Oral Medications
A rheumatologist should be involved as part of the treatment team as soon as possible after arthrofibrosis has been diagnosed. Tests for autoimmune and autoinflammatory conditions, and essential vitamins and nutrients, are necessary to ensure appropriate treatments are given in a timely manner. Blood tests for inflammatory cytokines will also guide the use of targeted biologics.
Traditional Approaches
Pharmaceutical treatments for arthrofibrosis have traditionally consisted of corticosteroids and non-steroidal anti-inflammatories (NSAIDs) such as Ibuprofen [1]. Oral or injected corticosteroids appear to help and their use is associated with a short-term reduction in pain [2]. However, recent research suggests that early post-operative treatment with either NSAIDs or steroids increases the duration of inflammation and increases the risk of chronic pain [3]. Other methods to control pain, such as paracetamol, did not have this negative effect. It is not known if early post operative icing is also associated with an increased risk of chronic pain, but it’s possible. In light of this research, it may be better to delay post-operative treatment with corticosteroids.
NSAIDs should only be used for a few days, since longer term use (more than 4 days) prevents the body from fighting inflammation and is associated with an increased risk of cardiac and renal disease (heart and kidney fibrosis). NSAIDs prevent the body from making resolvins [1], the body’s natural anti-inflammatory response. A recent report supports this, finding that long term use of NSAIDs increases inflammation and damage in knees. The exception to the “rule” that long-term use of NSAIDs supports chronic inflammation is aspirin. Although aspirin is an NSAID it actually increases the body’s production of resolvins [1] and reduces fibrosis. This is why low-dose aspirin is widely used for treating heart disease.
Modern Approaches
Recently developed medications that target specific pathways are more effective for treating inflammatory and autoimmune conditions, and some of these have shown efficacy for treating organ fibrosis. Since arthrofibrosis (fibrosis of a joint) shares the same underlying pathological mechanisms with fibrosis of organs [1], much can be learnt from the ways in which organ fibrosis is treated. Unfortunately, the more recently developed medications such as biologics (see Injections) are expensive and difficult to gain access to.
It is likely that targeting more than one pathway by using a combination of medications will be necessary for effective treatment. This is because the pathobiology of fibrosis is extremely complex, and there are a large number of positive feedback effects that keep myofibroblasts activated.
Metformin
Metformin is an old medication with a very well-known safety profile used for treating diabetes. Recent research indicates that metformin downregulates the major fibrotic cytokine, TGF-β, in a dose-dependent manner, and reduces organ fibrosis [1]. Metformin’s good safety profile makes it a good candidate for treating arthrofibrosis where the patient’s medical situation permits.
References
Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).
Metformin
Losartan
Some orthopaedic surgeons now prescribe post-operative losartan. Losartan has been shown to indirectly downregulate TGF-β and to reduce fibrosis, and dose-dependent effects have been reported in animal models of arthrofibrosis [1]. A reduced risk of severe arthrofibrosis in patients taking post-operative losartan has been reported [2].
References
Losartan
Disser, N. P., Yu, J. S., Yao, V. J. H. & Rodeo, S. A. Pharmacological Therapies for Connective Tissue Fibrosis in Orthopaedics. Am J Sports Med, 3635465221116358, doi:10.1177/03635465221116358 (2022).
Premkumar, A. et al. Perioperative Use of Antifibrotic Medications Associated With Lower Rate of Manipulation After Primary TKA: An Analysis of 101,366 Patients. J Arthroplasty, doi:10.1016/j.arth.2022.03.026 (2022).
JAK Inhibitors
Janus Kinase and signal transductors and activators of transcription: JAK / STAT Inhibitors
JAK inhibitors are a new group of medications that have shown promise for treating numerous autoimmune and inflammatory conditions [1,2] and they have demonstrated anti-fibrotic efficiacy [4]. The JAK/STAT pathway is a major regulatory pathway involved in the signalling of cytokines and growth factors, including TGF-β, with pro-fibrotic signals converging on STAT3 [3,4]. Chronic inflammation appears to uniquely activate these pathways, integrating signal intensities and timing to amplify the outcomes [5]. Positive feedback loops occur between STAT3 and TGF-β1 [6] with similar feedback between JAK2 and TGF-β1 [4].
Since STAT3 activation depends on the combined action of JAK1 and JAK2 [3], these kinases provide an alternative treatment target that indirectly downregulates STAT3. In addition, JAK2 may have fibrotic effects that are independent of STAT3 [4]. JAK1 and JAK2 inhibitors appear to give the best anti-fibrotic results [7], however, it’s not known which JAK inhibitor medication is the most effective and safest for treating arthrofibrosis, and they are not yet widely available.
References
JAK Inhibitors
Damsky, W. et al. The emerging role of Janus kinase inhibitors in the treatment of autoimmune and inflammatory diseases. J Allergy Clin Immunol 147, 814-826, doi:10.1016/j.jaci.2020.10.022 (2021).
