What Are the Best Alternatives to Opioids for Chronic Pain Relief

By Hugo Francisco de SouzaReviewed by Benedette Cuffari, M.Sc.

Introduction
Targeted pharmacologic approaches
Non-drug pain management
Safety, limitations, and future directions
References
Further reading

From first-in-class sodium channel inhibitors to inflammation-targeted and digital interventions, this article shows how pain science is reshaping chronic pain treatment beyond opioids.

Image Credit: Stanislau Valynkin / Shutterstock.com

Introduction

Recent advances in pain science, including the development of sodium channel-inhibiting drugs and a more thorough understanding of nociplastic pain, are expanding the landscape of non-opioid treatment options. Chronic pain is now increasingly understood as a multifactorial condition involving dysregulated nociceptive processing, central sensitization, and neuroimmune interactions, rather than only tissue damage. This article explores the mechanisms and physiological advantages of these emerging pain management strategies.

Targeted pharmacologic approaches

Modern pain science emphasizes therapies and pharmacological interventions that aim to provide precise, long-term relief by targeting the underlying biological mechanisms of pain signaling. These mechanism-specific approaches are being developed to improve pain control while reducing reliance on opioids and other broadly acting analgesics.^1,2

Nerve growth factor (NGF) inhibitors

NGF is a critical neurotrophic protein that modulates pain sensitization by binding to the tropomyosin receptor kinase A (TrkA) receptor on nociceptive neurons across the sensory, sympathetic, and cholinergic systems.²

Anti-NGF monoclonal antibodies (mAbs) like tanezumab have recently emerged as alternative strategies to mitigate nociceptive pain. Although these drugs were confirmed to significantly improve participants’ Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in phase III clinical trials, severe safety concerns regarding their long-term use have been reported.² These concerns, particularly rapidly progressive osteoarthritis and joint destruction, have substantially limited their clinical development.

Consequently, the United States Food and Drug Administration (FDA) Arthritis Advisory Committee determined that the risks of tanezumab, particularly rapidly progressive osteoarthritis (RPOA) and bone integrity issues, outweighed its benefits, leading to the termination of its global development program.²

TRPV1 and sodium channel modulators

The transient receptor potential vanilloid 1 (TRPV1) receptor is a polymodal cation channel involved in transmitting pain signals in response to heat and acid.² Early preclinical research indicates that TRPV1 antagonists effectively manage postoperative ocular pain and dermatitis; however, more recent human clinical trials have identified side effects like cold sensations and dysgeusia that have constrained their broader clinical use.²

The most significant advancement in ion channel research occurred on January 30, 2025, when the FDA approved suzetrigine (Journavx), a first-in-class selective inhibitor of the NaV1.8 sodium channel.³ Suzetrigine is a peripheral pain-signal inhibitor that acts on voltage-gated sodium channels expressed in nociceptors, interrupting pain transmission before signals reach the central nervous system. Suzetrigine targets voltage-gated channels expressed in peripheral sensory neurons, thereby blocking the transmission of pain signals to the spinal cord without the addictive potential characteristic of traditional opioid-based anti-pain interventions.⁴

Pivotal trials in acute surgical pain showed statistically significant improvement over placebo, supporting its role as a non-opioid option for moderate-to-severe acute pain. FDA approval for suzetrigine was contingent on clinical evidence from two pivotal phase III trials, which showed a median time to meaningful relief of 119 minutes in abdominoplasty patients and 240 minutes in bunionectomy patients, compared with 480 minutes for an equivalent placebo dose in both cohorts.⁴

Anti-inflammatory biologics and cytokines

Researchers are actively evaluating the efficacy of anti-inflammatory biologics, particularly those targeting cytokines, for managing chronic pain in patients with refractory conditions such as chronic low back pain (cLBP).^1,5 Recent cohort data also support inflammation as one contributor to symptom severity, with higher levels of IL-6, TNF, and leptin associated with worse pain or disability in some cLBP populations. Next-generation multi-omics investigations increasingly link chronic pain to systemic and local inflammation mediated by pro-inflammatory cytokines like interleukin 6 (IL-6), IL-1β, and tumor necrosis factors (TNF-α).^5,6

Novel biologics targeting TNF-α, like adalimumab and etanercept, have been associated with significant therapeutic improvement in specific inflammatory subsets of LBP; however, results in general radiculopathy remain mixed. At present, these therapies appear most promising for selected inflammatory phenotypes rather than the routine treatment of chronic low back pain. Current research aims to identify next-generation cytokine blockade interventions that target patient-specific inflammatory phenotypes.⁶

Non-drug pain management

Non-invasive non-pharmacological therapies (NINPT) are a relatively novel field in pain medicine that leverage endogenous modulatory pathways to restore neural balance and limit central sensitization.⁷ These approaches act across peripheral, spinal, and supraspinal levels of the pain pathway and are increasingly used alongside drug treatment.

