Beyond the Opioid Era: Navigating the $84B Non-Opioid Chronic Pain Therapeutics Market
Comprehensive analysis of non-opioid therapeutics and investment opportunities shaping the future of chronic pain management
Executive Summary
The chronic pain treatment landscape is undergoing a fundamental transformation as healthcare systems seek effective alternatives to opioid-based therapies. Our analysis of clinical-stage assets reveals substantial innovation across novel mechanisms, supported by $8.5B in strategic investments that signal a paradigm shift toward precision, non-addictive pain management solutions.
Introduction
The universal challenge of chronic pain demands innovative, non-addictive solutions as healthcare systems worldwide grapple with opioid dependency.
Pain is a universal theme in illness, with its perception being highly subjective and often reported in both psychological and pathophysiological contexts1,2. The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage"3. While often measured in severity, a fundamental classification of pain is by its duration, broadly classified as either acute or chronic. Acute pain has a sudden onset, is typically short-lived and disappears when the underlying cause is treated or healed. Conversely, chronic pain lasts or recurs for longer than three months, persisting after the original injury has healed2,3.
Chronic pain presents a major burden that is reported to impact more than 30% of people globally4. One in five adults in the US has chronic pain, while UK studies report prevalence rates of up to 43.5%5-7. The negative economic impact of this is severe, not only from a drug cost and medical expenses perspective, but also loss of productivity in the workplace8,9. Back pain, neck pain, osteoarthritis, and other musculoskeletal disorders rank among the top reasons individuals seek medical care for pain, which are leading causes of years lost to disability worldwide4.
While opioids were once commonly prescribed for chronic pain, the public health crisis of opioid use disorder (OUD) has augmented interest in developing non-opioid pharmacological alternatives for the management of chronic pain.
This paper will explore the non-opioid treatment and investment landscape for chronic pain, including emerging treatments, promising molecular targets and therapeutic approaches that are being leveraged for an opioid-free future.
Classification of Chronic Pain
Modern pain medicine recognizes distinct mechanisms underlying chronic pain, each requiring targeted therapeutic approaches for optimal patient outcomes.
In some chronic pain conditions, pain itself becomes a disease, a pathological process independent of an initial cause or origin. For instance, fibromyalgia is a chronic primary pain condition which is characterised by widespread musculoskeletal pain without a clear initiating injury10. In contrast, chronic post-surgical pain is a chronic secondary pain condition which persists beyond the healing process of an operation, and can often be traced back to tissue injury caused by the surgery itself11.
Until 2018, chronic pain conditions were not systematically represented in the WHO's International Classification of Diseases (ICD). This inadequate classification of chronic pain, merely confining it to being a symptom, was not ideal for the advancement of targeted therapies and the growth of pain medicine as a dedicated specialty12. It was responsible for limitations in epidemiological research, lack of effective health policy development and poor resource allocation. In June 2018, the IASP, in collaboration with the WHO addressed these shortcomings with the 11th revision of the ICD (ICD-11) in which systematic classification of chronic pain now distinguishes between chronic primary and chronic secondary pain syndromes, providing precise definitions and characteristic features for each diagnosis. It considers pain severity, its temporal course, and the influence of psychological and social factors12. This approach allows for a more nuanced and accurate diagnosis of chronic pain and facilitates better analgesic drug development through improved patient selection, more targeted research, and more accurate outcome measurements.
The Pathophysiology of Chronic Pain Involves Three Main Pathways
Understanding the complex neural pathways and cellular mechanisms that transform acute pain into persistent, debilitating chronic conditions.
Most pain signals start in nociceptive neurons located throughout the body, which relay these impulses to the spinal cord and up to the brainstem, completing the 'ascending pathway' that makes us aware of pain. In contrast, the 'descending pathway' from the brain modulates the perception of pain, typically acting to protect us by reducing pain signals when necessary, and interacting with the nervous, immune, endocrine, and autonomic systems to help restore physiological balance2,13.
In chronic pain, however, harmful pathophysiological adaptations occur in the central and peripheral nervous system (CNS and PNS respectively), including the formation of new neural pathways and pathology-specific brain alterations4,14. This can elicit modifications in the gene expression of proteins, receptors and neurotransmitters involved in pain signalling within the spinal cord and brain13. For instance, in diabetic neuropathy, abnormal nerve sprouts excessively produce substance P, a neuropeptide which activates nociceptive spinal neurons, and contributes to persistent pain4,15.
In terms of underlying causative mechanisms, chronic pain is broadly categorised into three types:
- Nociceptive pain arises from actual or threatened damage to non-neural tissue and is the most common form of chronic pain. It occurs in conditions like arthritis and most forms of spinal pain4.
- Neuropathic pain arises from injury or disease affecting neural tissue within the somatosensory nervous system, accounting for approximately 15-25% of chronic pain cases. It is commonly observed in conditions like diabetic neuropathy, postherpetic neuralgia and radiculopathy4,16.
- Nociplastic pain arises from altered nociception due to a sensitised CNS, despite no clear evidence of actual or threatened injury. It occurs in many primary chronic pain conditions such as fibromyalgia and complex regional pain syndrome (CRPS)17.
