Traditional treatment of sports injuries includes use of the PRICE principle (Protection, Rest, Ice, Compression, Elevation), nonsteroidal anti-inflammatories, physical therapy modalities, and corticosteroid injections. Recent evidence has raised concerns over this traditional treatment approach regarding the use of anti-inflammatories and injectable corticosteroids. More recent treatments, known as regenerative medicine, include platelet-rich plasma and stem cell therapies. Evidence for their efficacy in a variety of sports injuries has emerged, ranging from tendinopathy and muscle tears to ligament and chondral injuries. This article reviews the literature regarding established treatments for sports injuries and these more innovative treatments.
Key points
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Regenerative medicine is of particular interest in the treatment of sports injuries, as historical and recent evidence increasingly refute the commonly used treatments of anti-inflammatory medications and corticosteroid injections.
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The use of biological treatments using a patient’s own stem cells and growth factors to heal damaged tissues is an attractive option.
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Use of these treatments in conjunction with aggressive/comprehensive rehabilitation may maximize nonsurgical treatments of these various sports injuries.
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More rigorous studies using these biological agents to treat such injuries could potentially change the way most sports injuries are managed.
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The true utility of regenerative medicine for sports injuries will become clearer as more high-quality research is published.
Introduction
The treatment of sports injuries historically has included the use of the PRICE principle (Protection, Rest, Ice/cold, Compression, and Elevation), analgesics/nonsteroidal anti-inflammatory drugs (NSAIDs), and, commonly, corticosteroids. The PRICE principle, widely used in the initial treatment of soft-tissue sports injury, is thought to generally reduce hemorrhage into the injured area and thereby reduce pain and swelling. Rest is recommended to minimize additional stress or strain to promote healing, while cooling decreases bleeding and ultimately serves as a counterirritant to reduce pain. Both compression and elevation work to control swelling. The clinical basis for the application of the PRICE principle is well supported in experimental studies, though not by randomized controlled clinical trials.
NSAIDs are often used during and after acute injuries, and in chronic overuse injuries to control pain and inflammation. As a class of medications, they have varying effects on inflammation, analgesia, and fever. NSAIDs work to inhibit the cyclooxygenase enzymes from which prostaglandins, prostacyclins, and thromboxanes are produced from arachidonic acid. Cyclooxygenase has 2 isoforms, COX-1 and COX-2. Whereas COX-1 is physiologic and is present in numerous tissues in the body, COX-2 is released in response to injury. This isoform produces compounds that increase temperature, sensitize pain receptors, and play a role in inflammation. NSAIDs are used in sports injuries for their capabilities to inhibit COX-2, and are available as general cyclooxygenase inhibitors or COX-2–specific inhibitors.
NSAIDs have significant side effects, most notably in the upper gastrointestinal tract, which include gastrointestinal perforation/hemorrhage, peptic ulcer disease, abdominal pain, diarrhea, nausea/vomiting, and stricture formation. Other effects such as hypertension, congestive heart failure, renal insufficiency, and hyperkalemia have been reported. Furthermore, ibuprofen may potentially inhibit aspirin’s antiplatelet activity. A review of NSAIDs on various acute sports soft-tissue injuries showed that NSAIDs have a modest role in the treatment of acute injuries, without harmful effects when used for a short period. Ibuprofen, celecoxib, and diclofenac decreased synovial fluid levels of tumor necrosis factor α, interleukin-6, and vascular endothelial growth factor (VEGF), which in turn significantly improved patient Western Ontario and McMaster scores in a dose-dependent fashion after 14 days of treatment.
Injectable corticosteroids are another class of medications frequently used to treat sports injuries because of their anti-inflammatory effects. Corticosteroids inhibit cyclooxygenase enzyme isoforms and lipoxygenase, which converts arachidonic acid to leukotrienes. These compounds play a key role in chemotaxis and inflammation, which is the rationale for their ubiquitous use in sports injuries. Side effects include corticosteroid-induced cutaneous atrophy, hyperglucocorticoidism, temporary deterioration of diabetes mellitus, facial flushing, and anaphylaxis.
