naloxone nasal spray as commonplace as the seatbelt, we may see a similar influence on death rates as we did when cars started incorporating this safety feature however many years ago,” says Fipps. “There is ample evidence to support that when police are equipped with naloxone spray, opioid overdose deaths decrease.” And while this does not treat OUD, nor can we expect it to change use rates, it can address one of the disorder’s consequences and save lives in the process.

Bridging the Gap

In addition to immediate harm-reduction strategies, the past 12 months or so have brought advances in long-term treatment options. Take Barrett’s company, Cessation Therapeutics, for example. They have developed a therapeutic candidate called CSX-1004 to tackle fentanyl and fentanyl analogs. “It is a human monoclonal antibody that works by sequestering fentanyl molecules as they enter the bloodstream, effectively neutralizing them in the blood before they reach the brain and preventing them from exerting their harmful effects,” says Barrett. “This blocks all the effects of fentanyl, including the respiratory depressant that leads to life-threatening overdose, and the drug’s euphoric feeling (or ‘high’).”

CSX-1004 is also designed to be taken prophylactically in individuals who are at elevated risk for an overdose and, in a primate model, was shown to block the respiratory depressant effects of potentially lethal doses of fentanyl for up to one month. In contrast to other medications for OUD, it is restricted to the bloodstream and thus does not have intrinsic abuse potential or opioid-related side effects. This means it could be used not only as a stand-alone agent, but in combination with other medications too.

Despite their antiquity, many researchers are also convinced that long-acting injectable formulations of naltrexone and buprenorphine still have more to offer. A recent study demonstrated that a one-week formulation of extended-release buprenorphine had a low incidence of causing precipitated withdrawal, even though it was administered early in the withdrawal course. “Though most would concede that the initiation of buprenorphine has been wrought with challenges, especially in the age of fentanyl, advances like this show promise as patients could be easily initiated on buprenorphine in an ER setting and provided followup within a week,” says Fuehrlein. In agreement, Fipps notes that “a one-month injectable form of the medication could allow for a steadier and regular dose regimen.

Substitution treatments for opioids, on the other hand, have been explored for decades, with many attempts failing to create effective painkillers without addiction risks. Vertex Pharmaceuticals, for example, has faced repeated challenges in this area but now offers some hope. The company claims to have developed an experimental drug that relieves moderate to severe pain, blocking pain signals before they can get to the brain. It works only on peripheral nerves, which are those outside the brain and the spinal cord, making it unlike opioids.

The results come from two studies; the first included 1,118 people with abdominoplasties and the second included 1,073 people who had bunion surgery. The two procedures are commonly used in studies of people with acute pain; the temporary kind that is brought on by something like a surgical procedure and is likely to ease with time. The reports from the studies show that those who took the drug had a statistically and clinically meaningful reduction in pain.

Recent research is also starting to produce alternatives to opioids. For example, University of Utah engineers have developed a device that noninvasively stimulates deep brain regions, potentially disrupting the pain signals responsible for chronic pain. Additionally, AOS Society researchers have identified an experimental opioid that binds to an unusual site on the receptor, reducing pain in animal models with fewer side effects, particularly those related to fatal overdoses. Efforts in Germany have even seen opioids replaced with a natural product called aniquinazolin B that is isolated from the marine fungus Aspergillus nidulans that stimulates the opioid receptors and could possibly thus be used instead of opioids in future.

In Fuehrlein’s view, GLP-1 agonists that are being used for management of diabetes, as well as for weight loss, may also hold promise in treating substance use disorders too. Moreover, medications that prevent or ameliorate OUD, along with novel analgesics that are either non-addictive and/or don’t cause respiratory depression represent the prevailing focus area of researchers today.

The Road Ahead

We are, however, still a long way from having an arsenal of treatment options for OUD when compared with many other illnesses; instead, the field must look to the future for inspiration.

There are several achievable goals for the pharma industry, academia, and government to pursue over the next five to ten years. While reducing death rates remains a clear metric for success, improving other aspects of treatment is equally important. As Fipps notes, “New treatments that are easily accessible, affordable, have fewer side effects, offer better efficacy, protect against overdoses, address cravings and withdrawal symptoms, and can be easily prescribed in primary care settings are fundamental hopes.”

Current SUD drug approval processes are markedly slow; thus, favorable changes in the regulatory framework would be welcome. For example, accelerated pathways for new OUD-specific therapies could simplify – or perhaps even expedite – the barriers for both novel medications and non-traditional treatments, such as digital therapeutics and new delivery systems. This may even encourage greater investment and research into OUD. An additional target area in this regard would be updated guidelines that support the integration of treatment into primary care settings and expand reimbursement policies for comprehensive care models.

As the experts have laid out, reframing how society views substance use disorders, the language used, and treatment definitions will also play a major role in patient recovery. This involves replacing terms like “abuse,” “addict,” and “alcoholic” with “substance use disorder,” “opioid use disorder,” and “alcohol use disorder.” It can also help the public recognize OUD as a complex condition that requires a combination of medications, therapy programs, and recovery support groups, as opposed to the current principal endorsement of stigmatizing behaviors. Though such a change will require long-term support from the education and legal systems.

Since the late 1990s, over 560,000 people have died as a result of opioid misuse in the US. A conservative opinion might assume that the overall scale of the problem will remain steady, with the burden shifting from developed to developing countries. A less conservative opinion would be to assume that in developed countries, rates of opioid use and opioid-related deaths will continue to rise, as well as in developing countries. Afterall, many of the same problems that fueled the epidemic at its onset still persist today, except, with the introduction of synthetic drugs, things are arguably worse. To make a difference, society itself must change – and the next decade will be critical in addressing the ruinous effects of a now 20-year long dilemma.