Some chronic pain conditions such as those involving cancer, may span multiple categories.
| Nociceptive Pain | Neuropathic Pain | Nociplastic Pain | |
|---|---|---|---|
| Causes | Actual or potential damage to non-neural tissue | Injury or disease to neural tissue | CNS sensitisation without clear evidence of nerve or tissue damage |
| Primary Site | Typically, PNS (with CNS processing) | PNS or CNS | CNS |
| Chronic Pain Examples | Arthritic conditions e.g., rheumatoid arthritis, gout, osteoarthritis; Spinal pain e.g., neck and back pain; Inflammatory disorders e.g., tendonitis, bursitis | Peripheral neuropathic pain e.g., postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, radiculopathy; Central neuropathic pain e.g., spinal cord injury | Widespread pain syndromes e.g., fibromyalgia; Visceral pain e.g., irritable bowel syndrome; Other chronic pain e.g., some tension-type headaches and non-specific back pain |
| Common Descriptors | Throbbing, aching, pressure-like | Lancinating, shooting, electrical-like, stabbing | Similar to neuropathic pain. May also be described as diffuse, gnawing, aching, sharp |
Unfortunately, the early cellular changes that lead to chronic pain are often difficult to detect, making it harder to reverse or prevent the occurrence of chronic pain13. Understanding the tapestry of altered proteins, receptors and neurotransmitters involved in chronic pain offers hope for new targets in early diagnosis, prevention, and more effective treatments. However, present treatment regimens remain largely reactive rather than preventive, relying on analgesics which are broadly classified by therapeutic class into opioids and non-opioids.
Existing non-opioids
Current treatment options face significant limitations in efficacy and safety, highlighting the urgent need for innovative therapeutic approaches.
Opioids gained popularity during a time when there was little understanding of chronic pain mechanisms or the potential for opioid dependence and abuse18. Most clinically prescribed opioids bind to mu-opioid receptors, found in the CNS and peripheral tissues. They play a crucial role in mediating the effects of opioid drugs and endogenous opioid peptides, influencing pain relief, reward, and addictive behaviours. These receptors are classified as G protein-coupled receptors and are primarily activated by substances like morphine, leading to various physiological responses. While opioids binding to mu-opioid receptors trigger the brain's reward centres and effectively mask pain signals, repeated use causes long-lasting changes in the brain that lead to tolerance and dependence. As a result, higher doses are needed for the same therapeutic effect, and individuals on opioids ultimately become reliant on the drug for normal functioning19,20.
Existing non-opioid treatment options for chronic pain cut across various classes of drugs, as follows:
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Since their development in the mid-20th century, NSAIDs such as ibuprofen, naproxen and diclofenac have been among the most prescribed analgesics globally. They are useful for managing a certain degree of inflammation commonly present in chronic pain conditions like arthritis, complex regional pain syndrome and lower back pain13,21. NSAIDs' therapeutic effects are achieved through the selective or non-selective inhibition of cyclooxygenase (COX) enzymes, which in turn reduces prostaglandin (PG) synthesis. This leads to less inflammation and swelling and therefore, less pain at sites of injury. However, long-term use poses significant concerns especially related to gastrointestinal (GI) and cardiovascular (CV) side effects. Nonselective NSAIDs can damage the gut lining by inhibiting COX-1 and leading to ulcers, while COX-2 selective NSAIDs have a lower GI risk but may increase CV events by disrupting prostacyclin and thromboxane balance. Notably, some COX-2 selective NSAIDs like rofecoxib have been withdrawn from the market due to an increased risk of cardiovascular events such as heart attacks and strokes during long-term use13,22. Moreover, as NSAIDs mainly tackle inflammation that potentiates pain signals, they are less effective for neuropathic or more centralised chronic pain23.
Antidepressants
While not originally developed for chronic pain, antidepressants can alleviate chronic pain (especially neuropathic pain) in cases where depression is not a co-existing diagnosis13,24. For instance, amitriptyline, a tricyclic antidepressant has been widely used for the treatment of various chronic pain conditions including fibromyalgia and neuropathic pain. Another example is duloxetine, a serotonin-noradrenaline reuptake inhibitor (SNRI), which was the first FDA approved antidepressant for the treatment of diabetic neuropathic pain24. One proposed therapeutic mechanism is that some antidepressants modulate levels of serotonin and norepinephrine, thereby enhancing the activity of descending inhibitory pain pathways in the CNS, resulting in analgesic effects24.
But again, antidepressants tend to undergo extensive liver metabolism and have limited oral availability. For the management of chronic pain, adverse effects can range from mild symptoms like dry mouth to severe complications such as cardiac arrhythmias and serotonin syndrome. Serotonin syndrome is caused by excessive serotonin in the body and can lead to serious symptoms including hyperthermia and organ failure, and may be fatal if not treated promptly13,25.