Historical and recent evidence increasingly refute the commonly used treatments of anti-inflammatory medications and corticosteroid injections for most sports injuries. This view holds particularly true for tendinopathies. Cohen and colleagues revealed that indomethacin and celecoxib had a negative effect on rotator cuff tendon-to-bone healing, and organization of collagen fibrils in a murine model. Coombes and colleagues conducted a meta-analysis on the effect of corticosteroids in various tendons in comparison with other nonsurgical interventions. Although corticosteroids provided short-term (0–12 weeks) benefit, there was a decline in function and increased pain from intermediate (13–26 weeks) to long term (>1 year) for lateral epicondylalgia. Short-term effectiveness for rotator cuff tendon was inconclusive, and no significant difference was noted regarding intermediate and long-term results. There was a short-term decrease in pain for patellar tendon, but not for Achilles tendon. In a randomized placebo-controlled trial of unilateral epicondylalgia, the same group reported that patients treated with corticosteroid injection had poorer outcome and higher recurrence after 1 year. The corticosteroid group had better outcomes than the placebo group at 4 weeks, although this difference was not significant when physical therapy was taken into account. At 26 weeks and 1 year, patients who received corticosteroid had poorer outcomes in comparison with placebo.
Tendinopathy, also referred to as tendinosis, is a very common injury presenting to sports medicine physicians. These injuries have previously been improperly named tendonitis, implying the presence of an inflammatory process. It is now well recognized that chronic tendon complaints are an overuse injury that is degenerative in nature. Contributing factors to tendinopathy pain include excessive load or frequent microtrauma, in addition to intrinsic biomechanical changes predisposing to injury.
The pain accompanying tendinosis was previously thought to be due to inflammation; however, it is now known that tendinosis is histologically characterized by random and disorganized structure, hypercellularity, and neovascularization, and is devoid of inflammatory cells. Although the exact mediators of pain are uncertain, irritants and neurotransmitters seem to play a role; these include lactic acid, glutamate, and substance P.
Healing and repair of a tendon occurs in 3 stages. The inflammatory phase in the first few days is characterized by inflammation and migration of erythrocytes and polymorphonuclear leukocytes. Monocytes and macrophages are also present for phagocytosis of necrotic tissue. Chemokines are released, leading to chemotaxis of tenocytes, which lay down collagen III. This process is followed by the proliferative phase, which is characterized by more collagen III and increased ground substance, lasting several weeks. From week 6 up to 1 year, remodeling takes place. Collagen I is synthesized along the path of stress, followed by scar formation. Ligament and muscle injuries undergo basic stages of healing similar to those of tendons.
Based on the current literature, it is the opinion of the author that NSAIDs play a minor role, if any, in most postacute sports injuries, and may even truncate the healing response by interfering with physiology. A short course, (ie, 7–10 days) may be of benefit during the initial acute inflammatory phase of treatment. Similarly, although corticosteroids may offer short-term relief of symptoms, it is likely more harmful in the long term, for the same reasons.
The key to the successful treatment of most sports injuries, following the control of the initial pain and inflammation phase, is a functional rehabilitation program stressing restoration of normal range of motion, strength, and proprioceptive training, with a gradual return-to-sport program.
Introduction
The treatment of sports injuries historically has included the use of the PRICE principle (Protection, Rest, Ice/cold, Compression, and Elevation), analgesics/nonsteroidal anti-inflammatory drugs (NSAIDs), and, commonly, corticosteroids. The PRICE principle, widely used in the initial treatment of soft-tissue sports injury, is thought to generally reduce hemorrhage into the injured area and thereby reduce pain and swelling. Rest is recommended to minimize additional stress or strain to promote healing, while cooling decreases bleeding and ultimately serves as a counterirritant to reduce pain. Both compression and elevation work to control swelling. The clinical basis for the application of the PRICE principle is well supported in experimental studies, though not by randomized controlled clinical trials.
