By Tejaswini Divanji, Master of Science (Pharmaceutical Sciences) student at Monash University

Everyone knows what pain feels like, even though our individual scales for it might be different. But what exactly is pain?

Understanding and addressing pain is one of the oldest challenges of medicine. Broadly, pain is an unpleasant sensation; a warning signal that something is damaged, prompting action to limit further harm.  However, as many people know, this doesn’t always work exactly as described.

Pain can be divided into two broad categories: acute and chronic. Acute pain is short, and resolves as the body heals itself from injury. As painful as a papercut can feel, you’ll recover quickly, and the pain will go away. In contrast, chronic pain persists beyond the body’s healing process following the initial injury, illness, or trauma. Chronic pain loses its protective function and can severely impact the patients’ quality of life.

Opioids: the opium of the people

Opium has been used to relieve pain for millennia. Opium poppies (predominantly Papaver somniferum) contain several pain-relieving compounds including morphine and codeine, and evidence of medical prescriptions of the opium poppy is found in ancient Sumerian clay tablets from 2100 BC.¹

By the 20th century, opioids were increasingly the preferred drug for the treatment of severe pain. Claims that patients would not become addicted to opioid painkillers led healthcare providers to prescribe these drugs freely, but, as we now know, these claims were false.^2,3 The over prescription of opioids set the stage for an ‘opioid epidemic’, beginning in the 1990s and contributing to upwards of 630,000 deaths between 1999 and 2016 in the United States alone.² In 2017, the US Department of Health declared the opioid crisis a public health emergency due to increased misuse of opioids.⁴

Australia currently ranks eighth in the world in opioid use (daily doses of prescription per million people), at about 40% of the level of the US.⁵ The number of annual opioid-related deaths spiked in 1999 (1,245 deaths), and while there was a drop in the early 2000’s, the number climbed again to 1,385 and 1,355 deaths in 2017 and 2018 respectively.⁶ Over the last five years, the problem hasn’t slowed. Opioids continue to be the most common drug class present in drug-induced deaths in Australia (3.8 per 100,000 population in 2021),⁶ and prescription opioid overdose remains a significant problem on a global scale.

Non-opioid alternatives for pain management

To date, it has not been possible to simply halt opioid use altogether. Opioid painkillers are still in use, despite their high addiction potential and side effects of respiratory depression, nausea, physical dependence, and tolerance. Their continued prescription is owed to their effectiveness as treatments for acute postsurgical and postprocedural pain, as well as neuropathic pain, cancer-related pain, and vascular pain.⁷

But while their utility as a therapy for acute pain is well-established, there is very little evidence to justify their continued use for chronic pain, which affects 3.4 million Australians every year.⁷ A clinical study of 26,000 patients showed that opioids do not provide clinically significant relief from pain in patients with chronic non-cancer pain. Additionally, opioid painkillers were associated with less pain relief in longer clinical trials, because opioid-tolerance patients stopped responding to it as well.⁸ Overuse of opioids, ironically, causes more pain in patients, and ceasing the use of opioids after long-term use results in devastating withdrawal symptoms.⁷ The opioid crisis in the US showed that opioid use is surrounded by stigmas driven by stereotypes, prejudice, discrimination, and social devaluation of patients which further hinders the implementation of measures to address the crisis.⁹ Together, it highlights the need at both a clinical and societal level to identify better options for pain management.

With our thorough understanding of the risks vs benefits, opioids no longer need to be regarded as the first choice for managing chronic pain. Several non-opioid drugs already exist that can alleviate pain in a more targeted manner and with fewer negative side-effects.¹⁰

In addition to existing drugs, the pharmaceutical industry is also developing new non-opioid alternatives for pain. There are currently 546 painkillers in development, with cannabinoid receptors emerging as the most popular drug targets, as they modulate a variety of physiological processes (including pain).¹¹ Given the high priority of ensuring access to non-addictive painkillers, pharmaceutical companies and regulators have begun to fast-track novel drugs through the clinical trial process, such as tanezumab for chronic pain and osteoarthritis and Vertex Pharmaceuticals’ novel drug VX-548 for postoperative pain.¹²

Outside of the pharmaceutical industry, academic researchers are also developing painkillers. A new type of opioid molecule developed at the University of Bath and Wake Forest University has shown promising results in rhesus monkeys without impacting breathing or causing addiction.¹³ While it shows early promise in animals, it is still a long way to being developed for human use.¹³

Drugs alone cannot sufficiently alleviate chronic pain, and other treatments and therapies are needed as part of a holistic approach. Healthcare providers can use a combination of treatments such as exercise, physical therapy, and talk therapy to reduce the severity of the pain. The emergence of novel drugs and increasing use of behavioural interventions show the future direction of pain management. They provide hope for a future without opioid addiction, and a potential end to the epidemic.

References:

1. Bandyopadhyay, S. (2019). An 8,000-year History of Use and Abuse of Opium and Opioids: How That Matters For A Successful Control Of The Epidemic? Neurology, 92(15 Supplement).
2. Bernard, S. A. et al. (2018). Management of Pain in the United States—A Brief History and Implications for the Opioid Epidemic. Health Services Insights, 11. doi.org/10.1177/1178632918819440
3. US Department of Health and Human Services. (2022, December 16). Opioid Facts and Statistics. hhs.gov/opioids/statistics/index.html
4. Centers for Medicare & Medicaid Services. (2017, October 26). Ongoing emergencies and disasters. cms.gov/about-cms/what-we-do/emergency-response/current-emergencies/ongoing-emergencies
5. Therapeutic Goods Administration. (2019). Addressing prescription opioid use and misuse in Australia: Regulatory Impact Self-Assessment Report.
6. Australian Institute of Health and Welfare. (2023, November 1). Illicit Drug Use. aihw.gov.au/reports/illicit-use-of-drugs/illicit-drug-use#health%20impact
7. Grewal, N. & Huecker, M. R. (2023). Opioid Prescribing. StatPearls. ncbi.nlm.nih.gov/books/NBK551720/
8. NPS MedicineWise. (2019, October 2). If not opioids, then what? nps.org.au/news/if-not-opioids-then-what
9. Tsai, A. C., et al. (2019). Stigma as a fundamental hindrance to the United States opioid overdose crisis response. PLoS Medicine, 16(11). doi.org/10.1371/JOURNAL.PMED.1002969
10. Dey, S., & Vrooman, B. M. (2023). Alternatives to Opioids for Managing Pain. StatPearls. ncbi.nlm.nih.gov/books/NBK574543/
11. Pharmaceutical Technology. (2023, June 12). The future of pain medication: are cannabinoids the solution to the opioid epidemic? GlobalData Healthcare. pharmaceutical-technology.com/comment/cannabinoids-solution-opioid/
12. Collins, S. (2018, March 14). Beyond Opioids: The Future of Pain Management. WebMD. webmd.com/special-reports/opioids-pain/20180314/opioid-alternatives
13. Ding, H., et al. (2016). A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. PNAS, 113(37). doi: 10.1073/pnas.1605295113.
14. Bayer’s Pharmaceutical Specialties. (1899). BMJ, 1(1997), 28.