Anticonvulsants
Originally designed to treat epileptic seizures, anticonvulsants have been repurposed for the treatment of chronic pain, especially neuropathic pain. Their 'nerve-calming' and analgesic properties are attributable to the blockade of sodium, potassium and calcium channels, enhancement of inhibitory neurotransmitters like Gamma-Aminobutyric Acid (GABA) and the inhibition of excitatory glutamate neurotransmission13,26. A good example is pregabalin, a GABA analogue and gabapentinoid, which was the first anti-epileptic to receive FDA-approval in 2004 for the treatment of painful diabetic neuropathy and postherpetic neuralgia. It exerts its analgesic effects by binding to the α₂δ subunit of voltage-gated calcium channels, thereby reducing the release of excitatory neurotransmitters27. However, variable efficacy, delayed onset of pain relief, dose-limiting side effects, and unwanted drug interactions are some concerns that have limited the widescale adoption and efficacy of anti-convulsants for the treatment of chronic pain13.
Some other non-opioid pharmacological options for chronic pain include acetaminophen, topical agents like lidocaine, NMDA receptor antagonists like ketamine in sub-anaesthetic doses, and muscle relaxants like baclofen28. Most therapies offer modest benefit with significant response variability and often require combinatorial approaches for adequate pain relief13,28. This disappointing landscape of non-opioid anti-pain options is fuelling the need for the development of novel non-opioid analgesics with improved safety and efficacy profiles.
| Non-Opioid Class | Drug Name | Indication Labels |
|---|---|---|
| NSAIDs | Ibuprofen | Osteoarthritis, Rheumatoid Arthritis, Musculoskeletal Pain |
| Celecoxib | ||
| Diclofenac | ||
| Naproxen | ||
| Antidepressants | Amitriptyline | Fibromyalgia, Chronic Neuropathic Pain, Chronic Tension-type Headache |
| Duloxetine | Fibromyalgia, Diabetic Peripheral Neuropathic Pain, Musculoskeletal Pain | |
| Anticonvulsants | Gabapentin | Postherpetic Neuralgia |
| Pregabalin | Postherpetic neuralgia, Diabetic Peripheral Neuropathy, Fibromyalgia, Spinal Cord Injury-associated Neuropathic Pain | |
| Carbamazepine | Trigeminal Neuralgia |
Developing Effective Non-opioid Pain Solutions
Despite decades of research, breakthrough innovations are emerging with 154 clinical assets targeting novel mechanisms for safer, more effective chronic pain management.
Despite decades of research, the number of clinically validated molecular targets for analgesia remains limited. Most of the current non-opioid analgesics for chronic pain were originally developed for other indications, rather than being discovered through rational design for chronic pain. This dominance of 'repurposed therapeutics' for chronic pain highlights a key observation: target identification strategies have often failed to translate preclinical successes into effective clinical therapies in the pain space18.
From the current clinical-stage drug pipeline for chronic pain, assets targeting osteoarthritis pain, migraine, and diabetic neuropathic pain top the list, collectively accounting for about 40% (64) of the assets. Also, nearly 20% (26) of the current clinical-stage assets are in the late stages of clinical development.
For instance, after the transient receptor potential cation channel subfamily V member 1 (TRPV1) was cloned, there was great interest in developing small-molecule TRPV1 antagonists for pain relief, and indeed several leading drug candidates progressed to Phase I and II trials. These antagonists were expected to treat chronic pain by blocking TRPV1 mediated transmission of harmful stimuli from peripheral sensory neurons, consequently lowering pain perception. However, the enthusiasm in these assets waned due to significant adverse effects. Some candidates like AMG517 caused marked hyperthermia, while others, like MK-2295 obstructed heat pain perception, increasing the risk of burn injuries31.
Conversely, the wide-spread expression of mu-opioid receptors throughout both the peripheral and CNS is a strong contributor to their analgesic effect. This broad distribution allows opioids to provide relief, even when the specific underlying mechanisms are unclear or the root cause of the pain remains untreated. Moreover, the higher translatability of opioids from preclinical to clinical models may stem from the high conservation of opioid systems across vertebrate species18,33. Novel non-opioid analgesics that can provide effective treatment for chronic pain without targeting mu-opioid receptors, while minimising side effects and eliminating the risk of addiction, therefore seem to be the 'holy grail' in pain drug development.
A
Top Indications
B
Development Stage
C
Top Molecular Mechanisms
Figure 1:
Chronic pain pipeline as of July 2025, by Development Stage, Top Molecular Mechanism and Top Indication.
Source: GlobalData; Total assets analysed: 154. COX-1/2: Cyclooxygenase-1 and -2; Nav1.8: Voltage-gated sodium channel subtype 1.8; Nav1.7: Voltage-gated sodium channel subtype 1.7; NMDAR: N-methyl-D-aspartate receptor; CB1/CB2: Cannabinoid receptor type 1 and type 2.
Several clinical-stage pipeline assets target mechanisms that are distinct from existing non-opioids being prescribed for chronic pain. Among the top-targeted mechanisms identified are COX inhibitors and NMDAR antagonists such as ketamine, repurposed for pain management due to their ability to modulate excitatory neurotransmission. However, some of the mechanisms in the pipeline represent newer and emerging approaches to chronic pain management.