Electrical and neuromodulation therapies

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive, low-voltage electrical current-based therapy that activates large myelinated Aβ fibers and inhibits nociceptive transmission in small Aδ and C fibers through presynaptic inhibition in the dorsal horn. TENS may also modulate neuroimmune signaling and endogenous analgesic pathways, thereby contributing to its pain-relieving effects. While TENS is supported by clinical evidence validating its effectiveness in treating fibromyalgia- and osteoarthritis-associated pain, repeated use can lead to analgesic tolerance due to N-methyl-D-aspartate (NMDA) receptor desensitization.⁷

Behavioral, physical, and complementary approaches

Cognitive behavioral therapy (CBT) and mindfulness-based interventions are widely studied for their ability to target the supraspinal processing of pain. These interventions can improve coping, reduce catastrophizing, and support better functional outcomes in chronic pain populations. Similarly, physical therapies like acupuncture support pain modulation by locally releasing adenosine and promoting descending inhibition from the periaqueductal gray.⁷

Digital pain management tools, including mobile applications, telerehabilitation platforms, and virtual reality-based programs, have shown small improvements in pain intensity and disability in some studies. However, the certainty of this evidence remains low, and findings are not yet broadly generalizable across chronic pain populations.^10,11

Image Credit: muhammad sugiarto / Shutterstock.com

Safety, limitations, and future directions

Non-opioid strategies are increasingly replacing conventional pain management interventions. However, their efficacy is often attributed to patient-specific variability, as genetic variations may explain a substantial share of individual differences in pain sensitivity. No single therapy is universally effective, and multimodal, individualized care remains the most realistic near-term strategy for chronic pain treatment.⁹

Digital health technologies (DHTs), including VR-based analgesia and digital CBT, are promising solutions to modern data limitations. These tools may also expand access to non-pharmacological care, particularly for patients with mobility, cost, or geographic barriers to treatment. Even so, current evidence supports cautious optimism rather than definitive conclusions about long-term effectiveness.

References

1. Dey, S., Sanders, A. E., Martinez, S., et al. (2024). Alternatives to opioids for managing pain. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK574543/
2. Pulskamp, T. G., Johnson, L. M., & Berlau, D. J. (2024). Novel non-opioid analgesics in pain management. Pain Management 14(12; 641-651. DOI: 10.1080/17581869.2024.2442292. https://www.tandfonline.com/doi/full/10.1080/17581869.2024.2442292
3. FDA. (2025, January 30). FDA approves novel non-opioid treatment for moderate to severe acute pain. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-non-opioid-treatment-moderate-severe-acute-pain. Accessed 26^th March 2026
4. Vertex Pharmaceuticals. (2025, January 30). FDA approves JOURNAVX (suzetrigine), a first-in-class treatment for adults with moderate-to-severe acute pain. Vertex Press Release. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-fda-approval-journavxtm-suzetrigine-first-class. Accessed 26^th March 2026
5. Enrico, V. T., Anderst, W., Bell, K. M., et al. (2025). Plasma Pro‐ and Anti‐Inflammatory Cytokines in an Observational Chronic Low Back Pain Cohort. JOR SPINE 8(3). DOI: 10.1002/jsp2.70095. https://onlinelibrary.wiley.com/doi/10.1002/jsp2.70095
6. Anyfanti, P., Evangelidis, P., Tragiannidis, K., et al. (2025). Targeting Inflammatory Pathways in Chronic Low Back Pain: Opportunities for Novel Therapeutics. Pharmaceuticals 18(11); 1612. DOI: 10.3390/ph18111612. https://www.mdpi.com/1424-8247/18/11/1612
7. Shi, Y., & Wu, W. (2023). Multimodal non-invasive non-pharmacological therapies for chronic pain: mechanisms and progress. BMC Medicine 21(1). DOI: 10.1186/s12916-023-03076-2. https://link.springer.com/article/10.1186/s12916-023-03076-2
8. Lai, W., Tang, X., Chen, S., et al. (2026). Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization. Frontiers in Immunology 17. DOI: 10.3389/fimmu.2026.1677310. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1677310/full
9. Lange. J. (2025). Evaluating the Evidence for Genetics/Genomics in Chronic Pain: An Integrative Literature Review. Kansas Journal of Medicine 18(S3); 55. DOI: 10.17161/kjm.vol18.24480. https://journals.ku.edu/kjm/article/view/24480
10. Lee, J., & Park, S. (2025). Effectiveness Of Digital Therapeutics On Chronic Pain In Older People: A Systematic Review And Meta-Analysis. Innovation in Aging, 9(Supplement_2). DOI: 10.1093/geroni/igaf122.3213. https://academic.oup.com/innovateage/article/9/Supplement_2/igaf122.3213/8409499
11. Silva, A. G., Santos, A. J., Andias, R., & Rocha, N. P. (2025). Effectiveness of digital pain management for older adults with musculoskeletal pain: systematic review with meta-analysis. Frontiers in Pain Research 6. DOI: 10.3389/fpain.2025.1657014. https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2025.1657014/full

Further Reading

• All Pain Content
• Using a Pain Diary
• How Do We Sense Pain?
• Role of Dopamine in Pain
• Common Causes of Stomach Ache

Last Updated: Apr 16, 2026