NSAIDs are often used during and after acute injuries, and in chronic overuse injuries to control pain and inflammation. As a class of medications, they have varying effects on inflammation, analgesia, and fever. NSAIDs work to inhibit the cyclooxygenase enzymes from which prostaglandins, prostacyclins, and thromboxanes are produced from arachidonic acid. Cyclooxygenase has 2 isoforms, COX-1 and COX-2. Whereas COX-1 is physiologic and is present in numerous tissues in the body, COX-2 is released in response to injury. This isoform produces compounds that increase temperature, sensitize pain receptors, and play a role in inflammation. NSAIDs are used in sports injuries for their capabilities to inhibit COX-2, and are available as general cyclooxygenase inhibitors or COX-2–specific inhibitors.
NSAIDs have significant side effects, most notably in the upper gastrointestinal tract, which include gastrointestinal perforation/hemorrhage, peptic ulcer disease, abdominal pain, diarrhea, nausea/vomiting, and stricture formation. Other effects such as hypertension, congestive heart failure, renal insufficiency, and hyperkalemia have been reported. Furthermore, ibuprofen may potentially inhibit aspirin’s antiplatelet activity. A review of NSAIDs on various acute sports soft-tissue injuries showed that NSAIDs have a modest role in the treatment of acute injuries, without harmful effects when used for a short period. Ibuprofen, celecoxib, and diclofenac decreased synovial fluid levels of tumor necrosis factor α, interleukin-6, and vascular endothelial growth factor (VEGF), which in turn significantly improved patient Western Ontario and McMaster scores in a dose-dependent fashion after 14 days of treatment.
Injectable corticosteroids are another class of medications frequently used to treat sports injuries because of their anti-inflammatory effects. Corticosteroids inhibit cyclooxygenase enzyme isoforms and lipoxygenase, which converts arachidonic acid to leukotrienes. These compounds play a key role in chemotaxis and inflammation, which is the rationale for their ubiquitous use in sports injuries. Side effects include corticosteroid-induced cutaneous atrophy, hyperglucocorticoidism, temporary deterioration of diabetes mellitus, facial flushing, and anaphylaxis.
Historical and recent evidence increasingly refute the commonly used treatments of anti-inflammatory medications and corticosteroid injections for most sports injuries. This view holds particularly true for tendinopathies. Cohen and colleagues revealed that indomethacin and celecoxib had a negative effect on rotator cuff tendon-to-bone healing, and organization of collagen fibrils in a murine model. Coombes and colleagues conducted a meta-analysis on the effect of corticosteroids in various tendons in comparison with other nonsurgical interventions. Although corticosteroids provided short-term (0–12 weeks) benefit, there was a decline in function and increased pain from intermediate (13–26 weeks) to long term (>1 year) for lateral epicondylalgia. Short-term effectiveness for rotator cuff tendon was inconclusive, and no significant difference was noted regarding intermediate and long-term results. There was a short-term decrease in pain for patellar tendon, but not for Achilles tendon. In a randomized placebo-controlled trial of unilateral epicondylalgia, the same group reported that patients treated with corticosteroid injection had poorer outcome and higher recurrence after 1 year. The corticosteroid group had better outcomes than the placebo group at 4 weeks, although this difference was not significant when physical therapy was taken into account. At 26 weeks and 1 year, patients who received corticosteroid had poorer outcomes in comparison with placebo.
Tendinopathy, also referred to as tendinosis, is a very common injury presenting to sports medicine physicians. These injuries have previously been improperly named tendonitis, implying the presence of an inflammatory process. It is now well recognized that chronic tendon complaints are an overuse injury that is degenerative in nature. Contributing factors to tendinopathy pain include excessive load or frequent microtrauma, in addition to intrinsic biomechanical changes predisposing to injury.
The pain accompanying tendinosis was previously thought to be due to inflammation; however, it is now known that tendinosis is histologically characterized by random and disorganized structure, hypercellularity, and neovascularization, and is devoid of inflammatory cells. Although the exact mediators of pain are uncertain, irritants and neurotransmitters seem to play a role; these include lactic acid, glutamate, and substance P.
Healing and repair of a tendon occurs in 3 stages. The inflammatory phase in the first few days is characterized by inflammation and migration of erythrocytes and polymorphonuclear leukocytes. Monocytes and macrophages are also present for phagocytosis of necrotic tissue. Chemokines are released, leading to chemotaxis of tenocytes, which lay down collagen III. This process is followed by the proliferative phase, which is characterized by more collagen III and increased ground substance, lasting several weeks. From week 6 up to 1 year, remodeling takes place. Collagen I is synthesized along the path of stress, followed by scar formation. Ligament and muscle injuries undergo basic stages of healing similar to those of tendons.
