The journey of pain management has been a long and complex one, marked by significant advancements and daunting challenges. From the early use of natural substances to the development of synthetic opioids, the quest for effective pain relief has been a constant pursuit. The opioid crisis in the United States, where the over-use and misuse of opioids leading to over 80.000 opioid-related deaths in 2021 and surging rates of opioid use disorder¹ was a stark illustration of the risks of pain killers, especially in chronic use, and an illustration of the need for effective but non-addictive pain medications. Alternatives are on the horizon. Non-addictive pain medications offer hope to alleviate the disease burden associated with pain.

Acute pain is unwelcome and burdensome, though serves as a vital protective mechanism e.g., teaching us to avoid harm or to prevent further injury. Chronic pain on the other hand can be truly debilitating and in contrast to common perception is not purely psychological but has physical basis just like hunger and thirst². The most prevalent types of chronic pain are migraine and lower back & neck pain³. In 2020, lower back pain alone affected 619 million people globally and is forecast to grow to 843 million by 2050 (Figure 1 left panel). This is a worrying development with enormous consequences for already stressed healthcare systems that suffer from understaffing, HCP resignation or patient backlogs⁴. On average, chronic pain patients must wait 2.2 years for a diagnosis and another 1.9 years before their suffering is adequately managed⁵. Chronic pain exerts an enormous economic impact coming from direct costs for medical treatments and indirect costs due to absenteeism and presenteeism summing up to €300 billion annually on the European continent and $635 billion in the United States alone^6,7,8. Despite its massive toll on patient lives and economies, prescription drug spending for pain medicines remains underfunded relative to its overall disease burden (Figure 1 right panel). Pain accounts for 10% of years lived with disability (YLDs) and only 1% of all innovative prescription drug spending in 2023. Opioid medications remain a common acute and chronic pain treatment despite their addictive potential and following abuse that contributed to the opioid crisis in the U.S. Marketed pain medicines are also cheap with more than 85% of pain medicine volume being generic and except for CGRP antagonists in migraine, no drugs with novel modes of action were approved in the past decade.

Efforts to develop alternatives to opioids often resulted in failures with success rates at 0.7% compared to 6.5% for novel drugs across therapy areas⁹. In the 2010s, Eli Lilly and Pfizer’s biologic tanezumab showed promising results in moderate to severe osteoarthritis (OA) pain. The monoclonal antibody suppresses nerve growth factor (NGF) that are produced in response to inflammation and increase the sensitivity towards pain perception. Initial results were highly encouraging with pain reduction greater than placebo or standard of care. However, the drug was plagued by safety issues and development consequently discontinued. Both Acadia’s and Biogen’s clinical programs also disappointed during phase 2 clinical trials in 2021 and 2022 respectively^10,11.

Figure 1: The global burden of pain is high and growing

Figure 1: Pain disease burden; Source: IQVIA EMEA Thought Leadership, IQVIA MIDAS MAT Q3 2023, Rx-only; Global Burden of Disease 2019, IHME; Global, regional, and national burden of low back pain, 1990–2020, The Lancet Rheumatology June 2023

After years of painstaking clinical trials and repeatedly unsuccessful attempts to identify new modes of action for pain treatment, there is finally a glimmer of success. Vertex Pharmaceutical’s investigational compound VX-548 – now called Suzetrigine – met its primary endpoint in a phase 3 study to treat moderate-to-severe pain following surgery¹². The compound specifically targets the sodium ion channel Na_v1.8 – a member of a class of receptors in nerve cells closely associated with the transmission of pain signals to the brain. The general idea is not novel, but the specificity of the Vertex compound is. Lidocaine is used as a local anaesthetic and blocks all sodium ion flow but causes numbness and might leave patients feel dizzy. Suzetrigine in contrast, was well-tolerated, safe, and relieved pain following abdominoplasty or bunionectomy surgery. However, the drug failed its secondary endpoint and was not superior in pain suppression compared to hydrocodone bitartrate/acetaminophen (Vicodin). Vertex is now heading towards approval already receiving breakthrough status by the FDA. The regulatory agency has also granted the company a rolling NDA for Suzetrigine in moderate-to-severe-acute pain – expected completion date by end of Q2 2024. Moreover, Vertex is also advancing its program for chronic pain and is preparing to start a pivotal phase 3 study in the second half of this year¹³. Analysts and experts are excited about the initial results and see the Vertex data as the first step towards a new way of treating pain. Indeed, whilst the majority of the clinical R&D pipeline is investigating existing mechanisms of action, there are encouraging signs that the industry is exploring new ones to address the pain disease burden.