Voltage-Gated Sodium Channel Subtype 1.8 (Nav1.8) Blockers
Nav1.8 channels contribute to chronic pain by becoming upregulated and hyperactive after nerve or tissue injury, leading to increased ectopic and spontaneous neuronal firing in sensory neurons, which results in persistent pain and heightened sensitivity to stimuli (hyperalgesia and allodynia). Since Nav1.8 plays a crucial role in generating and conducting action potentials in sensory neurons involved in pain signalling, blocking these channels decreases neuronal excitability and the transmission of pain signals to the brain18,34,35.
Eli Lilly recently spent USD 1 billion to acquire SiteOne Therapeutics, with the centerpiece of this acquisition being STC-004, a Nav1.8 inhibitor currently in Phase II clinical development for chronic peripheral pain36. Vertex Pharmaceutical's Suzetrigine is another Nav1.8 blocker which made headlines in January 2025 as the first FDA approved non-opioid painkiller in two decades. It demonstrated significant pain relief in patients undergoing surgeries such as abdominoplasty and bunion removals, which involve injury to bone and soft tissue. While its current approval is limited to acute pain, Suzetrigine is currently being investigated for chronic pain conditions, with ongoing Phase III trials for diabetic peripheral neuropathy34,37. Other promising Nav1.8 inhibitors in the pipeline include Latigo Therapeutics' LTG-001, which recently reported positive Phase I results, and LTG-305 which just entered Phase I19.
Voltage-Gated Sodium Channel Subtype 1.7 (Nav1.7) Blockers
Multiple ion channels can support similar neuronal functions, and this is a key feature of sensory neurons. As such, Nav1.7 has also been a major focus for chronic pain therapies, with its analgesic potential discovered through human genetic studies in the early 2000s, before Nav1.8 became a therapeutic focus. While clinical strategies targeting this channel have yet to yield effective outcomes34, many Nav1.7 blockers remain in preclinical and clinical investigation for chronic pain management.
AlphaNavi Pharma acquired exclusive worldwide rights from Sumitomo Pharma to develop, manufacture and commercialize their pipeline assets, including ANP-230 and ANP-390, both Nav1.7 blockers. The company is now seeking out-licensing opportunities to support further clinical development38,39. ANP-230 uniquely inhibits Nav1.7, Nav1.8, and Nav1.9 channels and is currently in Phase II development in Japan, making it the only clinical-stage compound reported to target Nav1.9 for neuropathic and rare Nav-mutated pain diseases. ANP-390, a selective Nav1.7 inhibitor, has completed Phase I in the US. Both compounds demonstrate robust analgesic efficacy and minimal cardiovascular or CNS side effects due to high peripheral selectivity and low blood-brain barrier penetration38.
Another notable effort was the collaboration and licensing agreement established in 2022 between SiteOne Therapeutics (now owned by Eli Lilly) and Vertex Pharmaceuticals to develop potent and selective small-molecule Nav1.7 blockers as non-opioid pain treatments40.
Cannabinoid Receptor Type 1 and Type 2 (CB1/CB2) Agonists
Targeting the endocannabinoid system to modulate pain and inflammation is not new. Similar to the endogenous opioid system, the endocannabinoid system features receptors such as CB1 that are highly expressed in key pain-processing regions of the body, making it a viable target for analgesic drug discovery13. Both cannabinoids and opioids interact with the brain's reward system and carry potential for substance abuse, but cannabinoids pose a lower risk of addiction and dependence due to differences in their cellular mechanisms41. While large-scale trials with long-term follow-up are still needed to confirm their safety and efficacy, current clinical evidence suggests that cannabinoids provide moderate effectiveness in treating chronic pain conditions such as neuropathic pain, cancer-related pain, and fibromyalgia41.
Selective CB2 agonists are being actively explored in the hope that they may provide analgesic effects without the side effects or abuse potential associated with CB1 activation. For instance, Centrexion Therapeutic's CNTX-6016, a Phase II candidate for diabetic neuropathic pain, is designed to avoid the psychotropic effects of typical cannabinoids by restricting its agonistic effects on the CB2 receptor. Meanwhile, Orcosa Inc's Oravexx, a CB1 and CB2 agonist, is in a Phase III clinical trial for pain reduction in knee osteoarthritis42. Oravexx leverages rapid oral mucosal absorption through its tablet design. This enables fast therapeutic onset with improved bioavailability and reduction in systemic side effects43,44.
Transient Receptor Potential (TRP) Channel Blockers
As key molecular sensors of noxious stimuli that drive chronic hypersensitivity, TRP channels - including TRPV1, TRPA1, TRPM3, and TRPM8 - remain a notable drug class under active investigation for the treatment of chronic pain.
Drugs like AlzeCure Pharma's ACD-440, a TRPV1 blocker, are addressing the challenge of systemic side effects associated with oral TRPV1 blockers, by utilizing a local delivery approach. Clinical data from Phase II studies indicate that topical ACD-440 provides effective local pain relief for temperature-induced pain in patients diagnosed with peripheral neuropathic pain, with minimal systemic absorption and no reported treatment-related adverse events45.