Based on the current literature, it is the opinion of the author that NSAIDs play a minor role, if any, in most postacute sports injuries, and may even truncate the healing response by interfering with physiology. A short course, (ie, 7–10 days) may be of benefit during the initial acute inflammatory phase of treatment. Similarly, although corticosteroids may offer short-term relief of symptoms, it is likely more harmful in the long term, for the same reasons.
The key to the successful treatment of most sports injuries, following the control of the initial pain and inflammation phase, is a functional rehabilitation program stressing restoration of normal range of motion, strength, and proprioceptive training, with a gradual return-to-sport program.
Regenerative biological treatments
The application of regenerative biological treatments for ailments of the musculoskeletal system emerged in the 1930s. The purpose of regenerative medicine is to heal a pathologic process by augmenting the body’s physiology by nature or by means of bioengineering. The current practice of regenerative medicine encompasses prolotherapy, platelet-rich plasma (PRP), and mesenchymal stem cell therapy ( Table 1 ).
| Treatment | Mechanism of Action |
|---|---|
| Prolotherapy | Introduce irritating agent Trigger inflammatory cascade Proliferation of fibroblasts, deposition of collagen Healing |
| Platelet-rich plasma | Degranulation of activated platelets Increased vascular permeability leading to chemotaxis of inflammatory cells Cellular proliferation and formation of extrafibrillar matrix Formation of collagen |
| Stem cell therapy | Cells differentiate into various cells in the mesenchymal lineage including bone, cartilage, adipose, and other soft tissues |
Prolotherapy
Prolotherapy introduces an irritating agent to pathologic tissue to obtain a healing response. It first emerged in the musculoskeletal literature in the 1950s, although the concept has been around since the 1930s and possibly dates back to the time of Ancient Greek and Egyptian medicine. Although the exact mechanism of prolotherapy is uncertain, it is postulated that proliferant solutions increase collagen synthesis and cause transient neurolysis, which is accomplished by cytokines that mediate chemomodulation and chemoneuromodulation. The irritating vehicles, which include hyperosmolar dextrose, zinc sulfate, glycerin, phenol, guaiacol, pumic acid, and sodium morrhuate, are theorized to trigger the inflammatory cascade that ultimately leads to proliferation of fibroblasts and deposition of collagen. Although animal studies on tendons show benefit, the results on ligaments are inconclusive.
In humans, prolotherapy has been shown to be an effective treatment for the symptoms of pain in various sports injuries including groin pain, Achilles tendinosis, and plantar fasciitis. In a pilot study including 24 patients with chronic lateral epicondylar pain, Scarpone and colleagues found that an injection of a 10.7% dextrose/14.7% sodium morrhuate solution given every 4 weeks at baseline, 4, and 8 weeks, offered significant improvement in pain and isometric contraction strength 16 weeks after treatment when compared with baseline and controls.
In a randomized study, Yelland and colleagues compared prolotherapy with eccentric loading exercises for Achilles tendinosis. Although there was improved pain in favor of prolotherapy at 6 months, and prolotherapy combined with eccentric loading exercises at 12 months, the differences were not significant in the long term. Despite encouraging results, there are few quality trials with rigorous medical evidence from which to build a general consensus regarding prolotherapy and its use in sports injuries.
Platelet-Rich Plasma
PRP is broadly defined as plasma with platelet concentration higher than baseline. However, the concentration of platelets necessary to induce a healing response is thought to require a minimum of 1 million platelets per microliter in 5 mL of plasma. This burden necessitates centrifugation of whole blood to separate the various components, which include red blood cells, platelet-poor plasma, and a layer of PRP. Platelets have been well known to participate in blood-clot formation and in modulation of inflammation and healing, achieved through release of various growth factors, cytokines, and chemokines contained in mitochondria, dense granules, α granules, and lysosomal granules. Eicosanoids are also newly synthesized from arachidonic acid, partaking in the process of inflammation. Degranulation of 70% to 95% of growth factors occurs within 10 minutes of activation, with the remainder slowly released over a few days. Various methods of processing autologous venous blood exist with the goal of platelet concentration, activation, and release of bioactive proteins.
