Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury

Highlights

• Modeled manual therapy on rats over a 12-week repetitive motion task reduced adverse behaviors and improved task performance.

• Modeled manual therapy also attenuated increases in collagen and TGF-β1 deposition in forearm tissues, including nerve.

• Investigation of manual therapy as a preventative for hand and wrist work-related musculoskeletal disorders is indicated.

Abstract

Key clinical features of carpal tunnel syndrome and other types of cumulative trauma disorders of the hand and wrist include pain and functional disabilities. Mechanistic details remain under investigation but may involve tissue inflammation and/or fibrosis. We examined the effectiveness of modeled manual therapy (MMT) as a treatment for sensorimotor behavior declines and increased fibrogenic processes occurring in forearm tissues of rats performing a high repetition high force (HRHF) reaching and grasping task for 12 weeks. Young adult, female rats were examined: food restricted control rats (FRC, n = 12); rats that were trained for 6 weeks before performing the HRHF task for 12 weeks with no treatment (HRHF-CON, n = 11); and HRHF task rats received modeled manual therapy (HRHF-MMT, n = 5) for 5 days/week for the duration of the 12-week of task. Rats receiving the MMT expressed fewer discomfort-related behaviors, and performed progressively better in the HRHF task. Grip strength, while decreased after training, improved following MMT. Fibrotic nerve and connective tissue changes (increased collagen and TGF-β1 deposition) present in 12-week HRHF-CON rats were significantly decreased in 12-week HRHF-MMT rats. These observations support the investigation of manual therapy as a preventative for repetitive motion disorders.

Introduction

Work-related musculoskeletal disorders (WMSDs) are often termed work-related cumulative trauma disorders, overuse injuries and repetitive strain injuries, and include work-related carpal tunnel syndrome. The United States Occupational Safety and Health Administration estimates that WMSDs in the United States account for over 600,000 injuries and illnesses [61], [62] and 34% of all lost workdays reported to the Bureau of Labor Statistics [9]. These disorders are estimated at $20 billion a year in direct costs, and up to 5 times more in indirect costs for MSD-related workers' compensation, in addition to the substantial toll on affected workers who develop significant difficulties in performing simple upper extremity tasks [61], [62]. Studies in humans with upper extremity WMSDs find evidence of inflammation, fibrosis and degeneration in tissues, changes thought to cause the concurrent sensorimotor dysfunctions [16], [18], [30], [67], [68], [69]. There remains a call for effective, or ideally preventive, treatments for these often debilitating disorders [14], [61], [62], [78].

The use of various manual therapy modalities for the treatment of carpal tunnel syndrome has been recently reviewed [63], with the conclusion that there is only poor evidence supporting meaningful clinical efficacy of these modalities. However, two pilot reports on the effects of massage therapy on carpal tunnel syndrome report reduced symptoms and increased strength post-treatment [29], [56]. Reviews of massage therapy (sports massage) for post-exertional muscle soreness are equivocal, yet overall clinical utility is supported [55]. It is notable that most of the published literature reports results of short-term massage therapy treatment for repetitive motion disorders, which typically develop over weeks or even years. People with WMSDs tend to not use their affected limb, and disuse has been associated with increased fibrosis [32], [48]. Although it follows that early treatment might prevent these changes, we could not identify any studies using manual therapies as a preventative for the development of carpal tunnel syndrome or other types of WMSDs.

Patients with chronic (> 3 months) WMSDs show continued symptoms of pain and motor dysfunction, yet an absence of serum and tissue inflammatory markers, and instead, have increased tissue fibrosis and fibrogenic markers, such as transforming growth factor beta 1 (TGF-β1) [18], [30], [35], [46]. Although there is limited clinical evidence for a role of manual therapy in these processes, animal models have shown that passive movement allowed tendons to heal with less fibrosis [37], [38], and a model of active stretching showed findings of reduced subcutaneous collagen formation post-injury [10].

We have developed a unique rodent model of operant repetitive reaching and grasping in which the performance of a reaching and handle-pulling task causes injury and inflammation, followed by nerve, muscle and connective tissue fibrosis, and then compressive nerve pathology with reduced nerve conduction velocity [1], [19], [20], [26], [27], [28], [31], [33], [36], [47]. We observed exposure-dependent declines in sensorimotor function after short-term performance of these tasks (≤ 3 months), with a high repetition high force (HRHF) task inducing the greatest dysfunction [6], [31], [33]. We have shown that ibuprofen administered in weeks 5–6 of a 6-week HRHF task, or in weeks 5–12 of a 12-week HRHF task, attenuated inflammatory responses that drove tissue fibrosis [1], [47]. We have also shown that an anti-rat tumor necrosis factor alpha (TNFα) provided in weeks 5–6 of a 6-week HRHF task attenuated both tissue inflammatory and fibrogenic responses [1], [65]. Unfortunately, long-term use of ibuprofen or anti-TNFα drugs can have negative side effects, including ibuprofen-induced gastrointestinal bleeding, renal toxicity, increased risk of myocardial infarction, and hypertension [2], [54], or serious infections with long-term blocking of TNFα function [15], [53]. Therefore, we are interested in exploring the effectiveness of non-pharmacological secondary prevention interventions.

Our goal here was to examine the effectiveness of manual therapy in preventing the fibrosis and reduced function that occur as a consequence of overuse. Our approach in this study was to emulate what would typically occur in the clinical setting, where the person develops symptoms and seeks care. This qualifies as a “secondary prevention” approach [3].