Ruscitti, P. et al. Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-beta and IL-6. Pharmaceuticals (Basel) 15, doi:10.3390/ph15050622 (2022).
Chakraborty, D. et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun 8, 1130, doi:10.1038/s41467-017-01236-6 (2017).
Montero, P., Milara, J., Roger, I. & Cortijo, J. Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms. Int J Mol Sci 22, doi:10.3390/ijms22126211 (2021).
Kasembeli, M. M., Bharadwaj, U., Robinson, P. & Tweardy, D. J. Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment. Int J Mol Sci 19, doi:10.3390/ijms19082299 (2018).
Bharadwaj, U., Kasembeli, M. M., Robinson, P. & Tweardy, D. J. Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution. Pharmacol Rev 72, 486-526, doi:10.1124/pr.119.018440 (2020).
Hou, Z. et al. JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis. Front Med (Lausanne) 9, 859330, doi:10.3389/fmed.2022.859330 (2022).
Pregabalin
Pregabalin (brand name Lyrica etc) is prescribed for a range of conditions including pain, shingles and fibromyalgia. Pregabalin blocks the production of substance P (pain generating protein) [1], which is known to be involved in arthrofibrosis [2]. Pregabalin and the older formulation, gabapentin, are sometimes prescribed for post-surgical pain and osteoarthritis, but pregabalin has fewer side effects.
References
Pregabalin
Takasusuki, T. & Yaksh, T. L. The effects of intrathecal and systemic gabapentin on spinal substance P release. Anesth Analg 112, 971-976, doi:10.1213/ANE.0b013e31820f2a16 (2011).
Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).
Pentosan polysulphate sodium (PPS)
PPS is a sulphated polyanion that resembles glycosaminoglycans. Research indicates that it downregulates both fibrotic and inflammatory pathways, however the mechanism by which it does this is not well understood [1]. Oral PPS is prescribed for interstitial cystitis [2], a fibrotic disorder, and in an animal model of diabetic nephritis (fibrosis) oral PPS showed anti-inflammatory and anti-fibrotic effects that prevented disease progression [2]. However, subcutaneously injected PPS appears to have greater bioavailability than the oral form.
Recently there has been an increased interest in PPS to treat fibrosis [1,2], however, most PPS research has been in osteoarthritis (OA). In cell culture and animal models, PPS inhibited the expression of TGF-β1, IL-6, TNF-α, NF-κB and fibronectin induced by advanced glycation end products (AGEs)-induced activation of the p13K/AKT pathway [1]. Similar effects have been reported in dogs with OA, and HIF-1 α and IL-1 were also downregulated by PPS [3]. In addition, PPS has been reported to downregulate MMPs [4], reduce IL-6 [2] and decrease the production of the pain mediator nerve growth factor mRNA [5].
Injected PPS has been successfully used to treat osteoarthritis in dogs and horses for decades, demonstrating reduced inflammation, swelling and cartilage destruction [6]. Phase 3 clinical trials of twice weekly subcutaneous injections of PPS for 6 weeks are beginning for the treatment human OA (ClinicalTrials.gov Identifier: NCT04814719). Both OA and RA typically have some degree of fibrosis associated with them, and the beneficial effects observed are likely a combination of anti-inflammatory and anti-fibrotic effects.
References
Pentosan polysulphate sodium (PPS)
Xiao, L. et al. Pentosan polysulfate ameliorates fibrosis and inflammation markers in SV40 MES13 cells by suppressing activation of PI3K/AKT pathway via miR-446a-3p. BMC Nephrol 23, 105, doi:10.1186/s12882-022-02732-8 (2022).
Eita, M. A. H., Ashour, R. H. & El-Khawaga, O. Y. Pentosan polysulfate exerts anti-inflammatory effect and halts albuminuria progression in diabetic nephropathy: Role of combined losartan. Fundam Clin Pharmacol, doi:10.1111/fcp.12781 (2022).
Bwalya, E. C. et al. Pentosan polysulfate inhibits IL-1beta-induced iNOS, c-Jun and HIF-1alpha upregulation in canine articular chondrocytes. PLoS One 12, e0177144, doi:10.1371/journal.pone.0177144 (2017).
Ghosh, P., Edelman, J., March, L. & Smith, M. Effects of pentosan polysulfate in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled pilot study. Current Therapeutic Research 66, 552-571, doi:https://doi.org/10.1016/j.curtheres.2005.12.012 (2005).
Stapledon, C. J. M. et al. Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis. PLoS One 14, e0222602, doi:10.1371/journal.pone.0222602 (2019).
Sampson, M. J. et al. Improved clinical outcome measures of knee pain and function with concurrent resolution of subchondral Bone Marrow Edema Lesion and joint effusion in an osteoarthritic patient following Pentosan Polysulphate Sodium treatment: a case report. BMC Musculoskelet Disord 18, 396, doi:10.1186/s12891-017-1754-3 (2017).