There has also been a logical shift towards targeting other TRP channels that are less likely to cause the adverse effects historically observed with TRPV1 blockers. For instance, Biohaven Ltd's BHV-2100, a first-in-class, highly selective TRPM3 antagonist is currently in Phase II for migraine and neuropathic pain. Preclinical models and early human studies show potent analgesia without the temperature dysregulation that limited earlier TRPV1 programs46,47.
Inflammasome Inhibition
Chronic inflammation is a key driver of persistent pain, with pro-inflammatory mediators sensitizing nociceptors and amplifying pain perception. The NLR Family Pyrin Domain-Containing 3 (NLRP3) inflammasome is an intracellular multiprotein that recognises cellular danger signals and plays a central role in this process. On activation, it triggers caspase-1, promoting the release of pro-inflammatory cytokines, especially interleukin-1 beta (IL-1β) and interleukin-18 (IL-18). NLRP3 inflammasome activation has been linked to various chronic pain conditions, such as rheumatoid arthritis, which are characterised by sustained inflammation, highlighting it as a potential therapeutic target48.
Despite earlier safety challenges, recent advances highlight a few promising NLRP3 inflammasome inhibitors currently undergoing clinical research. NodThera Inc.'s NT-0249 is a Phase II ready candidate that has demonstrated strong selectivity as a peripherally restricted agent with potent anti-inflammatory activity48,49 Novartis' DFV890 is another NLRP3 inhibitor currently in Phase II trials for multiple indications, including symptomatic knee osteoarthritis50. Olatec's dapansutrile, also in Phase 2 trials for acute gout flares, has shown both safety and efficacy in reducing target joint pain, supporting its potential for broader application in chronic pain conditions involving NLRP3 activation51,52. An alternative approach involves the P2X purinoceptor 7 (P2X7R), a ligand-gated ion channel that responds to cellular damage by promoting inflammasome activation. Eli Lilly's LY3857210, a P2X7R inhibitor, is currently in Phase II clinical trials for chronic low back pain (CLBP) and is also being investigated for other chronic pain indications53.
Other Promising Assets
Besides these mechanisms, some other promising assets have recently made headlines:
- Tonix Pharmaceuticals' Tonmya acts through multiple mechanisms by antagonising several neurotransmitter receptors, including serotonin 2A (5-HT₂A), α₁-adrenergic, histamine H₁, and muscarinic M₁ receptors, which are involved in both pain processing and sleep regulation. In July 2024, it became the first fibromyalgia drug in 15 years to receive FDA Fast Track designation, underscoring its potential to address this debilitating chronic pain condition. Now in pre-registration phase, Tonmya is advancing towards regulatory approval as a novel therapeutic option for fibromyalgia54.
- Algiax Pharmaceutical's AP-325, a novel small molecule modulator of GABA_A receptors in peripheral pain-sensing neurons, recently demonstrated rapid and long-lasting pain reduction in a Phase IIa study involving patients with chronic neuropathic pain. The drug had a favourable safety profile, with no CNS-related side effects reported55.
- Levicept's LEVI-04 is a first-in-class neurotrophin-3 inhibitor that provides pain relief by restoring neurotrophin homeostasis through scavenging excess neurotrophins associated with chronic pain states. LEVI-04 is being prepared for a Phase III trial after showing significant pain relief in a successful Phase II study for osteoarthritis knee pain19,56.
- Other notable rational targets currently under investigation in the chronic pain pipeline include nerve growth factor (NGF) and its receptor tropomyosin receptor kinase A (TrkA), angiotensin II receptor inhibitors (AT2R inhibitors) and microsomal prostaglandin E synthase-1 inhibitors (mPGES-1 inhibitors) all of which play key roles in the pathogenesis of chronic pain.
Biologics and Advanced Therapies
The chronic pain pipeline has historically been dominated by small molecules, but there are some particularly interesting biologics being investigated:
- OliPass' OLP-1002, a subcutaneously administered antisense oligonucleotide (ASO) currently in Phase II, inhibits Nav1.7 for osteoarthritis pain57. ASOs are a class of therapeutics that selectively bind to RNA sequences, eliciting precise regulation of disease-causing genes. OLP-1002 uses exon skipping to suppress NaV1.7 expression in nociceptors that transmit pain signals. ASOs are typically developed to treat genetic disorders, so it is interesting to see emerging efforts to harness their potential in targeting chronic pain at the genetic level.
- Pacira Biosciences' PCRX-201, a gene therapy in development for knee osteoarthritis pain, utilizes a high-capacity adenoviral (HCAd) vector to deliver the gene for interleukin-1 receptor antagonist (IL-1RA) via intra-articular injection into the knee joint. This enhances local IL-1RA production, blocks interleukin-1 (IL-1) signalling, and aims to provide long-lasting relief from chronic inflammation and pain. PCRX-201 features a unique disease-modifying design, incorporating an inducible promoter that increases IL-1RA expression when inflammation is present and deceases it when inflammation subsides. Positive safety and efficacy results from Phase I studies have recently been announced, and the therapy has now advanced to Phase II clinical development58,59.
