Authors: Jacquot M, Klinefelter et al
Pract Pain Manag. 2023 January/February;23(1).
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.
Drug Brand Name
|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|
|Eli Lilly and Company: Tanezumab [PF04383119]||Musculoskeletal pain, back pain||Nerve growth factor inhibitor||Subcutaneous, intravenous||Arthralgia, headache, edema, osteonecrosis, pain, paresthesia, respiratory tract infections, urinary tract infections||Phase 3; Fat-tracked|
|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|
|Neurana Pharmaceuticals: Tolperisone [Agileo]||Back pain||Calcium channel antagonist; sodium channel antagonist||Oral||Headache||Phase 3; NME||As of March 2022, Neurana Pharmaceuticals reported that the phase 3 RESUME-1 trial did not meet its primary and key secondary endpoints|
|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|
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.
|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|
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 three 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
- Hurt A. NHIS survey uncovers chronic pain prevalence and treatment choice. Pract Pain Manage. May 16, 2022. Available at: https://www.practicalpainmanagement.com/news/nhis-survey-uncovers-chronic-pain-prevalence-and-treatment-choice Accessed November 28, 2022.
- Service RF. Spurred by opioid epidemic, new pain drugs may lower the risk of overdose and addiction. Science. August 29, 2018. Available at: https://www.science.org/content/article/spurred-opioid-epidemic-new-pain-drugs-may-lower-risk-overdose-and-addiction Accessed November 28, 2022.
- Yaras RJ. CDC 2022 Opioid Prescribing Guideline: Subsequent treatment visits. Pract Pain Manage. September 22, 2022. Available at: https://www.practicalpainmanagement.com/resources/clinical-practice-guidelines/cdc-opioid-prescribing-subsequent-treatment-visits
- FDA. Novel drug approvals for 2022. November 18, 2022. Available at: https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2022 Accessed November 28, 2022.
- AdisInsight. Adis International Ltd. Available at: https://adisinsight.springer.com/ Accessed Nov 28, 2022.
- U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ Accessed November 28, 2022.
- Lexicomp(R). Wolters Kluwer. Updated November 28, 2022. Accessed via subscription at: http://online.lexi.com/lco/action/home
- FDA. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). January 22, 2022. Available at: https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd
- NIH. DailyMed. Available at: https://dailymed.nlm.nih.gov/dailymed. Accessed November 28, 2022.
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