PRP is typically made in a 2-step centrifugation process. The first cycle separates venous blood into red blood cells, platelet-poor plasma, and a buffy coat. The platelets and leukocytes separate into the buffy coat. The second step isolates the buffy coat from the other 2 layers for application. Because the layers are separated by pipette, this process is subject to human error and therefore is imprecise.
Multiple devices are now available to process PRP, each yielding various concentrations of platelets, white blood cells, and red blood cells. The clinical significance of differing concentrations of cells is uncertain. Mazzocca and colleagues studied the effect of various PRP preparations and concentrations on cells of bone, muscle, and tendon. The investigators were unable to conclude which preparation was best suited to treat the various cell types in vitro, and also noted that a higher concentration of platelets did not necessarily result in better outcomes.
Dense granules contain serotonin, histamine, dopamine, calcium, and adenosine. Serotonin and histamine increase vascular permeability, allowing movement of cells that participate in inflammation to the area. This process results in activation of macrophages and chemotaxis of polymorphonuclear cells. Cellular proliferation and formation of extrafibrillar matrix follows, which leads to formation of collagen. This process works in synergy with other growth factors and cytokines released from platelets.
The α granules in platelets are mostly composed of transforming growth factor β (TGFβ), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF I and II), β fibroblast growth factor (βFGF), epidermal growth factor, VEGF, and endothelial cell growth factor. These various growth factors stimulate angiogenesis, epithelialization, granule tissue formation, extracellular matrix formation, and differentiation of cells.
The main function of IGF-I in inflammation and healing is thought to be in migration and multiplication of fibroblasts, which leads to collagen and extracellular matrix protein synthesis. Although IGF-I is present in all phases of healing and repair, it is most prominent during inflammation and proliferation. Molly and colleagues referenced a study by Sciore and colleagues, who demonstrated an increase of IGF-I and its receptor in rabbit medial collateral ligaments 3 weeks after injury. In transected Achilles tendon of rats, exposure to recombinant IGF-I resulted in improved healing starting 24 hours after injury/exposure to IGF-I, which lasted for 15 days.
The widespread effects of TGF-β include mitosis control, activation and differentiation of mesenchymal stem cells, production and secretion of collagen, migration of endothelial cells, and angiogenesis. TGF-β appears to have a large presence immediately following injury. A study of flexor tendon cells showed that lactic acid, a substance that builds in early response to tissue hypoxia, stimulates TGF-β. Research shows increased levels of TGF-β in the patellar ligament of rats up to 8 weeks after injury. As cited in Molly and colleagues, murine Achilles tendons exposed to cartilage-derived morphogenic protein 2, a growth factor in the TGF-β superfamily, had increased thickness and density in comparison with controls.
Another function of TGF-β1 is in fibrotic differentiation of skeletal muscle. In vitro stimulation of myoblasts with TGF-β1 resulted in a further increase of the cytokine, production of proteins that regulate fibrosis, and formation of scar tissue in murine skeletal muscle.
PDGF is found early in inflammation and stimulates production of growth factors such as IGF-I, in addition to remodeling of tissue. Molly and colleagues reviewed an in vivo study of rat medial collateral ligaments which showed that exposure to PDGF increased the strength, stiffness, and energy required to break the ligament.
The main function of VEGF is angiogenesis. Contrary to previously discussed growth factors, which are most active during the inflammatory phase of healing and repair, VEGF levels are highest in the later phases. As reviewed in Molly and colleagues, VEGF was shown to increase the length and density of vessels in the flexor tendons of canines, from days 3 to 21 after injury.
βFGF plays a key role in angiogenesis, cell proliferation, and migration. An article by Chan and colleagues, reviewed by Molly and colleagues, showed an increase in type III collagen and cellular proliferation with varying doses of βFGF injected into damaged patellar tendons of rats ( Table 2 ).
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