- Kolon Life Science's KLS-2031 is another Phase II gene therapy candidate for treating neuropathic pain associated with lumbosacral radiculopathy. It functions by both blocking pain signal transmission to the brain and improving the local pain environment. KLS-2031 is administered via the transforaminal epidural route and utilizes adeno-associated virus (AAV) vectors to deliver genes encoding three therapeutic agents: Glutamate decarboxylase (GAD) 65 - an enzyme that converts glutamate to GABA, thereby suppressing pain signals; Interleukin-10 (IL-10) - an anti-inflammatory cytokine; and Glial cell line-derived neurotrophic factor (GDNF) - a neuroprotective protein that promotes the survival and function of sensory neurons60.
- Mesoblast's MPC-06-ID, a Phase III drug for chronic lower back pain, consists of a single dose of 6 million mesenchymal precursor cells (MPCs) which are injected directly into the damaged intervertebral disc in an outpatient procedure. This disease-modifying approach could address the functional disability caused by intervertebral disc degeneration resulting from aging, genetic factors, or injury61.
If proven effective, these emerging cell and gene therapies represent advanced, non-conventional approaches that could offer more permanent solutions for chronic pain conditions where other treatments have failed.
| Drug | Company | Indication | Development Stage | Technology | Mechanism of Action | Description |
|---|---|---|---|---|---|---|
| ST-503 | Sangamo Therapeutics | Neuropathic Pain | Phase I | Gene Therapy | Sodium Channel Protein Type 9 Subunit Alpha Inhibitor | Delivered intrathecally and intravenously using adeno-associated virus (AAV) vector. Inhibits expression of Nav1.7s involved in pain signal transmission from dorsal root ganglion neurons. |
| BR-01T | Brise Pharmaceuticals | CLBP | Phase I | mAb | High Affinity Nerve Growth Factor Receptor Inhibitor | Administered through parenteral route. Inhibits Trk A, blocking NGF signalling, which supports neuron survival and is involved in pain sensitivity. |
| Urcosimod | OKYO Pharma | Neuropathic Pain | Phase II | Synthetic Peptide | Chemerin Like Receptor 1(CMKLR1) Agonist | Administered by ophthalmic route and developed based on membrane-tethered ligand technology and membrane-anchored-peptide (MAP) technology. Activates anti-inflammatory pathways and resolves pain-related inflammation. |
| KLS-2031 | Kolon Life Science | Neuropathic Pain; Radiculopathy | Phase II | Gene Therapy | GDNF Activator; GAD65 Activator; IL-10 Activator | AAV delivery of genes encoding GDNF, GAD65, and IL-10 to reduce pain transmission, protect neurons, and suppress inflammation. |
| LuAG-09222 | H. Lundbeck | Migraine | Phase II | mAb | Pituitary Adenylate Cyclase Activating Polypeptide (PACAP-38) Inhibitor | Administered through intravenous and subcutaneous route. Antagonizes PACAP-38 receptor, which is involved in migraine-related vasodilation and nociception. |
| OLP-1002 | OliPass Corp | Osteoarthritis Pain | Phase II | ASO | Sodium Channel Protein Type 9 Subunit Alpha Inhibitor | Administered subcutaneously. Uses exon skipping to suppress NaV1.7 expression in nociceptors that transmit pain signals. |
| PCRX-201 | Pacira BioSciences | Knee osteoarthritis | Phase II | Gene Therapy | IL-1R Antagonist | Administered via intra-articular route. Delivers gene encoding IL-1R via helper-dependent adenoviral vectors. This blocks IL-1β-driven inflammation, reducing pain and cartilage degradation in osteoarthritis. |
| XT-150 | Xalud Therapeutics | Peripheral Neuropathic Pain | Phase II | Gene Therapy | IL-10 Activator | Non-viral gene therapy delivered intraarticularly or intrathecally. Targets IL-10 to reverse glial activation and reduce pro-inflammatory cytokines in chronic pain. |
| Osteoarthritis | Phase III | |||||
| MPC-06ID | Mesoblast | CLBP | Phase III | Cell Therapy | Involves injection of mesenchymal precursor cells (MPCs) into damaged intervertebral discs to regenerate cartilage, reduce inflammation, and restore disc function. | |
| AMG334 | Novartis | Migraine | Phase III | mAb | Calcitonin Gene Related Peptide (CGRP) Type 1 Receptor Antagonist | Administered intravenously or subcutaneously. Blocks the CGRP receptor, preventing interaction with CGRP, a key player in migraine pain. |
The Non-Opioid Chronic Pain Investment Landscape
Detailed breakdown of capital flows, strategic partnerships, and market dynamics shaping the non-opioid chronic pain investment ecosystem.
- $84B 2024 Market Value: Current global chronic pain treatment market valuation, driven by aging populations and rising chronic disease prevalence across developed markets.
- $132B 2030 Market Projection: Projected market growth with neuropathic pain as the fastest-growing segment, representing a 57% increase from current levels.
- $4.5B Strategic Alliances: Total value of partnerships and licensing agreements representing over 50% of sector deal value.
- $1B Eli Lilly Acquisition: Record-breaking SiteOne Therapeutics acquisition validates Nav1.8 channel blockers.
