Non-Opioid Analgesic Mechanisms and Their Preclinical Pain Models

The FDA issued draft guidance on the development of non-opioid analgesics for acute pain in 2022, covering development programs, labeling claims and expedited pathways. In September 2025 the agency followed with draft guidance on non-opioid analgesics for chronic pain. Since January 2025, Medicare has paid separately for qualifying non-opioid pain management drugs and devices in outpatient surgical settings under the NOPAIN Act, a provision that runs through 2027. In the same month, the FDA approved suzetrigine, a selective NaV1.8 inhibitor, for moderate to severe acute pain, which the FDA described as the first drug approved in a new class of pain medicines.

The non-opioid mechanisms in clinical and preclinical development are pharmacologically diverse, and each requires a different preclinical study design. The sections below describe the principal non-opioid classes and the models used to evaluate them.

Sodium Channel Blockers

Voltage-gated sodium channels expressed in sensory neurons, NaV1.8 and NaV1.7 in particular, are among the most actively pursued targets in analgesic development. Suzetrigine established the approach clinically in acute pain. NaV1.7 is being pursued with small molecules and, more recently, with gene therapy. In October 2025, a vectorized microRNA delivered intrathecally by AAV9 was reported to knock down SCN9A, the gene encoding NaV1.7, in the lumbar dorsal root ganglia of non-human primates. The same construct produced analgesia in a rat spared nerve injury model that persisted through eight weeks after a single dose.

For acute pain, sodium channel candidates are evaluated in incisional models. The rat plantar incision model produces mechanical hypersensitivity and reduced weight bearing on the operated paw over ten days, with morphine and bupivacaine as positive controls and naproxen as a comparator. The pig flank incision model extends the same assessment to skin with human-like structure and to human-scale dose volumes. For neuropathic pain, candidates are evaluated in rodent nerve injury models and in the pig peripheral neuritis trauma model. In the pig model, three quarters of animals develop mechanical and tactile allodynia by day 28, and gabapentin raises withdrawal thresholds in a dose- and time-dependent manner.

Extended Duration Local Anesthetics

Bupivacaine and ropivacaine are established agents, and current development is concentrated on the formulation, whether liposomal, oleogel, or polymer based. The primary efficacy variable for these formulations is the duration of analgesia, and the pig post-operative pain models were characterized for that measurement. In the leg incision model, perineural Marcaine, Naropin and Exparel each produce a complete and reversible nerve block, with the liposomal formulation producing the longest duration of effect. In flank incision studies, the ranking of the three agents by analgesic effect matches the ranking observed in patients. A bupivacaine and meloxicam extended release formulation tested in the flank model produced analgesia through 72 hours. The meloxicam component restored tissue pH and thereby increased the fraction of bupivacaine reaching the nerve, a mechanism later confirmed in a human bunionectomy trial and now part of an approved product. An oleogel bupivacaine formulation produced roughly five days of analgesia by both local instillation and ultrasound-guided nerve block.

Botulinum Toxins

Botulinum toxin type A acts on the vesicular release machinery of the neuron rather than on a receptor or ion channel. In the pig skin and muscle incision and retraction model, intradermal abobotulinumtoxinA administered at the time of surgery reversed mechanical allodynia from day three at all doses tested and normalized the distress behavior score within hours. In the same model, the analgesic effect of liposomal bupivacaine resolved within one day. Spinal cord histology demonstrated cleaved SNAP25 in the dorsal horn, direct evidence of target engagement, together with reduced GFAP and Iba-1 staining. The study also reported reduced pain-associated anxiety and depression-like reactivity.

Nerve Growth Factor Antibodies and Joint Histology

Anti-NGF antibodies produced clear analgesia in osteoarthritis in phase 3 trials, and development was nevertheless discontinued. In 2021, the FDA declined to approve tanezumab because of rapidly progressive osteoarthritis in treated patients. The advisory committee voted that the proposed risk management plan would not ensure that the benefit outweighed that risk. Because of this precedent, a preclinical osteoarthritis pain study requires joint histology alongside the pain endpoints. The monosodium iodoacetate model is run in rats and pigs, and assessment of pain behavior and joint damage in the same animals allows an efficacy signal and a structural safety signal to be evaluated together.

Anti-Inflammatory Approaches

Inflammatory pain models remain the primary screen for candidates acting on the inflammatory cascade, from NSAIDs to biologics. Intraplantar complete Freund's adjuvant in rats and carrageenan in mice produce paw swelling and hypersensitivity within hours, with diclofenac as the reference compound. In collagen-induced arthritis, etanercept lowered the arthritis score and anti-collagen type II antibody levels. The same animals can be assessed with von Frey, Hargreaves, hot plate and weight bearing tests, so that the effect of an anti-inflammatory candidate on pain is measured directly rather than inferred from swelling.

Predictive Controls

Predictive validity is demonstrated with compounds that failed clinically as well as with compounds that succeeded. The NK1 antagonist aprepitant produced no analgesic effect in the pig peripheral neuritis trauma model, consistent with the compound's clinical record in neuropathic pain. Morphine serves as a positive control across most of the pain models and gabapentin across the neuropathic models. In the pig open field assay, morphine produces dose-dependent aggressiveness while gabapentin normalizes the walking pattern, so the behavioral profile of a candidate is interpreted alongside both reference compounds.

MD Biosciences Pain Model Capabilities

MD Biosciences runs the acute, neuropathic, inflammatory and osteoarthritis pain models described here in rodents, domestic pigs and Göttingen minipigs. Von Frey, thermal testing, weight bearing, distress behavior scoring, open field, electrophysiology, PK, histology and biomarker panels are applied across them. The work spans the technologies in the non-opioid pipeline, including small molecules, biologics, cell based therapies, AAVs, natural compounds, medical devices and combination products. These are administered by all standard routes and by direct nerve, intrathecal, intra-DRG and intracerebral administration. Study design conversations are welcome at neuro@mdbiosciences.com.

References:

Development of Non-Opioid Analgesics for Acute Pain (2022) and for Chronic Pain (September 2025). FDA draft guidance for industry.

Castel D et al. Journal of Pain Research, 2017 and 2018.

Ottoboni T et al. Regional Anesthesia and Pain Medicine, 2019.

Cornet S et al. Scientific Reports, 2022.

Wojtalewicz S et al. Drug Delivery and Translational Research, 2024.