With more than 1 in 5 Americans experiencing chronic pain, pain management is an important area of clinical research.¹ Ongoing studies are aimed at developing safe and effective analgesic drugs with a low risk of addiction and overdose.² In late 2022, an update to the CDC opioid prescribing guidelines³ reflected the shift in attitude toward more cautious opioid prescribing and the need for alternatives to manage pain, bringing us to the current landscape of pain research and emerging analgesics.

Emerging Agents
Table I: Agents in Phase 3 Clinical Trials or Recently Marketed for Pain-Related Conditions.⁴⁻⁷
Manufacturer:
Drug Brand Name
[Alternate Name]
Indication Mechanism
of
Action
Route
of
Administration
Adverse
Events
Status &
Approval
Pathway
Noteworthy
Alnylam Pharmaceuticals: Amvuttra [vutrisiran] Polyneuropathy of transthyretin-mediated hereditary amyloidosis Small interfering RNA (siRNA) targeting mutant and wild-type transthyretin Subcutaneous Arthralgia, AV block, vitamin A deficiency, antibody development, injection site reaction, dyspnea FDA approved in June 2022; Orphan drug
Helixmith: Engensis [VM202] Diabetic peripheral neuropathy Hepatocyte growth factor expression stimulant Intramuscular Ophthalmologic events, acute cardiac events, foot ulcers, symptoms of CNS depression Phase 3 Gene therapy/DNA plasmid
Hepion Pharmaceuticals: Postherpetic neuralgia Viral replication inhibitor Oral Headache, nausea Phase 3; NME
Biogen: Vixotrigine [BIIB074] Trigeminal neuralgia Nav1.7 voltage-gated sodium channel inhibitor Oral Dizziness, headache, vertigo, nausea Phase 3; Orphan drug
Sanofi: Venglustat [GZ402671] Neuropathic and abdominal pain in Fabry disease Glucosylceramide synthase inhibitor Oral Psychiatric, neurological, gastrointestinal (not specific) Phase 3; NME
Grünenthal: Resiniferatoxin [Lopain] Musculoskeletal pain, osteoarthritis of the knee TRPV1 receptor agonist Intra-articular Unknown Phase 3; NME 1 to 5 injections over 52 weeks in 3 studies
Mitsubishi Tanabe Pharmaceuticals: Fasinumab [MT5547] Back pain Nerve growth factor inhibitor Subcutaneous, intravenous Arthralgia, headache, injection site reactions, musculoskeletal pain, numbness, edema, paresthesia, respiratory tract infections Phase 3; Fast-tracked
Arbor Pharmaceuticals: AR 36 Stable angina Undefined Unspecified Unknown Phase 3; NME Very limited information and name is not conducive to search
Angionetics: Generx [Ad5FGF-4] Stable angina Angiogenesis inducing agent; fibroblast growth factor stimulant Intracoronary infusion via standard balloon catheter None specified Phase 3; new biologic
Abiogen Pharma: Neridronic acid [Neridronate] Complex regional pain syndromes Bone resorption factor inhibitor Intra-arterial, intravenous, intramuscular Diarrhea, fever, nausea Phase 3; Fast-tracked
Global Blood Therapeutics/Roche: Inclacumab [RG1512] Vaso-occlusive pain episode in sickle cell disease P selectin inhibitor Intravenous Dizziness, headache Phase 3; Orphan drug
Winston Pharmaceuticals: Civamide [Zucapsaicin] Episodic cluster headache TRPV1 receptor agonist Intranasal Nasal burning, lacrimation Phase 3; NME
Daewon Pharmaceuticals: Pelubiprofen [DW9801] Dysmenorrhea Cyclooxygenase inhibitor Oral Gastrointestinal (not specific) Phase 3; NME
Vivozon: Opiranserin [VVZ000149] Postoperative pain Glycine plasma membrane transport protein inhibitor; Serotonin 2A receptor antagonist Intravenous Unknown Phase 3; Fast track
Vertex Pharmaceuticals: VX-548 Acute pain Nav1.8 voltage-gated sodium channel inhibitor Oral Headache, nausea, constipation, dizziness, vomiting Phase 3; NME

Cannabis-Derived Pain Products

In terms of identified trends in the pain management R&D pipeline, cannabis-derived medications are thriving. It’s important to note that many CBD products are considered to be OTC supplements. The FDA has only approved one product containing cannabidiol and three products containing THC-related compounds, none of which are indicated for pain treatment.⁸

Eight new CBD and THC drug products were found to be in Phase 3 trials in 2022 with indications for many different pain conditions, from musculoskeletal pain to cancer pain.⁵˒⁶˒⁹ These eight trials are essential for the advancement of CBD and THC products in proving safety and efficacy for pain management.

Common adverse effects from FDA-approved CBD and CBD/THC products include somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, asthenia, rash, poor sleep quality, and infections.⁹ Table II contains details for those in development.

Table II: CBD and CBD/THC Preparations in Phase 3 Clinical Trials for Pain-Related Conditions.⁵˒⁶˒⁹
Investigator or Manufacturer: Drug Name Proposed Indication Route of Administration Status & Approval Pathway
Tetra Bio-Pharma: cannabidiol/delta 9 tetrahydrocannabinol, PPP-001 [QIXLEEF]* Cancer pain Inhalation (capsule and vaporizer kit) Orphan drug
University of Colorado: cannabidiol/delta 9 tetrahydrocannabinol Chronic spine pain Oral solution Phase 3
Medlab Clinical: cannabidiol/delta 9 tetrahydrocannabinol, MDCNB-01 [NanaBis] Bone pain from metastatic cancers Buccal spray Phase 3
University of Virginia: cannabidiol Musculoskeletal pain Topical cream Phase 3
Penn State Health Milton S. Hershey Medical Center: cannabidiol Endometriosis Sublingual Phase 3
NYU Langone Health: cannabidiol Osteoarthritis of the knee Orally dissolving tablets Phase 3
Mayo Clinic: cannabidiol [Epidiolex] Postoperative pain following ureteroscopy (Epidiolex is currently marketed by GW Pharmaceuticals for Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis) Oral solution Phase 3
University of Tennessee: cannabidiol Simple tooth extraction Oral (oil) Phase 3
*Orphan drug for complex regional pain syndrome (CRPS)
Discussion and Practical Takeaways

Among the analgesics in the 2022 and early 2023 pipeline, most are being investigated for indications of neuralgia, muscle pain, and back pain. Mechanisms of action for these agents vary greatly and, while none are opioid receptor agonists, several drugs exhibit new mechanisms for pain management, including monoclonal antibodies (fasinumab, inclacumab, and tanezumab), one drug utilizing siRNA (vutrisiran), and one plasmid gene therapy (engensis). Although most Phase 3 development appears to be focused on oral dosage forms, other routes of administration are being tested for outpatient pain management.

Of note, but not addressed in detail herein are several products in Phase 3 trials for new dosage formulations of existing drugs to help manage specific pain-related conditions. These include ophthalmic clobetasol for pain following cataract surgery, oral ketamine for vaso-occlusive pain, topical ibuprofen spray for osteoarthritis, and very low-dose sublingual cyclobenzaprine for fibromyalgia. Additionally, a small number of Phase 3 trials for biologic products are anticipated for 2023. These include platelet-rich plasma for the treatment of glenohumeral osteoarthritis and synthetic human secretin for the treatment of abdominal pain related to pancreatic insufficiency.⁵˒⁶

REFERENCES
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