- $250M 2024 Venture Financing: Significant increase in venture capital across four major deals, demonstrating growing investor confidence in non-opioid therapeutics.
- 96x Capital Growth: Remarkable capital raising growth between 2015-2016 and 2023-H1 2025 periods.
The chronic pain treatment market has experienced significant growth, driven by an increasing number of individuals seeking treatment for long-term pain related conditions. A key factor is the aging population, which is more prone to chronic pain conditions like osteoarthritis. Another top contributor is the rising prevalence of chronic diseases including cancer, fibromyalgia and autoimmune conditions such as rheumatoid arthritis62, all often associated with some level of chronic pain. In 2024, the global chronic pain treatment market was valued at approximately $84 billion and is projected to reach around $132 billion by 2030, with neuropathic pain reported to be the fastest-growing segment63. In parallel, the demand for safer non-opioid analgesics is expected to grow significantly and is shaping the funding and investment landscape for non-opioid treatments targeting chronic pain.
A
Distribution of Non-Opioid Chronic Pain Deal Types
(2015 - H1 2025)
B
Distribution Of Non-Opioid Chronic Pain Deal Values
(2015 - H1 2025)
Figure 2:
Non-Opioid Chronic Pain Investment Landscape (announced and completed deals) from 1 January 2015 to 30 June 2025, by Number of Deals and Deal Value.
Source: GlobalData; Total deals analysed: 160.
Grants awarded to non-opioid chronic pain research rose sharply in 2019 and have since remained stable (Figure 2A), reflecting sustained support for early-stage research from government agencies. In June 2025 the US National Institute on Drug Abuse (NIDA) awarded $3.14 million to Sparian Biosciences Inc. for the development of SBS-147, a preclinical stage, first-in-class, oral non-opioid arylepoxamide agonist. Other initiatives like the HEAL Pain Therapeutics Development Program, award phased grants to academic institutes and small businesses to accelerate the development of novel, non-opioid, and specifically non-addictive analgesics64. While there are almost as many grant awards in this space as there are other types of deals/fundraising activities combined, the 'big bucks' in pain R&D lie predominantly in the M&A and strategic alliance activity within the biotech and pharma industries, followed by capital raisings (Figure 2B).
Capital Raisings
C
Capital Raising by Type
Figure 3:
Deal Value Breakdown (by Capital-Raising Subtypes) of the Non-Opioid Chronic Pain Investment Landscape (announced and completed deals) from 1 January 2015 to 30 June 2025.
Source: GlobalData; Total capital raising deals analysed: 42.
Compared to other indications, capital raisings in the non-opioid chronic pain space have been dwarfish. It has long been an argument that more support from grant funding bodies could help de-risk early-stage R&D, encouraging greater private-sector investment. Illustrating this trend, the value and frequency of capital raisings, including all deals covering equity offerings, private equity, venture financing and debt offerings, have generally increased over the past decade with a remarkable 96-fold increase in value between 2015-2016 and 2023-H1 2025.
Debt offerings have historically been less common than equity-based financings in the chronic pain investment landscape. They are typically linked to later-stage companies with more predictable revenue streams. However, debt offerings have become more visible in recent years as more chronic pain companies have matured, and larger pharmaceutical firms have expanded their portfolios. For example, from 2023 to 2024, Scilex Holdings raised approximately $170 million through private placement debt offerings to support the acquisition, development, and commercialization of non-opioid acute and chronic pain therapeutics. One of their promising assets is SP102, a Phase III epidural therapy under development for the treatment of lumbosacral radicular pain.
While equity offerings have declined in financial value over the past four years, they have remained a principal source of capital over the past decade, peaking in 2019-2020 at around $200 million, which accounted for roughly 80% of all capital raisings during this period. Most interestingly, in 2024, venture financing went up, raising over $250 million across four deals, including Latigo Biotherapeutics which secured $135 million in Series A financing; and SiteOne Therapeutics which raised $100 million in Series C financing. An analysis of 15 venture financing deals in this space over the past decade shows that 13 of these occurred within the last five years, with more than 40% in Series C or later, indicating pipeline maturation and increasing investor confidence in this space.
Strategic Alliances
Strategic Alliances: Distribution of Non-Opioid Chronic Pain Deal Values (2015 - H1 2025)
Figure 4:
Deal Value Breakdown (by Strategic Alliance Subtypes) of the Non-Opioid Chronic Pain Investment Landscape (announced and completed deals) from 1 January 2015 to 30 June 2025.
Source: GlobalData; Total strategic alliance deals analysed: 23.
The frequency of strategic alliances, in the form of partnerships and licensing agreements, has fluctuated over the past decade. However, the financial value of these collaborations totals approximately $4.5 billion, representing more than 50% of all deal value in the non-opioid chronic pain sector during this period. Notable transactions include Eli Lilly's 2023 in-licensing agreement valued at $630 million for Confo Therapeutics' Phase I CFTX-1554 ($40 million upfront and $590 million in potential milestone payments and tiered royalties), in development for the treatment of peripheral neuropathic pain. Another is Merck's $340 million licensing agreement with King's College London and the Wellcome Trust to develop a new class of chronic pain medications, with Merck responsible for lead optimisation, preclinical development, and clinical trials. More recent is Polyrizon's $3 million in-licensing deal for SciSparc's CB2 agonist, SCI-160, a preclinical candidate for neuropathic and post-operative pain.