Clinical trials data shows 67 trials relating to pain treatment listed in 2023 (Figure 2 left panel). This is less than half the number of trials occurring a decade ago and continues a declining trend in the overall number of pain clinical trials since 2014. Despite this drop, half of these trials are in Phase III, a higher proportion than at any point in the past decade and an indication that new products – such as Vertex’s Suzetrigine – are likely to come to market soon. Furthermore, as the right-hand side of Figure 2 highlights, 40% of pain trials in 2023 are investigating novel mechanisms of action.

The leading novel mechanism in this set is cannabinoids, with 10 out of 12 trials in Phase III, and the majority being investigated in chronic pain. Although both synthetic cannabinoids and cannabis-derived compounds have been approved for other indications – the FDA has approved products for seizures associated with Dravet and Lennox-Gastaut Syndromes, nausea associated with chemotherapy, and anorexia associated with AIDS – there have not yet been any approvals for treatment of pain¹⁴. The leader in this space is Apurano Pharmaceuticals GmbH, a small biotech based in Germany and with multiple phase III pain trials for cannabinoids.

Following cannabinoids, the next leading mechanism in the pipeline are the selective sodium channel inhibitors like Suzetrigine mentioned previously. Whilst Vertex is certainly ahead of the pack it is not the only competitor, with both Jiangxi Jemincare Group and Latigo Biotherapeutics have assets in Phase I, although due to their early stage Vertex looks set to dominate this pain mechanism and could benefit from a significant first-mover advantage.

Figure 2: The clinical pain clinical trial activity

Figure 2: Clinical stage pain clinical trial activity; Source: IQVIA Global Trends in R&D Report Jan. 2024, Citeline Trialtrove; EMEA Thought Leadership analysis. Includes all trials including terminated and completed trials; Note: The pain pipeline here has been defined as products that seek to treat pain as a result of a condition, rather than necessarily seeking to treat the underlying condition itself. E.g., treating pain resulting from OA rather than treating OA itself.

Although the pain pipeline is dominated by smaller players, Top 10 pharma companies are also present in the pipeline. Eli Lilly, GSK and J&J are all represented, with Lilly and GSK both investigating assets with novel mechanisms of action. Lilly has a Phase I asset targeting somatostatin receptor 4 for excitation, whilst GSK has a Phase II asset that seeks to inhibit expression of CCL17, which has been associated with causing OA pain^15,16.

One mechanism that is conspicuously absent from 2023 pain clinical trials are the NGF inhibitors. Once hailed as a potential breakthrough in chronic pain, this class of products has since fallen from grace, with J&J, Lilly and Pfizer, and Teva and Regeneron all announcing the discontinuation of the development of their NGF assets in 2016, 2021 and 22 respectively.

The way forward

The year 2024 marks the end of a decade-long stride towards the development of alternatives in pain medicines. Vertex will likely get the FDA’s approval in moderate-to-severe acute pain whilst the far larger unmet need, and hence, opportunity is in chronic pain where the drug must still prove its effectiveness. Experts in the field are cautious whether blocking peripheral sources of pain itself is sufficient as the underlying biological causes of chronic pain are different. More clinical data is needed. Furthermore, Vertex and other pain innovators must understand the realities of the post-pandemic market environment and take some lessons to heart:

• Raise pain disease profile: Prescription of pain medications are under scrutiny in the aftermath of the opioid crisis and clinicians may tend to be cautious to prescribe. Time-constrained physicians must work through guidelines, understand the patient’s pain journey, and subsequently provide an individual treatment plan. Giving existing medical professionals access to tools and services including educational materials is key to realising improvements in pain management. The underlying pain biology and care must also become an integral part of medical training. Moreover, health systems must establish clear pain management pathways to ensure proper referrals to specialists and thus both simplify and shorten the route to diagnosis.
• Pain care beyond the pill: Pain is not a single issue – single solution type of disease. Hence, one approach will likely not be sufficient to effectively manage pain. Too often, patient feel dismissed, and their issues not taken seriously. Mental health issues, insomnia and other physiological effects related to chronic pain have massive impact on patients’ quality of life and must be incorporated when thinking about treatment. Patient support programs and digital technologies such as telemedicine or mobile health applications can address these often-overlooked additional aspects of pain.
• Convince payers: In the wake of the opioid abuse crisis, and as a highly generic market that has not seen innovation in decades, it will be even more paramount for next-generation pain medications to prove their value against the standard of care. Flipping the existing treatment paradigms from (cheap) opioids with a serious side effect profile will not be easy. Pharma must anticipate significant payer headwinds and engage with relevant stakeholders early to ensure that as many patients can benefit from these drugs as soon as possible.

The above points underly the importance of a holistic approach to pain management, where innovation is driven by a deep understanding of patient needs, the exploration of diverse treatment modalities, and collaborative efforts across the healthcare ecosystem. The stakes could not be higher. As the science is advancing, so must our thinking on how to ensure that novel treatments reach as many patients as early as possible.