**7. New treatment directions**

It is unlikely that a single drug will be effective in treating all WMSDs since their development is multi-factorial. Multipronged treatment should be developed that are individualized to the subject for complete reversal of WMSD-induced tissue inflammation/fibrosis/degeneration and recovery of function. **Figure 9** shows various points of interventional treatment, indicating that early treatment is needed to alter acute inflammatory responses, while chronic inflammatory responses are accompanied by several signs and symptoms of chronic pain and should be treated with secondary anti-inflammatory drugs such as ibuprofen or antitumor necrosis factor alpha drugs [89]. The latter drugs have yet to be tested in subjects with WMSDs, but have been tested in our animal model and show fair to strong efficacy [39, 61]. In subjects with chronic or persistent pain, negative neuroplasticity in the CNS, termed central  sensitization, may have occurred. Treatment options of such central sensitization should be explored carefully in future studies to reduce chronic pain. At the right side of this figure, we show the onset of fibrosis, which may compress and damage axons (such as in carpal tunnel syndrome), and tether tissues. We are currently exploring options of blocking fibrogenicsignaling pathways in our rat model.

Fortunately, systemic anti-inflammatory treatment with ibuprofen prevented these bone catabolic changes (**Figure 8**) [40, 70]. Eight weeks of continual ibuprofen treatment reduced bone inflammatory cytokine levels, and osteoclast numbers and activity, despite continued task performance. These results suggest that bone catabolism in the untreated HRHF rats was the result of increased inflammatory cytokines and their activating effects on osteoclasts. In summary, forearm bone osteopenia can be one consequence of prolonged high-intensity hand and wrist tasks. This increase in osteopenia and perhaps even fracture risk of workers performing this type of task is under-investigated in human and should be the focus of future studies.

A loss of bone mineral density has been reported in metacarpal bones and distal radius and ulna of patients with long-term carpal tunnel syndrome [80]. Surgical release treatment for carpal tunnel syndrome rescues this decline in distal forearm bone mineral density [81]. Those authors hypothesized that nerve-compression-induced muscle weakness led to bone loss as a consequence of reduced muscular loading on the bone [80], since the muscles involved in performing hand-grip actions produce forces on forearm bones [82, 83]. In our model, ibuprofen may be sparing bone volume by reducing osteoclastogenesis and activity as well as by reducing fibrotic nerve compression, thus sparing muscle activity and muscle-pulling forces

Ibuprofen treatment is inexpensive and readily available over the counter. Yet, its use should be limited to short-term treatments (we have tested only up to 8 weeks). Ibuprofen medication may inhibit skeletal muscle hypertrophy and adaptation [42, 84–86], although a more recent study shows no effect of ibuprofen on muscle hypertrophy [43]. Long-term use of ibuprofen-related NSIADs could increase gastrointestinal bleeding, renal toxicity, risk of myocardial infarction, and hypertension [87, 88]. NSAIDs are also not always successful for long-term treatment of pain and dysfunction [16], similar to our results with reflexive grip

It is unlikely that a single drug will be effective in treating all WMSDs since their development is multi-factorial. Multipronged treatment should be developed that are individualized to the subject for complete reversal of WMSD-induced tissue inflammation/fibrosis/degeneration and recovery of function. **Figure 9** shows various points of interventional treatment, indicating that early treatment is needed to alter acute inflammatory responses, while chronic inflammatory responses are accompanied by several signs and symptoms of chronic pain and should be treated with secondary anti-inflammatory drugs such as ibuprofen or antitumor necrosis factor alpha drugs [89]. The latter drugs have yet to be tested in subjects with WMSDs, but have been tested in our animal model and show fair to strong efficacy [39, 61]. In subjects with chronic or persistent pain, negative neuroplasticity in the CNS, termed central

on bones (refer to **Figure 3C** and **4A** again).

**6. Caveats of ibuprofen use**

**7. New treatment directions**

strength.

194 Occupational Health

**Figure 9.** Summary of results and possible points of intervention indicated. Repetitive tasks can cause local injury and acute inflammation that could be prevented with reduced loads. Acute and chronic inflammation can be treated by prophylactic and secondary ibuprofen treatment at anti-inflammatory doses. Means to treat fibrosis are still under investigation as are most effective ways to rescue persistent sensorimotor declines. Abbreviations: CTGF = connective tissue growth factor; IL-1 = interleukin 1; Macs = macrophages; TNF = tumor necrosis factor; TGFB1 = transforming growth factor beta 1. Modified and used by permission from Barr and Barbe [89].

One new non-pharmaceutical direction may be modeled manual therapy. A recent review examined the effectiveness of exercise versus several types of mobilization methods for the treatment of carpal tunnel syndrome and concluded that there was only poor support [90]. However, two recent pilot studies examined massage therapy methods specifically and observed reduced symptoms of discomfort and increased strength post treatment in patients being treated for carpal tunnel syndrome [91, 92]. Another type of massage termed "sports massage' has been used to treat post-exertional muscle soreness, which is also known as delayed onset muscle soreness (DOMS). While the clinical utility of sports massage for DOMS is supported overall, a comprehensive review of the literature by Moraska in 2005 shows its effectiveness in some studies and a lack thereof in others [93]. Perhaps, this is because sports massage therapy treatment is typically short term. With regard to the use of massage therapies for individuals with repetitive motion disorders, clinicians should be aware that these disorders are not acute in nature. Instead, repetitive motion disorders are the consequence of underlying tissue changes that take weeks to years. It is unlikely that a single, short-term treatment will be effective.

Because we could not identify any studies using manual therapies for WMSDs (other than carpal tunnel syndrome), we recently performed a study examining the effectiveness of modeled manual therapy (MMT) as a treatment for symptoms of discomfort, reduced grip strength, and increased tissue fibrosis occurring in forearms of rats performing a HRHF task for 12 weeks [33]. We began the MMT immediately post training to the high-force level, a time point when the rats began to display signs and symptoms consistent with WMSDs. Results were compared to untreated HRHF rats and to age-matched control rats. The MMT protocol included a mixture of manual therapy submodalities: gentle mobilization, skin rolling, and myofascial release (deep massage) of the forearm flexor compartment; joint mobilization of the wrist (gentle rotation and traction of the wrist); and stretching of the entire upper limb from the shoulder to the fingers. The therapy was provided 5 days per week for 12 weeks, while the animals performed the HRHF task for a food reward (as above, for 3 days/week, 2 h/day, in 30-min sessions). Compared to untreated HRHF rats, the HRHF rats receiving the MMT (called HRHF-MMT rats) showed significantly fewer behaviors suggestive of discomfort and had increased numbers of successful reaches. Grip strength had decreased significantly post training to the high-force levels, compared to the rats' naïve levels. However, the MMT protocol improved grip strength within 2 weeks of treatment, an improvement that continued through week 12 despite continued performance of the HRHF task by the HRHF-MMT rats. An examination of tissues post euthanasia showed decreased nerve and connective tissue fibrosis, and decreased collagen and TGF-B1 in the 12-week HRHF rats, compared to the untreated HRHF rats. These observations support further investigation of manual therapy as a preventative for repetitive motion disorders.