Partnerships differ slightly from licensing agreements; the former is predominantly driven by industry–academia collaborations, such as the co-development partnership between LifeArc and the University of Kent for a potassium channel subfamily K member 10 (KCNK10) activator for the treatment of pain and migraines. A standout co-development deal over the past decade was the $1.25 billion 2016 agreement between Regeneron Pharmaceuticals Inc. and Teva Pharmaceuticals for fasinumab, a β-NGF inhibitor that, despite its promising prospects, was discontinued at Phase III in 2022 for osteoarthritic pain. Since 2020, there have been no partnerships associated with non-opioids for chronic pain, and most of the earlier partnership deals do not report specific deal values that can be included in this analysis.
Mergers and Acquisitions
Mergers and acquisitions (M&As) have reached their highest frequency and value in the past three years. Notable transactions in 2025 include Eli Lilly's $1 billion acquisition of SiteOne Therapeutics and Pacira Biosciences' majority acquisition of GQ Bio for approximately $32 million, providing Pacira Biosciences with access to a preclinical stage asset portfolio and a novel high-capacity local delivery platform for genetic medicines in non-opioid pain management. In 2024, three mergers, Pulmatrix with Cullgen, Denali Capital Acquisition with Senmur Pharmaceuticals, and Virios Therapeutics with Wex Pharma to form Dogwood Therapeutics, demonstrated a significant focus on developing non-opioid chronic pain assets, many of which are in mid- to late-stage development.
Overall, it seems the investment landscape for non-opioid chronic pain therapeutics has grown in recent years. Venture capital financing going up in recent years demonstrates a highly optimistic change in attitude towards investing in this space. But of course, there is still tremendous room for more investment, as non-opioid chronic pain deals over the past decade account for less than 0.03% of all deals across the biotech and pharma industries.
Future Prospects
Advances in the formal classification of chronic pain have improved diagnostic accuracy and awareness. This will greatly spur efforts in developing effective chronic pain management therapies, supported by a deeper understanding of the pathophysiology underlying various chronic pain conditions.
The opioid epidemic has no doubt driven a necessary shift toward non-opioid pharmacological alternatives. But despite extensive research, there remains a lack of consistently effective non-opioid treatments for chronic pain, with some conditions being particularly underserved. For example, a recent systematic review and meta-analysis found that certain non-opioid psychiatric medications, such as duloxetine and mirogabalin, demonstrated significant short-term benefits for fibromyalgia, but were not effective for neuropathic pain or chronic low back pain. Moreover, no consistent long-term benefits were observed for any of the non-opioid drugs studied. These findings highlight a persistent gap in effective chronic pain management, especially for conditions such as chronic lower back pain and neuropathic pain, which continue to respond poorly to existing non-opioid options65.
While some promising candidates are currently under development, the limited range of clinically viable non-opioid targets highlights the need for innovative approaches to advance treatment and improve patient outcomes. So far, the selection of analgesic targets has largely focused on genetic findings or mechanistic insights from preclinical studies. However, genetic studies often lack large, well-characterised patient cohorts needed to identify polygenic risks for chronic pain, and rare genetic variants only tell part of the story. Likewise, preclinical models often fail to accurately reflect human pain conditions, resulting in poor clinical translation18.
Future progress will require a shift towards personalised medicine, incorporating predictive biomarkers that enable the prevention of chronic pain, rather than merely treating symptoms of established pain states. For example, in post-surgical neuropathic pain, genetic, proteomic, or neuroimaging markers could help identify individuals at heightened risk of developing persistent pain after surgery. This would allow clinicians to tailor preventive interventions such as targeted nerve blocks or other pharmacological agents, before maladaptive pain pathways become established. In addition, there is increasing discussion about labelling pain therapies based on specific biomarkers or mechanistic drivers, similar to approaches in oncology. Such targeted labelling could reduce subjectivity in pain assessment, currently reliant on scales like the Visual Analog Scale (VAS) and better align therapies with distinct patient subgroups66.
Comprehensive genome-wide screening and multi-omic profiling of pain-related cells and neural circuitry could facilitate the discovery of novel targets and multitarget networks specific to different pain types. Notable strides have already been made; for instance, a recent meta-analysis of Genome-Wide Association Studies (GWAS) has identified 67 new genetic regions linked to chronic back pain across diverse populations, more than doubling previously known associations. Interestingly, some of these genes are already targeted by existing drugs67,68. In parallel, advanced tools such as optogenetics and AI-driven behavioural analysis may enhance the preclinical assessment of therapeutic candidates toward increased chances of clinical success18.
Ultimately, continued research, investment in, and integration of these strategies could overcome the limitations of current treatments, facilitating effective chronic pain therapy.
References
Complete academic references supporting the analysis and findings presented in this whitepaper.