Clinical Trials for Non-Opioid Pain Treatment

Non-opioid pain treatment is a crucial area for research and development in the context of the opioid epidemic and the addictive nature of opioids. Alternative, non-opioid treatments for pain include medications, physical therapy, exercise, injections, and neuromodulation. This article will summarize previous and ongoing research on non-opioid pain treatment.

Physical activity and exercise have been shown to reduce the severity of pain, improving function, quality of life, and, in some situations, mental health. A review found that exercise therapy reduces pain and improves function in patients suffering from low back pain.¹ The evidence suggests that physical activity as an intervention may improve pain severity, function, and quality of life in chronic pain conditions such as complex regional pain syndrome (CRPS) and phantom limb pain.^2,3

Transcutaneous Electric Nerve Stimulation (TENS) is a non-pharmacological treatment modality that applies low-voltage electric currents to treat various pain problems. However, research has shown weak evidence supporting its efficacy as a non-opioid pain treatment in neuropathic pain, fibromyalgia, adult cancer pain, and chronic neck pain.⁴

NSAIDs are commonly used for mild to moderate pain, reducing inflammation, fever, and pain by inhibiting prostaglandin production. They may be taken in over-the-counter forms as well as stronger prescription forms. Research found that NSAIDs were more effective than placebo in reducing pain intensity in low back pain,⁵ and that topical diclofenac and ketoprofen produced significant improvement in pain intensity in osteoarthritis.⁶NSAIDs are also increasingly seen as a beneficial, non-opioid treatment option for post-operative pain.

Other non-opioid medications used for pain include acetaminophen, corticosteroids, gabapentin, and more. However, evidence supporting the efficacy of acetaminophen in chronic pain is limited.^7,8 And although oral corticosteroids are commonly used for the management of acute pain and acute flare-ups of chronic pain conditions, they have not shown significant improvement in pain intensity or function in radicular low back pain.^8,9

To manage chronic neuropathic pain, serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are commonly used. High-quality evidence supports their efficacy in treating neuropathic pain.¹⁰ Similarly, gabapentin and pregabalin are commonly used for chronic pain treatment, with strong evidence supporting the use of gabapentin for neuropathic pain. The efficacy of pregabalin and other anticonvulsants remains inconclusive.⁴

Another category of non-opioid pain treatment with varying levels of supportive research is injections. This category includes joint injections, peripheral nerve blocks, trigger point injections, and epidural steroid injections. While evidence supporting the efficacy of these interventions is mixed, they offer potential therapeutic value.¹¹

More recently, VX-548, a new type of painkiller, is set to move into phase III trials for acute pain. This small-molecule inhibitor of a specific sodium channel is currently one of the most advanced non-opioid pain treatment options. It marks the first of its kind to reach this stage of development, offering new hope for managing pain without opioids. Progress would provide welcome momentum for finding safer and more effective pain management solutions amid the ongoing opioid crisis.¹²

Non-opioid treatment for pain is a critical research area. However, not every patient is a candidate for every non-opioid pain therapy. Therefore, the care team must have a basic understanding of the mechanism of action, indications, associated complications, and existing evidence supporting the efficacy of these modalities. A biopsychosocial model is recommended for designing an individualized multimodal treatment plan.

References

van Middelkoop M, Rubinstein SM, Verhagen AP, Ostelo RW, Koes BW, van Tulder MW. Exercise therapy for chronic nonspecific low-back pain. Best Pract Res Clin Rheumatol. 2010 Apr;24(2):193-204. doi: 10.1016/j.berh.2010.01.002. PMID: 20227641.
Smart KM, Wand BM, O’Connell NE. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst Rev. 2016 Feb 24;2(2):CD010853. doi: 10.1002/14651858.CD010853.pub2. Update in: Cochrane Database Syst Rev. 2022 May 17;5:CD010853. PMID: 26905470; PMCID: PMC8646955.
Herrador Colmenero L, Perez Marmol JM, Martí-García C, Querol Zaldivar MLÁ, Tapia Haro RM, Castro Sánchez AM, Aguilar-Ferrándiz ME. Effectiveness of mirror therapy, motor imagery, and virtual feedback on phantom limb pain following amputation: A systematic review. Prosthet Orthot Int. 2018 Jun;42(3):288-298. doi: 10.1177/0309364617740230. Epub 2017 Nov 20. PMID: 29153043.
Moisset X, Bouhassira D, Avez Couturier J, Alchaar H, Conradi S, Delmotte MH, Lanteri-Minet M, Lefaucheur JP, Mick G, Piano V, Pickering G, Piquet E, Regis C, Salvat E, Attal N. Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations. Rev Neurol (Paris). 2020 May;176(5):325-352. doi: 10.1016/j.neurol.2020.01.361. Epub 2020 Apr 7. PMID: 32276788.
Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW. Non-steroidal anti-inflammatory drugs for chronic low back pain. Cochrane Database Syst Rev. 2016 Feb 10;2(2):CD012087. doi: 10.1002/14651858.CD012087. PMID: 26863524; PMCID: PMC7104791.
Derry S, Conaghan P, Da Silva JA, Wiffen PJ, Moore RA. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016 Apr 22;4(4):CD007400. doi: 10.1002/14651858.CD007400.pub3. PMID: 27103611; PMCID: PMC6494263.
Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegård A. Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. Basic Clin Pharmacol Toxicol. 2016 Mar;118(3):184-9. doi: 10.1111/bcpt.12527. Epub 2015 Dec 28. PMID: 26572078.
Chou R, Deyo R, Friedly J, Skelly A, Weimer M, Fu R, Dana T, Kraegel P, Griffin J, Grusing S. Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017 Apr 4;166(7):480-492. doi: 10.7326/M16-2458. Epub 2017 Feb 14. PMID: 28192790.
Knezevic NN, Jovanovic F, Voronov D, Candido KD. Do Corticosteroids Still Have a Place in the Treatment of Chronic Pain? Front Pharmacol. 2018 Nov 1;9:1229. doi: 10.3389/fphar.2018.01229. PMID: 30443214; PMCID: PMC6221932.
Obata H. Analgesic Mechanisms of Antidepressants for Neuropathic Pain. Int J Mol Sci. 2017 Nov 21;18(11):2483. doi: 10.3390/ijms18112483. PMID: 29160850; PMCID: PMC5713449.
Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, Kraus VB, Lohmander LS, Abbott JH, Bhandari M, Blanco FJ, Espinosa R, Haugen IK, Lin J, Mandl LA, Moilanen E, Nakamura N, Snyder-Mackler L, Trojian T, Underwood M, McAlindon TE. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Nov;27(11):1578-1589. doi: 10.1016/j.joca.2019.06.011. Epub 2019 Jul 3. PMID: 31278997.
Jones J, Correll DJ, Lechner SM, Jazic I, Miao X, Shaw D, Simard C, Osteen JD, Hare B, Beaton A, Bertoch T, Buvanendran A, Habib AS, Pizzi LJ, Pollak RA, Weiner SG, Bozic C, Negulescu P, White PF; VX21-548-101 and VX21-548-102 Trial Groups. Selective Inhibition of Na_V8 with VX-548 for Acute Pain. N Engl J Med. 2023 Aug 3;389(5):393-405. doi: 10.1056/NEJMoa2209870. PMID: 37530822.