Low-Dose Naltrexone
Opioid receptor antagonist
Naltrexone is an opioid receptor antagonist that is used at high doses to treat drug addiction and dependence [1]. However, there is a lot of interest in using low-dose naltrexone (LDN) to treat chronic pain and inflammation [1,2], and it is used off-label for this purpose. At low doses naltrexone acts as an immune system modulator and increases opioid signalling and pain relief [2], and there is some evidence to suggest that it improves quality of life in people with chronic pain [2].
Unfortunately, it is not possible to make definite recommendations about the use of LDN because the studies are small and often not high quality [2] (not double blinded, placebo controlled). Nonetheless, LDN appears to be safe and well tolerated, and it may have efficacy for treating a range of chronic pain conditions from complex regional pain syndrome, chronic fatigue syndrome, fibromyalgia, inflammatory bowel disease etc.
Typical amounts of LDN range from 0.5 to 4.5 mg daily [1,2], with many studies starting at 1 mg per day increasing to 4.5 mg per day [2]. The low dose and short half-life appear to be essential for the beneficial effects [3]. At low doses naltrexone is cleared from the body in 4 hours, and this intermittent blockade of opioid receptors is believed to increase the number and sensitivity of opioid receptors [3]. These effects reduce pain and inflammation and modulate the immune system, and a number of studies have shown that LDN has greater benefits than placebo [3]. Some papers state that people taking it must be opioid-free [2].
We are not aware of any studies investigating the efficacy of LDN for treating arthrofibrosis. Naltrexone is no longer under patent [3], and there is little financial incentive for expensive large-scale trials [1]. With the limited data we cannot draw definitive conclusions at this stage [3].
LDN is a compounded medication that can only be supplied by compounding pharmacies [1]. At higher doses naltrexone may be counterproductive for chronic pain conditions. It is believed to increase cellular proliferation and the number of immune cells that produce inflammatory cytokines, and consequently is likely to increase pain and inflammation.
Anti-inflammatory effect
LDN has an anti-inflammatory effect on the nervous system. It downregulates Toll-like receptor 4, nitric oxide and inflammatory cytokines including IL-1, TNF-α [1]. It also increases endorphins and opioid growth factor levels, upregulating natural opioid signalling and improves mood and the sense of well-being [1].
Chronic pain that persists for longer than 3 months leads to changes in the nervous system [2] and hypersensitivity, particularly following traumatic nerve injury from surgery [2]. These changes can occur in both the local level and in the central nervous system. As a result inflammatory cytokine levels increase [2] as well as substance P [4], which further sensitises nerves. Interestingly, some conditions such as chronic myofascial pain are also associated with alterations in the nervous system [2]. Fascia is made of connective tissue, and this condition likely also involves chronic myofibroblast activation.
References
Low-Dose Naltrexone
Kim, P. S. & Fishman, M. A. Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review. Curr Pain Headache Rep 24, 64, doi:10.1007/s11916-020-00898-0 (2020).
Hatfield, E., Phillips, K., Swidan, S. & Ashman, L. Use of low-dose naltrexone in the management of chronic pain conditions: A systematic review. J Am Dent Assoc 151, 891-902 e891, doi:10.1016/j.adaj.2020.08.019 (2020).
Patten, D. K., Schultz, B. G. & Berlau, D. J. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn’s Disease, and Other Chronic Pain Disorders. Pharmacotherapy 38, 382-389, doi:10.1002/phar.2086 (2018).
Ganjaei, K. G., Ray, J. W., Waite, B. & Burnham, K. J. The Fascial System in Musculoskeletal Function and Myofascial Pain. Current Physical Medicine and Rehabilitation Reports 8, 364-372, doi:10.1007/s40141-020-00302-3 (2020).
Ketotifen
(Recent Research)
Ketotifen is an antihistamine that has shown promise for treating arthrofibrosis, but further research in humans is needed [1]. It downregulates a type of immune cell called mast cells that are involved in fibrosis. Side effects of the oral form include drowsiness and weight gain.
References
Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).
Ketitofen
Relaxin
(Recent Research)
Relaxin is a natural compound made by the body during pregnancy that has anti-fibrosis properties, including the break-down of scar tissue, inhibition of myofibroblast activation and prevention of arthrofibrosis in animal models [1]. Injected relaxin is short lived and of limited use, however, recent research has successfully prolonged release by encapsulating relaxin in polymeric capsules [1]. This product is not yet approved for use in humans.
References
Kirsch, J. R. et al. Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis. Science Translational Medicine 14, eabo3357, doi:10.1126/scitranslmed.abo3357.
Relaxin
References
Introduction
Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).
Disser, N. P., Yu, J. S., Yao, V. J. H. & Rodeo, S. A. Pharmacological Therapies for Connective Tissue Fibrosis in Orthopaedics. Am J Sports Med, 3635465221116358, doi:10.1177/03635465221116358 (2022).
Parisien, M. et al. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Science Translational Medicine 14, eabj9954, doi:doi:10.1126/scitranslmed.abj9954 (2022).
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